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Chemical Structure| 171567-86-5 Chemical Structure| 171567-86-5

Structure of Moc-D-Val-OH
CAS No.: 171567-86-5

Chemical Structure| 171567-86-5

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Product Details of [ 171567-86-5 ]

CAS No. :171567-86-5
Formula : C7H13NO4
M.W : 175.18
SMILES Code : CC(C)[C@@H](NC(OC)=O)C(O)=O
MDL No. :MFCD21234526
InChI Key :CEFVHPDFGLDQKU-RXMQYKEDSA-N
Pubchem ID :28377962

Safety of [ 171567-86-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 171567-86-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 0
Fraction Csp3 0.71
Num. rotatable bonds 5
Num. H-bond acceptors 4.0
Num. H-bond donors 2.0
Molar Refractivity 42.01
TPSA ?

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

75.63 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.52
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

0.9
Log Po/w (WLOGP)?

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

0.45
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.

0.18
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

-0.41
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.53

Water Solubility

Log S (ESOL):?

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

-1.16
Solubility 12.0 mg/ml ; 0.0687 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-2.07
Solubility 1.48 mg/ml ; 0.00845 mol/l
Class?

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

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

-0.25
Solubility 98.5 mg/ml ; 0.562 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

No
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

No
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

No
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

No
Log Kp (skin permeation)?

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

-6.73 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

1.0
Bioavailability Score?

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

0.56

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

0.0 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<1.0
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)

2.26

Application In Synthesis of [ 171567-86-5 ]

* 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.

  • Downstream synthetic route of [ 171567-86-5 ]

[ 171567-86-5 ] Synthesis Path-Downstream   1~35

YieldReaction ConditionsOperation in experiment
87% With sodium carbonate; sodium hydroxide; at 20℃; for 3.25h;Cooling with ice; General procedure: Preparative Example 1 Preparation of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid Sodium carbonate (1.83 g, 17.2 mmol) was added to 1 M sodium hydroxide solution (33 ml, 33 mmol) containing L-valine (3.9 g, 33.29 mmol) dissolved therein, which was cooled down by using ice water. Methyl chloroformate (2.8 ml, 36.1 mmol) was slowly added to the cooled reaction mixture. Once the loading was completed, the iced water was eliminated and the temperature of the mixture was raised to room temperature, followed by stifling for 3.25 hours. Then, the reaction product was washed with ether (17 ml) three times. The water later was cooled down with ice water and then acidized with HCl (conc. HCl) to pH 1?pH 2. The acidized water layer was extracted with dichloromethane (17 ml) three times, and the extracted organic was dried over MgSO4 and filtered. The filtered organic layer was concentrated under reduced pressure and as a result the target compound was obtained as a white solid (5 g, yield: 86%) without any additional purification procedure. 1H NMR (400 MHz, DMSO-d6, delta=2.5 ppm): 12.51 (br s, 1H), 7.32 (d, 1H), 3.84 (t, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.88 (d, J=12, 6H).
  • 2
  • [ 171567-86-5 ]
  • 2,6-bis-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)benzo[1,2-d:4,5-d']bis[1,3]thiazole tetratrifluoroacetate [ No CAS ]
  • methyl ((1R)-1-(((2S)-2-(4-(6-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)[1,3]thiazolo[5,4-f][1,3]benzothiazol-2-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate bistrifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
44.0% With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; HATU (43.6 mg, 0.115 mmol) was added to a stirred solution of 2, 6-bis (2- ( (2S) -2 -pyrrolidirxyl) -lH-imidazol- 5-yl)benzo[l,2~d:4,5~d']bis[l,3] thiazole (27 mg, 0.029 mmol), (JR) -2- (methoxycarbonylamino) ~3-methylbutanoic acid (20.6 mg, 0.118 mmol) and DIEA (0.051 mL, 0.29 mmol) in dimethylformamide (2 mL) . The reaction was stirred overnight at room temperature. The reaction mixture was diluted with methanol (2 mL) and water (2 mL) , stirred for 15 min at room temperature and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (acetonitrile/ water/ 0.1% TFA) to afford methyl ( (IR) -1- { { (2S) -2- {4- (6- (2- ( (2S) -1- ( (2R) -2- ( (methoxycarbonyl) amino) -3-methylbutanoyl) -2- pyrrolidinyl) -lH-imidazol-4-yl) [1, 3] thiazolo [5,4- f] [l,3]benzothiazol-2-yl) -IH- imidazol-2-yl) -1- pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate bistrifluoroacetate (13.0 mg, 0.013 mmol, 44.0 % yield) as a pale yellow solid.LC-MS retention time 1.30 min; m/z 777.2 (MH+) . LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 tnL/rain, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solventB, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% water / 0.1% TFA and solvent B was 90% acetonitrile / 10% water / 0.1% TPA. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD-O4) delta ppm 8.64 - 8.55(m, 2H) , 8.15 - 7.95 (m, 2H), 5.29 (dd, J=Q.1, 3.5 Hz, 2H), 4.27 (d, J 7.3 Hz, 2H), 4.16 - 4.04 (m, 2H) ,78 3.87 - 3.79 (m, 2H) , 3.68 (s, 6H) , 2.53 - 2.39 (m, 2H) , 2.31 - 2.01 (m, 8H) , 1.07 ~ 0.82 {m, 12H) .
  • 3
  • [ 171567-86-5 ]
  • [ 1307303-85-0 ]
  • [ 76-05-1 ]
  • methyl ((1R)-1-(((2S)-2-(4-(5'-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2,2'-bithiophen-5-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
23% HATU (84 mg, 0.22 mmol) was added to a stirred solution of 5 '-(2,2'- bithiene-5,5'-diyl)bis(2-((2S)-2-pyrrolidinyl)-lH-imidazole) (40 mg, 0.092 mmol), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (40 mg, 0.23 mmol) and DIEA (0.16 mL, 0.92 mmol) in dimethylformamide (3 mL) at room temperature. The reaction was stirred for 16 h, diluted with methanol (2 mL) and water (2 mL) and stirred for 15 min. The reaction mixture was concentrated to dryness and purified by preparative HPLC (Waters Sunfire C18 column 30 X 150 mm 5u, eluted with a gradient of 20 to 90 % acetonitrile/water/0.1 % TFA). Fractions containing the desired product were concentrated and repurified by preparative HPLC (Waters Sunfire CI 8 column 30 X 150 mm 5u, eluted with a gradient of 30 to 100 % acetonitrile/water/10 mmol ammonium acetate) to yield the free base of the desired compound. A final preparative HPLC (Waters Sunfire C18 30 X 100 mm 5 u, eluted with a gradient of 10 to 85 % methanol/water/0.1 % TFA) purification was performed to yield a trifluoroacetate salt of methyl ((lR)-l-(((2S)-2-(4-(5'-(2-((2S)-l-((2R)-2- ((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-4-yl)- 2,2'-bithiophen-5-yl)-lH-imidazol-2-yl)-l-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate (21 mg, 0.021 mmol, 23 % yield) as an orange solid.[00134] LC-MS retention time 1.18 min; m/z 751.0 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nm. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/ 100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS Platform for LC in electrospray mode. XH NMR (500 MHz, MeOD-d4) delta ppm 7.71 (s, 2H), 7.46 (d, J=4.0 Hz, 2H), 7.35 (d, J=4.0 Hz, 2H), 5.30 - 5.26 (m, 2H), 4.24 (d, J=7.2 Hz, 2H), 4.14 - 4.07 (m, 2H), 3.86 - 3.77 (m, 2H), 3.65 (s, 6H), 2.56 - 2.46 (m, 2H), 2.24 - 2.14 (m, 6H), 2.11 - 1.99 (m, 2H), 1.02 (t, J=7.5 Hz, 12H).
  • 4
  • [ 171567-86-5 ]
  • 2,2'-bis(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-5,5'-bi-1,3-thiazole trifluoroacetate [ No CAS ]
  • [ 76-05-1 ]
  • methyl ((1R)-1-(((2S)-2-(4-(2'-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-5,5'-bi-thiazol-2-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% HATU (66 mg, 0.17 mmol) was added to a stirred solution of a TFA salt of 2,2'-bis(2-((2S)-2-pyrrolidinyl)-lH-imidazol-5-yl)-5,5'-bi-l,3-thiazole (40 mg, 0.045 mmol), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (31.3 mg, 0.179 mmol) and DIEA (0.078 mL, 0.45 mmol) in dimethylformamide (2 mL) at room temperature. The reaction was stirred for 3 h, diluted with methanol (2 mL) and water (2 mL) and stirred for 15 min. The reaction mixture was concentrated to dryness in vacuo and purified by preparative HPLC (Waters Sunfire CI 8 column 30 X 150 mm 5u, eluted with a gradient of 10 to 80 % acetonitrile/water/0.1 % TFA) to yield a trifluoroacetate salt of methyl ((lR)-l-(((2S)-2-(4-(2'-(2-((2S)-l-((2R)-2- ((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-4-yl)- 5,5'-bi-l,3-thiazol-2-yl)-lH-imidazol-2-yl)-l-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate (16 mg, 0.016 mmol, 36 % yield) as an orange solid. [00160] LC-MS retention time 2.24 min; m/z 753.2 (MH ). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX Luna C18 4.6x50mm S10 column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nm. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 90% methanol/10% water/0.1% TFA. MS data was determined using a MICROMASS Platform for LC in electrospray mode. XH NMR (500 MHz, MeOD-d4) delta ppm 8.1 1 (s, 2H), 7.96 (s, 2H), 5.30 - 5.29 (m, 2H), 4.25 (d, J=7.3 Hz, 2H), 4.12 - 4.01 (m, 2H), 3.84 - 3.76 (m, 2H), 3.68 (s, 6H), 2.52 - 2.43 (m, 2H), 2.26 - 2.20 (m, 6H), 2.09 - 1.99 (m, 2H), 1.05 - 0.95 (m, 12H).
  • 5
  • [ 171567-86-5 ]
  • [ 1307303-89-4 ]
  • [ 76-05-1 ]
  • methyl ((1R)-1-(((2S)-2-(4-(5'-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2,2'-bi-1,3-thiazol-5-yl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% HATU (135 mg, 0.356 mmol) was added to a stirred solution of 5,5'-bis(2- ((2S)-2-pyrrolidinyl)-lH-imidazol-4-yl)-2,2'-bi-l,3-thiazole (40 mg, 0.091 mmol), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (80 mg, 0.456 mmol) and DIEA (0.16 mL, 0.91 mmol) in dimethylformamide (2 mL) at room temperature. The reaction was stirred for 16 h, diluted with methanol (2 mL) and water (2 mL), stirred for 15 min and concentrated to dryness in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire C18 column 30 X 150 mm 5u, eluted with a gradient of 10 to 70 % acetonitrile/water/0.1 % TFA) to yield a trifluoroacetate salt of methyl ((lR)-l-(((2S)-2-(4-(5'-(2-((2S)-l-((2R)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-4-yl)-2,2'-bi-l,3-thiazol-5-yl)-lH- imidazol-2-yl)-l-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate (53 mg, 0.052 mmol, 46 % yield) as a yellow solid.[00188] LC-MS retention time 1.1 1 min; m/z 753.1 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nm. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/ 100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS Platform for LC in electrospray mode. XH NMR (500 MHz, MeOD-d4) delta ppm 8.27 (s, 2H), 7.87 (s, 2H), 5.32 - 5.35 (m, 2H), 4.24 (d, J=7.3 Hz, 2H), 4.12 - 4.04 (m, 2H), 3.86 - 3.86 (m, 2H), 3.65 (s, 6H), 2.57 - 2.43 (m, 2H), 2.25 - 2.02 (m, 8H), 1.07 - 0.95 (m, 12H).
  • 6
  • [ 171567-86-5 ]
  • [ 1282563-99-8 ]
  • [ 1310695-52-3 ]
YieldReaction ConditionsOperation in experiment
55% Example 68Compound 95aTo a solution of <strong>[171567-86-5]N-methoxycarbonyl-D-valine</strong> (420 mg, 2.4 mmol) in DCM (10 mL) was added HOBt.H2O (367 mg, 2.4 mmol) in one portion and stirred at room temperature for 10 min. To the reaction mixture, EDC (460 mg, 2.4 mmol) was added and continually stirred for 30 min. A solution of compound 5a (458 mg, 1.0 mmol) in DCM (5 mL) was added and then stirred overnight at room temperature. After HOBt salt was removed by washing with water, the organic layer was dried over MgSO4, filtered and concentrated to give viscous yellow liquid. The liquid was purified by column chromatography over silica gel (methanol:DCM=1:20) to yield white solid 95a (425 mg, 55%). LC/MS (ESI): [M+2]+/2: 387, [M+1]+: 773, [M+23]+: 795
  • 7
  • [ 171567-86-5 ]
  • C30H30N6*(x)ClH [ No CAS ]
  • [ 1312608-55-1 ]
YieldReaction ConditionsOperation in experiment
35% With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; Example I-XXPreparation of Compounds 324 and 325General Procedure I-GATo a solution of compound I-Ii (80 mg, 0.169 mmol) in anhydrous DCM (5 mL) were added compound I-XXa (59.2 mg, 0.338 mmol), HATU (128.4 mg, 0.338 mmol) and DIEA (54.4 mg, 0.42 mmol). The resulting mixture was stirred at r.t. overnight. After completion of the reaction, monitored by TLC, the mixture was poured into water (10 mL), extracted with CH2Cl2 (30 mL×3), the combined organic layers were dried over Na2SO4, concentrated in vacuo. The residue was purified by Prep-HPLC to afford compound 324 as a white solid (46 mg, yield 35%). MS (ESI) m/z (M+H)+ 789.4.
  • 8
  • [ 171567-86-5 ]
  • (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride [ No CAS ]
  • [ 76-05-1 ]
  • C42H58N8O6*C2HF3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.06 g Example N-28 To a mixture of (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine), 4 HCl (0.07 g, 0.116 mmol), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (0.041 g, 0.232 mmol) and HATU (0.097 g, 0.256 mmol) in DMF (1 mL) was added DIEA (0.081 mL, 0.465 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was purified by reverse phase HPLC to yield TFA salt of Example N-28 (0.06 g) as a white solid. LC/MS (Cond. N-1): [M+H]+ 771.71, Rt=3.29 min. 1H NMR (400 MHz, MeOD) ppm 7.79-8.02 (10H, m), 4.95 (2H, s), 4.06 (2H, d, J=7.53 Hz), 3.58-3.72 (6H, m), 2.03 (2H, dq, J=13.87, 6.84 Hz), 1.10-1.25 (18H, m), 0.89-1.08 (12H, m).
0.06 g To a mixture of (lS,l'S)-l,l'-(4,4'-(biphenyl-4,4'-diyl)bis(lH-imidazole-4,2- diyl))bis(2,2-dimethylpropan-l -amine), 4 HC1 (0.07 g, 0.116 mmol), (R)-2- (methoxycarbonylamino)-3-methylbutanoic acid (0.041 g, 0.232 mmol) and HATU (0.097 g, 0.256 mmol) in DMF (1 mL) was added DIEA (0.081 mL, 0.465 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was purified by reverse phase HPLC to yield TFA salt of Example N-28 (0.06 g) as a white solid. LC/MS (Cond. N-l): [M+H]+771.71, Rt= 3.29 min. NMR (400 MHz, MeOD) ppm 7.79 - 8.02 (10 H, m), 4.95 (2 H, s), 4.06 (2 H, d, J=7.53 Hz), 3.58 - 3.72 (6 H, m), 2.03 (2 H, dq, J=13.87, 6.84 Hz), 1.10 - 1.25 (18 H, m), 0.89 - 1.08 (12 H, m).
  • 9
  • [ 171567-86-5 ]
  • [ 1447940-12-6 ]
  • [ 1447740-82-0 ]
YieldReaction ConditionsOperation in experiment
0.015 g With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; Example N-1 [0396] To a mixture of (1S,1?S)-1,1?-(5,5?-(biphenyl-4,4?-diyl)bis(oxazole-5,2-diyl))bis(2-methylpropan-1-amine) (0.03 g), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (0.024 g, 0.139 mmol) and HATU (0.058 g, 0.153 mmol) in DMF (1 mL) was added DIEA (0.049 mL, 0.279 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was purified by reverse phase HPLC to yield Example N-1 (0.015 g) as a white solid. LC/MS (Cond. N-1): [M+H]+ 745.49, Rt=4.183 min. 1H NMR (400 MHz, MeOD) ppm 7.74-7.87 (8H, m), 7.50 (2H, s), 4.92-5.01 (4H, m), 3.63 (6H, s), 2.30-2.44 (2H, m), 2.10 (2H, d, J=6.78 Hz), 1.04-1.12 (6H, m), 0.99 (16H, dd, J=9.41, 6.90 Hz), 0.96 (2H, s).
  • 10
  • [ 1007882-27-0 ]
  • [ 171567-86-5 ]
  • [ 76-05-1 ]
  • methyl N-[(2R)-1-[(2S)-2-{5-[4-(4-{2-[(2S)-1-[(2R)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)phenyl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate trifluoroacetic acid [ No CAS ]
  • 11
  • [ 640-68-6 ]
  • [ 79-22-1 ]
  • [ 171567-86-5 ]
YieldReaction ConditionsOperation in experiment
87% With sodium carbonate; sodium hydroxide; In water; at 20℃; for 3.25h;Cooling with ice; Na2CO3 (276mg, 2.6mmol) was added to aq NaOH (5mL of 1M/H2O, 5mmol) solution of d-valine (586mg, 5.00mmol) and the resulting solution was cooled with ice-water bath. Methyl chloroformate (0.420mL, 5.40mmol) was added dropwise, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3.25h. The reaction mixture was washed with ether (3×9mL), and the aqueous phase was cooled with ice-water bath and acidified with conc HCl to a pH region of 1-2, and extracted with CH2Cl2 (3×9mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford Cap-1 as a white solid (760mg, 87%). 1H NMR (DMSO-d6, delta=2.5ppm, 300MHz): 12.54 (s, 1H), 7.32 (d, 1H), 3.84 (t, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.87 (d, 6H).
87% With sodium carbonate; sodium hydroxide; In water; at 20℃; for 3.25h;Cooling with ice; Sodium carbonate (276 mg, 2.6 mmol) was dissolved in an aqueous sodium hydroxide solution (5 mL of 1 M / H 2 O, 5 mmol) of D-vailine (586 mg, 5.00 mmol) The reaction mixture was cooled in an ice-water bath. Methylene chloroformate (0.420 mL, 5.40 mmol) was added portionwise, The ice bath was removed and the reaction mixture was stirred at room temperature for 3.25 hours. The reaction mixture was washed with ether (3 X 9 mL), the water layer was cooled in an ice bath, Conc.HCl was added to acidify to pH 1-2 and extracted with dichloromethane (3 X 9 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo to give the desired compound (760 mg, 87% yield) as a white solid.
  • 12
  • [ 171567-86-5 ]
  • C22H26N4O2*2C2HF3O2 [ No CAS ]
  • [ 1512624-39-3 ]
  • 13
  • [ 171567-86-5 ]
  • C25H31F2N7 [ No CAS ]
  • [ 1228668-60-7 ]
  • 14
  • [ 171567-86-5 ]
  • 5-[4-(((S)-2-pyrrolidin-2-yl-3H-imidazol-4-yl)buta-1,3-diynyl)phenyl]-2-[(S)-pyrrolidin-2-yl]-1H-imidazole tetrahydrochloride [ No CAS ]
  • methyl [(R)-1-((2S)-2-{5-[4-(4-{2-[(2S)-1-((2R)-2-(methoxycarbonylamino)-3-methylbutyryl)pyrrolidin-2-yl]-3H-imidazol-4-yl}phenyl)buta-1,3-diynyl]-1H-imidazol-2-yl}pyrrolidine-1-carbonyl)-2-methylpropyl]carbamate dihydrochloride [ No CAS ]
  • 15
  • [ 171567-86-5 ]
  • C31H35N7O3*4ClH [ No CAS ]
  • methyl [(R)-1-((2S)-2-{5-[4-(4-{2-[(2S)-1-((2S)-2-(methoxycarbonylamino)-3-methylbutyryl)pyrrolidin-2-yl]-3H-imidazol-4-yl}buta-1,3-diynyl)phenyl]-1H-imidazol-2-yl}pyrrolidine-1-carbonyl)-2-methylpropyl]carbamate dihydrochloride [ No CAS ]
  • 16
  • [ 171567-86-5 ]
  • C24H24N6*4ClH [ No CAS ]
  • methyl [(R)-1-((2R)-2-{5-[4-(4-{2-[(2R)-1-((2R)-2-(methoxycarbonylamino)-3-methylbutyryl)pyrrolidin-2-yl]-3H-imidazol-4-yl}buta-1,3-diynyl)phenyl]-1H-imidazol-2-yl}pyrrolidine-1-carbonyl)-2-methylpropyl]carbamate dihydrochloride [ No CAS ]
  • 17
  • [ 171567-86-5 ]
  • [ 1447940-13-7 ]
  • [ 1447740-82-0 ]
YieldReaction ConditionsOperation in experiment
0.015 g With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; EXAMPLE N-1 [0396] To a mixture of (1S,1?S)-1,1?-(5,5?-(biphenyl-4,4?-diyl)bis(oxazole-5,2-diyl))bis(2-methylpropan-1-amine) (0.03 g), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (0.024 g, 0.139 mmol) and HATU (0.058 g, 0.153 mmol) in DMF (1 mL) was added DIEA (0.049 mL, 0.279 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was purified by reverse phase HPLC to yield Example N-1 (0.015 g) as a white solid. LC/MS (Cond. N-1): [M+H]+ 745.49, Rt=4.183 min. 1H NMR (400 MHz, MeOD) ppm 7.74-7.87 (8H, m), 7.50 (2H, s), 4.92-5.01 (4H, m), 3.63 (6H, s), 2.30-2.44 (2H, m), 2.10 (2H, d, J=6.78 Hz), 1.04-1.12 (6H, m), 0.99 (16H, dd, J=9.41, 6.90 Hz), 0.96 (2H, s).
0.015 g With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h; To a mixture of (lS,l'S)-l,l'-(5,5'-(biphenyl-4,4'-diyl)bis(oxazole-5,2- diyl))bis(2-methylpropan- 1 -amine) (0.03 g), (R)-2-(methoxycarbonylamino)-3- methylbutanoic acid (0.024 g, 0.139 mmol) and HATU (0.058 g, 0.153 mmol) in DMF (1 mL) was added DIEA (0.049 mL, 0.279 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was purified by reverse phase HPLC to yield Example N-1 (0.015 g) as a white solid. LC/MS (Cond. N-1): [M+H]+745.49, Rt= 4.183 min.XH NMR (400 MHz, MeOD) ppm 7.74 - 7.87 (8 H, m), 7.50 (2 H, s), 4.92 - 5.01 (4 H, m), 3.63 (6 H, s), 2.30 - 2.44 (2 H, m), 2.10 (2 H, d, J=6.78 Hz), 1.04 - 1.12 (6 H, m), 0.99 (16 H, dd, J=9.41, 6.90 Hz), 0.96 (2 H, s).
  • 18
  • [ 171567-86-5 ]
  • (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride [ No CAS ]
  • [ 76-05-1 ]
  • (x)C2HF3O2*C42H58N8O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.06 g EXAMPLE N-28 [0431] To a mixture of (1S,1?S)-1,1?-(4,4?-(biphenyl-4,4?-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine), 4 HCl (0.07 g, 0.116 mmol), <strong>[171567-86-5](R)-2-(methoxycarbonylamino)-3-methylbutanoic acid</strong> (0.041 g, 0.232 mmol) and HATU (0.097 g, 0.256 mmol) in DMF (1 mL) was added DIEA (0.081 mL, 0.465 mmol). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was purified by reverse phase HPLC to yield TFA salt of Example N-28 (0.06 g) as a white solid. LC/MS (Cond. N-1): [M+H]+ 771.71, Rt=3.29 min. 1H NMR (400 MHz, MeOD) ppm 7.79-8.02 (10H, m), 4.95 (2H, s), 4.06 (2H, d, J=7.53 Hz), 3.58-3.72 (6H, m), 2.03 (2H, dq, J=13.87, 6.84 Hz), 1.10-1.25 (18H, m), 0.89-1.08 (12H, m).
  • 19
  • [ 171567-86-5 ]
  • C28H36N6*4ClH [ No CAS ]
  • [ 76-05-1 ]
  • C42H58N8O6*2C2HF3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Examples Y-17 and Y-18 were prepared by using the standard amide coupling method as shown in scheme 3 and purified by reverse phase HPLC and isolated as bis-TFA salts. [0555] Example Y-17: LC-MS (retention time: 2.616 min, method P-1), MS m/z 771.57 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) delta ppm 0.94 (d, J=6.78 Hz, 6H), 0.98-1.03 (m, 12H), 1.23 (d, J=6.53 Hz, 6H), 1.93-2.08 (m, J=14.24, 7.03, 6.81, 6.81 Hz, 2H), 2.38-2.53 (m, 2H), 3.53 (s, 6H), 3.87 (d, J=8.03 Hz, 2H), 4.05 (s, 6H), 4.85 (d, J=10.29 Hz, 2H), 7.87 (s, 8H), 7.88 (s, 2H).
  • 20
  • [ 171567-86-5 ]
  • C28H36N6 [ No CAS ]
  • [ 76-05-1 ]
  • C42H58N8O6*2C2HF3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Examples Y-i7 and Y-i8 were prepared by using the standard amidecoupling method as shown in scheme 3 and purified by reverse phase HPLC andisolated as bis-TFA salts.Example Y-i7: LC-MS (retention time: 2.616 mm, method P-i), MS mlz 771.57 (M+H7. ?H NMR (400 MHz, METHANOL-d4) ppm 0.94 (d, J=6.78 Hz, 6 H), 0.98 - 1.03 (m, 12 H), 1.23 (d, J=6.53 Hz, 6 H), 1.93 - 2.08 (m, J=i4.24, 7.03, 6.81,6.81 Hz, 2 H), 2.38 - 2.53 (m, 2 H), 3.53 (s, 6 H), 3.87 (d, J=8.03 Hz, 2 H), 4.05 (s, 6H), 4.85 (d, J=10.29 Hz, 2 H), 7.87 (s, 8 H), 7.88 (s, 2 H).
  • 21
  • [ 171567-86-5 ]
  • (2S,2'S)-N,N'-(4,4'-(phenylazanediyl)bis(methylene)bis(4,1-phenylene))dipyrrolidine-2-carboxamide [ No CAS ]
  • [ 76-05-1 ]
  • dimethyl (2R,2'R)-1,1'-((2S,2'S)-2,2'-(4,4'-(phenylazanediyl)bis(methylene)bis(4,1-phenylene)bis(azanediyl))bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobulane-2,1-diyl)dicarbamate trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% To a solution of the product from Example 1D (12 mg, 0.024 mmol), (R)-2-(methoxycarbonylamino)-3-methylbutanoicacid (8.87 mg, 0.051 mmol), and HATU (19.25 mg, 0.051 mmol) in anhydrous DMSO (0.25 ml) was addedHunig?sBase (0.013 ml, 0.072 mmol), and the resulting mixture was stirred at rt for 90 min. The mixture was partitionedbetween water (5 ml) and EtOAc (3 x 5 ml) and the combined organic layers were dried over Na2SO4. The mixture wasfiltered and concentrated in vacuo, and the crude product was purified by chromatography on silica gel (C18) elutingwith a gradient of 10-100 % acetonitrile in water (0.1% TFA). Fractions containing pure product were pooled and concentratedin vacuo to give the title compound as a solid (7 mg, 31%) as a TFA salt. 1H NMR (500 MHz, DMSO-D6) deltappm 10.23 (s, 0.5 H) 9.67 (s, 1.5 H) 7.49 - 7.56 (m, 4 H) 7.43 (d, J=8.39 Hz, 0.5 H) 7.35 (d, J=8.24 Hz, 1.5 H) 7.14 -7.22 (m, 4 H) 7.03 - 7.11 (m, 2 H) 6.65 (d, J=8.24 Hz, 2 H) 6.57 (t, J=7.02 Hz, 1H) 4.98 (d, J=8.09 Hz, 0.5 H) 4.56 - 4.63(m, 4 H) 4.40 (dd, J=8.55, 2.75 Hz, 1.5 H) 4.05 - 4.11 (m, 2 H) 3.75 - 3.84 (m, 2 H) 3.56 - 3.65 (m, 3 H) 3.51 - 3.56 (m,6 H) 3.42 - 3.49 (m, 1 H) 2.05 - 2.15 (m, 2 H) 1.87 - 2.04 (m, 6 H) 0.83 - 0.93 (m, 12 H).
  • 22
  • [ 171567-86-5 ]
  • C22H26N4O4S [ No CAS ]
  • dimethyl ((2R,2'R)-((2S,2'S)-(((sulfonylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate [ No CAS ]
  • 23
  • [ 171567-86-5 ]
  • C22H26N4O6S [ No CAS ]
  • bis(4-((S)-1-((methoxycarbonyl)-D-valyl)pyrrolidine-2-carboxamido)phenyl)sulphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
58 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; A mixture of Di-tert-butyl 2,2'-((((sulfonylbis(oxy))bis(4,1-phenylene))bis(azanediyl))bis(carbonyl))(2S,2?S)-bis(pyrrolidine-1-carboxylate) 12a (48.9mg, 0.0725mmol) in CF3CO2H (1mL)/ CH2Cl2 (1mL) was stirred at room temperature for 30m. The volatile component was removed in vacuo, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (36.1mg, 0.188mmol), Hydroxybenzotriazole hydrate (25.5mg, 0.188mmol), Cap-1 (30.5mg, 0.174mmol) were added in batches over 4min to a solution of N,N-Diisopropylethylamine (63.1muL, 0.362mmol) in CH2Cl2 (5mL) and the reaction mixture stirred at room temperature for overnight. The mixture was then poured in 1N aq HCl solution and extracted with CH2Cl2. The organic layer dried over magnesium sulfate, and then was purified by the column chromatography (CH2Cl2/MeOH). The compound 13 was obtained as white solid (58.0mg, 86%). 1H NMR (DMSO-d6, delta=2.5ppm, 400MHz): 10.00 (s, 2H), 7.74-7.72 (d, 4H), 7.42-7.34 (q, 6H), 4.42-4.40 (d, 2H), 4.11-4.07 (t, 2H), 3.79 (s, 2H), 3.63-3.60 (d, 2H), 3.54 (s, 6H), 2.13-1.91 (m, 10H), 0.89-0.86 (t, 10H), 0.80-0.78 (d, 1H), 0.72-0.70 (d, 1H). 13C NMR (DMSO-d6, delta=39.52ppm, 100MHz): 170.69, 170.2, 156.9, 145.0, 138.6, 121.5, 120.5, 60.3, 58.0, 54.9, 51.6, 47.1, 29.7, 29.4, 24.3, 19.1, 18.3. HRMS (ESI) m/z: Anal. calcd. for [M+Na]+ C36H48N6NaO12S: 811.2943; found 811.2941.
  • 24
  • [ 171567-86-5 ]
  • C26H28N6O4S [ No CAS ]
  • bis(4-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)sulphate [ No CAS ]
  • 25
  • [ 171567-86-5 ]
  • tert-butyl (S)-2-((3-(((5-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-2-fluorophenoxy)sulfonyl)oxy)-2-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]
  • 2-fluoro 3-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxamido)phenyl-2-fluoro-5-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxamido)phenyl sulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
21% (S) -2 - ((3 - ((5 - ((S) -1- (tert- butoxycarbonyl) pyrrolidine- 2- carboxamido) -2-fluorophenoxy Cy) sulfonyl) oxy) -2-fluorophenyl) carbamoyl) pyrrolidine-1-carboxylate (90.1 mg, 0.127 mmol) Of trifluoroacetic acid (3 mL) / methylene chloride (3 mL) were stirred at room temperature for 30 minutes. The volatiles were removed under vacuum, EDCI (63.2 mg, 0.330 mmol), hydroxybenzotriazole hydrate (44.5 mg, 0.330 mmol), the compound obtained in Preparation Example 1 (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (53.3 mg, 0.304 mmol) Was added over 4 minutes a solution of N, N-diisopropylethylamine (110 [mu] L, 0.634 mmol) Methylene chloride (10 mL) was added and the reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N HCl aqueous solution and extracted with methylene chloride. The organic layer was washed with magnesium sulfate , And purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (22.3 mg, 21%) as white Obtained as a color solid.
  • 26
  • [ 171567-86-5 ]
  • (2S,2'S)-di-tert-butyl 2,2'-(5,5'-(3,3'-sulfonylbis(oxy))bis(4-fluoro-3,1-phenylene)bis(1H-imidazol-5,2-diyl))dipyrrolidine-1-carboxylate [ No CAS ]
  • bis(2-fluoro-5-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazole-5-yl)phenyl)sulphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% Synthesis of di-tert-butyl 2,2 '- (((sulfonylbis (oxy)) bis (4-fluoro-3,1-phenylene)(1H-imidazol-5,2-diyl)) (2S, 2'S) -bis (pyrrolidine-1-carboxylate)(57.4 mg, 0.076 mmol)Of trifluoroacetic acid (3 mL) / methylene chloride (3 mL) were stirred at room temperature for 30 minutes. The volatiles were removed under vacuum,Hydroxybenzotriazole hydrate (26.6 mg, 0.197 mmol), EDCI (37.8 mg, 0.197 mmol) and (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid 31.9 mg, 0.182 mmol) was added methylene chloride (10 mL) of N, N-diisopropylethylamine (66.1 [mu] L, 0.379 mmol) over 4 minutes and the reaction mixture was stirred overnight at room temperature.The mixture was poured into 1N HCl aqueous solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (34.5 mg, 52%) as a yellow solid.
  • 27
  • [ 171567-86-5 ]
  • tert-butyl (S)-2-(5-(3-(((4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenoxy)sulfonyl)oxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate [ No CAS ]
  • 3-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl-4-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl sulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% Tert-butyl (S) -2- (5- (3 - ((4- (2 - ((S) -1- (tert- butoxycarbonyl) pyrrolidin- Yl) phenoxy) sulfonyl) oxy) phenyl) -1H-imidazol-2-yl) pyrrolidin- Carboxylate (108 mg, 0.149 mmol) Of trifluoroacetic acid (3 mL) / methylene chloride (3 mL) were stirred at room temperature for 30 minutes. The volatiles were removed under vacuum, EDCI (74.3 mg, 0.388 mmol), hydroxybenzotriazole hydrate (52.4 mg, 0.388 mmol), the compound obtained in Preparation Example 1 (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (62.7 mg, 0.358 mmol) Was added methylene chloride (10 mL) of N, N-diisopropylethylamine (130 [mu] L, 0.746 mmol) over 4 minutes and the reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N HCl aqueous solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (40.5 mg, 33%) as a yellow solid.
  • 28
  • [ 171567-86-5 ]
  • (2S,2'S)-di-tert-butyl 2,2'-(5,5'-(4,4'-sulfonylbis(oxy))bis(4,1-phenylene)bis(1H-imidazol-5,2-diyl))dipyrrolidine-1-carboxylate [ No CAS ]
  • bis(4-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)sulphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% Di-tert-butyl 2,2 '- (((sulfonylbis (oxy)) bis (4,1-phenylene) Bis (1H-imidazol-5,2-diyl)) (2S, 2'S) -bis (pyrrolidine -1-carboxylate) (89.5 mg, 0.124 mmol) Was dissolved in a mixed solution (2 mL) of trifluoroacetic acid / dichloromethane (1/1) And the mixture was stirred at room temperature for 30 minutes. After concentrating the solvent in vacuo, the concentrated reaction product, Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (61.9 mg, 0.323 mmol), Hydroxybenzotriazole hydrate (43.6 mg, 0.323 mmol) And (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid obtained in Preparation Example 1 (52.2 mg, 0.298 mmol) was blanketed over a period of 4 minutes A solution of N, N-diisopropylethylamine (108 [mu] L, 0.142 mmol) in dichloromethane (5 mL) And the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to obtain the desired compound (76.9 mg, 74% yield) as a white solid.
  • 29
  • [ 171567-86-5 ]
  • tert-butyl (S)-2-((4-((4-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)phenyl)sulfonyl)phenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]
  • dimethyl ((2R,2'R)-((2S,2'S)-(((sulfonylbis(4,1-phenylene))bis(azanediyl))bis(carbonyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% Di-tert-butyl 2,2 '- (((sulfonylbis (4,1-phenylene)) bis (azaendiyl) Bis (carbonyl)) (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (82.0 mg, 0.128 mmol) Of trifluoroacetic acid (3 mL) / methylene chloride (3 mL) were stirred at room temperature for 30 minutes. The volatiles were removed under vacuum, EDCI (63.6 mg, 0.332 mmol), hydroxybenzotriazole (44.8 mg, 0.332 mmol), the (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid obtained in Preparation Example 1 (53.6 mg, 0.536 mmol) in methylene chloride (10 mL) was added methylene chloride (10 mL) of N, N-diisopropylethylamine (111 nuL, 0.638 mmol) over 4 minutes and the reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N HCl aqueous solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (53.1 mg, 55%) as a white solid
  • 30
  • [ 171567-86-5 ]
  • di-tert-butyl 2,2'-((((sulfonylbis(oxy))bis(2-methyl-3,1-phenylene))bis(azanediyl))bis(carbonyl))(2S,2'S)-bis(pyrrolidine-1-carboxylate) [ No CAS ]
  • bis(3-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxamido)-2-methylphenyl)sulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% Bis (2,2 '- ((((sulfonylbis (oxy)) bis (2-methyl-3,1-phenylene) 2S, 2'S) -bis (pyrrolidine-1-carboxylate) (81.1 mg, 0.115 mmol) Of trifluoroacetic acid (3 mL) / methylene chloride (3 mL) were stirred at room temperature for 30 minutes. The volatiles were removed in vacuo, EDCI (38.8 mg, 0.300 mmol), hydroxybenzotriazole hydrate (40.5 mg, 0.300 mmol), the compound obtained in Preparation Example 1 (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (48.5 mg, 0.277 mmol) was added methylene chloride (10 mL) of N, N-diisopropylethylamine (149 nuL, 0.577 mmol) Was added and the reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N HCl aqueous solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, Purification by rum chromatography (methylene chloride / methanol) gave the desired compound (52.4 mg, 56%) as a white solid.
  • 31
  • [ 171567-86-5 ]
  • C43H48FN9O4SSi*3ClH [ No CAS ]
  • C50H59FN10O7SSi [ No CAS ]
YieldReaction ConditionsOperation in experiment
45.9 mg With N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 1h; Step 4- Synthesis of Compound 1 (0459) To a 8 mL pressure vial with pressure release cap was added Int-7c (0460) (50 mg, 0.060 mmol), Int-4 (13.65 mg, 0.078 mmol), HATU (34.2 mg, 0.090 mmol), and DMF (599 mu). The reaction was allowed to stir at room temperature for 2 minutes, then was cooled to 0 C and DIPEA was added. The reaction mixture was allowed to stir at 0 C for 1 hour, then water (0.3 mL) and TFA (0.3 mL) were added. The solution was allowed to stir at room temperature for 30 minutes, and then the product was purified using a C18 column (50 g, CF^CN/water 10% to 70%, with (0461) 0.05% TFA) to provide compound 1 (45.9 mg). IH-NMR (500 Mz), LC/MS: Anal. Calcd. For [(M+2H)/2]+ C50H59FN10O7SSi: 496.2; found 496.4.
  • 32
  • [ 171567-86-5 ]
  • C43H48FN9O4SSi*3ClH [ No CAS ]
  • C50H59FN10O7SSi [ No CAS ]
YieldReaction ConditionsOperation in experiment
12.7 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 5h; Step 4- Synthesis of Compound 6 (0473) To a 4 mL pressure vial with pressure release cap was added Int-4 (5.57 mg, 0.032 mmol), HOBT (5.84 mg, 0.038 mmol), EDC (7.32 mg, 0.038 mmol) and Int-8c tris HC1 salt (30 mg, 0.032 mmol), and DMF (318 mu). The reaction mixture was allowed to stir at 25 C for 5 minutes, then DIPEA (33.3 mu, 0.191 mmol) was added and the reaction was allowed to stir at 25 C for 5 hours. TFA (0. 1 mL) was then added and the reaction was allowed to stir at 25 C for 30 minutes. The reaction mixture was then diluted with DMSO to 1.5 mL and the resulting solution was directly purified using HPLC (Column: Xbridge CI 8 5um 19X50mm; Flow rate: 25mL/min; Temperature: 25C; Mobile phase: 17% ACN (0.1% NH4OH) to 90% over 8min; Detector: UV 215nm) to provide compound 6 (12.7 mg). XH NMR (500MHz, METHANOL-d4) delta: 7.89 (d, J = 5 Hz, 1H), 7.80 (s, 1H), 7.51 (d, J = 10 Hz, 1H), (0474) 7.38 (d, J = 10 Hz, 1H), 7.29 (d, J = 10 Hz, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 6.99 (d, J = 5 Hz, 1H), 5.79 (t, J= 5 Hz, 1H), 5.18 (t, J = 5 Hz, 1H), 4.53 (d, J = 10 Hz, 1H), 4.23 (d, J = 10 Hz, 1H), 3.98 (m, 1H), 3.87 (m, 1H), 3.65 (s, 6H), 3.38 (d, J = 20 Hz, 1H), 3.06 (d, J = 20 Hz, 1H), 2.40 ~ 2.05 (m, 8H), 1.34 (d, J = 10, 2H), 1.06-0.86 (m, 15 H), 0.30 (s, 3 H), 0.23 (d, 3H). LC/MS: Anal. Calcd. For [(M+2H)/2]+ (0475) C50H59FN10O7SSi: 496.2; found 496.5. Separation method: Xbridge C18 5um 19X50mm, 25mL/min, 25C, 17% ACN (0.1% NH4OH) to 90% over 8min, UV 215nm
  • 33
  • [ 171567-86-5 ]
  • C44H49FN8O4SSi*3ClH [ No CAS ]
  • C51H60FN9O7SSi [ No CAS ]
YieldReaction ConditionsOperation in experiment
12.7 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 5h; Step 3- Synthesis of Compound 13 (0495) To a 4 mL pressure vial with pressure release cap was added Int-4 (5.57 mg, 0.032 mmol), HOBT (5.84 mg, 0.038 mmol), EDC (7.32 mg, 0.038 mmol), Int-lOb tris HCl salt (30 mg, 0.032 mmol), and DMF (318 mu). The reaction was allowed to stir at 25 C for 5 minutes, then DIPEA (33.3 mu, 0.191 mmol) was added. The reaction was allowed to stir at 25 C for 5 hours. TFA (0.1 mL) were added and the reaction was then allowed to stir at 25 C for an additional 30 minutes. The reaction mixture was diluted with DMSO to a volume of 1.5 mL and the resulting residue was purified to provide compound 13 (12.7 mg). XH NMR (500MHz, METHANOL-d4) delta: 7.56 (t, J = 15 Hz, 1H), 7.47 (d, J = 10 Hz 1H), 7.38 (d, J = 10 Hz 1H), 7.24 (m, 1H), 7.17 (s, 1H), 6.95 (d, J = 5 Hz 1H), 6.47 (d, J = 5Hz 1H), 6.38 (d, J = 5Hz, 1H), 5.80 (dd, J = 5, 10 Hz, 1H), 5.13 (t, J = 5 Hz, 1H), 4.51 (d, J = 10 Hz, 1H), 4.22 (d, J = 10 Hz, 1H), 3.98 (m, 1 H), 3.88 (m, 1H), 3.65 (s, 6H), 3.40 (d, J = 15 Hz, 1H), 3.04 (d, J = 20 Hz, 1H), 2.28 (m, 3H), 2.19 (m, 1 H), 2.03 (m, 3H), 1.93 (m, 1H), 1.36 (d, J = 15 Hz, 1H), 1.24 (m, 1H), 1.08 (d, J = 10 Hz, 1H), 1.02 (d, J = 10 Hz, 1H), 0.93-0.89 (m, 12H), 0.55 (m, 2H), 0.35 (s, 3 H), 0.29 (s, 3H), 0.24 (m, 2H). LC/MS: Anal. Calcd. For [(M+2H)/2]+ C51H60FN9O7SSi: 495.7; found 496.0. Separation method used: Xbridge C18 5um 19X50mm, 25mL/min, 25C, 17% ACN (0.1 % NH40H) to 90% over 8min, UV 215nm.
  • 34
  • [ 171567-86-5 ]
  • C46H47FN8O5 [ No CAS ]
  • C53H58FN9O8 [ No CAS ]
YieldReaction ConditionsOperation in experiment
520 mg To a solution of (R) -2- ( (methoxycarbonyl) amino) -3-methylbutanoic acid (173 mg, 1 mmol) and DIPEA (358 mg, 2 mmol) in DMF (10 mL) was added HATU (380 mg, 1 mmol) . The mixture was allowed to stir at 25 for 20 minutes, then compound 11H (810 mg, 1 mmol) was added. The reaction was allowed to stir at 25 for 30 minutes, then filtered. The reaction mixture was directly purified using prep-HPLC to provide a racemic mixture of diastereomers 29 and 30 (520 mg, 53.7yield). Step 9 A racemic mixture of diastereomers 29 and 30 was resolved using chiral SFC to provide pure diastereomers 29 and 30. Conditions: Chiralpak AS-H 250×20 mm, 5 mum Mobile phase: 40of EtOH (0.05DEA) in CO2, Flow rate: 50 mL/min, wavelength: 220 nm. 29: 1H-NMR (MeOH-d4, 400MHz) delta : 8.01 (s, 1 H) , 7.88 (s, 1 H) , 7.71 (s, 1 H) , 7.48 -7.45 (m, 2 H) , 7.33 -7.12 (m, 4H) , 6.90 -6.88 (d, 1 H, J8) , 6.42 -6.40 (m, 1 H) , 6.29 (s, 1 H) , 5.19 -5.10 (m, 2 H) , 4.54 -4.52 (m, 1 H) , 4.22 -4.20 (m, 1 H) , 4.03 -4.00 (m, 3 H) , 3.92 -3.73 (m, 2 H) , 3.64 -3.63 (m, 6 H) , 2.66 -2.64 (m, 3H) , 2.53 -2.45 (m, 2 H) , 2.26 -2.00 (m, 6 H) , 1.87 -1.84 (m, 2 H) , 1.08 -0.86 (m, 14 H) . MS (ESI) : m/z 968.5 [M+H]+. 30: MS (ESI) : m/z 968.5 [M+H]+.
  • 35
  • [ 171567-86-5 ]
  • C22H26N4O6S [ No CAS ]
  • 3-((S)-1-((methoxycarbonyl)-D-valyl)pyrrolidine-2-carboxamido)phenyl (4-((S)-1-((methoxycarbonyl)-D-valyl)pyrrolidine-2-carboxamido)phenyl) sulfate [ No CAS ]
 

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