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Structure of 419572-18-2

Chemical Structure| 419572-18-2

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Product Details of [ 419572-18-2 ]

CAS No. :419572-18-2
Formula : C11H19NO3
M.W : 213.27
SMILES Code : O=C(N1C[C@@]2([H])[C@H](CO)[C@@]2([H])C1)OC(C)(C)C
MDL No. :MFCD14525755
InChI Key :JVIDPFGQYMFQDZ-JVHMLUBASA-N
Pubchem ID :49757489

Safety of [ 419572-18-2 ]

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

Computational Chemistry of [ 419572-18-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 0
Fraction Csp3 0.91
Num. rotatable bonds 4
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 60.45
TPSA ?

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

49.77 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.67
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

0.75
Log Po/w (WLOGP)?

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

0.71
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.

1.15
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

0.52
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.16

Water Solubility

Log S (ESOL):?

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

-1.37
Solubility 9.08 mg/ml ; 0.0426 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.

-1.37
Solubility 9.0 mg/ml ; 0.0422 mol/l
Class?

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

Very 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

-0.64
Solubility 48.6 mg/ml ; 0.228 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

Yes
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.

-7.07 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

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)

2.99

Application In Synthesis of [ 419572-18-2 ]

* 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 [ 419572-18-2 ]

[ 419572-18-2 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 419572-18-2 ]
  • [ 4214-79-3 ]
  • C16H21ClN2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dibenzyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Product distribution / selectivity; In a flame-dried flask under N2, was combined 807 mg (6.24 mmol, 1.33 eq) of 5- chloro 2-pyridyl phenol and 1.64 g (6.23 mmol, 1.33 eq) of triphenylphosphine in 20 mL of anhydrous THF at room temperature. To this solution was added 1.86 g (6.233 mmol, 1.33 eq) of DBAD, followed by 1.0 g (4.69 mmol, 1.0 eq) of 6-hydroxymethyl-3-aza- <n="58"/>bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in 5 ml_ of anhydrous THF. The yellow solution was stirred at room temperature overnight. To this solution was added 6.3 mL (25.2 mmol, 5.4 eq) of 4M HCI in 1 ,4-dioxane and the resulting solution was stirred at room temperature overnight. The solution was concentrated under reduced pressure and the resulting residue was dissolved in 95 mL methylene chloride. The solution was extracted with 63 mL of 15percent aqueous citric acid. The aqueous layer was extracted with 95 mL of methylene chloride. The aqueous layer was basified with 32 mL of cone. NH4OH and extracted three times with 65 mL of methylene chloride. The combined organic layers were dried over anhydrous MgSO4, filtered and stripped in vacuo to give yellow oil which crystallized while drying under high vaccum (588 mg). The crude material was purified via flash chromatography, eluting with 5percent methanol/ methylene chloride- with 0.1 percent triethyl amine to yield 242 mg of desired compound. 400 MHz 1H NMR (CDCI3) delta 8.0 (d, 1 H), 7.5 (m, 1H), 6.7 (d, 1 H), 4.1 (d, 2H), 3.1 (d, 2H), 2.9-3.0 (m, 3H), 1.5 (m, 2H), 1.2 (m, 1H); MS (M+1) 225, 227.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 64h;Product distribution / selectivity; 19.5 mmol of triphenyl phosphine was dissolved in 9.75 mL of anhydrous THF and vortexed. 75 mul (0.15 mmol) of this solution was added to each 0.1 mmol of varying phenols of general foumula (III) in 2-dram vials. 13.0 mmol of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3- <n="59"/>aza-bicycio[3.1.0]hexane-3-carboxylate (Preparation 1 ) was dissolved in 6.5 mL of anhydrous THF and vortexed. 50 muL (0.10 mmol) of this solution was added to each vial. 19.5 mmol of Diethylazodicarboxylate (DEAD) was dissolved in 9.75 mL of anhydrous THF and vortexed. 75 muL (0.15 mmol) of this solution was added to each vial. The vials were sealed and placed on shaker at room temperature for 64 hours. 200 muL of 4 M HCI in 1 ,4-dioxane was then added to each vial and the vials were placed on a shaker at room temperature for 16 hours. The reactions were evaporated under nitrogen. MCX SPE columns were conditioned by eluting twice with 4 mL of CH3OH. The reaction residues were dissolved with 1.0 mL of CH3OH, vortexed, and the reaction residues were added to the MCX columns. The reaction vials were rinsed two times with 1.0 mL of CH3OH, vortexed, and the reaction residues were added to the columns. The columns were eluted three times with 4.0 mL of CH3OH. 4.0 mL of 2 M NH3 in CH3OH was added to each vial with the eluent collected in tared 2-dram vials. The vials were evaporated under nitrogen, tared, and used without further purification in the next reaction. To each of the vials prepared above were added 500 muL of 1 ,2-dichloroethane and 28 muL (0.2 mmol) of triethylamine. 4.3 mmol of an aldehyde of general formula (V) was dissolved in 4.3 mL of 1 ,2-dichloroethane and 0.1 mL (0.1 mmol) was added to the vials. 0.3 mmol of sodium triacetoxyborohydride was added to vials. The vials were sealed and placed on shaker at room temperature for 16 hours. 1.5 mL of 1 N NaOH, followed by 1.0 mL of 1 ,2- dichloroethane was added to each vial and vortexed for 4 minutes. The layers were allowed to separate and 1.5 mL was removed from the lower layer to empty SPE barrels, which were allowed to drip into tared 2-dram vials. 1.0 mL of 1 ,2-dichloroethane was added and the mixture was vortexed for 4 minutes. The layers were allowed to separate and 1 mL was removed from the lower layer to empty SPE barrels, which were allowed to drip into the tared 2-dram vials. 1.0 mL of 1 ,2-dichloroethane was added to the each vial and vortexed for 4 minutes. The layers were allowed to separate and 1 mL was removed from the lower layer to empty SPE barrels, which were allowed to drip into tared 2-dram vials. The combined SPE eluents remaining in the 2 dram tared vials were evaporated in a Savant SpeedVac Plus. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl).Alternatively, compounds of formula I can be prepared as highlighted below in method C, utilizing parallel chemistry or high-speed synthesis methods.
With triphenylphosphine on polystyrene; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 20℃; for 17h;Product distribution / selectivity; Prepared a 2 M stock solution of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxyiate (Preparation 1 ) in THF. Prepared 2 M stock solutions of varying phenols of a general formula (III) <n="60"/>in THF. Prepared a 0.5 M stock solution of DEAD in toluene. To each reaction vial, added 0.200 ml_ of the varying phenol followed by 0.075 mL of (1S,5R,6R)-tert-butyl 6- (hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate. Added 0.600 mL of the DEAD solution, followed by 0.750 mL of toluene. Added 140 mg of triphenylphosphine-polystyrene resin. Vials were capped and shaken at room temperature for 17 hours. Added 2.5 mL of THF to each reaction vial. The top layer was transferred to empty 6 mL SPE cartridges over collection tubes. Added 3.0 mL of THF to the reaction vials and then aspirated the top layer to the SPE cartridges over collection tubes. Transferred solutions from collection tubes to new reaction vials and evaporated. Added 0.600 mL of CH3OH followed by 0.300 mL of 4 M HCI in 1 ,4-dioxane to each reaction vial. Vials were capped and shaken at room temperature for 24 hours. The solvent was evaporated and the intermediates used without further purification in the next reaction.Prepared a 0.25 M solution of an aldehyde of general formula (V) in 1 ,2- dichloroethane. Prepared a 0.25 M solution of sodium triacetoxyborohydride in 1 ,2- dichloroethane. Added 0.600 mL of the aldehyde solution to each of the reaction vials from the step above, followed by 0.070 mL of DIPEA. Added 2.0 mL of the sodium triacetoxyborohydride solution, capped vials and shaken at room temperature for 17 hours. Added 1.0 mL of 1 ,2-dichloroethane followed by 2.0 mL of 10percent NaOH. Vials were vortexed and/or shaken and removed top layer. Added 2.0 mL of 10percent NH4OH, with vials shaken well and/ or vortexed. The bottom layers were aspirated to empty 6 mL SPE cartridges over tared collection tubes. Added 1.0 mL of 1 ,2-dichloroethane to the aqueous layer and aspirated the bottom layer to the SPE cartridge over the collection tubes. Evaporated solutions to dryness. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl) Alternatively, compounds of formula I can be prepared as highlighted below in method D utilizing parallel chemistry or high-speed synthesis methods.
With triphenylphosphine on polystyrene; di-tert-butyl-diazodicarboxylate; In tetrahydrofuran; at 20℃; for 1h;Product distribution / selectivity; Prepared a 2 M stock solution of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza- bicyclo[3.1.0]hexane-3-carboxylate (Preparation 1) in THF. Prepared 2 M stock solutions of varying phenols of a general formula (III) in THF. Prepared a 2 M stock solution of DBAD (di-t- butylazodicarboxylate) in THF. To each reaction vial, added 0.075 mL of the varying phenol followed by 0.075 mL of 2 M solution of triphenylphosphine in THF. The prepared solutions of (1S,5R,6R)-tert-butyl 6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate and DBAD were mixed in 3:4 ratio and 0.1313 mL of this mixture was added to each reaction vial. Vials are capped and shaken at room temperature for 1 hour. Added 0.15 mL of 4 M HCI in 1 ,4- dioxane to each reaction vial. Vials are capped and shaken at room temperature for 16 hours. The solvent was evaporated and to each vial was added 3 mL of dichloromethane and 2 mL <n="61"/>of 15percent aqueous citric acid solution. The vials were shaken and centrifuged followed by removal of the lower organic layer. 3 mL of dichloromethane was added too each via) and the vials were shaken and centrifuged followed by removal of the lower organic layer. The last operation was repeated. To each vial was added 2 mL of 28percent aqueous NH4OH. After cooling, 2 mL of dichloromethane was added. The vials were shaken and centrifuged followed by collecting of the lower organic layer. The solvent was evaporated and the obtained products were used in the next step without further purification.Prepared a 0.25 M solution of an aldehyde of general formula (V) in 1 ,2- dichloroethane. Prepared a 0.25 M solution of sodium triacetoxyborohydride in chloroform. To each vial from the step above was added 0.45 mL of 1 ,2-dichoroethane and, following dissolution, 0.45 mL of the aldehyde followed by 1.51 mL of the sodium triacetoxyborohydride solution. The vials were capped and shaken at room temperature for 17 hours. To each vial was added 2 mL of 10percent aqueous NaOH. Vials were shaken and centrifuged followed by transfer of the lower organic layer to phase separation cartridges. Organic layer was collected and the solvent was removed by evaporation. The resulting crude mixtures were purified via preparative LC/MS chromatography to yield compounds of general formula (Vl).Alternatively, compounds of formula I can be prepared as highlighted below in method E, utilizing parallel chemistry or high-speed synthesis methods.

 

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Technical Information

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