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Chemical Structure| 109-01-3 Chemical Structure| 109-01-3

Structure of 109-01-3

Chemical Structure| 109-01-3

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Product Details of [ 109-01-3 ]

CAS No. :109-01-3
Formula : C5H12N2
M.W : 100.16
SMILES Code : CN1CCNCC1
MDL No. :MFCD00005966
InChI Key :PVOAHINGSUIXLS-UHFFFAOYSA-N
Pubchem ID :53167

Safety of [ 109-01-3 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H225-H303-H312+H332-H314
Precautionary Statements:P241-P242-P264-P270-P271-P272-P280-P304+P340-P305+P351+P338-P310-P330-P331-P363-P370+P378-P403+P233-P501
Class:3(8)
UN#:2924
Packing Group:

Computational Chemistry of [ 109-01-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 37.56
TPSA ?

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

15.27 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.66
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

-0.39
Log Po/w (WLOGP)?

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

-1.24
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.

-0.16
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

0.62
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.1

Water Solubility

Log S (ESOL):?

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

-0.22
Solubility 61.0 mg/ml ; 0.609 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.

0.53
Solubility 342.0 mg/ml ; 3.41 mol/l
Class?

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

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

-0.69
Solubility 20.7 mg/ml ; 0.207 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

Low
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.

-7.19 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)

1.1

Application In Synthesis of [ 109-01-3 ]

* 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 [ 109-01-3 ]
  • Downstream synthetic route of [ 109-01-3 ]

[ 109-01-3 ] Synthesis Path-Upstream   1~11

  • 1
  • [ 109-01-3 ]
  • [ 109-70-6 ]
  • [ 2031-23-4 ]
YieldReaction ConditionsOperation in experiment
44.1% With sodium hydroxide In acetone at 20℃; for 24 h; Cooling with ice N-methylpiperazine (30 mmol, 3.3 ml), 4 ml of 25percent NaOH solution and 40 ml of acetone were added to a 100 ml round-bottomed flask under ice-cooling, then 1-bromo-3-chloropropane (30 mmol, 3 ml) After completion of ice bath stirring to insoluble material dissolved, and then at room temperature for 24h.The solvent was concentrated under reduced pressure, 20 ml of water-soluble concentrate was added, extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give a clear oil. The reaction flask was placed in an ice bath and 50 ml of ethyl acetate was added. 2.5 ml of concentrated hydrochloric acid was added dropwise slowly until a large amount of white solid was formed. The pH was controlled to about 2 during the reaction. The solvent was concentrated under reduced pressure, recrystallized from 100 ml of anhydrous ethanol, filtered and dried to obtain 3.3 g of a white solid,
25%
Stage #1: With sodium hydroxide In water; acetone at 0 - 20℃; for 24 h;
Stage #2: With hydrogenchloride In ethanol
A modified procedure of Mahesh et al, Pharmazie, 2005, 60, 6, 411-414, was used. After cooling a stirred solution of N-methylpiperazine (50 mmol, 5.55 ml) in 100 ml acetone to 0 °C, 10 ml of an aqueous 25 percent NaOH-solution and l-bromo-3-chloropropane (50 mmol, 7.87 g = 4.92 ml) were added cautiously. The reaction was stirred at RT for 24 hours. After concentrating the mixture under reduced pressure, the residue was diluted with water and extracted with dichloromethane. The collected organic phases were dried over Na2S04, filtered and concentrated. The residue was diluted with ethanol and after adding 2.3 M ethanolic HC1 l-(3-chloropropyl)-4-methylpiperazin-dihydrochloride crystallized as white crystals(12.5 mmol, 25 percent). Mp = 257 °C. ]H NMR (300 MHz, DMSO) 3.74 (t; 2H; 3J = 6.4 Hz; NCH7CH7CH7CI); 3.37 (m; 12H: NCH7CH7CH7Cl+4xpiperazin-CH7+2x H); 2.81 (s; 3H; CH3); 2.19 (d; 2H; J = 6.8 Hz; NCH2CH2CH2CI).
References: [1] Patent: CN105884699, 2016, A, . Location in patent: Paragraph 0044; 0045.
[2] Patent: WO2011/73092, 2011, A1, . Location in patent: Page/Page column 29; 30.
  • 2
  • [ 109-01-3 ]
  • [ 555-16-8 ]
  • [ 70261-81-3 ]
YieldReaction ConditionsOperation in experiment
90% With sodium tetrahydroborate; acetic acid In chloroform at 0 - 20℃; for 13 h; General procedure: AcOH (100percent) (140 mL, 2.44 ml) was added over 1 h to a flask containing stirred NaBH4 (20.0 g, 0.53 ml) and CHCl3 (220 mL) at 0-5 °. The resulting mixture was stirred at 0-5 ° for 1.5 h and 1-methylpiperazine (1) (28.0 ml, 0.25 ml) and a solution of methyl 4-formylbenzoate (2a) (43.4 g, 0.26 ml) in CHCl3 (60 mL) were added. The resulting mixture was stirred at 0-5 ° for 1 h and then for 12 h at rt. the mixture was treated with H2O (150 mL) and Na2CO3 until pH 8.0-9.0. The aqueous phase was extracted with EtOAc (2 .x. 100 ml) then both organic layers were combined, washed with H2O (1 .x. 100 ml), and dried over anhydrous Na2SO4. Filtration and evaporation of the solvents gave methyl 4-[(4-methylpiperazin-1-yl)methyl]benzoate (4a): yellowish oil; yield: 61.6 g, 99percent.
References: [1] Tetrahedron Letters, 2012, vol. 53, # 38, p. 5056 - 5058.
[2] Russian Journal of Organic Chemistry, 2013, vol. 49, # 4, p. 563 - 567[3] Zh. Org. Khim., 2013, vol. 49, # 4, p. 580 - 584.
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8801 - 8815.
[5] Russian Journal of Organic Chemistry, 2011, vol. 47, # 10, p. 1556 - 1563.
  • 3
  • [ 109-01-3 ]
  • [ 100-11-8 ]
  • [ 70261-81-3 ]
YieldReaction ConditionsOperation in experiment
92% With potassium carbonate; potassium iodide In acetonitrile for 5 h; 4-nitrobenzylbromide (4.30 g, 20 mmol) was dissolved in 40 ml of acetonitrile solvent,Then K2CO3 (5.52 g, 40 mmol) was added,KI (0.33 g, 2 mmol),Then, 4-methylpiperazine (2.20 g, 22 mmol) was added thereto,After 5 h, the reaction was complete.The reaction solution was concentrated and dried,And further adding 100 ml of H2O thereto,Extracted with ethyl acetate (150 ml x 3)The organic layer was collected, concentrated,4.32 g of a solid was obtained in 92percent yield.
References: [1] Medicinal Chemistry Research, 1999, vol. 9, # 3, p. 149 - 161.
[2] Patent: CN106432235, 2017, A, . Location in patent: Paragraph 0220; 0221.
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 15, p. 5738 - 5748.
[4] Patent: WO2005/54238, 2005, A1, . Location in patent: Page/Page column 88.
[5] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 3, p. 238 - 246.
[6] Patent: EP2955185, 2015, A1, . Location in patent: Paragraph 0079.
[7] Patent: CN103739550, 2016, B, . Location in patent: Paragraph 0173-0176.
[8] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 86 - 106.
[9] Patent: CN107245073, 2017, A, . Location in patent: Paragraph 0121; 0122; 0123.
[10] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8801 - 8815.
[11] Journal of Medicinal Chemistry, 2018, vol. 61, # 4, p. 1499 - 1518.
[12] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 303 - 315.
  • 4
  • [ 109-01-3 ]
  • [ 100-14-1 ]
  • [ 70261-81-3 ]
YieldReaction ConditionsOperation in experiment
50% at 20℃; for 24 h; The First Step:
Preparation of 1-methyl-4-(4-nitrobenzyl)-piperazine (F652-01)
Monomethylpiperazine (15 mL) and tetrahydrofuran (60 mL) were placed in a 200 mL eggplant shaped flask, and a solution of 4-nitrobenzylchloride (8.58 g, 50 mmol) in tetrahydrofuran was added dropwise to the mixture at room temperature while stirring.
After finishing the instillation, the mixture was stirred at room temperature for 24 hours.
The reaction mixture was mixed with distilled water, and the precipitated solids were collected by filtration and dried under reduced pressure to obtain the title compound (5.9 g, 50percent). LC/MS (Method 3): m/z (ESI, POS): 236[M+H]+; retention time: 1.28 minutes.
59% With sodium carbonate; triethylamine In ethylene glycol A.
1-methyl-4-[(4-nitrophenyl)methyl]piperazine
To a solution of p-nitrobenzyl chloride (5.2 g, 10mM) and 3.2 g of triethylamine in 30 ml of ethylene glycol is added a solution of N-methylpiperazine (3 g, 30 mM) in 20 ml of ethylene glycol.
After complete addition, the resulting solution is heated to 80° C. under nitrogen for 30 minutes.
The reaction mixture is quenched into aqueous 10percent sodium carbonate solution and extracted with methylene chloride.
The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 4.15 g (59percent) of 1-methyl-4-[(4-nitrophenyl)methyl]piperazine.
References: [1] Farmaco, 1992, vol. 47, # 3, p. 335 - 344.
[2] Patent: EP1857446, 2007, A1, . Location in patent: Page/Page column 45.
[3] Patent: WO2008/94575, 2008, A2, . Location in patent: Page/Page column 52-53.
[4] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 2917 - 2929.
[5] Patent: US4140775, 1979, A, .
  • 5
  • [ 109-01-3 ]
  • [ 70261-81-3 ]
References: [1] Patent: WO2006/88949, 2006, A1, . Location in patent: Page/Page column 178-180.
  • 6
  • [ 109-01-3 ]
  • [ 100-00-5 ]
  • [ 70261-81-3 ]
YieldReaction ConditionsOperation in experiment
99% at 90℃; for 18 h; 31.5 g of 4-chloro-1-nitrobenzene and 44.4 ml of 1-methyl-piperazine are combined and stirred for 18 hours at 90° C. Then the solution is poured onto ice water and the precipitate formed is suction filtered, washed with water and recrystallised from ethanol/water (1:1). The residue is dried in vacuo at 75° C. [00369] Yield: 44.0 g (99percent of theory), [00370] Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) [00371] Melting point: 108-112° C.
References: [1] Patent: US6794395, 2004, B1, . Location in patent: Page/Page column 23.
  • 7
  • [ 109-01-3 ]
  • [ 555-16-8 ]
  • [ 7556-55-0 ]
  • [ 619-73-8 ]
  • [ 70261-81-3 ]
References: [1] Chemistry of Heterocyclic Compounds, 2007, vol. 43, # 12, p. 1540 - 1543.
  • 8
  • [ 109-01-3 ]
  • [ 100986-89-8 ]
  • [ 138199-71-0 ]
References: [1] Patent: US2003/130507, 2003, A1, .
  • 9
  • [ 109-01-3 ]
  • [ 342417-00-9 ]
  • [ 342417-01-0 ]
YieldReaction ConditionsOperation in experiment
95% at 100℃; for 2 h; Step 3
1.0 g (4.05 mMol) 6-Chloro-4-o-tolyl-nicotinamide in 9.0 ml 1-methyl-piperazine was heated to 100° C. for 2 hours.
The excess N-methyl-piperazine was removed under high vacuum and the residue was filtered on silica gel (eluent: dichloromethane) to yield 1.2 g (95percent) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide as a light yellow crystalline foam. MS (ISP): 311 (M+H+, 100), 254 (62).
95% at 100℃; for 2 h; Step 3: (0177) 1.0 g (4.05 mMol) 6-Chloro-4-o-tolyl-nicotinamide in 9.0 ml 1-methyl-piperazine was heated to 100° C. for 2 hours. The excess N-methyl-piperazine was removed under high vacuum and the residue was filtered on silica gel (eluent: dichloromethane) to yield 1.2 g (95percent) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide as a light yellow crystalline foam. (0178) MS (ISP): 311 (M+H+, 100), 254 (62).
References: [1] Patent: US8426450, 2013, B1, . Location in patent: Page/Page column 25.
[2] Patent: US9403772, 2016, B2, . Location in patent: Page/Page column 30.
[3] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2000 - 2008.
[4] Patent: JP2015/17121, 2015, A, . Location in patent: Paragraph 0153.
  • 10
  • [ 109-01-3 ]
  • [ 342417-01-0 ]
References: [1] Organic Process Research and Development, 2006, vol. 10, # 6, p. 1157 - 1166.
  • 11
  • [ 109-01-3 ]
  • [ 7461-50-9 ]
  • [ 57005-71-7 ]
References: [1] ACS Infectious Diseases, 2018, vol. 4, # 4, p. 577 - 591.
[2] Patent: US2013/345120, 2013, A1, . Location in patent: Page/Page column.
[3] Patent: US8901119, 2014, B2, . Location in patent: Page/Page column.
 

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