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[ CAS No. 193902-78-2 ] {[proInfo.proName]}

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Chemical Structure| 193902-78-2
Chemical Structure| 193902-78-2
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Product Details of [ 193902-78-2 ]

CAS No. :193902-78-2 MDL No. :MFCD07369779
Formula : C14H20N4O4 Boiling Point : -
Linear Structure Formula :- InChI Key :WWFJYZONBJARJT-UHFFFAOYSA-N
M.W : 308.33 Pubchem ID :16217943
Synonyms :

Calculated chemistry of [ 193902-78-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 22
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.57
Num. rotatable bonds : 5
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 90.26
TPSA : 91.49 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.46
Log Po/w (XLOGP3) : 1.8
Log Po/w (WLOGP) : 1.29
Log Po/w (MLOGP) : 0.59
Log Po/w (SILICOS-IT) : -1.02
Consensus Log Po/w : 1.02

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.76
Solubility : 0.539 mg/ml ; 0.00175 mol/l
Class : Soluble
Log S (Ali) : -3.34
Solubility : 0.141 mg/ml ; 0.000457 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.07
Solubility : 2.61 mg/ml ; 0.00847 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.84

Safety of [ 193902-78-2 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P301+P310-P305+P351+P338 UN#:2811
Hazard Statements:H301-H319 Packing Group:Ⅲ
GHS Pictogram:

Application In Synthesis of [ 193902-78-2 ]

* 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 [ 193902-78-2 ]

[ 193902-78-2 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 4487-59-6 ]
  • [ 57260-71-6 ]
  • [ 193902-78-2 ]
YieldReaction ConditionsOperation in experiment
93% With potassium carbonate;tetra-(n-butyl)ammonium iodide; In dimethyl sulfoxide; at 50℃; for 3h; 2-Bromo-5-nitro-pyridine (11.39 g, 56.1 mmol), tetrabutylammonium iodide (TBAI) (1.04 g, 0.05 mmol), potassium carbonate (8.53 g, 61.7 mmol) and piperazine-1-carboxylic acid tert-butyl ester (11.5 g, 61.7 mmol) were mixed together in DMSO (100 mL) and gently warmed to 50 C. for 3 hours and cooled to room temperature overnight. The reaction was diluted with EtOAc (200 mL), the salts were filtered and then the EtOAc was evaporated to leave the DMSO solution. This was diluted with water and a precipitate formed. This precipitate was filtered, washed with water, and then dried in an oven vacuum to give 4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (16.1 g, 93%) as a light orange solid. 1H NMR (400 MHz, CDCl3) ppm 1.47 (s, 9H), 3.55 (m, 4H), 3.75 (m, 4H), 6.55 (d, J=9.3 Hz, 1H), 8.21 (dd, J=9.5, 2.7 Hz, 1H), 9.03 (d, J=2.7 Hz, 1H). 4-(5-Nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (16.0 g, 51.9 mmol) was dissolved in THF (400 mL), RaNi (4 g) added and placed under a H2 atmosphere at 50 psi for 5 h. The catalyst was removed by filtration through celite and the solvent evaporated in vacuo to give 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (14.5 g, 100%). 1H NMR (400 MHz, CDCl3) ppm 1.46 (s, 9H), 3.31 (m, 6H), 3.53 (m, 4H), 6.56 (d, J=8.8 Hz, 1H), 6.98 (dd, J=8.8, 2.9 Hz, 1H), 7.78 (dd, J=2.9, 0.7 Hz, 1H). m/z 279.1 (M+1).
84.18% With potassium carbonate; at 150℃; for 0.25h;Microwave irradiation; To a stirred solution of 367 2-bromo-5-nitropyridine (1.0 g, 4.926 mmol, 1 eq) and 63 tert-butyl piperazine-1-carboxylate (0.917 g, 4.926 mmol, 1.0 eq) in 4 mL of 368 H2O was added 64 K2CO3 (1.02 g, 7.389 mmol, 1.5 eq). The reaction mixture was heated at 150 C. for 15 min in microwave. The progress of reaction was monitored by LCMS. Upon the consumption of starting material, the precipitated compound was filtered off and dried to obtain the desired product, 369 tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (1.283 g, 84.18%) as a yellow solid. (0461) LCMS: 309 [M+1]+
71% With potassium carbonate; In water; at 150℃; for 0.25h;Microwave irradiation; In a 5 mL glass microwave tube were placed 2-bromo-5-nitro pyridine 1 (1015 mg, 5 mmol), 1-Boc-piperazine 2a (930 mg, 5 mmol), K2CO3 (690 mg, 5 mmol), H2O (3 mL) and a magnetic stir bar. The vessel was sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 300 W initial was used, the temperature being ramped from rt to 150 C. Once 150 C was reached, the reaction mixture was held at this temperature for 15 min. Thereafter the mixture was allowed to cool to rt, extracted with ethyl acetate (15 mL) and washed with water (10 mL) then dried over MgSO4. After filtration, the solvent was evaporated to afford a yellow solid 1100 mg (71%) yield. 1H NMR CDCl3 delta = 9.03 (1H, s), 8.18 (1H, d, J = 9.1 Hz), 6.53 (1H, d, J = 9.5 Hz), 3.77-3.52 (8H, m), 1.44 (9H, s). 13C NMR CDCl3 delta = 164.2, 154.7, 145.3, 135.0, 133.2, 105.0, 79.8, 52.9 (2C), 46.0 (2C), 28.4 (3C).
70% With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In toluene; at 20 - 80℃; for 1.25 - 2.25h; BINAP [[ (R)-2,] 2'-Bis [(DIPHENYLPHOSPHINO)-1,] [1'-BINAPHTHYL]] (2.5 g, 3.94088 mmoles) and tris (dibenzylidene acetone) dipalladium (o) (7.2 g, 7.88177 mmoles) were taken in dry toluene (400 ml) and stirred under argon atmosphere at room temperature for 15 minutes. 2-Bromo-5-nitro-pyridine (40 g, 197.044 mmoles) was dissolved in toluene (200 ml) and added to the reaction mixture followed by N-t-butoxycarbonyl piperazine (44 g, 236.45 mmoles). To this cesium carbonate (90 g, [275,] 862 mmoles) was added at room temperature under argon atmosphere. The reaction mixture was heated to [80 C] for 1-2 hours under argon atmosphere and was cooled to RT and filtered through celite. Washed the residue thoroughly with ethylacetate. The combined filtrates were washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel column using dichloromethane and methanol as eluent to yield the title compound (42.4 g, yield 70%).
60.3% With potassium carbonate; In tetrahydrofuran; for 4h;Reflux; 2-Bromo-5-nitropyridine (20.0 g, 98.0 mmol) was dissolved in 300 mL of tetrahydrofuran, and potassium carbonate (27.0 g, 197.0 mmol) and tert-butyl piperazine-1-carboxylate (27.5 g, 148.0 mmol) were added and heated. Reflux for 4 h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE: EA=3:1, v/v) to give solid 29a, yield: 60.3%;
54% In acetonitrile; for 2.5h;Reflux; Example 197a tert-Butyl 4-(5-Nitropyridin-2-yl)piperazine-1-carboxylate 197a A mixture of 2-bromo-5-nitropyridine (5.0 g, 24.6 mmol), tert-butyl piperazine-1-carboxylate (13.8 g, 74.2 mmol), acetonitrile (150 mL) was stirred at reflux for 2.5 h. After the reaction was completed, the solvent was removed under reduced pressure to afford 197a as a yellow solid (4.1 g, 54%). MS-ESI: [M+H]+ 309.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 1h; To a stirred solution of 2-bromo-5-nitro-pyridine (2.9 g) and N-terbutyloxycarbonyl-piperazine (3.2 g) in DMF (100 mL) was added potassium carbonate (1.98 g). The mixture was heated at 80 C. during 1 hour and then concentrated. The residue was taken in CH2Cl2 and the organic phase was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The titled compound was obtained as a yellow solid (4.4 g). [0253] m.p.: 169 C.

  • 2
  • [ 193902-78-2 ]
  • [ 119285-07-3 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen;nickel; In tetrahydrofuran; under 2585.81 Torr; for 5h; 2-Bromo-5-nitro-pyridine (11.39 g, 56.1 mmol), tetrabutylammonium iodide (TBAI) (1.04 g, 0.05 mmol), potassium carbonate (8.53 g, 61.7 mmol) and piperazine-1-carboxylic acid tert-butyl ester (11.5 g, 61.7 mmol) were mixed together in DMSO (100 mL) and gently warmed to 50 C. for 3 hours and cooled to room temperature overnight. The reaction was diluted with EtOAc (200 mL), the salts were filtered and then the EtOAc was evaporated to leave the DMSO solution. This was diluted with water and a precipitate formed. This precipitate was filtered, washed with water, and then dried in an oven vacuum to give <strong>[193902-78-2]4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester</strong> (16.1 g, 93%) as a light orange solid. 1H NMR (400 MHz, CDCl3) ppm 1.47 (s, 9H), 3.55 (m, 4H), 3.75 (m, 4H), 6.55 (d, J=9.3 Hz, 1H), 8.21 (dd, J=9.5, 2.7 Hz, 1H), 9.03 (d, J=2.7 Hz, 1H). 4-(5-Nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (16.0 g, 51.9 mmol) was dissolved in THF (400 mL), RaNi (4 g) added and placed under a H2 atmosphere at 50 psi for 5 h. The catalyst was removed by filtration through celite and the solvent evaporated in vacuo to give 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (14.5 g, 100%). 1H NMR (400 MHz, CDCl3) ppm 1.46 (s, 9H), 3.31 (m, 6H), 3.53 (m, 4H), 6.56 (d, J=8.8 Hz, 1H), 6.98 (dd, J=8.8, 2.9 Hz, 1H), 7.78 (dd, J=2.9, 0.7 Hz, 1H). m/z 279.1 (M+1).
98% With hydrogen;palladium 10% on activated carbon; In methanol; ethyl acetate; at 20℃; for 20h; Place 4-(5-nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester (1.14 g, 3.70 mmol) in 1:1 EtOAc:MeOH (20 mL). Add 10% Pd on carbon using EtOAc (5 mL). Purge the reaction and then add hydrogen. Repeat the purge/fill cycle twice, and place the reaction under a balloon of hydrogen and stir at room temperature for 20 hours. Filter the reaction through a pad of Celite and wash the filter cake with EtOAc. Collect the filtrate and concentrate under reduced pressure to yield 1.01 g (98%) of the title compound. MS(ES): m/z = 279 [M+H].
91% With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 15h; Example 197b tert-Butyl 4-(5-Aminopyridin-2-yl)piperazine-1-carboxylate 197b A 250-mL round-bottomed flask was purged with nitrogen and charged with 197a (4.0 g, 13.0 mmol), 10% palladium on carbon (10% wet, 500 mg), and methanol (130 mL). The flask was evacuated, charged with hydrogen gas, and stirred at room temperature for 15 h. Hydrogen was then evacuated and nitrogen was charged to the flask. The catalyst was removed by filtration through a pad of CELITE and the filtrate was concentrated under reduced pressure to afford 197b (3.3 g, 91%). MS-ESI: [M+H]+ 279
91% With palladium on activated charcoal; hydrogen; In ethyl acetate; at 20℃; for 4h;Inert atmosphere; To a stirred solution of compound 46-3 (4-(5-Nitro-pyridin-2-yl)-piperazine-1-carboxylicacid tert-butyl ester) (1.7 g, 5.519 mmol) in EtOAc (50 mL) argon was purged for 10 min then PdC(800 mg) was added and the reaction was stirred under hydrogen atmosphere (balloon) for 4 hours. The reaction mixture was filtered through celite and concentrated under reduced pressureto afford compound 46-4 (1.4 g, 91%) as brown solid. LC MS: ES+ 278.9.
90% With palladium 10% on activated carbon; hydrogen; In ethanol; ethyl acetate; at 70℃; under 750.075 Torr; for 0.5h;H-Cube; (General flow chemistry reduction method). Using 10% Pd/C as catalyst, a solution of compound 3b (1 mmol, 208 mg) in a 1:1 mixture of ethyl acetate: ethanol (30 mL) was pumped though the H-Cube. The pressure of the system was set to 1 bar, and the temperature to 70 C. After 30 minutes, all the reaction mixture had passed though the HCube. The fraction was analyzed using TLC, which showed complete conversion of the product, and the solvent was reduced to dryness, affording a dark red oil 171 mg (96%) yield. The CatCart was then washed with ethanol for approximately 10 minutes and the washings were discarded.
68% With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 5h; A suspension of <strong>[193902-78-2]4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester</strong> (10.8 g) obtained in Example (38a) and 10% palladium-carbon catalyst (2.15 g) in ethanol (300 mL) was stirred at room temperature under a hydrogen atmosphere for five hours. The reaction mixture was filtered and concentrated. The residue was vigorously stirred in isopropyl ether, collected by filtration and dried under reduced pressure, and 6.59 g (68%) of the title compound was obtained as a pale pink solid. MS(FAB) m/z:279 (M + H)+.
40% With iron; ammonium chloride; In ethanol; water; at 50℃; for 0.5h; To a stirred solution of 369 <strong>[193902-78-2]ter<strong>[193902-78-2]t-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate</strong></strong> (2.9 g, 9.405 mmol, 1.0 eq) in 6 mL of 6 ethanol: 7 water (1:1) mixture were added 217 ammonium chloride (4.04 g, 75.24 mmol, 4 eq) and Fe(0) (2.10 g, 37.62 mmol, 4.0 eq). Reaction mixture was heated at 50 C. for 30 min. Progress of reaction was monitored by LCMS. Upon the consumption of starting material, the reaction mixture was filtered over celite and filtrate was concentrated under reduced pressure. The crude obtained was diluted with 50 mL of water and extracted with ethyl acetate (200 mL×2). Combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography using 0-2% 30 MeOH in 82 CH2Cl2 as eluents to obtain the desired product, 372 tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (1.072 g, 40%). (0463) LCMS: 279 [M+1]+
With hydrogen;palladium on activated charcoal; In ethanol; at 20℃; for 3h; A solution of 1-(terbutyloxycarbonyl)-4-(5-nitro-piridin-2-yl)-piperazine (4.4 g) in EtOH (150 mL) containing Pd/C (0.5 g) was hydrogenated at room temperature during 3 hours. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The titled compound was obtained as a brown oil (3.9 g). [0270] MS: m/z 279 (M+1).
With hydrogen;palladium 10% on activated carbon; In methanol; ethyl acetate; at -10 - 45℃; under 3102.97 Torr; for 3h; [2- (N-T-BUTOXYCARBONYLPIPERAZINE)-5-NITRO] pyridine (82 g, 266.233 mmoles) was dissolved in 1: 1 mixture of methanol and ethylacetate [(1L).] This solution was cooled [TO-5 TO-10 C.] To this, 8.2 g of 10% palladium carbon was added and hydrogenated the reaction mixture at [45 C,] 60 psi for 3 hours. Filtered the reaction mixture through celite and washed the residue thoroughly with methanol. Concentrated the filtrate to dryness and dried under high vacuum to give the title compound (74 g).
With hydrogen;palladium 10% on activated carbon; In methanol; ethyl acetate; at -10 - 45℃; under 3102.97 Torr; for 3h; 2- (PIPERAZINE-N-T-BUTOXYCARBONYL)-5-NITRO pyridine (82 g, 0.266233 moles) was dissolved in 1: 1 mixture of methanol and ethylacetate (1L). This solution was cooled TO-5o TO-10 oC. To this, 8.2 g of 10% palladium carbon was added and hydrogenated the reaction mixture at 45 oC, 60 psi for 3 hours. Filtered the reaction mixture through celite and washed the residue thoroughly with methanol. Concentrated the filtrate to dryness and dried under high vacuum to give the title compound (74 g).
With hydrogen;palladium 10% on activated carbon; In ethanol; under 3102.97 Torr; for 2h; 4-(5-Nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester (5 g), 10% Pd/C (0.5 g) and ethanol (200 ml) were taken together in a hydrogenation flask and the reaction mixture was hydrogenated at 60 psi for 2 hrs. On completion, the reaction mixture was filtered through a celite bed and the ethanol was removed under reduced pressure to give the curde product. The compound was further purified by crystallization from 50% EtOAc/n-hexane (200 ml) to yield 4-(5-Amino-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester. EPO <DP n="52"/>4-r5-d-Oxy-benzori,2,41triazin-3-ylamino)-pyridm-2-vn-piperazine-l-carboxylic acid tert-butyl ester
With hydrogen;5% palladium over charcoal; In ethyl acetate; at 20℃; under 2327.23 Torr; for 3h; Method B:Step 1: tert-Butyl 4-(5-aminopyridin-2-yl)piperazine-l-carboxylate: To a stirred solution of tert-Butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (20 g, 64.935 mmol) in EtOAc (200 ml) was added 5 % Pd/C (4 g) and the mixture was maintained under hydrogen pressure (45 psi) for 3 h at room temperature. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to afford 16.24 g of the amine as a light brown solid which was used as such for the next step.
With palladium 10% on activated carbon; hydrogen; acetic acid; at 30℃; for 1h; 29a (15.0 g of 54.0 mmol) was dissolved in 150 mL of acetic acid, and 1.6 g of 10% palladium carbon was added thereto, and hydrogenation was carried out at 30 C for 1 h.After completion of the reaction, the mixture was filtered under reduced pressure, and the filtrate was directly poured, and 4-fluorobenzaldehyde (8.9 g, 72.0 mmol) was added to the filtrate, stirred at room temperature for 1 hour, then cooled to about 10 C, and sodium borohydride was added.(4.13 g, 108.0 mmol), the reaction was kept for 30 min after the addition. After the completion of the reaction, the reaction mixture was poured into water, and the mixture was evaporated. Purification (PE: EA = 4:1, v/v) gave solid 29c.The yield in two steps was 65.0%;

  • 3
  • [ 4548-45-2 ]
  • [ 57260-71-6 ]
  • [ 193902-78-2 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 16h; Step 1 : t-Butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (B-2) To 5-nitro-2-chloropyridine (10.0 g, 0.0631 mol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 ml_) was added N1N- diisopropylethylamine (24.5 g, 31.3 ml_, 0.189 mol). The reaction mixture was heated at 100 0C for 16 h then cooled to RT and concentrated. Water (300 ml_) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 5% EtOAc-CH2CI2) gave t-butyl 4-(5-nitropyridin-2-yl)piperazine-1 -carboxylate (B-2) as a yellow solid (19.45 g, 100% yield). MS (M+1): 309.
100% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 16h; Intermediate B-54-(5-Aminopyridin-2-yl)-N-(2-fluorophenyl)piperazine- 1 -carboxamide (B-5) Step 1 : t-Butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (B-2)To 5-nitro-2-chloropyridine (10.0 g, 0.0631 raol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 mL) was added N,N-diisopropylethylamine (24.5 g, 31.3 mL, 0.189 mol). The reaction mixture was heated at 100 C for 16 h then cooled to RT and concentrated. Water (300 mL) was added, and the aqueous solution was extracted with CH2G2. The combined organic extract was dried (MgS0 ), filtered, and concentrated.Purification by vacuum filtration through silica gel (eluant: 5% EtOAc-CFkCL.) gave t-butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (B-2) as a yellow solid (19.45 g, 100% yield). MS (M+l): 309.
95% With potassium carbonate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 4h; N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml). The resulting mixture was heated at 1200C for 4 hours.After cooling to room temperarure, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95%.LCMS (ES+) 209.05 (MH+-BOC)
95% With potassium carbonate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 4h; N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml). The resulting mixture was heated at 1200C for 4 hours.After cooling to room temperarure, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95%. LCMS (ES+) 209.05 (MH+-BOC).
90% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; for 5h; To a stirred solution of compound 46-1 (2-Chloro-5-nitro-pyridine) (1 g, 6.30 mmol) inAcetonitrile (20 mL), Piperazine-1-carboxylic acid tert-butyl ester 46-2 (1.17 g, 6.30 mmol) andDIPEA (3.29 mL, 18.92 mmol) were added and the reaction was heated at 70 oc for 5 hours. Thereaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodiumsulfate and concentrated to afford compound 46-3 (1.75 g, 90%) as yellow solid. LC MS: ES+ 309.0.
88% With potassium carbonate; In 1,4-dioxane; for 4h;Heating / reflux; Potassium carbonate (1.7g, 12.31 mmol) was added to a solution of 2-Chloro- 5-nitropyridine (1.33g,8.38mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.57g, 8.42mmol) in dioxane (10ml) then stirred at reflux for 4hours. The reaction was cooled, and solvent evaporated. The residue was extracted with MeCI2 (100ml) washed with H2O (50ml), separated organic layer washed with brine (50ml) dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 10% v/v EtOAc/hexanes yielding desired product as a pale yellow solid (2.3g,88%)Partial 1H NMR (400MHz, CDCI3)? 9.0 (s,1H) 8.20(d,1H)6.50 (d,1 H) .
87% With potassium carbonate; In acetonitrile; for 4h;Heating / reflux; A suspension of 2-chloro-5-nitropyridine (7.90 g), piperazine-1-carboxylic acid tert-butyl ester (11.2 g) and potassium carbonate (6.90 g) in acetonitrile (250 mL) was heated under reflux for four hours. The reaction mixture was concentrated and diluted with ethyl acetate and washed with water and saturated brine and dried over sodium sulfate and filtered and concentrated. The residue was vigorously stirred in ethyl acetate/isopropyl ether, collected by filtration and dried under reduced pressure, and 16.1 g (87%) of the title compound was obtained as a yellow solid. MS(FAB) m/z:309 (M + H)+.
83% To a solution of tert-butyl piperazine-1-carboxylate (64 g, 346 mmol) in 600 ml. of THF at O0C was added NaH (16.4 g, 409 mmol, 60% in mineral oil) portionwise. The reaction mixture was stirred for 15 min and 2-chloro-5-nitropyridine (50 g, 314 mmol) was added. The reaction mixture was allowed to warm to rt and then heated to 5O0C for 4 h. The reaction was quenched by water (30 ml.) and extracted with DCM (1.5 Lx 3). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was subjected to wash with petroleum ether to give the desired product of Step A (80 g, yield 83%). 1H NMR (CDCI3, 400 MHz) delta 8.95 (d, J = 2.4 Hz, 1 H), 8.24 (d, J = 12 Hz, 1 H), 6.92 (d, J = 6.0 Hz, 1 H), 3.75 (s, 4 H), 3.44 (s, 4H), and 1.41 (s, 9 H).
58% With potassium carbonate; In butan-1-ol; at 120℃; for 17h; Place 2-chloro-5-nitro-pyridine (1.0 g, 6.31 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.76 g, 9.45 mmol), and triethylamine (1.76 mL, 12.6 mmol) in ra-butanol (20 mL). Heat to 120 C for 17 hours. Cool to room temperature and add ethyl acetate and water. Separate organic layer and wash with water and saturated aq. sodium chloride. Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 20% EtOAc:hexane to yield 1.14 g (58%) of 4-(5-nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester. MS(ES): m/z = 309 [M+H].
50% To a solution containing 5.8 g (31.5 mmol) of tert-butyl 1-piperazinecarboxylate and 20 mL of THF at 00C was added 1.5 g (37 mmol) of a 60% dispersion of NaH in mineral oil. The reaction mixture was allowed to stir for 20 min and 5.0 g (31.5 mmol) of 2-chloro-5-nitropyridine was added. The reaction mixture was heated at 500C <n="96"/>overnight, quenched by the addition of water, and extracted with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was subjected to silica gel chromatography to give 4.89 g (50%) of tert-butyl 4-(5-nitro-2-pyridinyl)-1-piperazinecarboxylate as a yellow solid: 1H NMR (400 MHz, DMSOd6) delta 8.25 (dd, J = 9.5 and 2.9 Hz, 1 H), 6.93 (d, J = 9.5 Hz, 1 H), 3.76 -3.78 (m, 4 H), 3.41 - 3.48 (m, 4 H), and 1.42 (s, 9 H).
50% To a solution containing 5 8 g (31 5 mmol) of fert-butyl 1-piotaperaziotanecarboxylate and 20 mL of THF at 0 C was added 1 5 g (37 mmol) of a 60% dispersion of NaH in mineral oil The reaction mixture was allowed to stir for 20 mm and 5 0 g (31 5 mmol) of 2-chloro-5-niotatropyriotadiotane was added The reaction mixture was heated at 50 C overnight, quenched by the addition of H2O, and extracted with DCM The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure The residue was subjected to silica gel chromatography to give 4 89 g (50%) of fert-butyl 4-(5-niotatro-2-pyriotadiotanyl)-1-piotaperaziotanecarboxylate as a yellow solid 1H-NMR (400 MHz, DMSO-d6) delta 8 25 (dd, J =9 5 and 2 9 Hz, 1 H), 6 93 (d, J =9 5 Hz, 1 H), 3 76 -3 78 (m, 4 H), 341 - 3 48 (m, 4 H), and 1 42 (s, 9 H)
With copper diacetate; potassium carbonate; In water; N,N-dimethyl-formamide; at 85℃; for 3h; Potassium carbonate (5 g) and Cu(OAc)2.2H2O (0.4 g) were added to a solution of piperazine-1-carboxylic acid tert-butyl ester (5 g) and 2-Chloro-5-nitropyridine (4.5 g) in DMF (75 ml) and the reaction mixture was stirred at 85 C for 3 h. On completion, the reaction mixture was allowed to cool to RT and the DMF was removed under reduced pressure. Water (200 ml) was added to the reaction mixture resulting in the formation of a solid that was filtered and dissolved in ethyl acetate (400 ml). The organic layer was washed with water (200 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to give 4-(5-Nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester.
With potassium hydrogencarbonate; In N,N-dimethyl-formamide; at 70℃; for 3h; Step 1 : fert-Butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate: To a stirred solution of 2-chloro-5-nitropyridine (20.00 g, 126.151 mmol) in DMF (200 ml) was added JV- BOC-piperazine (25.81 g, '138.766 mmol) and KHCO3 (18.94 g, 189.226 mmol) and the mixture was stirred at 70 C for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate (300 ml) and water (3 x 200 ml). The layers were separated. The aqueous layer was extracted with ethyl acetate (300 ml). The combined organic extracts were washed <n="28"/>with water (3 x 200 ml), brine (200 ml) and dried over anhydrous Na2SO4. The residue obtained after evaporation of the solvent was triturated with /-pentane to give 32.34 g of the product as a yellow solid; IR (KBr) 3430, 2975, 1691, 1512, 1292, 937 cm"1; 1H NMR (CDCl3, 300 MHz) delta 1.49 (s, 9H), 3.57 (br s, 4H), 3.77 (br s, 4H), 6.57 (d, J= 9.0 Hz, IH), 8.24 (d, J= 6.0 Hz, IH), 9.04 (s, IH); MS (ESI) m/z 413.22 (MH)+.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 16h; Intermediate 2Step A: t-butyl 4-(5-nitropyridin-2-yl)piperazine- -carboxylateTo 5-nitro-2-chloropyridine (10.0 g, 0.0631 mol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 mL) was added N,N-diisopropylethylamine (24.5 g, 31.3 mL, 0.189 mol). The reaction mixture was heated at 100 C for 16 h then cooled to RT and concentrated. Water (300 mL) was added, and the aqueous solution was extracted with 0??. The combined organic extract was dried (MgS04), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 5% EtOAc/C?Cl2) to yield t-butyl 4-(5-nitropyridin-2-yl)piperazine- 1 -carboxylate as a yellow solid. LC/MS = 309 [M+l ].
4.94 g In ethanol; at 70℃; for 16h; To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert-butyl piperazine-l-carboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70C for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgS04 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-l- carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 mlz 309.0 (M+H).
4.94 g In ethanol; at 70℃; for 16h; Step 1 To a solution of 2-chloro-5-nitropyridine (LVII) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert-butyl piperazine-1-carboxylate (LXXII) (7.05 g, 37.9 mmol). The reaction was headed at 70 C. for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgSO4 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (LXXIII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 m/z 309.0 (M+H).
4.94 g In ethanol; at 70℃; for 16h; To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added fert-butyl piperazine-l-carboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70C for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgS04 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 mlz 309.0 (M+H).

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  • 4
  • [ 193902-78-2 ]
  • [ 82205-58-1 ]
YieldReaction ConditionsOperation in experiment
100% 309. Step 2: /V-(5-nitropyridin-2-yl)piperazine (B-3)To compound B-2 (19.45 g, 0.0631 mol) dissolved in CH2CI2 (250 ml_) and cooled to 0 0C was added trifluoroacetic acid (50 ml_). The resulting reaction mixture was stirred at RT for 16 h then concentrated. The crude product was dissolved in CH2CI2 (250 ml_) and made basic with the addition of 1 N aqueous NaOH (200 ml_) and 3 N aqueous NaOH (100 ml_). The layers were separated, and the aqueous solution extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give the product N-(2-fluorophenyl)-4-(5-nitropyridin-2-yl)piperazine-1-carboxamide (B- 3) as a yellow solid (13.13 g, 100% yield). MS (M+1): 209
100% Step 2: N-(5-nitropyridin-2-yl)piperazine (B-3)To compound B-2 (19.45 g, 0.0631 mol) dissolved in CH2C12 (250 mL) and cooled to 0 C was added trifiuoroacetic acid (50 mL). The resulting reaction mixture was stirred at RT for 16 h then concentrated. The crude product was dissolved in CH2C12 (250 mL) and made basic with the addition of 1 N aqueous NaOH (200 mL) and 3 N aqueous NaOH (100 mL). The layers were separated, and the aqueous solution extracted with CH2CI2. The combined organic extract was dried (MgS04), filtered, and concentrated to give the product N-(2-fluorophenyl)- 4-(5-mtropyridin-2-yl)piperazine-l-carboxamide (B-3) as a yellow solid (13.13 g, 100% yield). MS (M+l): 209.
84% In a 250 mL round-bottom flask, a dichloromethane: TFA (10:1) (50 mL) solution of compound 3a (1100 mg, 3.57 mmol) was stirred under argon at rt for 2 h. The solvent was concentrated and re-evaporated with dichloromethane (2x 20 mL), then the reaction mixture was extracted with dichloromethane (50 mL) and washed with Na2CO3 (30 mL). The organic layer was dried over MgSO4, filtered and evaporated in vacuum to afford a yellow solid: 625 mg (84%) yield. 1H NMR CDCl3 delta = 9.02 (1H, d, J = 2.9 Hz), 8.17 (1H, dd, J1, J2 = 2.9 Hz), 6.54 (1H, d, J = 9.5 Hz), 3.73 (4H, t, J = 10.2 Hz), 2.97 (4H, t, J = 10.2 Hz) (as in many cases herein, NH exchanges and is not always obeserved). 13C NMR CDCl3 delta = 164.2, 146.5, 135.0, 133.0, 104.5, 46.0 (2C), 45.8 (2C). HRMS m/z calculated for C9H13N4O2 (MH+): 209.1033, Found: 209.1032.
71% With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 4h; Compound from Description 43 (0.78g) was dissolved in dry DCM (18ml), cooled in an ice bath to ~ O0C before adding TFA (2ml) slowly over 5 minutes. The resultant solution was then allowed to warm up to R.T. and was stirred for 4 hours, under argon. The reaction solution was poured slowly onto ice saturated potassium carbonate before extracting with DCM (3x 50ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered and solvent removed in vacuo to afford the title compound as a yellow solid in 71%.1H NMR ( 400MHz, CDCI3) delta 9.03 ( d, 1H), 8.20 (dd, 1 H), 6.55 (d, 1 H), 3.75 ( m, 4H), 2.98 (m, 4H)
71% With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 4.08333h; Compound from Description 43 (0.78g) was dissolved in dry DCM (18ml), cooled in an ice bath to ~ 00C before adding TFA (2ml) slowly over 5 minutes. The resultant solution was then allowed to warm up to RT. and was stirred for 4 hours, under argon. The reaction solution was poured slowly onto ice saturated potassium carbonate before extracting with DCM (3x 50ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered and solvent removed in vacuo to afford the title compound as a yellow solid in 71%.1 H NMR ( 400MHz, CDCI3) delta 9.03 ( d, 1 H), 8.20 (dd, 1 H), 6.55 (d, 1 H), 3.75 ( m, 4H), 2.98 (m, 4H)
With trifluoroacetic acid; In dichloromethane; at 0℃; for 1.08333h; Step 2: 4-(5-Nitropyridin-2-yl)piperazine: To a stirred solution of Step 1 intermediate (32 g, 103.896 mmol) in dichloromethane (200 ml) was added trifiuoroacetic acid (96 ml) at 0 C over 5 min. The reaction mixture was stirred for another 1 h at the same temperature. The residue obtained after evaporation of the solvent was dissolved in ethyl acetate (180 ml) and washed with saturated NaHCO3 (2 x 100 ml) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to afford 19.5 g of the desired salt as a yellow solid.
Step B: N-(5 -nitropyridin-2-yl)piperazineTo t-butyl 4-(5-nitropyridin-2-yl)piperazine-l -carboxylate (19.45 g, 0.0631 mol) dissolved in CH2CI2 (250 mL) and cooled to 0 C was added trifluoroacetic acid (50 mL). The resulting reaction mixture was stirred at RT for 16 h then concentrated. The crude product was dissolved in CH2CI2 (250 mL) and made basic with the addition of 1 N aqueous NaOH (200 mL) and 3 N aqueous NaOH (100 mL). The layers were separated, and the aqueous solution extracted with CH2CI2. The combined organic extract was dried (MgS04), filtered, and concentrated to yield N-(2-fluorophenyl)-4-(5-nitropyridin-2-yl)piperazine-l-carboxamide as a yellow solid. LC/MS - 209 [M+l].

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; ;