479691-42-4|tert-Butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate| Ambeed

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Quality Control of [ 479691-42-4 ] Purity: 95% SDS Specification

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Product Details of [ 479691-42-4 ]

CAS No. :	479691-42-4
Formula :	C₁₃H₁₉ClN₄O₂
M.W :	298.77
SMILES Code :	CC(C)(C)OC(=O)N1CCN(CC1)C1=NC=CC(Cl)=N1
MDL No. :	MFCD09743711
InChI Key :	SPSXSTDJXLNVJF-UHFFFAOYSA-N
Pubchem ID :	46738270

Safety of [ 479691-42-4 ]

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

Computational Chemistry of [ 479691-42-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	20
Num. arom. heavy atoms	6
Fraction Csp3	0.62
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	84.24
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	58.56 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.08
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.28
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.43
Log P_o/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.	1.38
Log P_o/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	1.22
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.88

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.09
Solubility	0.245 mg/ml ; 0.000819 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.	-3.15
Solubility	0.213 mg/ml ; 0.000713 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < 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	-2.94
Solubility	0.343 mg/ml ; 0.00115 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	Yes
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	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.	-6.5 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)	2.66

Application In Synthesis of [ 479691-42-4 ]

* 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 [ 479691-42-4 ]

[ 479691-42-4 ] Synthesis Path-Downstream 1~25

1
[ 3934-20-1 ]
[ 57260-71-6 ]
[ 221050-88-0 ]
[ 479691-42-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In ethanol; at 100℃; for 1.0h;Heating / reflux;Product distribution / selectivity;	A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of 2,4-dichloropyrimidine and 8.6 g of NaHCO3 in 50 ml of EtOH is heated at reflux for 1 hour. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40; v/v) mixture. Two compounds are separated: the less polar compound, corresponding to tert-butyl 4-(4-chloro-2-pyrimidinyl)-1-piperazinecarboxylate, of which 1.75 g are obtained; the more polar compound, corresponding to the compound of step A), of which 12.9 g are obtained, and which is used as it is; A) tert-Butyl 4-(4-chloropyrimidin-2-yl)-1-piperazinecarboxylate and tert-butyl 4-(2-chloropyrimidin-4-yl)-1-piperazinecarboxylate A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of 2,4-dichloropyrimidine and 8.6 g of NaHCO3 in 90 ml of EtOH is heated at 100 C. for one hour. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40; v/v) mixture. Two compounds are separated: the less polar compound, tert-butyl 4-(4-chloropyrimidin-2-yl)-1-piperazinecarboxylate, of which 1.75 g are obtained; the more polar compound, tert-butyl 4-(2-chloropyrimidin-4-yl)-1-piperazinecarboxylate, of which 12.9 g are obtained.

References: [1]Patent: US2005/176722,2005,A1 .Location in patent: Page/Page column 20; 22.

2
[ 479691-42-4 ]
[ 1185316-90-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; diethyl ether; at 20℃; for 18.0h;	A mixture of 1.75 g of the less polar compound obtained in the preceding step and 100 ml of 2N hydrochloric ether solution in 10 ml of MeOH is left with stirring at AT for 18 hours. It is concentrated under vacuum, the residue is taken up in ether and the crystalline product formed is isolated with suction. This gives 1.6 g of the expected product.
	With hydrogenchloride; In diethyl ether; at 20℃; for 1.0h;Inert atmosphere;	Preparation of compound 38: A solution of compound 37 in 20 ml of ether/HCl was allowed to stir at room temperature under nitrogen atmosphere for 1 h. The excess solvent was distilled off under reduced pressure and the crude material was washed with n-pentane and dried to yield 180 mg of compound 38 in quantitative yield.

References: [1]Patent: US2005/176722,2005,A1 .Location in patent: Page/Page column 22.
[2]Patent: US2010/331307,2010,A1 .Location in patent: Page/Page column 26.

3
[ 479691-42-4 ]
[ 4152-90-3 ]
[ 479691-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In ethanol; hexane; ethyl acetate;	Example 4 Preparation of Intermediate 4-[4-(3-Chloro-benzylamino)-pyrimidin-2-yl]-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-4a): A mixture of <strong>[479691-42-4]4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester</strong> I-2a (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (218 mL). The combined organic extracts were washed with H2O (210 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography using 40% EtOAc in hexane as an eluding solvent to afford the title compound I-4a (93 mg) as a colorless oil. 1H NMR (400 MHz, CD3OD) delta 7.69 (d, 1H); 7.32 (s, 1H); 7.28-7.19 (m, 3H); 5.88 (d, 1H); 4.49 (s, 2H); 3.64-3.61 (m, 4H); 3.37-3.29 (m, 4H); 1.45 (s, 9H). MS (ES+) Calc: 403.2, Found: 404.0 (M+1).

References: [1]Patent: US2003/105106,2003,A1 .

4
[ 479691-42-4 ]
[ 13524-04-4 ]
[ 479691-43-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; mineral oil;	Preparation of Intermediate 4-{4-[1-(2-chloro-phenyl)-ethoxy]-pyrimidin-2-yl}-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-2b): 1-(2-Chloro-phenyl)-ethanol (31.4 mg, 0.20 mmol) was dissolved into 1.7 mL of anhydrous tetrahydrofuran and treated with sodium hydride (8.0 mg, 60% dispersion in mineral oil, 0.20 mmol). This was stirred under nitrogen for 1 hour at ambient temperature, then the reaction was treated with <strong>[479691-42-4]4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester</strong> (I-2a) (50 mg, 0.17 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (20 mL) and extracted with ethyl acetate (2*25 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (7:13 ethyl acetate:hexanes) to afford 64.3 mg of the title product (I-2b). 1H NMR (400 MHz, CDCl3) delta 8.00 (d, 1H); 7.38-7.13 (m, 4H); 6.35 (q, 1H); 6.02 (d, 1H); 3.62 (m, 4H); 3.30 (m, 4H); 1.57 (d, 3H); 1.45 (s, 9H). MS (APCI+) Calc: 418, Found: 419.1 (M+1).

References: [1]Patent: US2003/105106,2003,A1 .

5
[ 3934-20-1 ]
[ 53788-49-1 ]
[ 479691-42-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	In toluene; at 110℃;	A mixture of 2,4-dichloropyrimidine (50g, 336mmol), tert-butyl 4-methylpiperazine-1-carboxylate (67.2g, 336mmol), and toluene (500mL) was stirred at 110 C overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 10 (109g, 73%) as a colorless powder. 1H NMR (300MHz, CDCl3) delta: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1Hz), 8.16 (1H, d, J=5.1Hz). MS (ESI): m/z 299 [M+H]+.
62%	In toluene; at 110℃;Product distribution / selectivity;	(2) Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate A mixture of 4-methyltert-butyl piperazine-1-carboxylate (2.0 g, 9.98 mmol), 2,4-dichloropyrimidine (1.49 g, 9.98 mmol) and toluene (20 ml) was stirred at 110 C. overnight. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (1.83 g, 62%) as a solid. 1H NMR (CDCl3) delta: 1.49 (9H, s), 3.44-3.53 (4H, m), 3.75-3.84 (4H, m), 6.53 (1H, d, J=5.1 Hz), 8.16 (1H, d, J=5.1 Hz).
	In water; toluene;	Example 2 Preparation of Intermediate 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic Acid Tert-Butyl Ester (I-2a): To a suspension of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in 13.4 mL of toluene was added 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.34 g, 6.71 mmol). The reaction was heated to reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 20 mL of water and extracted with ethyl acetate (2*40 mL). The combined organic layers were washed with brine (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to an off-white solid. Flash column chromatography (silica gel, gradient elution from 5% ethyl acetate-hexanes to 20% ethyl acetate-hexanes) yielded 1.14 g of the title compound (I-2a). 1H NMR (400 MHz, CDCl3) delta 8.15 (d, 1H); 6.52 (d, 1H); 3.80 (m, 4H); 3.48 (m, 4H); 1.47 (s, 9H). MS (APCI+) Calc: 298, Found: 299.1 (M+1).

References: [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1468 - 1478.
[2]Patent: US2009/163508,2009,A1 .Location in patent: Page/Page column 20.
[3]Patent: US2003/105106,2003,A1 .

6
[ 3934-20-1 ]
[ 57260-71-6 ]
[ 479691-42-4 ]

Yield	Reaction Conditions	Operation in experiment
6%	With sodium hydrogencarbonate; In ethanol; for 1.5h;Heating / reflux;Product distribution / selectivity;	(1) Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate To a solution of 2,4-dichloropyrimidine (50.0 g, 0.338 mol) in ethanol (500 ml) was added tert-butyl piperazine-1-carboxylate (62.8 g, 0.338 mol) and sodium hydrogencarbonate (56.8 g, 0.676 mol) and heated under reflux for 1.5 hours. The reaction was filtered and the filtrate was concentrated. To the residue was added methylene chloride and water followed by extracted. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the title compound (6.30 g, 6%). 1H NMR (CDCl3) delta: 1.49 (9H, s), 3.45-3.52 (4H, m), 3.75-3.83 (4H, m), 6.53 (1H, d, J=4.8 Hz), 8.16 (1H, d, J=4.8 Hz).
	With sodium hydrogencarbonate; In ethanol; for 1.0h;Reflux;	Preparation of compound 37: 2,4-dichloropyrimidine (801 mg, 0.0053 mole, 1 eq), N-Boc-piperazine (1.0 gm, 0.0053 mole, 1 eq) and sodium bicarbonate (903 mg, 0.0107 mole, 2 eq) were dissolved in ethanol (50 ml) and stirred at reflux for 1 h. Progress of the reaction was monitored by TLC. The excess solvent was removed, dissolved in water and extracted with DCM. The organic layer was washed with water, dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 15% ethyl acetate-hexane to afford coupled product compound 37 (230 mg).

References: [1]Patent: US2009/163508,2009,A1 .Location in patent: Page/Page column 39.
[2]Patent: US2010/331307,2010,A1 .Location in patent: Page/Page column 26.

7
[ 479691-42-4 ]
[ 98-80-6 ]
[ 1143578-27-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; for 14.0h;Heating / reflux;	(2) 4-phenyl-2-piperazin-1-ylpyrimidine Dihydrochloride To a solution of <strong>[479691-42-4]tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate</strong> (6.30 g, 20.7 mmol) and phenylboric acid (3.75 g, 31.1 mmol) in anhydrous toluene (250 ml) was added potassium phosphate (9.20 g, 41.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (480 mg, 0.83 mmol) and trisdibenzylideneacetone dipalladium (119 mg, 0.21 mmol) under nitrogen atmosphere, and the reaction was degassed and heated under reflux for 14 hours. The reaction was distilled off under reduced pressure and to the residue was added to methylene chloride and water followed by extracted. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain tert-butyl 4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxylate (5.00 g, 70%).

References: [1]Patent: US2009/163508,2009,A1 .Location in patent: Page/Page column 39.

8
[ 479691-42-4 ]
[ 1993-03-9 ]
[ 1143578-66-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20 - 95℃;	(1) 4-(2-fluorophenyl)-2-piperazin-1-ylpyrimidine Dihydrochloride To a solution of <strong>[479691-42-4]tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate</strong> (10 g, 33.5 mmol), 2-fluorophenyl boronic acid (7.02 g, 50.2 mmol), and 2 N aqueous sodium carbonate solution (45 ml) in 1,2-dimethoxyethane (300 ml) was added tetrakistriphenylphosphine palladium (4.64 g, 40.2 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred at 95 C. overnight. The reaction was poured into the saturated saline, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain tert-butyl 4-[4-(2-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylate.

References: [1]Patent: US2009/163508,2009,A1 .Location in patent: Page/Page column 45.

9
[ 479691-42-4 ]
[ 162101-25-9 ]
[ 1143579-00-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; In tetrahydrofuran; hexane; water; at 20 - 60℃; for 2.0h;	(1) Tert-butyl 4-[4-(2,6-difluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylate To a solution of <strong>[479691-42-4]tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate</strong> (6.00 g, 20.1 mmol), 2,6-difluorophenyl boronic acid (3.80 g, 24.1 mmol), potassium fluoride (3.5 g, 60.3 mmol) in tetrahydrofuran-water (10:1)(66 ml) was added trisbenzylidene acetone dipalladium (1.80 g, 2.01 mmol) and tri-tert-butylphosphine (10 wt % in hexane) (8.4 g, 4.02 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred at 60 C. for 2 hours. The reaction solution was cooled to the room temperature, and concentrated. To the residue was poured water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography on silica gel (ethyl acetate:hexane=1:5) to obtain the title compound (6.60 g, 87%) as a solid. 1H-NMR (CDCl3) delta: 1.42 (9H, s), 3.32-3.42 (4H, m), 3.72-3.75 (4H, m), 6.84-6.85 (1H, m), 7.22-7.26 (2H, m), 7.54-7.62 (1H, m), 8.51 (1H, d, J=4.9 Hz).

References: [1]Patent: US2009/163508,2009,A1 .Location in patent: Page/Page column 51.

10
[ 479691-42-4 ]
[ 144025-03-6 ]
[ 1143577-33-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 20 - 100℃;	(3) Tert-butyl 4-[4-(2,4-difluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylate To a mixture of <strong>[479691-42-4]tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate</strong> (1.0 g, 3.35 mmol), 2,4-difluorophenylboric acid (793 mg, 5.02 mmol), 2N aqueous sodium carbonate solution (13.4 ml) and toluene (33 ml) was added tetrakistriphenylphosphine palladium (464 mg, 0.402 mmol) at room temperature under nitrogen atmosphere, and the mixture was stirred at 100 C. overnight. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (894 mg, 71%) as an oily material. 1H NMR (CDCl3) delta: 1.50 (9H, s), 3.46-3.58 (4H, m), 3.85-3.93 (4H, m), 6.83-7.08 (3H, m), 8.08-8.22 (1H, m), 8.39 (1H, d, J=5.3 Hz).
71%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In toluene; at 100℃;Inert atmosphere;	General procedure: A mixture of tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (1.80g, 6.02mmol), (2,4-difluorophenyl)boronic acid (1.43g, 9.04mmol), 1M aq Na2CO3 (24 mL, 48.2 mmol), tetrakis(triphenylphosphine)palladium (0) (835mg, 0.723mmol), and toluene (60mL) was stirred at 100C overnight under N2 atmosphere. The mixture was diluted with water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 8 (907mg, 40%) as a colorless viscous oil.

References: [1]Patent: US2009/163508,2009,A1 .Location in patent: Page/Page column 20.
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1468 - 1478.

11
[ 1193-21-1 ]
[ 57260-71-6 ]
[ 479691-42-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In isopropyl alcohol; for 2.0h;Heating; Reflux;	Production Example 1062-{ 4- [2- (6~piperazin-l-ylpyrimidin-4- yl) ethyl] phenyl }acetohydrazide tetrahydrochloride step 1[0323] [0324]To a solution (60 ml) of 4, 6-dichloropyrimidine (2.00 g, 13.4 mmol) and tert-butyl piperazine-1-carboxylate (3.00 g, 16.1 mmol) in 2-propanol was added triethylamine (4.7 ml, 33.6 mmol), and the mixture was heated under reflux for 2 hrs . The mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 1:2) to give tert-butyl 4- ( 6-chloropyrimidin-2-yl) piperazine-1-carboxylate (3.80 g, yield 95%) as a white solid.

References: [1]Patent: WO2009/145360,2009,A1 .Location in patent: Page/Page column 116.

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[ 1378368-16-1 ]

Yield	Reaction Conditions	Operation in experiment
16%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide;Inert atmosphere;	Step 4: tert-butyl 4-(4-(3-(tert-butyl)-4-(cyclopentylamino)phenyl)pyrimidin-2- yl)piperazine- 1 -carboxylate:To a solution of 2-(ie -butyl)-/V-cyclopentyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)aniline (390 mg, 1 .136 mmol) in DMF (2 ml) was added a mixture of terf-butyl 4-(2- chloropyrimidin-4-yl)piperazine-1 -carboxylate and terf-butyl 4-(4-chloropyrimidin-2- yl)piperazine-1 -carboxylate (339 mg, 1 .136 mmol) and 2M aq. Na2C03 (1 .136 ml, 2.272 mmol). The reaction mixture was degassed by bubbling nitrogen through the mixture for 10 min and then PdCI2(dppf)-CH2CI2 (93 mg, 0.1 14 mmol) was added. The mixture was heated for 16 h at 80 C under nitrogen. After cooling to RT the reaction mixture was diluted with EtOAc. The mixture was washed with brine. The organic layer was dried with Na2S04, filtered and concentrated in vacuo. The resultant crude was subjected to flash chromatography (Si02, gradient 0 to 30 % EtOAc in cyclohexane) to afford the title compound (89 mg, 16%).LCMS (Method F): RT = 2.02 min, M+H+ = 480; H-NMR (500 MHz, CDCI3): 8.26 (1 H, d), 8.03 (1 H, d), 7.82 (1 H, dd), 6.88 (1 H, d), 6.73 (1 H, d), 4.25 (1 H, d), 3.96-3.93 (1 H, m), 3.90-3.88 (4H, m), 3.54-3.52 (4H, m), 2.10-2.04 (2H, m), 1 .77-1 .67 (4H, m), 1 .57-1 .55 (2H, m), 1 .50 (9H, s), 1 .45 (9H, s).

References: [1]Patent: WO2012/69852,2012,A1 .Location in patent: Page/Page column 128-129.

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[ 156545-07-2 ]
[ 1567327-01-8 ]