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Chemical Structure| 766545-20-4 Chemical Structure| 766545-20-4
Chemical Structure| 766545-20-4

2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride

CAS No.: 766545-20-4

4.5 *For Research Use Only !

Cat. No.: A134174 Purity: 98%

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Product Details of [ 766545-20-4 ]

CAS No. :766545-20-4
Formula : C8H10Cl2N2
M.W : 205.08
SMILES Code : ClC1=NC2=C(CNCC2)C=C1.[H]Cl
MDL No. :MFCD09835503
InChI Key :FRACHJCOMOVESL-UHFFFAOYSA-N
Pubchem ID :18449165

Safety of [ 766545-20-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 766545-20-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.38
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 55.55
TPSA ?

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

24.92 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

2.05
Log Po/w (WLOGP)?

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

1.65
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.

1.44
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

2.57
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.54

Water Solubility

Log S (ESOL):?

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

-2.77
Solubility 0.346 mg/ml ; 0.00169 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.

-2.2
Solubility 1.29 mg/ml ; 0.00628 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

-3.52
Solubility 0.0625 mg/ml ; 0.000305 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

Yes
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.

-6.1 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

1.0 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)

1.91

Application In Synthesis of [ 766545-20-4 ]

* 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 [ 766545-20-4 ]

[ 766545-20-4 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 766545-20-4 ]
  • [ 24424-99-5 ]
  • [ 1151665-15-4 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; To a slurry of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (106.1 g, 517 mmol, commercially available from D-L Chiral Chemicals, ST-0143) and N,N-diisopropylethylamine (80 g, 108 mL, 621 mmol, 1.2 eq) in DCM (1 L) was added a solution of di-tert-butyl dicarbonate (119 g, 543 mmol, 1.05 eq) in DCM (100 mL) via an addition funnel within 1 hr. The reaction mixture became a clean solution and the solution thus obtained was stirred at room temperature for an additional hour and monitored using LCMS. Upon completion, the reaction mixture was concentrated. The residue was dissolved in EtOAc (1 L) and washed with water (3*300 mL), washed with brine (300 mL) and dried over Mg504. The solvent was evaporated under vacuum to give the title compound as an off-white solid (139 g, yield: 100%). 1H NMR (400 MHz, CDCl3) delta ppm 1.49 (9H, s), 2.97 (2H, t, J=5.9 Hz), 3.73 (2H, t, J=6.0 Hz), 4.57 (2H, s), 7.17 (1H, d, J=8.0 Hz), 7.38 (1H, d, J=8.0 Hz) ppm; LCMS m/z: 269 (M+1).
95.41% With triethylamine; In dichloromethane; at 15℃; for 12h;Inert atmosphere; 2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (2.00 g, 9.75 mmol, 1.00 eq) was dissolved in DCM (20.00 mL) and triethylamine (2.47 g, 24.38 mmol, 2.50 eq) and di-tert-butyl dicarbonate (3.19 g, 14.63 mmol, 1.50 eq) were added at 15 C under the nitrogen gas atmosphere. The mixture was stirred at 15 C for 12 hours. The mixture was poured into water (30 mL) and the aqueous phase was extracted with dichloromethane (100 mL * 4). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to deliver tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (2.50 g, 9.30 mmol, 95.41% yield) as a white solid. LCMS (ESI) m / z: 269 (M + 1).
92% To a solution of compound 36 (5 g, 24.4 mmol, 1 eq) in DCM (40 mL) was added DIEA (9.45 g, 73.1 mmol, 3 eq) and stirred for 20 mins, B0C2O (6.5 g, 29.3 mmol, 1.2 eq) in DCM (30 mL) was added drop wise and then stirred for lh. After LCMS and TLC indicated completion, the mixture was concentrated and the residue was dissolved in EA (200 mL), washed with water (100 mL X 3) and brine (100 mL), dried over sodium sulfate, concentrated and purified by silica column to give the desired product as white solid (6 g, 92%). *H NMR (300 MHz, CDCb-de): delta 7.39 (d, J= 8.1 Hz, 1 H), 7.18 (d, J= 8.1 Hz, 1 H), 4.57 (s, 2 H), 3.74 (t, J= 6.0 Hz, 2 H), 2.98 (t, J= 5.4 Hz 2 H), 1.53 (s, 9 H). LCMS: (M+H)+: 268.9.
89% With triethylamine;dmap; In dichloromethane; at 0 - 20℃; Di-tert-butyl dicarbonate (2.40 g, 11 mmol) was added to a solution of 2-chloro-5,6,7,8- tetrahydro-l,6-naphthyridine hydrochloride (available from Activate Scientific) (2.05 g, 10 mmol) and Et3N (3.33 g, 4.59 mL, 33 mmol) in DCM at 00C. DMAP (0.12 g, 1.00 mmol) was added and the reaction was stirred at RT for 3 days. The reaction was diluted with DCM and washed successively with 10% w/v citric acid (aq.), saturated NaHCO3 (aq.), water, dried (Na2SO4), filtered and concentrated at reduced pressure. The residue (2.8g) was purified by FCC (SiO2, eluting with 9:1 to 3:1 heptane / EtOAc) to give the title compound (2.63 g, 89%). LCMS data: Calculated MH+ (269); Found 100% (MH+) m/z 269, Rt = 1.33 min. 1H NMR (250 MHz, CHLOROFORM-J) delta ppm 1.49 (8 H, s) 2.97 (2 H, t, J=5.86 Hz) 3.73 (2 H, t, J=5.94 Hz) 4.57 (2 H, s) 7.17 (1 H, d, J=8.07 Hz) 7.38 (1 H, d, J=8.07 Hz).
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; To a solution of 2-chloro-5,6,7,8-tetrahydro-[l,6]naphthyridine hydrochloride (1.54 g, 7.5 mmol) in DCM (25 mL) was added EtsN (2 mL, 15 mmol). After the addition and stirring - 139 -at room temperature for 5 min, the solution was cooled to 0 C, followed by the addition of (Boc)20 (1.88 g, 8.63 mmol). The resulting reaction mixture was then allowed to stir at room temperature for 2 hours. It was then washed with H20 and brine. The organic layer was dried over anhy. Na2S04, filtered and concentrated in vacuo to give the title compound (1.87 g, 93%) as a white solid. MS: 269.1 (M+H+). It was used directly in the next step without further purification.

 

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