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Chemical Structure| 5070-13-3 Chemical Structure| 5070-13-3

Structure of Bis(4-nitrophenyl) carbonate
CAS No.: 5070-13-3

Chemical Structure| 5070-13-3

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Product Details of [ 5070-13-3 ]

CAS No. :5070-13-3
Formula : C13H8N2O7
M.W : 304.21
SMILES Code : [O-][N+](=O)C1=CC=C(OC(=O)OC2=CC=C(C=C2)[N+]([O-])=O)C=C1
MDL No. :MFCD00007322
InChI Key :ACBQROXDOHKANW-UHFFFAOYSA-N
Pubchem ID :78756

Safety of [ 5070-13-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319
Precautionary Statements:P305+P351+P338

Computational Chemistry of [ 5070-13-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 22
Num. arom. heavy atoms 12
Fraction Csp3 0.0
Num. rotatable bonds 6
Num. H-bond acceptors 7.0
Num. H-bond donors 0.0
Molar Refractivity 77.18
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

127.17 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.42
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.29
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.08
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.85
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.87
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.55

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.81
Solubility 0.0475 mg/ml ; 0.000156 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-5.64
Solubility 0.000704 mg/ml ; 0.00000231 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.09
Solubility 0.246 mg/ml ; 0.000809 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

Yes
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

Yes
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

Yes
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.82 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

3.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.3

Application In Synthesis of [ 5070-13-3 ]

* 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.

  • Downstream synthetic route of [ 5070-13-3 ]

[ 5070-13-3 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 120277-39-6 ]
  • [ 5070-13-3 ]
  • [ 129943-30-2 ]
  • 2
  • [ 5070-13-3 ]
  • [ 4089-07-0 ]
  • [ 70779-94-1 ]
  • 3
  • [ 5070-13-3 ]
  • [ 105601-04-5 ]
  • [ 948829-23-0 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5 - 4h;Product distribution / selectivity; Example 4; Synthesis of the compound (L-R); Reaction scheme:Process:1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2). The solution was cooled with an ice-water bath (0-50C). 0.92 g trie thy lamine was added.2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred in an ice- water bath.[0062] Reaction progress was monitored by HPLC. After 4 hours, 715 mg N- ethylmethylamine was added and the yellow solution was stirred for 17 hours at 40C. The reaction mixture was allowed to warm to room temperature and was then washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2- phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0063] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. <n="19"/>Isolated yield: 1.37 g (90%), yellow oilHPLC: 98% purity1H-NMR: confirmed the expected structure; Example 5; Synthesis of the compound (JL-R); [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9
With triethylamine; In ethyl acetate; at 0 - 5℃; for 2.5h;Product distribution / selectivity; Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results:
With triethylamine; In acetonitrile; at 0 - 5℃; for 2.5h;Product distribution / selectivity; Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results:
With triethylamine; In tetrahydrofuran; at 0 - 5℃; for 2.5h;Product distribution / selectivity; Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results:
With triethylamine; In acetone; at 0 - 5℃; for 2.5h;Product distribution / selectivity; Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results:
In dichloromethane; at 20℃; for 2h;Product distribution / selectivity; Example 10; Synthesis of the compound (I-R); [0070] 0.5 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 10 ml dichloromethane (distilled from CaCl2).[0071] 1.1 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0072] Reaction progress was monitored with HPLC. After 2 hours, 358 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0073] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 0.62 g (82%), yellow oilHPLC: 97.4% purity
In acetone; at 20℃; for 1.5h;Product distribution / selectivity; Example 11; Synthesis of the compound (I-R); [0074] 1.0 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml acetone.[0075] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0076] Reaction progress was monitored with HPLC. After 1.5 hour, 537 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred at ambient temperature for 1.5 hour. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 20 ml t-butylmethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml t-butylmethyl ether.[0077] 20 ml t-Butylmethyl ether was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.34 g (88%), yellow oilHPLC: 95.6% purity

  • 4
  • [ 5070-13-3 ]
  • [ 91183-71-0 ]
  • C16H22N2O6S [ No CAS ]
  • 5
  • [ 5070-13-3 ]
  • [ 1791-13-5 ]
  • [ 438246-17-4 ]
  • 6
  • [ 34107-46-5 ]
  • [ 5070-13-3 ]
  • [ 144163-02-0 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; In dichloromethane; at 20℃; for 42h; To a solution of the (6-methyl-pyridin-3-yl)-methanol in DCM (180 mL) was added bis-(4- nitrophenyl)carbonate (10.4 g, 34 mmol) followed by NMM (3.75 mL, 34 mmol). The reaction mixture was stirred at r.t. for 42 hours and then concentrated in vacuo. The residue <n="26"/>- -was dissolved in DCM (100 mL), washed with sat aq NaHCCh solution (6 x 100 mL), dried (MgSO4) and concentrated in vacuo. The crude product was recrystallised from EtOAc to give (6-methylpyridin-3-yl)methyl 4-nitrophenyl carbonate (7.38 g, 77%) as an orange solid. Analytical LCMS: (System A, RT = 1.74 min), ES+: 289.4 [MH]+.
  • 7
  • [ 5344-27-4 ]
  • [ 5070-13-3 ]
  • [ 92812-96-9 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; In dichloromethane; at 20℃; for 48h; To a solution of <strong>[5344-27-4]4-(2-hydroxyethyl)pyridine</strong> (0.25 mL, 2.2 mmol) in DCM (10 mL) was added bis-(/?-nitrophenyl)carbonate (0.67 g, 2.2 mmol) and NMM (0.24 mL, 2.2 mmol). The reaction mixture was stirred at r.t. for 2 days and then concentrated in vacuo to give an orange oil. The oil was dissolved in EtOAc (30 mL), washed with sat aq NaHCO3 solution (3 x 20 mL), dried (MgSO4) and concentrated in vacuo to give 4-nitrophenyl 2-(pyridin-4- yl)ethyl carbonate as an oil which was used without further purification in the next step. <n="32"/>- -To a solution of 4-nitrophenyl 2-(pyridin-4-yl)ethyl carbonate (~2.2 mmol) in DMF (10 mL) was added DIPEA (0.383 mL, 2.2 mmol) and c-2,6-dimethylmorpholine (0.27 mL, 2.2 mmol). The reaction mixture was stirred overnight at r.t. and then concentrated in vacuo. The residue was purified by normal phase chromatography (gradient eluting with MeOH in DCM from 0% to 2%) followed by reverse phase chromatography to give 2- pyridin-4-ylethyl (2R,6S)-2,6-dimethylmorpholine-4-carboxylate (128 mg, 22%) as a light yellow oil.Analytical HPLC: purity 99.6% (System B, Rtau = 3.44 min); Analytical LCMS: purity 100% (System F, Rtau = 5.18 min), ES+: 265.6 [MH]+; HRMS calcd for Ci4H20N2O3: 264.1474, found 264.1480.
  • 8
  • [ 5070-13-3 ]
  • [ 126049-37-4 ]
  • [ 1151989-04-6 ]
YieldReaction ConditionsOperation in experiment
With dmap; In dichloromethane; at 20℃; for 12.0h; EXAMPLE 1.3. Synthesis of an M3 type compound of substituent 1 (8 in this Example); The carbonate 7 was prepared by reacting the disulfide 4 with bis(4-nitrophenyl) carbonate (Fardis, M.; Pyun, H.-J.; Tario, J.; Jin, H.; Kim, C. U.; Ruckman, J.; Lin, Y.; Green, L.; Hicke, B. Bioorg. Med. Chem. 2003, 11, 5051-5058.). Treatment of paclitaxel with 7 gave the M3 type paclitaxel disulfide 8 (Liu, C; Schilling, J. K.; Ravindra, R.; Bane, S.; Kingston, D. G. I. Bioorg. Med. Chem. 2004, 12, 6147-6161.); Synthesis of compound 8.; A solution of the disulfide 4 (see Senter, P. D.; Pearce, W. E.; Greenfield, R. S. /. Org Chem. 1990, 55, 2975-2978) (7 mg, 28 mumol) in dry dichloromethane (2 mL) was added to a stirred solution of bis(4-nitrophenyl) carbonate (12.8 mg, 42 mumol) and 4-(dimethylamino) pyridine (10.3 mg, 84 mumol) in dry <n="54"/>dichloromethane (2 mL). After being stirred at room temperature for 12 h, paclitaxel (47.8 mg, 56 mumol) was added. The reaction mixture was allowed to stir at room temperature for another 12 h (see Fardis, M.; Pyun, H.-J.; Tario, J.; Jin, H.; Kim, C. U.; Ruckman, J.; Lin, Y.; Green, L.; Hicke, B. Bioorg. Med. Chem. 2003, 11, 5051-5058; Liu, C; Schilling, J. K.; Ravindra, R.; Bane, S.; Kingston, D. G. I. Bioorg. Med. Chem. 2004, 12, 6147-6161.) Workup as described above and purification by preparative TLC (30% EtOAc/hexanes) afforded compound 8 (25.3 mg, 80%): 1H NMR (CDCl3). delta 8.48 (IH, d, / = 4.6 Hz), 8.13 (2H, d, J = 8.0 Hz), 7.71 (2H, d, / = 8.3 Hz), 7.25-7.65 (17H, m), 7.13 (IH, br dd, / = 5.1, 3.3 Hz), 6.88 (IH, d, J = 9.2 Hz), 6.29 (2H, br s), 5.97 (IH, br d, / = 9.2 Hz), 5.68 (IH, d, / = 7.0 Hz), 5.42 (IH, br s), 5.13 (IH, d, / = 12.3 Hz), 5.09 (IH, d, / = 12.3 Hz), 4.97 (IH, d, / = 9.4 Hz), 4.43 (IH, dd, J = 10.6, 6.9 Hz), 4.31 (IH, d, / = 8.5 Hz), 4.20 (IH, d, / = 8.5 Hz), 3.80 (IH, d, J = 7.0 Hz), 2.56 (IH, m), 2.44 (3H, s), 2.39 (IH, dd, J = 15.4, 9.4 Hz), 2.23 (3H, s), 2.19 (IH, dd, J = 15.4, 8.7 Hz), 1.91 (3H, s), 1.88 (IH, m), 1.68 (3H, s), 1.25 (3H, s), 1.13 (3H, s); 13C NMR (CDCl3) delta 203.8, 171.3, 169.8, 167.8, 167.1, 167.1, 159.2,154.0, 149.6, 142.6, 137.4, 136.6, 133.6, 133.4, 133.4, 132.8, 132.1, 130.2, 129.1, 129.1,129.1, 128.7, 128.7, 128.5, 127.4, 127.1, 126.5, 121.1, 119.8, 84.4, 81.1, 79.2, 77.2, 76.9, 76.4, 75.6, 75.1, 72.1, 72.1, 70.0, 58.5, 52.7, 45.6, 43.2, 35.6, 35.6, 26.8, 22.7, 22.2, 20.8, 14.8, 9.6; HRFABMS m/z 1129.3433 [M + H+] (calcd for C60H6IN2Oi6S2, 1129.3463).
  • 9
  • [ 1585-90-6 ]
  • [ 5070-13-3 ]
  • 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl (4-nitrophenyl)carbonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h; 2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)ethyl (4-nitrophenyl) carbonate To a solution of 1-(2-hydroxyethyl)-1 H-pyrrole-2,5-dione (250 mg, 1.77 mmol) in DCM (8.9 ml) was added diisopropylethylamine (1.5 ml, 8.86 mmol) and bis(4-nitrophenyl) carbonate (701 mg, 2.30 mmol) and the reaction mixture was stirred at RT for 3h. The reaction was extracted with water and DCM. The organic layers were combined, dried over Na2S04, filtered and concentrated to dryness. Purification of the crude product by chromatography on silica eluting with 0 - 100percent EtOAc in heptane afforded the title compound as a pale yellow solid in 88percent yield; H-NMR (DMSO, 400 MHz): delta 8.34-8.32 (2H, m), 7.54-7.51 (2H, m), 7.09 (2H, s), 4.36-4.34 (2H, m), 3.81-3.79 (2H, m).
  • 10
  • [ 5070-13-3 ]
  • [ 134272-64-3 ]
  • allyl N2-acetyl-N5-((S)-1-(((S)-1-((2-(((S)-6-((tert-butoxycarbonyl)amino)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxohexan-2-yl)amino)-2-oxoethyl)amino)-1-oxo-3-(trityloxy)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-L-glutaminate [ No CAS ]
  • allyl N2-acetyl-N5-((S)-1-(((S)-1-((2-(((S)-6-((tert-butoxycarbonyl)amino)-1-((4-((((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxohexan-2-yl)amino)-2-oxoethyl)amino)-1-oxo-3-(trityloxy)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-L-glutaminate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.1 g To a solution of intermediate 4 (785 mg, 0.739 mmol) in DMF (3695 mul) was added bis(4-nitrophenyl) carbonate (337 mg, 1.108 mmol) and DIPEA (193 mul, 1.108 mmol). The reaction was stirred at RT for 1.5 h. To the mixture was then added <strong>[134272-64-3]1-(2-aminoethyl)-1H-pyrrole-2,5-dione hydrochloride</strong> (261 mg, 1.478 mmol) and DIPEA (386 muL, 2.217 mmol). The resulting solution was stirred at RT for 30 min before it was added to Et2O (50 mL). The resulting precipitate was collected by vacuum filtration, washing with Et2O (2*5 mL), to provide allyl N2-acetyl-N5-((S)-1-(((S)-1-((2-(((S)-6-((tert-butoxycarbonyl)amino)-1-((4-((((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxohexan-2-yl)amino)-2-oxoethyl)amino)-1-oxo-3-(trityloxy)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-L-glutaminate (1.1 g). MS(ESI+) m/z 1228.7 (M+H)+.
  • 11
  • [ 5070-13-3 ]
  • [ 134272-64-3 ]
  • C71H104N8O19 [ No CAS ]
  • C78H110N10O22 [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% To a solution of intermediate 12 (69 mg, 0.050 mmol) in DMF (251 mul) was added bis(4-nitrophenyl) carbonate (22.92 mg, 0.075 mmol) and DIPEA (13.12 mul, 0.075 mmol). The reaction was stirred at RT for 1 h before <strong>[134272-64-3]1-(2-aminoethyl)-1H-pyrrole-2,5-dione hydrochloride</strong> (17.74 mg, 0.100 mmol) and DIPEA (26.2 mul, 0.151 mmol) was added. The resulting mixture was stirred at RT for an additional 1 h and was then added, dropwise, to a vial of Et2O (15 mL). The resulting precipitate was collected by vacuum filtration, washed with Et2O (3×3 mL), and dried under vacuum to provide compound 13 (60 mg, 78%). MS(ESI+) m/z 1539.8 (M+H)+.
 

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