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Chemical Structure| 639068-43-2 Chemical Structure| 639068-43-2

Structure of 639068-43-2

Chemical Structure| 639068-43-2

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Product Details of [ 639068-43-2 ]

CAS No. :639068-43-2
Formula : C11H22N2O2
M.W : 214.30
SMILES Code : C(=O)(OC(C)(C)C)N1CC(NC(C1)C)C
MDL No. :MFCD07371499
InChI Key :NUZXPHIQZUYMOR-UHFFFAOYSA-N
Pubchem ID :22219990

Safety of [ 639068-43-2 ]

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

Computational Chemistry of [ 639068-43-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 0
Fraction Csp3 0.91
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 68.12
TPSA ?

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

41.57 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

1.32
Log Po/w (WLOGP)?

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

0.84
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.

1.15
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

0.69
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.4

Water Solubility

Log S (ESOL):?

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

-1.8
Solubility 3.38 mg/ml ; 0.0158 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.

-1.79
Solubility 3.44 mg/ml ; 0.0161 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

-1.6
Solubility 5.42 mg/ml ; 0.0253 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.

-6.67 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<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)

3.09

Application In Synthesis of [ 639068-43-2 ]

* 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 [ 639068-43-2 ]

[ 639068-43-2 ] Synthesis Path-Downstream   1~28

  • 1
  • [ 50-00-0 ]
  • [ 639068-43-2 ]
  • [ 741287-39-8 ]
YieldReaction ConditionsOperation in experiment
65% Referential Example 88]; 3,4,5-Trimethylpiperazine-1-carboxylic acid tert-butyl ester ; 3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.31 g) obtained from Referential Example 87 was dissolved in methanol (50 mL). To the resultant solution, 10percent palladium-carbon (0.504 g), 35percent aqueous formalin (1.85 mL), and 1M HCl in ethanol (15.4 mL) were added at room temperature, and the mixture was stirred in a hydrogen atmosphere for 19 hours. 10percent Palladium-carbon (0.95 g), 35percent aqueous formalin (1.8 mL), and 1M HCl-ethanol (15 mL) were added thereto, followed by stirring in a hydrogen atmosphere for 23 hours. After the system was purged with nitrogen, the resultant mixture was neutralized through addition of the aqueous sodium hydroxide, and insoluble matter was removed by filtration. The filtrate was brought to dryness under reduced pressure. The residue was purified through silica gel column chromatography (chloroform - 7N ammonia/methanol), to thereby give the title compound as an oily product (2.28 g, 65percent).1H-NMR(400MHz,CDCl3)delta: 1.08(6H,d,J=6.1Hz), 1.45(9H,s), 2.00-2.20(2H,m), 2.25(3H,s), 2.60(2H,br), 3.85(2H,br). MS(FAB)m/z: 229(M+H)+.
27% With sodium tetrahydroborate; In methanol; water; at 20℃; for 12h; tert-Butyl 3,5-dimethylpiperazin-1-carboxylate (200.0 mg, 0.93 mmol) and 37percent formaldehyde (440.0 muL, 5.56 mmol) were dissolved in MeOH (5.0 mL), and NaBH4 (172.6 mg, 5.56 mmol) was slowly added thereto and stirred at room temperature for 12 hours. Brine was poured into the reaction mixture, and it was extracted with DCM (30.0 mL). The organic layer was dried over anhydrous Na2SO4, filtered and then distilled under reduced pressure. The residue was purified column chromatography (DCM:MeOH=95:5) on silica to obtain yellow liquid compound of tert-butyl 3,4,5-trimethylpiperazin-1-carboxylate (57.0 mg, 27percent).
  • 2
  • cis-2,6-dimethylpiperazine [ No CAS ]
  • [ 91612-43-0 ]
  • [ 639068-43-2 ]
YieldReaction ConditionsOperation in experiment
72% In tetrahydrofuran; at 0℃; for 2h; [Referential Example 87] ;3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester ; cis-2,6-Dimethylpiperazine (5.08 g) was added to 2-(tert-butoxycarbonylimino)-2-phenylacetonitrile (11.35 g) in tetrahydrofuran (150 mL) at 0°C, followed by stirring for 2 hours. The reaction solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform - 7N ammonia/methanol mixture), to thereby give the title compound (15.36 g, 72percent) .1H-NMR(400MHz,CDCl3)delta: 1.16(6H,d,J=6.5Hz),1.47(9H,s), 2.50(2H,br), 2.90(2H,br), 4.02(2H,br). MS(ESI)m/z: 214(M+H)+.
  • 3
  • [ 24424-99-5 ]
  • [ 21655-48-1 ]
  • [ 639068-43-2 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; PREPARATION 76 1-(1,1-Dimethylethoxycarbonyl)-cis-3,5-dimethylpiperazine Di-tert-butyldicarbonate (5.42 g) in dry methylene chloride (20 ml) is added to a solution of cis-2,6-dimethylpiperazine in dry methylene chloride (70 ml) over one hour. The mixture is stirred an additional 30 rain, washed with water and saline, dried over sodium sulfate and concentrated to give the title compound, NMR (chloroform-d) 3.95, 2.77, 2.32, 1.46, 1.06 delta.
  • 4
  • [ 50-00-0 ]
  • sodium dihydrogen phosphite [ No CAS ]
  • [ 639068-43-2 ]
  • [ 10294-56-1 ]
  • [ 4204-16-4 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; trifluoroacetic acid; In 1,4-dioxane; dichloromethane; water; PREPARATION 77 cis 3,4,5-Trimethylpiperazine To a solution of 1-(1,1,dimethylethoxycarbonyl)-cis-3,5-dimethylpiperazine (PREPARATION 76, 4.28 g) in dioxane (100 ml) is added 1M sodium dihydrogen phosphite (100 ml, made by mixing equal volumes of 2M sodium hydroxide and 2M phosphorous acid) followed by the addition of formalin solution (37percent, 16 ml). The mixture is heated at 65° for 2.5 hr and extracted with methylene chloride. The organic phase is washed with water and saline, dried over sodium sulfate and concentrated to ca. 50 ml. The remaining methylene chloride and dioxane are removed by distillation leaving 4.3 beta of residue in the distillation flask. This material is dissolved in methylene chloride (40 ml), cooled to 0°, and trifluoroacetic acid (14.5 ml) is added. The mixture is stirred for 1.25 hr and sodium hydroxide (11.3 g) in water (30 ml) is added. The phases are separated and the aqueous phase is extracted with additional methylene chloride. The total combined organics are dried over magnesium sulfate and concentrated by distillation to give a mixture of the title compound and residual starting material. On standing the mixture partially crystallizes. Filtration and washing with ethyl ether gives the title compound, NMR (chloroform-d) 3.09, 2.67, 2.39, 1.16 delta.
  • 5
  • [ 639068-43-2 ]
  • [ 637-59-2 ]
  • cis-1-tert-butoxycarbonyl-3,5-dimethyl-4-(3-phenylpropan-1-yl)piperazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In water; N,N-dimethyl-formamide; 1) Synthesis of cis-1-tert-butoxycarbonyl-3,5-dimethyl-4-(3-phenylpropan-1-yl)piperazine To a suspension of 10 g (46.66 mmol.) of <strong>[639068-43-2]cis-1-tert-butoxycarbonyl-3,5-dimethyl piperazine</strong> and 12.90 g (93.3 mmol.) of potassium carbonate in N,N-dimethylformamide (50 ml) was added, at room temperature, 11.15 g (56 mmol.) of 1-bromo-3-phenylpropane. The mixture was stirred for 40 hours at 120° C., which was then cooled to room temperature. To the reaction system was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (ethyl acetate/hexane 20-30percent) to give the object compound as a yellow oily product. The yield was 12.21 g (79percent). 1H-NMR (CDCl3, 200 MHz) delta: 1.00 (6H, d, J=5.8 Hz), 1.45 (9H, s), 1.57-1.69 (2H, m), 2.43-2.62 (6H, m), 2.67-2.85 (2H, s), 3.68-3.96 (2H, m), 7.13-7.35 (5H, m). IR (neat): 2974, 2931, 2856, 1695, 1454, 1427, 1273, 1248, 1174, 1142, 748, 700 cm-1.
  • 6
  • [ 639068-43-2 ]
  • [ 100-39-0 ]
  • cis-1-tert-butoxycarbonyl-3,5-dimethyl-4-benzyl piperazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In water; N,N-dimethyl-formamide; 2) Synthesis of cis-1-tert-butoxycarbonyl-3,5-dimethyl-4-benzyl piperazine To a suspension of 10 g (46.66 mmol.) of <strong>[639068-43-2]cis-1-tert-butoxycarbonyl-3,5-dimethyl piperazine</strong> and 12.90 g (93.3 mmol.) of potassium carbonate in N,N-dimethylformamide (100 ml) was added, at room temperature, 11.97 g (70 mmol.) of benzyl bromide. The mixture was stirred for 16 hours at 120° C. To the reaction system was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a column chromatography (ethyl acetate/hexane 30percent) to give the object compound as a pale yellow oily product. The yield was 13.56 g (95percent). 1H-NMR (CDCl3, 200 MHz) delta: 1.04 (6H, d, J=5.8 Hz), 1.45 (9H, s), 2.45-2.75 (4H, m), 3.67-3.92 (2H, m), 3.81 (2H, s), 7.15-7.39 (5H, m). IR (neat): 2980, 1693, 1423, 1136, 1061, 924, 883, 766, 729, 700 cm-1.
  • 7
  • [ 24424-99-5 ]
  • [ 108-49-6 ]
  • [ 639068-43-2 ]
YieldReaction ConditionsOperation in experiment
100% dmap; In dichloromethane; Step 1. tert-Butyl 3,5-dimethylpiperazine-1-carboxylate. To a solution of 2,6-cis-dimethylpiperazine (2.0 g, 17 mmol) in CH2Cl2 (60 ml) were sequentially added di-tert-butyl dicarbonate (3.8 g, 17 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred at room temperature overnight before it was washed with water (50 ml), brine (10 ml), and extracted with CH2Cl2 (3*30 ml). The extracts were dried (MgSO4) and concentrated under reduced pressure to give product 146 as colorless oil (3.95, ~100percent).
56% With triethylamine; In dichloromethane; at 0 - 20℃; for 12h; 2,6-Dimethylpiperazine (200.0 mg, 1.75 mmol) and TEA (0.6 mL, 4.37 mmol) were dissolved in DCM (6.0 mL), and (Boc)2O (458.7 mg, 2.10 mmol) was slowly added thereto at 0° C. The reaction mixture was stirred at room temperature for 12 hours and then distilled under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=95:5) on silica. The fractions containing the product were collected and evaporated to obtain yellow liquid compound of tert-butyl 3,5-dimethylpiperazin-1-carboxylate (210.0 mg, 56percent). [0559] 1H-NMR (300 MHz, CDCl3); delta: 3.95 (m, 2H), 2.79 (m, 2H), 2.33 (m, 2H), 1.46 (s, 9H), 1.07 (d, 6H, J=6.3 Hz)
In ethanol; water; 1) Synthesis of cis-1-tert-butoxycarbonyl-3,5-dimethyl piperazine To an ethanol (42 ml) solution of 5.0 g (21.07 mmol.) of cis-3,5-dimethyl piperazine was added, at room temperature, 2.5 ml (32.3 mmol.) of di-tert-butyl dicarbonate. The mixture was stirred for one hour. The solvent was distilled off under reduced pressure. To the residue was added water, which was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give the object compound as a pale yellow solid product. The yield was 5.77 g (72percent). 1H-NMR (CDCl3, 200 MHz) delta: 1.06 (6H, d, J=6.4 Hz), 1.46 (9H, s), 2.21-2.40 (2H, m), 2.68-2.86 (2H, m), 3.79-4.09 (2H, m). IR (KBr): 3319, 2972, 1680, 1425, 1367, 1315, 1267, 1173, 1144, 1072, 895, 866, 797 cm-1.
In 1,4-dioxane; at 20℃; 2,6-Dimethylpiperazine (5.71 g) was dissolved in dioxane (150 ml), di-tert-butyl bicarbonate (3.64 g) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated, water (50 ml) was added to the residue, and the mixture was extracted with dichloromethane (once with 100 ml and once with 50 ml). The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (3.58 g). 1H-NMR(CDCl3)delta:1.06(3H,d,J=6.3 Hz), 1.46(9H,s), 2.23-2.31(2H,m), 2.27-2.84(2H,m), 3.80-4.15(2H,m). MS:214(M++1).
In chloroform; at 20℃; Step 1 Synthesis of 3,5-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester A solution of BOC-anhydride (374 mg, 1.71 mmol) in chloroform (2 mL) was added dropwise to a stirred solution of 2,5-dimethyl-piperazine (20 g, 266.5 mmol) in chloroform (2 mL) and the resulting mixture was stirred at room temperature for 4 hr. The reaction mixture was then diluted with cold water and extracted with chloroform, dried the organic layer over sodium sulfate and concentrated under reduced pressure to afford 331 mg (88.6percent yield) of 3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester. LCMS Purity: 91.3percent.

  • 8
  • [ 1722-12-9 ]
  • [ 639068-43-2 ]
  • [ 1088528-66-8 ]
YieldReaction ConditionsOperation in experiment
at 120℃; for 5.5h; 3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.676 g) and 2-chloropyrimidine (716 mg) were combined, melted in an oil bath at 120°C, and stirred for 5 hr 30 min. Water (10 ml) was added and the mixture was stirred, extracted with ethyl acetate (30 ml), and washed with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (Yamazen HI-FLASH.(TM). COLUMN size L, elution solvent: hexane/ethyl acetate) to give the title compound (333 mg). 1H-NMR (CDCl3)delta:1.25(6H,d,J=6.9 Hz), 1.51(9H,s), 2.97-3.08(2H,m), 3.95-4.16(2H,m), 4.65-4.82(2H,m), 6.51(1H,t,J=4.5 Hz), 8.34(2H,d,J=4.8 Hz). MS:237 (M++1 when tert-butyl group was cleaved).
  • 9
  • [ 639068-43-2 ]
  • [ 312-94-7 ]
  • [ 1232028-14-6 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; at 20℃; for 0.5h; Step 3 Synthesis of 3,5-Dimethyl-4-(2-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester Triethyl amine (55.6 mg, 0.07 mL, 0.55 mmol) was added to a stirred solution of 2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (98.6 mg, 0.45 mmol) followed by 2-trifluoromethyl-benzoyl chloride (95.6 mg, 0.45 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to get the residue. The residue thus obtained was purified by column chromatography using 60-120 silica gel and 50percent ethyl acetate in hexane to afford 74 mg (41.71percent yield) of 3,5-dimethyl-4-(2-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS Purity: 96.7percent.
  • 10
  • [ 639068-43-2 ]
  • [ 4204-16-4 ]
  • 11
  • [ 639068-43-2 ]
  • 2,7-dichloro-3-(3,4,5-trimethylpiperazin-1-yl)pyrido[2,3-b]pyrazine [ No CAS ]
  • 12
  • [ 639068-43-2 ]
  • 7-chloro-2-hydrazinyl-3-(3,4,5-trimethylpiperazin-1-yl)pyrido[2,3-b]pyrazine [ No CAS ]
  • 13
  • [ 639068-43-2 ]
  • 8-chloro-4-(3,4,5-trimethylpiperazin-1-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazine [ No CAS ]
  • 14
  • [ 639068-43-2 ]
  • 5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid [ No CAS ]
  • C27H33ClF3N5O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h; To a mixture of 5-(((3-chloro-5-(trifluoromethyl)benzyl)oxy)carbonyl)-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid (140 mg, 0.35 mmol), tert-butyl 3,5- dimethylpiperazine-l-carboxylate (97 mg, 0.45 mmol) and HATU (198 mg, 0.52 mmol) in DMF (3 mL) was added DIPEA (90 mg, 0.69 mmol). The mixture was stirred at rt for 2 h and then concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 1:2) to give the Boc-protected intermediate as yellow oil (120 mg, 57percent yield). ESI-MS (M+H)+: 600.2.
  • 15
  • [ 639068-43-2 ]
  • [ 72593-77-2 ]
  • C18H36N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In water; at 120℃; for 1.5h;Microwave irradiation; A solution of potassium carbonate (1.4370 g, 10.40 mmol) in water (3 mL) was added to a mixture of l-N-/-Boc-3,5-dimethyl piperazine (0.6882 g, 3.21 mmol) and mPEG3- Br (0.8872 g, 3.91 mmol) in a vial. The resulting mixture was heated at 120 °C for 1.5 h by using microwave. The mixture was diluted with water, extracted with dichloromethane (3 x 30 mL). The combined organic solution was washed with brine, dried over brine, concentrated. The residue was dried under high vacuum. The residue was separated with flash column chromatography on silica gel column using 1-5percent methanol/dichloromethane, and NH-column using 0-5percent methanol/ dichloromethane to afford the intermediate.
  • 16
  • [ 639068-43-2 ]
  • 1-N-mPEG<SUB>3</SUB>-2,6-dimethylpiperazine [ No CAS ]
  • 17
  • [ 639068-43-2 ]
  • 5-amino-6-chloro-3-N-(4-mPEG3-3,5-dimethylpiperazinyl)-1,2,4-triazine [ No CAS ]
  • 18
  • [ 639068-43-2 ]
  • 5-amino-6-chloro-3-N-(4-mPEG3-3,5-dimethylpiperazinyl)amino-1,2,4-triazine hydrochloride [ No CAS ]
  • 19
  • [ 639068-43-2 ]
  • 7-(2,6-dimethylpiperazin-1-yl)-2-ethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 3 7-(2,6-dimethylpiperazin-1-yl)-2-ethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one This example is prepared by following the same procedures as described in Example 1 above except substituting <strong>[639068-43-2]tert-butyl 3,5-dimethylpiperazine-1-carboxylate</strong> for Boc-piperazine. 1H NMR (400 MHz, DMSO-d6) delta ppm 5.32 (s, 1H), 4.03 (d, J=9.78 Hz, 2H), 2.92 (q, J=7.43 Hz, 2H), 2.53-2.66 (m, 2H), 2.18-2.30 (m, 2H), 1.23 (t, J=7.43 Hz, 3H), 0.94 (d, 6H); LCMS: (electrospray +ve), m/z 294.2 (MH)+; HPLC: tR=2.86 min, UV254=100percent. HRMS (ESI): m/z calcd for C13H20N5OS [M+H]+ 294.1383. found 294.1382.
  • 20
  • [ 639068-43-2 ]
  • [ 75-03-6 ]
  • 4-ethyl-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
510 mg General procedure: Add to 100mL three-necked bottle under argon protectiontert-Butyl 3,5-dimethylpiperazine-1-carboxylate (520 mg, 2.43 mmol) and THF (10 mL), cooled to about 0 ° C,Add NaH (70 mg, 2.91 mmol),After stirring for half an hour, a solution of CH3I (690 mg, 4.86 mmol) in THF (1 mL) was added dropwise.After the dropwise addition, the mixture was stirred for 1 hour, and the reaction was further stirred up to room temperature. The reaction was monitored by TLC. After the reaction was completed, 50 mL of purified water and 30 mL of ethyl acetate were added, and the mixture was stirred. The aqueous phase was extracted twice with ethyl acetate (30 mL×2), and the organic phase was combined and washed with saturated brine (50 mL×2) After 2 times, anhydrous sodium sulfate was dried, filtered, and the mother liquid was concentrated under reduced pressure to give 510 mg of product.
  • 21
  • [ 639068-43-2 ]
  • [ 741287-41-2 ]
  • 22
  • [ 639068-43-2 ]
  • [ 74-88-4 ]
  • [ 741287-39-8 ]
YieldReaction ConditionsOperation in experiment
510 mg Add to 100mL three-necked bottle under argon protectiontert-Butyl 3,5-dimethylpiperazine-1-carboxylate (520 mg, 2.43 mmol) and THF (10 mL), cooled to about 0 ° C,Add NaH (70 mg, 2.91 mmol),After stirring for half an hour, a solution of CH3I (690 mg, 4.86 mmol) in THF (1 mL) was added dropwise.After the dropwise addition, the mixture was stirred for 1 hour, and the reaction was further stirred up to room temperature. The reaction was monitored by TLC. After the reaction was completed, 50 mL of purified water and 30 mL of ethyl acetate were added, and the mixture was stirred. The aqueous phase was extracted twice with ethyl acetate (30 mL×2), and the organic phase was combined and washed with saturated brine (50 mL×2) After 2 times, anhydrous sodium sulfate was dried, filtered, and the mother liquid was concentrated under reduced pressure to give 510 mg of product.
  • 23
  • [ 639068-43-2 ]
  • [ 1595290-90-6 ]
  • N-(2-(3,5-dimethylpiperazin-1-yl)-5-methoxypyrimidin-4-yl)-1H-indazol-5-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
A solution of compounds of general structure 1 (1 equiv), Boc protected amine (1-3 equiv) and DIPEA (3 equiv) in DMSO were reacted at 100-110 °C. The reaction mixture was cooled to room temperature and quenched by addition of water and crude residue extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to provide crude compound of general strucutre 2, which was used in the following step without further purification. To a solution of compounds of general structure 2 in CH2C12 was added HCl/dioxane (4 N) or TFA. The reaction was stirred at room temperature for 2 hrs and mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford final compounds of general structure 3.
  • 24
  • [ 639068-43-2 ]
  • [ 1257302-90-1 ]
  • N-(2-(3,5-dimethylpiperazin-1-yl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
A solution of compounds of general structure 1 (1 equiv), Boc protected amine (1-3 equiv) and DIPEA (3 equiv) in DMSO were reacted at 100-110 °C. The reaction mixture was cooled to room temperature and quenched by addition of water and crude residue extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to provide crude compound of general strucutre 2, which was used in the following step without further purification. To a solution of compounds of general structure 2 in CH2C12 was added HCl/dioxane (4 N) or TFA. The reaction was stirred at room temperature for 2 hrs and mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford final compounds of general structure 3.
  • 25
  • [ 639068-43-2 ]
  • (4-(methoxyimino)cyclohexyl)methyl 4-methylbenzenesulfonate [ No CAS ]
  • C19H35N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 18-crown-6 ether; potassium carbonate; potassium iodide; In acetonitrile; at 80℃; General procedure: To a stirred solution of compound 13a-b, 17a-b (1.0 mmol) inCH3CN (20 mL) were added N-Boc-piperazine (180.9 mg,0.9 mmol), K2CO3 (205.9 mg, 1.5 mmol), KI (166.0 mg, 1.0 mmol)and 18-crown-6 (26.4 mg, 0.1 mmol) at room temperature. Themixture was stirred overnight at 80 C and filtered. The filtrate wasdiluted by DCM and washed by brine. The organic layer was concentrated for next step. To a stirred solution of the abovecompounds in DCM (20 mL) was added TFA (3 mL) at room temperature.The mixture was stirred for 3e4 h and concentrated toafford the crude products 15a-o and 19a-f in a yield of 35%e42%. Toa stirred solution of above crudes in anhydrous MeOH (10 mL) wasadded BTZ core compound 11 (403.2 mg, 1.0 mmol) and Et3N(0.2 mL, 1.5 mmolj) at room temperature. The mixture was stirredfor 1e3 h at 40 C and concentrated. The residue was purified bysilica gel column (DCM: MeOH 20: 1) to give 1a-f and 2a-e (25%e41% for two steps).
  • 26
  • [ 639068-43-2 ]
  • (4-(ethoxyimino)cyclohexyl)methyl 4-methylbenzenesulfonate [ No CAS ]
  • C20H37N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 18-crown-6 ether; potassium carbonate; potassium iodide; In acetonitrile; at 80℃; General procedure: To a stirred solution of compound 13a-b, 17a-b (1.0 mmol) inCH3CN (20 mL) were added N-Boc-piperazine (180.9 mg,0.9 mmol), K2CO3 (205.9 mg, 1.5 mmol), KI (166.0 mg, 1.0 mmol)and 18-crown-6 (26.4 mg, 0.1 mmol) at room temperature. Themixture was stirred overnight at 80 C and filtered. The filtrate wasdiluted by DCM and washed by brine. The organic layer was concentrated for next step. To a stirred solution of the abovecompounds in DCM (20 mL) was added TFA (3 mL) at room temperature.The mixture was stirred for 3e4 h and concentrated toafford the crude products 15a-o and 19a-f in a yield of 35%e42%. Toa stirred solution of above crudes in anhydrous MeOH (10 mL) wasadded BTZ core compound 11 (403.2 mg, 1.0 mmol) and Et3N(0.2 mL, 1.5 mmolj) at room temperature. The mixture was stirredfor 1e3 h at 40 C and concentrated. The residue was purified bysilica gel column (DCM: MeOH 20: 1) to give 1a-f and 2a-e (25%e41% for two steps).
  • 27
  • [ 639068-43-2 ]
  • C6H11NO2 [ No CAS ]
  • C17H31N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 18-crown-6 ether; potassium carbonate; potassium iodide; In acetonitrile; at 80℃; General procedure: To a stirred solution of compound 13a-b, 17a-b (1.0 mmol) inCH3CN (20 mL) were added N-Boc-piperazine (180.9 mg,0.9 mmol), K2CO3 (205.9 mg, 1.5 mmol), KI (166.0 mg, 1.0 mmol)and 18-crown-6 (26.4 mg, 0.1 mmol) at room temperature. Themixture was stirred overnight at 80 C and filtered. The filtrate wasdiluted by DCM and washed by brine. The organic layer was concentrated for next step. To a stirred solution of the abovecompounds in DCM (20 mL) was added TFA (3 mL) at room temperature.The mixture was stirred for 3e4 h and concentrated toafford the crude products 15a-o and 19a-f in a yield of 35%e42%. Toa stirred solution of above crudes in anhydrous MeOH (10 mL) wasadded BTZ core compound 11 (403.2 mg, 1.0 mmol) and Et3N(0.2 mL, 1.5 mmolj) at room temperature. The mixture was stirredfor 1e3 h at 40 C and concentrated. The residue was purified bysilica gel column (DCM: MeOH 20: 1) to give 1a-f and 2a-e (25%e41% for two steps).
  • 28
  • [ 639068-43-2 ]
  • C7H13NO2 [ No CAS ]
  • C18H33N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 18-crown-6 ether; potassium carbonate; potassium iodide; In acetonitrile; at 80℃; General procedure: To a stirred solution of compound 13a-b, 17a-b (1.0 mmol) inCH3CN (20 mL) were added N-Boc-piperazine (180.9 mg,0.9 mmol), K2CO3 (205.9 mg, 1.5 mmol), KI (166.0 mg, 1.0 mmol)and 18-crown-6 (26.4 mg, 0.1 mmol) at room temperature. Themixture was stirred overnight at 80 C and filtered. The filtrate wasdiluted by DCM and washed by brine. The organic layer was concentrated for next step. To a stirred solution of the abovecompounds in DCM (20 mL) was added TFA (3 mL) at room temperature.The mixture was stirred for 3e4 h and concentrated toafford the crude products 15a-o and 19a-f in a yield of 35%e42%. Toa stirred solution of above crudes in anhydrous MeOH (10 mL) wasadded BTZ core compound 11 (403.2 mg, 1.0 mmol) and Et3N(0.2 mL, 1.5 mmolj) at room temperature. The mixture was stirredfor 1e3 h at 40 C and concentrated. The residue was purified bysilica gel column (DCM: MeOH 20: 1) to give 1a-f and 2a-e (25%e41% for two steps).
 

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Technical Information

Categories

Related Functional Groups of
[ 639068-43-2 ]

Amides

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A110889 [163765-44-4]

(R)-1-Boc-3-Methylpiperazine

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tert-Butyl cis-2,6-dimethylpiperazine-1-carboxylate

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(3R,5R)-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate

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Related Parent Nucleus of
[ 639068-43-2 ]

Piperazines

Chemical Structure| 163765-44-4

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(R)-1-Boc-3-Methylpiperazine

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tert-Butyl cis-2,6-dimethylpiperazine-1-carboxylate

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(3R,5R)-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate

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