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Structure of 127116-19-2

Chemical Structure| 127116-19-2

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Product Details of [ 127116-19-2 ]

CAS No. :127116-19-2
Formula : C11H17ClN4O
M.W : 256.73
SMILES Code : CC1=NC(Cl)=CC(N2CCN(CCO)CC2)=N1
MDL No. :MFCD17084928
InChI Key :NIIXBFHSTHMFFD-UHFFFAOYSA-N
Pubchem ID :14479558

Safety of [ 127116-19-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Computational Chemistry of [ 127116-19-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 17
Num. arom. heavy atoms 6
Fraction Csp3 0.64
Num. rotatable bonds 3
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 74.24
TPSA ?

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

52.49 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.59
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

1.15
Log Po/w (WLOGP)?

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

-0.21
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.

0.53
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

1.27
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.07

Water Solubility

Log S (ESOL):?

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

-2.22
Solubility 1.55 mg/ml ; 0.00603 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.

-1.85
Solubility 3.65 mg/ml ; 0.0142 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

-2.68
Solubility 0.541 mg/ml ; 0.00211 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

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

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.

-7.05 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<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)

2.43

Application In Synthesis of [ 127116-19-2 ]

* 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 [ 127116-19-2 ]

[ 127116-19-2 ] Synthesis Path-Downstream   1~22

  • 1
  • [ 103-76-4 ]
  • [ 1780-26-3 ]
  • [ 127116-19-2 ]
YieldReaction ConditionsOperation in experiment
89.8% Example 1: synthesis of 2-(4-(6-chloro-2-methylpyrimidin-4-yl) piperazin-1-yl) ethanol (Compound 4); 1-(2-hydroxyethyl) piperazine (Compound 3) (16.6g, 127.6mmol)) and 2-methyl-4,6-dichloropyrimidine (Compound 2) (10.4g, 63.8mmol) were mixed with methylene dichloride (80mL) in reaction flask to be stirred for 2.5h at 30C, and then triethylamine (1.8mL) was added with the reaction overnight in thermal insulation. After vacuum filtration, the cake was rinsed by methylene dichloride. The filtrate was vacuum condensed to dry, and then n-hexane (40mL) was added to grow the grains for 1h by stirring. After vacuum filtration, the cake was rinsed by n-hexane (20mL) and dried at 40C to constant weight to give white solid target Compound 4 (14.7g, yield: 89.8%). Element analysis: C11H17ClN4O, Calculated: C, 51.46; H, 6.67; N, 21.82; Found: C, 51.45; H, 6.69; N, 21.82.
89.8% [0138]1-(2-hydroxyethyl)piperazine (Compound 3) (16.6 g, 127.6 mmol)) and 2-methyl-4,6-dichloropyrimidine (Compound 2) (10.4 g, 63.8 mmol) were mixed with methylene dichloride (80 mL) in reaction flask to be stirred for 2.5 h at 30 C., and then triethylamine (1.8 mL) was added with the reaction overnight in thermal insulation. After vacuum filtration, the cake was rinsed by methylene dichloride. The filtrate was vacuum condensed to dry, and then n-hexane (40 mL) was added to grow the grains for 1 h by stirring. After vacuum filtration, the cake was rinsed by n-hexane (20 mL) and dried at 40 C. to constant weight to give white solid target Compound 4 (14.7 g, yield: 89.8%).[0139]Element analysis: C11H17ClN4O, Calculated: C, 51.46; H, 6.67; N, 21.82. Found: C, 51.45; H, 6.69; N, 21.82.
85% In dichloromethane; at 20℃; General procedure: 4,6-dichloro-2-methylpyrimidine 10a (1 mmol) and corresponding piperazine (2 mmol) were mixed in CH2Cl2 (40 mL) and stirred at room temparature overnight. The mixture was purified by flash chromatography (DCM: MeOH = 20:1) to give the product 1e-g.
85% In dichloromethane; at 20℃; A mixture of 4,6-dichloro-2-methylpyrimidine (162 mg, 1 mmol) and 1-(2-ethanol)-ylpiperazine (260 mg, 2 mmol) was stirred in dichloromethane (40 mL) at room temperature overnight. After the nucleophilic substitution reaction, after TLC monitoring the reaction, The product 1c (218mg) was isolated through a silica gel column, a white solid, melting point: 72 C, The yield was 85% and the purity was 95%.
83% To a solution of 4,6-dichloro-2-methylpyrimidine (2.86 g, 17.5 mmol) in 1,4- dioxane (200 niL) was added 2~(piperazin-l-yl)ethanol (1.14 g, 1.08 mmol) and N5N- diisopropylethylamine (12.2 mL, 70 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo. The residue was dissolved in EtOAc (150 mL) and washed with saturated NaHCO3 (2 x 50 mL). The organic layer was dried (Na2SO4). The solvent was removed in vacuo to afford the crude product (1.86 g, 83%) as yellow oil.
39% With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane;Heating / reflux; Example 145 Synthesis of 2-(4-{6-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-2-methyl-pyrimidin-4-yl}-piperazin-1-yl)-ethanol To synthesize the title compound (CLXIX), two intermediate compounds 62 (2-[4-(6-chloro-2-methyl-pyrimidin-4-yl)-piperazin-1-yl]-ethanol) and 63 (7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine) shown below were used. To synthesize compound 62, to a solution of 4,6-dichloro-2-methyl-pyrimidine (5.0 g, 31 mmol) and 2-piperazin-1-yl-ethanol (2.7 g, 21 mmol) in dioxane (25 mL) was added DIPEA (3.0 mL, 17 mmol). The mixture was heated at reflux for 16 h. The mixture was allowed to cool to room temperature and poured into water. The reaulting aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (5-10% MeOH/DCM) to afford compound 62 as a brown liquid (2.1 g, 39%). MS (ESI+): m/z 257.
39% With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; for 16h;Heating / reflux; Example 127. 2-[4-(6-Chloro-2-methvl-pyrimidin-4-vl)-piperaziii-l-vll-ethanoϖ71); [0307] To a solution of 4,6-dichloro-2-methyl-pyrimidine (5.0 g, 31 mmol) and 2- piρerazin-1-yl-ethanol (2.7 g, 21 mmol) in dioxane (25 mL) was added DEPEA (3.0 mL, 17 mmol). The mixture was heated at reflux for 16 h. The mixture was allowed to cool to room temperature and poured into water. The resulting aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (5-10% MeOH/DCM) to afford the title compound as a brown liquid (2.1 g, 39%). MS (ES+): m/z 257 (M+H)+.
2-Piperazin-1-yl-ethanol (8.2g, 63.1 mmol) was added to a solution of 4,6-dichloro-2- methylpyrimidine (5.2g, 31.9 mmol) in dichloromethane (80 ml) at rt. The mixture was stirred for two hours and triethylamine (0.9 ml) was added. The mixture was stirred at rt for 20h. The resultant solid was filtered. The cake was washed with dichloromethane (20 ml). The filtrate was concentrated to give an oil. This oil was dried under high vacuum for 20h to give a solid. This solid was stirred with heptane (50 ml) at rt for 5h. Filtration gave 7C (8.13g) as a white solid
4.08 g To a solution of 4,6-dichloro-2-methylpyrimidine (3.00 g) in dichloromethane (35 mL) was added 2-(piperazin-1-yl)ethanol (4.51 mL) at room temperature, and the mixture was stirred for 4 hr. To the reaction mixture was added triethylamine (0.513 mL) at room temperature, and the reaction mixture was stirred overnight. The resulting solid was collected by filtration, washed with dichloromethane, and dried under reduced pressure to give the title compound (4.08 g). 1H NMR (400 MHz, CDCl3) δ 2.48 (3H, s), 2.55-2.63 (6H, m), 3.63-3.73 (6H, m), 6.34 (1H, s)

  • 2
  • [ 127116-19-2 ]
  • [ 302964-24-5 ]
  • [ 302962-49-8 ]
YieldReaction ConditionsOperation in experiment
83.2% In 1,4-dioxane; at 75℃; for 3h; 13.4 g (50 mmol) of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamideMethyl-4-chloro-6- (4-hydroxyethyl-piperidinyl) pyrimidine15.4 g (60 mmol)In 1,4-dioxane at 75 C3 hours,Dumped into the water,The organic phase was concentrated and washed with water, then recrystallized from methanol and dried to obtain 20.3 g of dasatinib. The yield was 83.2% and the purity was 99.71%.
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; at 100 - 110℃; for 20h; To a 250 ml of round bottom flask were charged compound 5C (1.9g, 7.1 mmol), compound 7C (1.5 g, 5.9 mmol), K2CO3 (16g, 115.7 mmol), Pd (OAc) 2 (52 mg, 0.23 mmol) and BINAP (291 mg, 0.46 mmol). The flask was placed under vacuum and flushed with nitrogen. Toluene was added (60 ml). The suspension was heated to 100-110C and stirred at this temperature for 20h. After cooling to room temperature, the mixture was applied to a silica gel column. The column was first eluted with EtOAC, and then with 10% of MeOH in EtOAC. Finally, the column was washed with 10% 2M ammonia solution in MeOH/90% EtOAC. The fractions which contained the desired product were collected and concentrated to give compound IV as a yellow solid (2.3 g).
  • 3
  • [ 867330-72-1 ]
  • [ 127116-19-2 ]
  • C26H29ClN8O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With potassium tert-butylate;palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; DMF (N,N-dimethyl-formamide); at 160℃; for 0.333333h;Irradiated with microwave; Example 146 Synthesis of 4-chloro-3-(3-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-2-methyl-pyrimidin-4-ylamino}-5-methyl-benzo[1,2,4]triazin-7-yl)-phenol To synthesize the title compound (CLXX), an intermediate compound 64 (2-(4-{6-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-2-methyl-pyrimidin-4-yl}-piperazin-1-yl)-ethanol) shown below was used. To synthesize compound 64, a suspension of compound 16 (scheme (CXXXV), Example 124) (0.10 g, 0.33 mmol), compound 53 (Example 145) (0.10 g, 0.39 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.045 mmol) and potassium tert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (2.5 mL, 4/1 v/v) was sealed in a microwave reaction tube and irradiated with microwave at 160 C. for 20 min. After cooling down to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (5-10% MeOH/DCM) to yield compound 64 as a yellow solid (43 mg, 25%). MS (ESI+): m/z 521.
  • 4
  • [ 867333-31-1 ]
  • [ 127116-19-2 ]
  • 2-(4-{6-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-2-methyl-pyrimidin-4-yl}-piperazin-1-yl)-ethanol hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% To synthesize the title compound (CLXIX), a suspension of compound 62 (0.15 g, 0.49 mmol), compound 63 (0.16 g, 0.62 mmol), Pd(OAc)2 (7 mg, 0.031 mmol), Xantphos (36 mg, 0.062 mmol) and potassium tert-butoxide (0.11 g, 0.98 mmol) in dioxane/DMF (4 mL, 3/1 v/v) was sealed in a microwave reaction tube and irradiated with microwave at 160 C. for 20 min. After cooling down to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (5-10% MeOH/DCM) to afford the free base compound. The free base compound was converted to HCl salt according to method C and furnished the title compound as a yellow solid (0.18 g, 65% overall). 1H NMR (DMSO-d6): δ 2.54 (s, 3H), 2.75 (s, 3H), 3.15-3.25 (m, 4H), 3.59-3.72 (m, 6H), 3.82 (t, J=4.6 Hz, 2H), 4.56 (br s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.91-7.93 (m, 1H), 8.31 (d, J=1.5 Hz, 1H), 10.93 (br s, 1H), 11.83 (br s, 1H). MS (ESI+): m/z 525.
  • 5
  • [ 3073-77-6 ]
  • [ 127116-19-2 ]
  • [ 910908-24-6 ]
YieldReaction ConditionsOperation in experiment
52% With potassium tert-butylate;palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; for 15h;Heating / reflux; Example 128. 2-{4-f2-MethvI-6-(5-nitro-pyrimidin-2-ylaminoVpyrimidm-4-yll- piperazin-l-yl}-etlianol (72); [0308] A mixture of 5-nitro-pyrimidin-2-ylamine (0.45 g, 3.2 mmol), compound 71 described in Example 127 (1.0 g, 3.9 mmol), Pd(OAc)2 (50 mg, 0.22 mmol), Xantphos (0.26 g, 0.45 mmol) and potassium tert-butoxide (0.72 g, 6.4 mmol) were suspended in dioxane (15 niL) and heated at reflux under the argon atmosphere for 15 h. The mixture was allowed to cool to room temperature, filtered and washed with DCM. The filtered solid was washed with water and DCM to afford the title compound (0.60 g, 52%), which was used in the next step without further purification. MS (ES+): m/z 361 (M+H)+.
  • 6
  • [ 32955-21-8 ]
  • [ 127116-19-2 ]
  • [ 1245157-39-4 ]
YieldReaction ConditionsOperation in experiment
70.5% Employing the above-mentioned synthetic method: Prepared from ethyl 2-aminothiazole-5-formate and Compound 4: ethyl (6-(4-(2-hydroxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-formate was obtained (yield: 70.5%). Element analysis: C17H24N6O3S, Calculated: C, 52.02; H, 6.16; N, 21.41; Found: C, 52.08; H, 6.15; N, 21.42.
  • 13
  • [ 6633-61-0 ]
  • [ 127116-19-2 ]
  • [ 1245157-35-0 ]
YieldReaction ConditionsOperation in experiment
75.2% Example 2: Synthesis of methyl 2-(6-(4-(2-hydroxylethyl) piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-formate (Compound 6); 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl) ethanol (Compound 4) (25.7g, 0.1mol) <strong>[6633-61-0]methyl 2-aminothiazole-5-formate</strong> (Compound 5) (18.9g, 0.12mol), cesium carbonate (45.6g, 0.14mol), palladium acetate (2.2g, 0.01mol) and BINAP(6.2g, 0.01mol) were mixed with toluene(1100mL) in reaction flask, and heated by stirring to reflux for 16h. The reactant was cooled and 2mol/L hydrochloric acid was added and stirred for 10 mins. After vacuum filtration the filtrate was phase-separated and the aqueous phase was extracted by toluene (500mL). The separated aqueous phase was neutralized by NaOH solution (6mol/L) at 10-15C, and then grew the grains for 1h. After vacuum filtration the cake was rinsed by water to give yellow solid target Compound 6 (28.5g, yield: 75.2%). Melting Point: 243C Purity: 97.5% (HPLC, normalization method); Element analysis: C16H22N6O3S, Calculated: C, 50.78; H, 5.86; N, 22.21; Found: C, 50.75; H, 5.87; N, 22.40. 1H-NMR(500MHz,DMSO-d6): delta(ppm): 2.416-2.438(t, 3H), 2.480-2.489(d, 2H), 2.547-2.583(s, 4H), 3.486-3.546(m, 6H), 3.797(s, 1H), 4.471(s, 1H) (which disappeared after adding D2O), 6.063(s, 1H), 8.060(s, 1H), 10.232(s, 1H) (which disappeared after adding D2O). 13C-NMR(500MHz, DMSO-d6): delta(ppm): 25.987, 43.955, 44.081, 51.264, 52.197, 53.162, 58.924, 60.547, 83.355, 120.180, 146.107, 157.222, 162.778, 164.276, 165.578. ESI: (M+1): 379.23.
75.2% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 16h;Reflux; [0140] 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol (Compound 4) (25.7 g, 0.1 mol), <strong>[6633-61-0]methyl 2-aminothiazole-5-formate</strong> (Compound 5) (18.9 g, 0.12 mol), cesium carbonate (45.6 g, 0.14 mol), palladium acetate (2.2 g, 0.01 mol) and BINAP (6.2 g, 0.01 mol) were mixed with toluene (1100 mL) in reaction flask, and heated by stirring to reflux for 16 h. The reactant was cooled and 2 mol/L hydrochloric acid was added and stirred for 10 mins. After vacuum filtration the filtrate was phase-separated and the aqueous phase was extracted by toluene (500 mL). The separated aqueous phase was neutralized by NaOH solution (6 mol/L) at 10-15 C., and then grew the grains for 1 h. After vacuum filtration the cake was rinsed by water to give yellow solid target Compound 6 (28.5 g, yield: 75.2%).[0141]Melting Point: 243 C.[0142]Purity: 97.5% (HPLC, normalization method) [0143]Element analysis: C16H22N6O3S, Calculated: C, 50.78; H, 5.86; N, 22.21. Found: C, 50.75; H, 5.87; N, 22.40.[0144]1H-NMR (500 MHz, DMSO-d6): delta(ppm): 2.416-2.438 (t, 3H), 2.480-2.489 (d, 2H), 2.547-2.583 (s, 4H), 3.486-3.546 (m, 6H), 3.797 (s, 1H), 4.471 (s, 1H) (which disappeared after adding D2O), 6.063 (s, 1H), 8.060 (s, 1H), 10.232 (s, 1H) (which disappeared after adding D2O).[0145]13C-NMR (500 MHz, DMSO-d6): delta(ppm): 25.987, 43.955, 44.081, 51.264, 52.197, 53.162, 58.924, 60.547, 83.355, 120.180, 146.107, 157.222, 162.778, 164.276, 165.578.[0146]ESI: (M+1): 379.23.
  • 14
  • 2-amino-thiazole-5-carboxylic acid isopropyl ester [ No CAS ]
  • [ 127116-19-2 ]
  • [ 1245157-41-8 ]
YieldReaction ConditionsOperation in experiment
65.2% Prepared from isopropyl 2-aminothiazole-5-formate and Compound 4: isopropyl 2-(6-(4-(2-hydroxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-formate was obtained (yield: 65.2%). Element analysis: C18H26N6O3S, Calculated: C, 53.18; H, 6.45; N, 20.67; Found: C, 53.15; H, 6.48; N, 20.65.
  • 15
  • [ 127116-19-2 ]
  • [ 18162-48-6 ]
  • 4-(4-(2-((tert-butyl(dimethyl)silyl)oxy)ethyl)piperazin-1-yl)-6-chloro-2-methylpyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.42 g With 1H-imidazole; In N,N-dimethyl-formamide; at 10 - 35℃; for 2h; To a solution of <strong>[127116-19-2]2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol</strong> obtained in Step A (1.00 g) and imidazole (0.636 g) in N,N-dimethylformamide (13 mL) was added tert-butyl(chloro)dimethylsilane (0.793 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.42 g). 1H NMR (400 MHz, CDCl3) δ 0.06 (6H, s), 0.90 (9H, s), 2.47 (3H, s), 2.55-2.60 (6H, m), 3.63 (4H, brs), 3.78 (2H, t, J = 6.0 Hz), 6.32 (1H, s)
  • 16
  • [ 127116-19-2 ]
  • 1-phenyl-1H-imidazole-4-amine hydrochloride [ No CAS ]
  • 2-(4-(2-methyl-6-((1-phenyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)piperazin-1-yl)ethanol [ No CAS ]
  • 17
  • [ 127116-19-2 ]
  • [ 121952-97-4 ]
  • 2-(4-(6-((5-benzylthiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol [ No CAS ]
  • 18
  • (2-methyl-6-chloro-pyrimidin-4-yl)piperazin [ No CAS ]
  • [ 107-07-3 ]
  • [ 127116-19-2 ]
YieldReaction ConditionsOperation in experiment
85.5% then the filtrate by adding 2 - chloro ethanol 41.0g, triethylamine 65g, heating reflux reaction for 3.5 hours, the reaction is completed, the room temperature, for 1 mol / L hydrochloric acid 100 ml washing, then 100 ml saturated sodium Bicarbonate solution to wash a, 100 ml purified water wash once, then concentrated at reduced pressure of the organic layer, adding 440 g normal hexane and 110 g ethyl acetate, heating to 50 C, stirring 1 hour; Stirred for 30 minutes, filtered, washing the 91.8g white solid, yield 85.5%, purity 99.8%.
  • 19
  • [ 127116-19-2 ]
  • [ 4970-53-0 ]
  • 5-{6-[4-(2-hydroxy-ethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
20% With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate; In N,N-dimethyl-formamide; at 110℃; for 36h;Schlenk technique; Inert atmosphere; General procedure: A 10-ml Schlenk tube equipped with a stir-bar was charged with compound 1 (0.2 mmol), compound 2 (0.3 mmol), Pd(OAc)2 (0.02 mmol), Xantphos (0.04 mmol), NaOtBu (0.3 mmol), anhydrous DMF (2 mL).The reaction tube was purged with argon. The Schlenk tube was placed in an oil-bath at 110 oC for 36 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure and the crude residue purified by flash chromatography on silica gel. The purified material was dried in vacuo to afford the corresponding products 3a-w.
20% With xantphos; palladium diacetate; sodium t-butanolate; In N,N-dimethyl-formamide; at 110℃; for 36h;Schlenk technique; Inert atmosphere; In a 10 ml Schlenk tube, add compound 1c (51.2 mg, 0.2 mmol), 5-amino-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester (47.1 mg, 0.3 mmol), Pd (OAc)2 (4.5 mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol), NaOtBu (29 mg, 0.3 mmol) and anhydrous DMF (2 mL).Under the protection of argon, the reaction tube was placed in an oil bath at 110 C. for 36 h for Buchwald-Hartwig reaction, and then cooled to room temperature. The reaction mixture was extracted with EtOAc (3 × 20 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure. The corresponding product 2e (15 mg) was separated on a silica gel column, white solid, melting point: 134 C, yield 20%, purity 96%.
  • 20
  • [ 127116-19-2 ]
  • [ 31803-00-6 ]
  • 2-{4-[6-(5-benzyl-[1,3,4]oxadiazol-2-ylamino)-2-methylpyrimidin-4-yl]piperazin-1-yl}ethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
18% With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate; In N,N-dimethyl-formamide; at 110℃; for 36h;Schlenk technique; Inert atmosphere; General procedure: A 10-ml Schlenk tube equipped with a stir-bar was charged with compound 1 (0.2 mmol), compound 2 (0.3 mmol), Pd(OAc)2 (0.02 mmol), Xantphos (0.04 mmol), NaOtBu (0.3 mmol), anhydrous DMF (2 mL).The reaction tube was purged with argon. The Schlenk tube was placed in an oil-bath at 110 oC for 36 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure and the crude residue purified by flash chromatography on silica gel. The purified material was dried in vacuo to afford the corresponding products 3a-w.
18% With xantphos; palladium diacetate; sodium t-butanolate; In N,N-dimethyl-formamide; at 110℃; for 36h;Schlenk technique; Inert atmosphere; In a 10 ml Schlenk tube, add compound 1c (51.2 mg, 0.2 mmol), 5-benzyl[1,3,4]oxadiazole-2-amino (52.5 mg, 0.3 mmol), Pd (OAc) 2 (4.5 mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol), NaOtBu ( 29mg, 0.3mmol) and anhydrous DMF (2mL), Under the protection of argon gas, the reaction tube was placed in an oil bath at 110 C for 36 h for Buchwald-Hartwig reaction, and then cooled to room temperature the reaction mixture was extracted with EtOAc (3 × 20 mL). The organic phase was dried over MgSO4, concentrated under reduced pressure, and separated with a silica gel column to obtain the corresponding product 2b (14.2 mg), a white solid, melting point: 135 C., yield 18%, and purity 96%.
  • 21
  • [ 127116-19-2 ]
  • [ 1612-76-6 ]
  • 2-{4-[2-methyl-6-(5-phenyl-[1,3,4]oxadiazol-2-ylamino)pyrimidin-4-yl]piperazin-1-yl}ethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
23% With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate; In N,N-dimethyl-formamide; at 110℃; for 36h;Schlenk technique; Inert atmosphere; General procedure: A 10-ml Schlenk tube equipped with a stir-bar was charged with compound 1 (0.2 mmol), compound 2 (0.3 mmol), Pd(OAc)2 (0.02 mmol), Xantphos (0.04 mmol), NaOtBu (0.3 mmol), anhydrous DMF (2 mL).The reaction tube was purged with argon. The Schlenk tube was placed in an oil-bath at 110 oC for 36 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure and the crude residue purified by flash chromatography on silica gel. The purified material was dried in vacuo to afford the corresponding products 3a-w.
23% With xantphos; palladium diacetate; sodium t-butanolate; In N,N-dimethyl-formamide; at 110℃; for 36h;Schlenk technique; Inert atmosphere; In a 10 ml Schlenk tube, add compound 1c (51.2 mg, 0.2 mmol), 5-phenyl- [1,3,4]oxadiazole-2-amino (48.3 mg, 0.3 mmol), Pd (OAc) 2 (4.5 mg, 0.02 mmol), xantphos (23mg, 0.04mmol), NaOtBu (29mg, 0.3mmol) and anhydrous DMF (2mL) under the protection of argon,The reaction tube was placed in an oil bath at 110 C. for 36 h for a Buchwald-Hartwig reaction, then cooled to room temperature, and the reaction mixture was extracted with EtOAc (3 × 20 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure. The corresponding product 2a (17.5 mg) was separated on a silica gel column, white solid, melting point: 180 C, yield 23%, purity 96%.
  • 22
  • [ 127116-19-2 ]
  • C23H30N8O6 [ No CAS ]
 

Historical Records

Technical Information

Categories

Related Functional Groups of
[ 127116-19-2 ]

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Alcohols

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Related Parent Nucleus of
[ 127116-19-2 ]

Piperazines

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