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Structure of 372118-67-7

Chemical Structure| 372118-67-7

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Product Details of [ 372118-67-7 ]

CAS No. :372118-67-7
Formula : C5H8ClN3
M.W : 145.59
SMILES Code : Cl.NCC1=NC=CC=N1
MDL No. :MFCD08062208
InChI Key :RZNKMZKAXJTLQR-UHFFFAOYSA-N
Pubchem ID :17848325

Safety of [ 372118-67-7 ]

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

Computational Chemistry of [ 372118-67-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 36.67
TPSA ?

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

51.8 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

-0.1
Log Po/w (WLOGP)?

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

0.59
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.

-0.61
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

0.55
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.09

Water Solubility

Log S (ESOL):?

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

-1.11
Solubility 11.4 mg/ml ; 0.0782 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.

-0.54
Solubility 42.5 mg/ml ; 0.292 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

-1.63
Solubility 3.38 mg/ml ; 0.0232 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.

-7.26 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.

0.55

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)

1.33

Application In Synthesis of [ 372118-67-7 ]

* 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 [ 372118-67-7 ]

[ 372118-67-7 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 372118-67-7 ]
  • [ 330785-84-7 ]
  • [ 330784-47-9 ]
YieldReaction ConditionsOperation in experiment
145 g With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 5℃; for 14h; Hydroxybenzotriazole (51.6 g) followed by (S)-4-(3-chloro-4-methoxybenzylamino)- 2-(2-(hydroxymethyl)pyrrolidin-l-yl) pyrimidine-5-carboxylic acid (150 g) and l -ethyl-3-(3- dimethylamino propyl)carbodiimide hydrochloride (128.1 g) were added to a pre-cooled mixture of pyrimidin-2-ylmethanamine hydrochloride compound of formula- 12a (72.3 g), triethylamine (77.3 g) and dimethylformamide (750 ml) at 0-5C and stirred for 14 hours at 0-5C. Quenched the reaction mixture with 5% aqueous potassium carbonate solution (3.75 lit) at a temperature below 30C and stirred for 3 hours at 25-30C. Filtered the solid and washed with water. Water followed by dichloromethane were added to the obtained solid and separated the organic and aqueous layers. Carbon (7.5 g) was added to the organic layer. Filtered the reaction mixture, washed with dichloromethane and distilled off the solvent completely from the filtrate and co-distilled with methanol. Cooled the obtained compound to 30-35C and methanol (1500 ml) was added to it. Heated the reaction mixture to 65-70C and stirred for 10 minutes. Cooled the reaction mixture to 25-30C and stirred for 1 hour. Filtered the solid, washed with methanol and then dried to get title compound. Yield: 145 g; Melting range: 158-163C; Purity by HPLC: 99.6%; Particle Size Distribution: D(0.1): 5.501 μιη; D(0.5): 20.469 um; D(0.9): 52.006 um; D(4,3): 25.457 μηι.PXRD pattern of the obtained compound is represented in figure- 1 and DSC thermogram of the obtained compound is represented in figure-2.
  • 2
  • [ 372118-67-7 ]
  • [ 330785-84-7 ]
  • C41H45Cl2N11O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
40 g With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In ethyl acetate; at 50 - 55℃; for 6h; A mixture of l -Ethyl-3-(3-dimethylaminopropyl)carbodiimide (48.8 g), Hydroxy benzotriazole (17.1 g), pyrimidin-2-ylmethanamine hydrochloride (12.9 g) and triethylamine (25.75 g) was added to a mixture of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxy methyl)pyrrolidin-l-yl) pyrimidine-5-carboxylic acid compound of formula-l 1 (50 g) and ethyl acetate (500 ml) at 25-30C. Heated the reaction mixture to 50-55C and stirred for 6 hours. Cooled the reaction mixture to 25-30C and water followed by ethyl acetate were added to the reaction mixture. Separated the organic and aqueous layers and washed the organic layer with water. Distilled off the solvent from the organic layer and then co-distilled with methanol. Methanol (150 ml) was added to the reaction mixture at 25-30C and stirred for 45 minutes. The solvent was decanted from the reaction mixture and water (500 ml) was added to the reaction mixture and stirred for 5 hours. Filtered the precipitated solid, washed with water and then dried to get the title compound. The obtained compound was further purified by preparative HPLC to get pure title compound. Yield: 40 g; Purity by HPLC: 96%. NMR (CHC13, 300 MHz) δ 1.62-2.16 (m, 9H), 3.48-3.77 (m, 6H), 3.82-3.87 (d, 7H), 4.77- 4.78 (d, 2H), 4.24-4.27 (d, 2H), 4.43-4.45 (d, 2H), 4.57-4.59 (d, 4H), 4.78-4.79 (d, 2H), 6.79- 6.87 (d, 2H), 7.15-7.18 (d, 2H), 7.26-7.46 (m, 4H), 8.43 (s, 1H), 8.49 (s, 1 H), 8.71-8.72 (d, 2H), 9.0-9.04 (t, 1 H). EIMS (M+l) m/z = 858.3. FTIR: v 3339.55, 1678.41 cm'1.
  • 3
  • [ 1260843-26-2 ]
  • [ 372118-67-7 ]
YieldReaction ConditionsOperation in experiment
5.3 g With hydrogenchloride; In water; Hydrogenation bottle was added 100mL (20vol) of ethyl acetate,50 mL water (10 vol) (purified water),2.28 g sodium hydroxide (0.0571 mol, 1.2 eq),10.9 g BoC2O anhydride (0.05 mol, 1.05 eq)Cool to room temperature (20-25 C)0.5 g of 20% palladium hydroxide on carbon (0.000712 mol, 0.015 eq)5 g of 2-cyanopyrimidine (0.0476 mol, 1.0 eq),Sealed,Nitrogen was substituted 3 times,Hydrogen replacement 3 times,Keep hydrogen pressure 2atm,After stirring at room temperature (20-25 C) for 16 hours,TLC confirmed no raw materials,Insoluble matter was removed by filtration,Liquid separation,The organic phase was washed once with 50 mL of saturated brine,Cooled to 0-5 ,Into the hydrogen chloride gas of about 15g,Stir for 8 hours,TLC confirmed the reaction was complete,All off the protective group.The crude product was filtered,30mL ethanol beating,Filtered, dried to give 5.3g hydrochloride,Yield 76.8%Purity 99.1%.
  • 4
  • [ 372118-67-7 ]
  • [ 330785-84-7 ]
  • avanafil [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 30℃; for 24h; In a 1L three bottle,Add (39.28 g, 0.10 mol) (S)-4-(3-chloro-4-methoxybenzylamino)-5-carboxylic acid-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine (AFZJT-3),(21.84 g, 0.15 mol) 2-aminomethylpyrimidine hydrochloride,(28.76 g, 0.15 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,(20.26 g, 0.15 mol) 1-hydroxybenzotriazole, 0.8L N,N-dimethylformamide,(30.36g, 0.30mol) triethylamine, reacted at 30C for 24h,HPLC showed that the reaction was complete, adding 1.2L of water, extraction with dichloromethane,Wash it twice with about 5% aqueous sodium carbonate,Deionized water was washed once, dried over anhydrous sodium sulfate, suction filtered, and the desiccant removed.Concentrate the dichloromethane solvent under reduced pressureAdd ethyl acetate to beat,The filter was filtered and dried under reduced pressure at 50 C for 5 h.40.72 g of atorvapine crude was obtained with a yield of 84.13%.The crude product prepared in the example is 10g,Perform column chromatography and recrystallize twice with methanol,5.48 g of purified valvafil was obtained with a purification yield of 54.80%;
 

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Technical Information

Categories

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[ 372118-67-7 ]

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