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Structure of 622867-52-1

Chemical Structure| 622867-52-1

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Product Details of [ 622867-52-1 ]

CAS No. :622867-52-1
Formula : C15H21NO3
M.W : 263.33
SMILES Code : O=C(N1CC2=C(C=C(CO)C=C2)CC1)OC(C)(C)C
MDL No. :MFCD12408124
InChI Key :VVTNAXCVGQIIOV-UHFFFAOYSA-N
Pubchem ID :59132278

Safety of [ 622867-52-1 ]

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

Computational Chemistry of [ 622867-52-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 19
Num. arom. heavy atoms 6
Fraction Csp3 0.53
Num. rotatable bonds 4
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 77.75
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.

3.11
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

1.75
Log Po/w (WLOGP)?

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

1.79
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.

1.93
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

2.33
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.18

Water Solubility

Log S (ESOL):?

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

-2.54
Solubility 0.751 mg/ml ; 0.00285 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.

-2.41
Solubility 1.02 mg/ml ; 0.00387 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

-3.29
Solubility 0.134 mg/ml ; 0.000507 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

Yes
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.

-6.66 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<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)

2.36

Application In Synthesis of [ 622867-52-1 ]

* 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 [ 622867-52-1 ]

[ 622867-52-1 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 170097-67-3 ]
  • [ 622867-52-1 ]
YieldReaction ConditionsOperation in experiment
99.3%
Stage #1: With borane-THF In tetrahydrofuran at 25℃; for 16 h; Inert atmosphere
Stage #2: With sodium carbonate In tetrahydrofuran; water for 0.25 h;
Example 16
Preparation of intermediate 6-bromomethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (D-1)
To a solution of 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester (12.50 g, 45.08 mmol) in dry THF (125.0 mL), under nitrogen at 25° C., is added via syringe borane THF complex (99.17 mL, 99.17 mmol) The mixture is stirred at 25° C. for 16 h then water (10.0 mL) is slowly added followed by 2.0 M Na2CO3 (15.0 mL).
This mixture is stirred for 15 min and then is diluted with EtOAc and the organic layers are collected.
The organics are rinsed with 1M HCl, dried over MgSO4, and concentrated under reduced pressure to afford an oil.
The oil is purified by silica gel chromatography to yield D-1-1 (11.8 g, 99.3percent yield), as a white solid.
To a solution of alcohol, D-1-1, (9.50 g, 36.1 mmol) and N,N-diisopropylethylamine (9.43 mL, 54.1 mmol) in dichloromethane (200.0 mL) is added triphenylphosphine dibromide (23.79 g, 54.11 mmol) at 0° C.
The reaction is stirred for 1 h then concentrated under reduced pressure.
The resulting residue is purified by silica gel chromatography to yield D-1 (8.74 g, 74percent yield), as a white solid.
11.78 g
Stage #1: With borane-THF In tetrahydrofuran at 25℃; for 16 h; Inert atmosphere
Stage #2: With water; sodium carbonate In tetrahydrofuran for 0.25 h;
Preparation of intermediate 6-bromomethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4-19) Compound 4-17 (12.50 g, 45.08 mmol) is dissolved in dry THF (125.0 mL) under nitrogen at 25° C. Borane THF complex (99.17 mL, 99.17 mmol) is added via syringe and the mixture is stirred at 25° C. for 16 h. Water (10.0 mL) is slowly added and then 2.0 M Na2CO3 (15.0 mL). This mixture is stirred for 15 min and then is diluted with EtOAc and the organic layers are collected. The organics are rinsed with 1.0 M HCl, dried over MgSO4, and concentrated in vacuo to afford an oil. The oil is purified by silica gel chromatography using a gradient of 10-80percent EtOAc in heptane to yield the desired product, 4-18 (11.78 g), as a white solid.
2 g With borane-THF In tetrahydrofuran at 20℃; for 3 h; Sealed tube; Inert atmosphere Borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M, 15.87 mL, 15.87 mmol) was added dropwise to a stirred solution of 2-(tert-butoxycarbonyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylic acid (2.0 g, 7.21 mmol) in tetrahydrofuran (50 mL) at ambient temperature under argon in a sealed flask. After stirring for 3 hours, the mixture was carefully quenched with water and sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate (x2) and the combined extracts were washed with brine, dried (anhydrous Na2SO4) and evaporated to give tert-butyl 6- (hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.0 g). LCMS m/z = 207.9 [M+H–isobutylene]+.
References: [1] Patent: US2016/24059, 2016, A1, . Location in patent: Paragraph 0308-0309.
[2] Patent: WO2012/122340, 2012, A1, . Location in patent: Page/Page column 77.
[3] Patent: US2014/73629, 2014, A1, . Location in patent: Paragraph 0100; 0101.
[4] Patent: WO2017/160632, 2017, A1, . Location in patent: Page/Page column 78; 79.
[5] Patent: WO2017/216726, 2017, A1, . Location in patent: Page/Page column 643-644.
  • 2
  • [ 170097-66-2 ]
  • [ 622867-52-1 ]
YieldReaction ConditionsOperation in experiment
4.5 g
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1 h;
Stage #2: With water In tetrahydrofuran at 0℃; for 0.25 h;
Add lithium aluminum hydride (716.49 mg, 18.88 mmol) dropwise to a solutionof 02-tert-butyl 06-methyl 3 ,4-dihydro- 1H-isoquinoline-2,6-dicarboxylate (5.00 g, 17.16mmol) in tetrahydrofuran (85.81 mL) at 0 °C and stir at that temperature for 1 hour. Thenadd water (6 mL) and stir for 15 minutes at 0 °C, filter over CELITE® and wash theCELITE® with ethyl acetate. Concentrate the filtrate under reduced pressure to afford the title compound (4.5 g, 17.09 mmol). MS (m/z): 264 (M+1).
References: [1] Patent: US2011/112103, 2011, A1, . Location in patent: Page/Page column 91.
[2] Patent: WO2015/54060, 2015, A1, . Location in patent: Page/Page column 22; 10.
[3] Patent: WO2017/205193, 2017, A1, . Location in patent: Page/Page column 137.
  • 3
  • [ 371222-37-6 ]
  • [ 622867-52-1 ]
References: [1] Patent: US2017/275301, 2017, A1, . Location in patent: Paragraph 0210; 0213.
  • 4
  • [ 893566-74-0 ]
  • [ 622867-52-1 ]
References: [1] Patent: WO2017/205193, 2017, A1, .
  • 5
  • [ 24424-99-5 ]
  • [ 622867-52-1 ]
References: [1] Patent: WO2017/205193, 2017, A1, .
  • 6
  • [ 226942-29-6 ]
  • [ 622867-52-1 ]
References: [1] Patent: WO2017/205193, 2017, A1, .
 

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