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Product Details of [ 1231930-25-8 ]

CAS No. :1231930-25-8
Formula : C12H18BrN3
M.W : 284.20
SMILES Code : CCN1CCN(CC2=CC=C(Br)N=C2)CC1
MDL No. :MFCD25977325
InChI Key :DMNPLEDMMNWHTL-UHFFFAOYSA-N
Pubchem ID :86642886

Safety of [ 1231930-25-8 ]

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

Computational Chemistry of [ 1231930-25-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 6
Fraction Csp3 0.58
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 77.25
TPSA ?

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

19.37 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.01
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

1.89
Log Po/w (WLOGP)?

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

1.07
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.

1.54
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

1.97

Water Solubility

Log S (ESOL):?

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

-2.87
Solubility 0.381 mg/ml ; 0.00134 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.

-1.92
Solubility 3.42 mg/ml ; 0.012 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

-3.85
Solubility 0.0401 mg/ml ; 0.000141 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

Yes
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.

-6.69 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<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)

2.24

Application In Synthesis of [ 1231930-25-8 ]

* 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 [ 1231930-25-8 ]

[ 1231930-25-8 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 5308-25-8 ]
  • [ 149806-06-4 ]
  • [ 1231930-25-8 ]
YieldReaction ConditionsOperation in experiment
92% With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 5 h; To 100ml of anhydrous DCM was added 6a (10 g, 54 mmol) and 7a (6.20 g, 54.00 mmol),.followed NaHB(OAc)3 (17.20 g, 81.00 mmol) was added in parts, The mixture was stirred at RT for 5hdiluted with DCM (100 mL), Saturated Na2CO3 solution was added to the mixture until the pH reached 8–10. The mixture was partitioned between water and dichloromethane. The water phase was extracted twice with dichloromethane. The organic phases were combined and washed with water and brine, dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM/MeOH = 50:1) to give compound 8a (14.00 g, 92.00percent) as yellow soild. MS (ESI): mass calcd. for C12H18BrN3 283, m/z found 284 [M+H] +.
91.4%
Stage #1: for 2 h;
Stage #2: With sodium tetrahydroborate; acetic acid In dichloromethane for 16 h;
6-bromo-pyridine-3-carbaldehyde (5 g, 26.9 mmol, 1.0 eq.) and 4-ethyl-piperidine was dissolved in dichloromethane (100 ml), stirred for 2 hours, acetic acid was added portionwise inside borohydride sodium (6.2 g, 29.2 mmol, 1.1 eq). After 16 hours of reaction, an aqueous solution of sodium hydroxide was added thereto 2 mol/L to adjust the PH to alkaline, extracted with dichloromethane, and concentrated under reduced pressure to give a white solid of 1-(6-bromopyridin-3-yl)methyl-4-ethylpiperidine (6.98g, yield: 91.4percent).
80% With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 12 h; 1-ethylpiperazine (1.8 g, 16 mmol), 6-bromo-pyridine-3-carbaldehyde (3 g, 16 mmol) and dichloromethane (50 mL) were added to the reaction flask,Sodium triacetoxyborohydride (3.7 g, 17.5 mmol) was added portionwise with stirring,The mixture was stirred at room temperature for 12 hours.Dichloromethane (20 mL) and aqueous sodium hydroxide (2N, 15 mL) were added to the reaction solution.The aqueous phase was extracted with dichloromethane (20 mL x 2). Combine organic phase,Saturated sodium chloride solution (20mL × 2), dried over anhydrous sodium sulfate, suction filtration,The filtrate was concentrated under reduced pressure to give the title compound (3.6 g, yellow oil) in 80percent yield.
71% With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; NaHB(OAc)3 (2.60g, 12.23mmol) was added to a solution of 137 6-bromonicotinaldehyde (1.50g, 8.15mmol) and 92 1-ethylpiperazine (0.90g, 8.15mmol) in 103 DCM (15mL). The mixture was allowed to stir at RT overnight, after which it was filtered and concentrated under a vacuum, and purified by silica gel column chromatography (DCM/MeOH=100:1–10:1) to obtain 138 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (1.65g; yield, 71percent) as a yellow oil. Lithium bis(trimethylsilyl)amide (1N) (20mL, 20.0mmol) under N2 was added to a solution of 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (2.80g, 10.0mmol), Cy-John-Phos (700.0mg, 2.0mmol), and Pd2(dba)3 (915.0mg, 1.0mmol) in dry toluene (30mL). Then the mixture was heated to 80°C overnight, cooled to RT, filtered and concentrated under a vacuum, and purified by silica gel column chromatography (DCM/MeOH=100:1–10:1) to give INT-7 (1.52g; yield, 69percent) as a brown solid. ESI-MS: m/z 221.2 [M+H]+.
46%
Stage #1: at 20℃; for 0.5 h;
Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 12 h;
To a solution of compound 5 (10 g, 54 mmol, 1 eq) in DCM (170 mL) was added compound 6 (7.4 g, 65 mmol, 1.2 eq). The mixture was stirred at rt for 30 minutes, then NaBH(OAc)3 (17.1 g, 81 mmol, 1.5 eq) was added portion wise. The mixture was stirred at rt for 12 h. After completion, the mixture was diluted with DCM (300 mL) and 2N NaOH (100 mL). The organic layer was separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by silica column chromatography to give the desired product (7 g, 46percent). NMR (300 MHz, CDCb) δ 8.30 (s, 1 H), 7.55 (d, J= 8.1 Hz, 1 H), 7.44 (d, J= 8.1 Hz, 1 H), 3.49 (s, 2 H), 2.55- 2.48 (m, 10 H), 1.12 (t, J= 7.2 Hz, 3 H). LCMS: (M+H)+: 283.9.
11.5 kg With sodium tris(acetoxy)borohydride In dichloromethane at 20 - 30℃; for 12 h; Large scale Add neat 1-ethylpiperazine (5.6 kg) to a mixture of 6-bromo-pyridine-3- carbaldehyde (8.3 kg) and dichloromethane (186 kg). Then, add sodium (0086) triacetoxyborohydride (10.9 kg) in portions and stir at 20-30 °C for 12 hours. Quench the reaction into a mixture of dichloromethane (36 kg) and aqueous solution of sodium hydroxide 2 N (46 kg). Separate the layers and extract twice the aqueous layer with dichloromethane (24 X 2 kg). Combine the organic layers, wash with brine (50 X 2 kg) and remove the solvent under vacuum to afford 11.5 kg of the title compound. MS (ES+): m/z= 285 (M+H)+.
1.48 g With formic acid; trimethyl orthoformate In acetonitrile for 4 h; Reflux; Inert atmosphere N-ethylpiperazine (1.59 g, 13.95 mmol), 2-bromo-5-pyridinecarbaldehyde (3.14 g, 16.88 mmol) were added successively to acetonitrile,To a solution of formic acid (2.10 mL, 55.80 mmol)Trimethyl orthoformate (3.07 mL, 27.90 mmol).Heating under reflux under nitrogen,After 4 hours the reaction solution was cooled to room temperature,Add 30 mL of water,15 mL of ethyl acetate,Liquid separation.The organic layer is the remaining 2-bromo-5-pyridinecarboxaldehyde.The aqueous layer was added with saturated sodium hydroxide to adjust the pH to 10,30 mL of ethyl acetate was added,Liquid separation,The aqueous layer was again added with 30 mL of ethyl acetate,Combined organic layer,Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.The product of formula XII-1 (1.48 g) was purified by column chromatography,As a colorless liquid.
1.48 g With formic acid; trimethyl orthoformate In acetonitrile for 4 h; Reflux; Inert atmosphere N-Ethylpiperazine (1.59 g, 13.95 mmol) and 2-bromo-5-pyridinecarbaldehyde (3.14 g, 16.88 mmol) were sequentially added to acetonitrile and formic acid (2.10 mL, 55.80 mmol) Ester (3.07 mL, 27.90 mmol).The mixture was heated to reflux under nitrogen and the reaction was cooled to room temperature after 4h. 30mL of water and 15mL of ethyl acetate were added to separate the layers.The organic layer is the remaining 2-bromo-5-pyridinecarboxaldehyde.The aqueous layer was added with saturated sodium hydroxide to adjust the pH to 10, added with 30 mL of ethyl acetate, separated and the aqueous layer was added with 30 mL of ethyl acetate again. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.Purification by column chromatography gave 1.48 g of a colorless liquid.1H-NMR (300 MHz, CDCl 33)?: 8.29 d, J = 1.74Hz), 7.53-7.55 (1H, dd, J = 1.98Hz, 8.10Hz), 7.43 (1H, d, J = 8.10Hz), 3.47 (2H, s) , 2.38-2.48 (10H, m), 1.08 (3H, t, J = 7.14 Hz).HRMS (ESI): m / z 283.0684
1.64 g With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; 2-bromo-5-formylpyridine (1.5 g, 8.15 mmol), 1-ethylpiperazine (0.93 g, 8.15 mmol), and
dichloromethane (15 mL) were added to the reaction flask, and then NaHB(OAc)3 (2.58 g, 12.23 mmol) was added in batches.
Reaction was carried out at room temperature overnight.
The reaction product was filtered, concentrated and separated by column chromatography (DCM/MeOH = 100:1 to 10:1) to obtain the titled product (1.64g, yellow oil).
MS (ESI): mass calcd. for C12H18BrN3 285.1, m/z found 286.1 [M+H]+.

References: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 974 - 978.
[2] Patent: CN105622638, 2016, A, . Location in patent: Paragraph 0220.
[3] Patent: CN106608879, 2017, A, . Location in patent: Paragraph 0142-0145.
[4] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 1 - 28.
[5] Patent: WO2019/35008, 2019, A1, . Location in patent: Paragraph 616; 621; 622.
[6] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1892 - 1915.
[7] Patent: US2010/160340, 2010, A1, . Location in patent: Page/Page column 9.
[8] Patent: WO2015/130540, 2015, A1, . Location in patent: Page/Page column 20-21.
[9] Patent: WO2016/14904, 2016, A1, . Location in patent: Page/Page column 21; 23; 24.
[10] Patent: CN106467517, 2017, A, . Location in patent: Paragraph 0107; 0108; 0109; 0110; 0111; 0112.
[11] Organic Process Research and Development, 2017, vol. 21, # 9, p. 1447 - 1451.
[12] Patent: CN107266421, 2017, A, . Location in patent: Paragraph 0164; 0165; 0166.
[13] Patent: EP3385262, 2018, A1, . Location in patent: Paragraph 0097; 0098; 0099; 0100.
 

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