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CAS No. : | 34803-66-2 | MDL No. : | MFCD00006216 |
Formula : | C9H13N3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GZRKXKUVVPSREJ-UHFFFAOYSA-N |
M.W : | 163.22 | Pubchem ID : | 94459 |
Synonyms : |
Pyridylpiperazine
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.44 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 55.6 |
TPSA : | 28.16 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.77 cm/s |
Log Po/w (iLOGP) : | 1.73 |
Log Po/w (XLOGP3) : | 0.74 |
Log Po/w (WLOGP) : | -0.27 |
Log Po/w (MLOGP) : | 0.66 |
Log Po/w (SILICOS-IT) : | 1.18 |
Consensus Log Po/w : | 0.81 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.62 |
Solubility : | 3.9 mg/ml ; 0.0239 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.91 |
Solubility : | 20.1 mg/ml ; 0.123 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.51 |
Solubility : | 0.502 mg/ml ; 0.00308 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.86 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P233-P260-P261-P264-P270-P271-P280-P301+P312-P302+P352-P304-P304+P340-P305+P351+P338-P312-P321-P330-P332+P313-P337+P313-P340-P362-P403-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | at 150℃; for 0.333333 h; Microwave irradiation | Step l0.1 g (0.63 mmol) of 2-bromopyridine and 0.065 g (0.75 mmol) of piperazine was reacted at 150°C for 20 mins in a dried 5 mL microwave reactor provided with nitrogen gas. After cooling to room temperature, the reaction mixture was filtered using a cellite with in concurrence with washing with ethyl acetate, and distilled under a reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=4: l) to obtain l-(pyridin-2-yl)piperazine (yield: 54percent). |
36% | With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 18 h; Heating / reflux | To a 5ml round bottom flask equipped with magnetic stirrer, condenser, and argon inlet, 2-bromopyridine (320mg, 2.0 mmole), piperazine (520mg, 6.0 mmole), Pd2(dba)3 (46mg, 0.050mmole), BINAP (31mg, O.lOmmole), NaO-?- Bu (277mg, 2.8mmole) were added. The reaction mixture was purged with argon for 10 minutes. Toluene (2.0ml) was added. The reaction mixture was heated to reflux for 18hrs. The reaction was partitioned with EtOAc, and filtered through Celite. The solvent was then removed under vacuum. The desired product EPO <DP n="39"/>(74mg, 36percent yield) was isolated via column chromatography with CH2Cl2/MeOH saturated with NH3 (9/1) as eluent. 1H -NMR(400 MHz, CDCl3): δ 3.30-3.09 (m, 4H), 3.51-3.59 (m, 4H), 6.64-6.71 (m, 2H), 7.50-7.55 (m,lH), 8.22-8.27 (m, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 20 h; | 2-Chloropyridine (0.8 g, 7.2 mmol) was dissolved in N,N-dimethylformamide (10 mL).Then, potassium carbonate (1.0 g, 7.2 mmol) and anhydrous piperazine (1.2 g, 14.4 mmol) were added thereto.Heat to 120 ° C reaction.After 20 hours,Cool to room temperature,Pour the reaction solution into 10 mL of water.Extracted with ethyl acetate (20 mL x 3),The organic phases are combined and the organic phase is dried over anhydrous sodium sulfate.filter,The filtrate is concentrated,Purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20/1)The title compound was obtained as a yellow oil (0.38 g, 32.0percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: With trifluoroacetic acid In dichloromethane at 30℃; for 1 h; Stage #2: With sodium hydroxide In dichloromethane; water |
A solution of i-butyl 4-(pyridin-2-yl)piperazine-l-carboxylate (500 mg, 1.90 mmol, 1.00 equiv) in DCM/CF3COOH (10/3 mL) was placed in a 50-mL round bottom flask and stirred for 1 h at 30°C in an oil bath. The pH value of the solution was adjusted to 9 with aqueous sodium hydroxide (1M), then extracted with 3x10 mL of dichloromethane. The organic layers combined, dried over anhydrous sodium sulfate, and filtered to remove solids. The resulting solution was concentrated under vacuum, yielding 300 mg (97percent) of l-(pyridin-2-yl)piperazine as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In dimethyl sulfoxide | 2 1-(4-nitro-phenyl)-4-pyridin-2-yl-piperazine (26b) To a mixture of 4- fluoro nitro benzene 19b (425 mg, 3.01 MMOL) and K2CO3 (623 mg, 4.52 MMOL) in dimethyl sulfoxide (3 mL) was added 1-PYRIDIN-2-YL-PIPERAZINE (0.91 mL, 6.02 MMOL) and the reaction continued as described above to afford amine 770 mg of 26b in 90% YIELDS. 1H-NMR (500 MHz, CDC13) : No. 3.6 (4Hs, t, J = 5.12 Hz), 3.76 (4Hs, t, J = 5. 61 Hz), 6.65-6. 72 (2Hs, m), 6.86 (2Hs, d, J = 9. 52 HZ), 7.54 (1 H, dt, J = 1.95, 7.07 Hz), 8.16 (2Hs, d, J = 9.5 Hz), 8.22-8. 25 (1H, m); ESI-MASS : 285.5 (M+1). |
85% | ||
81% | With potassium carbonate In dimethyl sulfoxide at 90℃; for 1.5h; Inert atmosphere; | 1.a a) l-(4-Nitrophenyl)-4-(pyridin-2-yl)piperazine l-(Pyridin-2-yl)piperazine (4.90 g, 30 mmol) was dissolved at 22 °C in DMSO (10 ml) under an inert atmosphere. K2CO3 (6.22 g, 45 mmol) was added at 22 °C followed by 1- fluoro-4-nitrobenzene (4.66 g, 3.5 ml, 33 mmol). The reaction mixture was heated to 90 °C and stirred at this temperature for 90 min. The mixture was diluted with H20 (150 ml) and extracted with DCM (3 x 150 ml). The organic layers were washed with sat. aq. NaCl (1 x 150 ml), dried over MgS04 (35 g), filtered over a glass-frit and washed with DCM (2 x 100 ml). The filtrate was evaporated at 40 °C and finally dried in HV to mainly remove DMSO. The residue (9.18 g) was partially dissolved in DCM/MeOH 1:1 (60 ml), adsorbed on 32 g Isolute HM-N 9800, evaporated and then purified by flash chromatography (silica gel, 330 g; MeOH in DCM 0% to 5%). Pure fractions corresponding to the product were collected to give after evaporation at 40 °C the title compound (6.89 g, 81%) as an orange solid. LC-MS: m/z = 285.1 [M+H]+. |
76% | Reflux; | 39 EXAMPLE 39 The following reaction pathway was employed. PRM0208-63-1 a. 1 -(4-Nitrophenyl)-4-(pyridin-2-yl)piperazine was synthesized. A solution of 1 -(pyridin-2-yl)piperazine (900 mg, 6.8 mmol), 1 -fluoro-4-nitrobenzene (960 mg, 6.8 mmol), and potassium carbonate (1 .24 g, 6.8 mmol) in acetonitrile (30 mL) was stirred at reflux overnight. The solvent was removed in vacuo and the residue was triturated with 10% methanol in dichloromethane. The insolubles were filtered and the solvent evaporated to provide a yellow solid which was then triturated with hexanes. The product was collected by filtration (1 .2 g, 76%). 1 H NMR (500 MHz, Chloroform-d) d 8.27 - 8.22 (m, 1 H), 8.18 (d, J = 9.4 Hz, 2H), 7.55 (ddd, J = 8.8, 7.2, 2.1 Hz, 1 H), 6.91 - 6.84 (m, 2H), 6.74 - 6.67 (m, 2H), 3.81 - 3.75 (m, 4H), 3.62 (td, J = 5.1 , 2.4 Hz, 4H). LRMS (ESI+ve): Calculated for CisHi6N402, [M+H] = 285.14, observed [M+H] = 285.07 |
73% | In N,N-dimethyl-formamide at 20℃; | 1.1 General procedure for the synthesis of 1-(4-Nitro phenyl)-4-aryl/alkyl piperazine (1-18) General procedure: Synthesisof compounds (1-18) has been carriedout according to the procedure previously standardized in our laboratory with severalmodifications.1 Briefly, an equimolar mixture (0.01 mol) of 1-fluoro-4-nitrobenzeneand respective alkyl /heteroaryl/ aryl substituted piperazinein 30 ml of dried dimethylformamide (DMF)/ dried dimethylsulfoxide (DMSO) was stirredat room temperature for 4-8 h. Reaction completion was monitored by TLC andreaction mixture diluted with water (40 ml). Product has been extracted withchloroform and dried over anhydrous sodium sulphate. The chloroform was thenevaporated under reduced pressure to give pure 1-(4-nitro phenyl)-4-substituedpiperazine derivatives (1-18). |
With TEA In N,N-dimethyl-formamide | ||
16.i (i) (i) 1-(4-Nitrophenyl)-4-(2-pyridyl)piperazine Treatment of 1-(2-pyridyl)piperazine with 4-fluoronitrobenzene according to the method of Example (i) gave the title compound, m.p. 187°-188° C. | ||
With potassium carbonate In dimethyl sulfoxide | Scheme 2 1-(4-Nitro-phenyl)-4-pyridin-2-yl-piperazine (26b). To a mixture of 4-fluoro nitro benzene 19b (425 mg, 3.01 mmol) and K2CO3 (623 mg, 4.52 mmol) in dimethyl sulfoxide (3 mL) was added 1-pyridin-2-yl-piperazine (0.91 mL, 6.02 mmol) and the reaction continued as described above to afford amine 770 mg of 26b in 90% yields. 1H-NMR (500 MHz, CDCl3): δ 3.6 (4Hs, t, J=5.12 Hz), 3.76 (4Hs, t, J=5.61 Hz), 6.65-6.72 (2Hs, m), 6.86 (2Hs, d, J=9.52 Hz), 7.54 (1H, dt, J=1.95, 7.07 Hz), 8.16 (2Hs, d, J=9.5 Hz), 8.22-8.25 (1H, m); ESI-MASS: 285.5 (M+1). | |
With potassium carbonate In N,N-dimethyl-formamide at 110 - 120℃; | ||
With N-ethyl-N,N-diisopropylamine In acetonitrile for 6h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; | |
37% | With triethylamine In N,N-dimethyl-formamide; acetonitrile at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 24h; | 5-Fluoro-1H-indole-2-carboxylic acid (4.0 g) and EDCI (4.29 g) were combined in dichloromethane (90 mL) and treated with 1-(2-pyridinyl)piperazine (3.64 g). After stirring at 25 C. for 24 hours, the mixture was washed with 150 mL of water and filtered. The filter cake was washed in succession with 300 mL of water, 250 mL of dichloromethane and 20 mL of ethyl acetate to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) delta 3.61 (m, 4H), 3.85 (m, 4H), 6.67 (dd, 1H, J=7.5,4.8 Hz), 6.85 (m, 2H), 7.06 (m, 1H), 7.40 (m, 2H), 7.65 (m, 1H), 8.04 (dd, 1H, J=4.5,1.8 Hz), 11.72 (bs, 1H). MS (DCI/NH3) m/z 325 (M+H)+. | |
In dichloromethane; water; ethyl acetate; | EXAMPLE 17A 5-fluoro-2-[4-(2-pyridinyl)-1-piperazinyl]carbonyl}-1H-indole 5-Fluoro-1H-indole-2-carboxylic acid (4.0 g) and EDCI (4.29 g) were combined in dichloromethane (90 mL) and treated with 1-(2-pyridinyl)piperazine (3.64 g). After stirring at 25 C. for 24 hours, the mixture was washed with 150 mL of water and filtered. The filter cake was washed in succession with 300 mL of water, 250 mL of dichloromethane and 20 mL of ethyl acetate to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) delta3.61 (m, 4H), 3.85 (m, 4H), 6.67 (dd, 1H, J=7.5,4.8 Hz), 6.85 (m, 2H), 7.06 (m, 1H), 7.40 (m, 2H), 7.65 (m, 1H), 8.04 (dd, 1H, J=4.5,1.8 Hz), 11.72 (bs, 1H). MS (DCI/NH3) m/z 325 (M+H)+. | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 24h; | [5-FLUORO-LH-INDOLE-2-CARBOXYLIC] acid (4.0 g) and EDCI (4.29 g) were combined in dichloromethane (90 mL) and treated with [1- (2-PYRIDINYL)] piperazine (3.64 g). After stirring at [25 C] for 24 hours, the mixture was washed with 150 mL of water and filtered. The filter cake was washed in succession with 300 mL of water, 250 mL of dichloromethane and 20 [ML] of ethyl acetate to provide the title [COMPOUND. 1H] NMR (d6-DMSO, 300 MHz) 8 3.61 [(M,] 4H), 3.85 (m, 4H), 6.67 (dd, 1H, J=7.5, 4.8Hz), 6.85 [(M,] 2H), 7.06 [(M,] 1H), 7.40 [(M,] 2H), 7.65 [(M,] 1H), 8.04 (dd, [1H,] J=4.5, 1.8Hz), 11. [72] (bs, 1H). MS (DCI/NH3) m/z 325 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In dimethyl sulfoxide at 90℃; for 24h; | |
90% | With potassium carbonate; dimethyl sulfoxide | Scheme 2 1-(3-Nitro-phenyl)-4-pyridin-2-yl-piperazine (31 b). To a mixture of 3-fluoro nitro benzene 20b (425 mg, 3.01 mmol) and K2CO3 (623 mg, 4.52 mmol) in. dimethyl sulfoxide (3 mL) was added 1-pyridin-2-yl-piperazine (0.91 mL, 6.02 mmol) and the reaction continued as described above to afford amine 770 mg of 31b in 90% yields. 1H-NMR (300 MHz, CDCl3): δ 3.43 (4Hs, t, J=5.41 Hz), 3.76 (4Hs, t, J=5.38 Hz), 6.67-6.78 (2Hs, m), 7.24 (1H, ddd, J=0.7, 2.49, 8.33 Hz), 7.42 (1H, t, J=8.14 Hz), 7.55 (1H, ddd, J=1.99, 7.16, 8.64 Hz), 7.7 (1H, ddd, J=0.81, 2.09, 8.04 Hz), 7.78 (1H, t, J=2.29 Hz), 8.24 (1H, ddd, J=0.9, 1.95, 4.91 Hz); ESI-MASS: 285.2 (M+1). |
90% | With potassium carbonate In dimethyl sulfoxide | 2 1-(3-nitro-phenyl)-4-pyridin-2-yl-piperazine (31b) To a mixture of 3- fluoro nitro benzene 20b (425 mg, 3.01 MMOL) and K2CO3 (623 mg, 4.52 MMOL) in. dimethyl sulfoxide (3 mL) was added 1-PYRIDIN-2-YL-PIPERAZINE (0.91 mL, 6.02 MMOL) and the reaction continued as described above to afford amine 770 mg of 31 b in 90% YIELDS. 1 H-NMR (300 MHz, CDCI3) : A 3.43 (4Hs, t, J = 5.41 Hz), 3.76 (4Hs, t, J = 5.38 Hz), 6.67-6. 78 (2Hs, m), 7.24 (1 H, ddd, J = 0.7, 2.49, 8. 33 Hz), 7.42 (1H, t, J = 8. 14 HZ), 7.55 (1 H, ddd, J = 1. 99,7. 16,8. 64 HZ), 7.7 (1 H, ddd, J = 0. 81, 2.09, 8. 04 Hz), 7.78 (1H, t, J = 2.29 Hz), 8.24 (1H, ddd, J = 0.9, 1.95, 4.91 Hz); ESI-MASS : 285. 2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 20 9-{4-[4-Pyridin-2-yl-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide Prepared analogously to Example 2 b from 1-pyridin-2-yl-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide. Yield: 0.15 g (35.9% of theoretical). Melting point: 123 C. C29H31F3N4O (M=508.59). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 0 - 20℃; for 13h; | 1-Benzothiophene-3-carbaldehyde (6.17 mmole), 1-(2-pyridinyl)piperazine (6.17 mmole), and sodium triacetoxyborohydride (9.26 mmole) were combined in 25 mL of 1,2-dichloroethane and stirred at 0 C. for one hour. The mixture was allowed to warm to room temperature and stir for 12 hours. The mixture was poured into a diethyl ether:dichloromethane mixture and washed with a solution of saturated aqueous NaCl made basic with sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography with 96:4:0.5 dichloromethane/methanol/saturated aqueous ammonia to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) delta 2.62 (t, 4H, J=4.5 Hz), 3.51 (t, 4H, J=4.5 Hz), 3.82 (s, 2H), 6.65 (m, 1H), 6.80 (d, 1H, J=8.7 Hz), 7.40 (m, 2H), 7.48 (s, 1H), 7.53 (m, 1H), 7.86 (m, 1H), 8.04 (m, 2H); MS (DCI/NH3) m/z 310.0 (M+H)+. | |
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 0 - 20℃; for 13h; | [1-BENZOTHIOPHENE-3-CARBALDEHYDE] (6.17 mmole), 1-(2-pyridinyl) piperazine (6.17 mmole), and sodium triacetoxyborohydride (9.26 mmole) were combined in 25 mL of 1,2- dichloroethane and stirred at 0C for one hour. The mixture was allowed to warm to room temperature and stir for 12 hours. The mixture was poured into a diethyl ether : dichloromethane mixture and washed with a solution of saturated aqueous NaCl made basic with sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography with 96: 4: 0.5 dichloromethane/methanol/saturated aqueous ammonia to provide the title [COMPOUND. IH] NMR (d6-DMSO, 300 MHz) 8 2.62 (t, 4H, J=4. [5HZ),] 3.51 (t, 4H, [J=4.] [5HZ),] 3.82 (s, 2H), 6.65 (m, 1H), 6.80 (d, [1H,] J=8.7Hz), 7.40 [(M,] 2H), 7.48 (s, [1H),] 7.53 [(M,] 1H), 7.86 [(M,] 1H), 8. 04 [(M,] 2H); MS (DCI/NH3) m/z 310.0 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate In ethanol Heating / reflux; | 194 EXAMPLE 194; 3-chloro-N-[4-(2-pyridinyl)-1-piperazinyl]methyl}benzamide [1598] A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), 3-chlorobenzamide (78 mg, 0.5 mmol, Maybridge), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 26 mg (52%) pure compound; 1H NMR (500 MHz, DMSO-d6) δb2.58 (t, J=4 Hz, 4H), 3.50 (t, J=4 Hz, 4H), 4.19 (d, J=5 Hz, 1H), 6.62 (t, J=5 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.51 (m, 2H), 7.61 (m, 1H), 7.82 (d, J=6 Hz, 1H), 7.92 (s, 1H), 8.12 (d, J=5 Hz, 1H), 8.93 (t, J=5 Hz, 1H); MS (ESI/APCI-) m/e 329 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium carbonate In ethanol Heating / reflux; | 195 EXAMPLE 195; 4-fluoro-3-methyl-N-[4-(2-pyridinyl)-1-piperazinyl]methyl}benzamide [1600] A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), 4-fluoro-3-methylbenzamide (77 mg, 0.5 mmol, Oakwood), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 25 mg (51%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ2.25 (s, 3H), 2.58 (t, J=4 Hz, 4H), 3.52 (t, J=4 Hz, 4H), 4.18 (d, J=5 Hz, 1H), 6.61 (t, J=5 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.21 (t, J=6 Hz, 1H), 7.51 (t, J=5 Hz, 1H), 7.75 (t, J=5 Hz, 1H), 7.82 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.76 (t, J=5 Hz, 1H); MS (ESI/APCI-) m/e 327 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate; In ethanol;Heating / reflux; | [1566] A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), <strong>[1801-10-1]3-trifluoromethylbenzamide</strong> (95 mg, 0.5 mmol), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 30 mg (55%) pure compound. 1H NMR (500 MHz, DMSO-d6) delta2.60 (t, J=4 Hz, 4H), 3.52 (t, J=4 Hz, 4H), 4.22 (d, J=5 hz, 1H), 6.62 (t, J=5 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.51 (t, J=6 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.92 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.10 (m, 2H), 9.05 (t, J=5 Hz, 1H); MS (ESI/APCI-) m/e 363 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With sodium carbonate In DMF (N,N-dimethyl-formamide); water at 20℃; for 18h; | 187 EXAMPLE 187; N-benzyl-2-[4-(2-pyridinyl)-1-piperazinyl]acetamide [1584] A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-benzyl-2-chloroacetamide (37 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ2.58 (m, 4H), 3.05 (s, 2H), 3.52 (m, 4H), 4.35 (d, J=5 Hz, 2H), 6.63 (t, J=5 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 7.28 (m, 5H), 7.55 (t, J=6 Hz, 1H), 8.12 (t, J=5 Hz, 1H), 8.35 (s, 1H); MS (ESI/APCI+) m/e 311 (M+H)+. |
16 mg (32%) | With sodium carbonate In water; N,N-dimethyl-formamide | 187 N-benzyl-2-[4-(2-pyridinyl)-1-piperazinyl]acetamide EXAMPLE 187 N-benzyl-2-[4-(2-pyridinyl)-1-piperazinyl]acetamide A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-benzyl-2-chloroacetamide (37 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ2.58 (m, 4H), 3.05 (s, 2H), 3.52 (m, 4H), 4.35 (d, J=5 Hz, 2H), 6.63 (t, J=5 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 7.28 (m, 5H), 7.55 (t, J=6 Hz, 1H), 8.12 (t, J=5 Hz, 1H), 8.35 (s, 1H); MS (ESI/APCI+) m/e 311 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium carbonate; In DMF (N,N-dimethyl-formamide); water; at 20℃; for 18h; | [1574] A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-fluorophenyl)-2-chloroacetamide (38 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 45 mg (95%) of the desired product. 1H NMR (500 MHz, DMSO-d6) delta2.60 (m, 4H), 3.18 (s, 2H), 3.58 (m, 4H), 6.63 (m, 1H), 6.83 (d, J=5 Hz, 1H), 7.14 (dd, J=8.7, 8.7 Hz, 2H), 7.55 (m, 1H), 7.66 (m, 2H), 8.18 (d, J=5 Hz, 1H), 9.80 (s, 1H); MS (ESI/APCI+) m/e 315 (M+H)+. |
45 mg (95%) | With sodium carbonate; In water; N,N-dimethyl-formamide; | EXAMPLE 182 N-(4-fluorophenyl)-2-[4-(2-pyridinyl)-1-piperazinyl]acetamide A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-fluorophenyl)-2-chloroacetamide (38 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 45 mg (95%) of the desired product. 1H NMR (500 MHz, DMSO-d6) delta2.60 (m, 4H), 3.18 (s, 2H), 3.58 (m, 4H), 6.63 (m, 1H), 6.83 (d, J=5 Hz, 1H), 7.14 (dd, J=8.7, 8.7 Hz, 2H), 7.55 (m, 1H), 7.66 (m, 2H), 8.18 (d, J=5 Hz, 1H), 9.80 (s, 1H); MS (ESI/APCI+) m/e 315 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium carbonate In DMF (N,N-dimethyl-formamide); water at 20℃; for 18h; | 190 EXAMPLE 190; N-(4-chlorophenyl)-2-[4-(2-pyridinyl)-1-piperazinyl]acetamide [1590] A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-chlorophenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 42 mg (85%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δb2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.38 (d, J=6 Hz, 2H), 7.54 (t, J=6 Hz, 1H), 7.70 (d, J=6 Hz, 2H), 8.12 (d, J=5 Hz, 1H), 9.90 (s, 1H); MS (ESI/APCI+) m/e 331 (M+H)+. |
42 mg (85%) | With sodium carbonate In water; N,N-dimethyl-formamide | 190 N-(4-chlorophenyl)-2-[4-(2-pyridinyl)-1-piperazinyl]acetamide EXAMPLE 190 N-(4-chlorophenyl)-2-[4-(2-pyridinyl)-1-piperazinyl]acetamide A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(4-chlorophenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 42 mg (85%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ2.60 (t, J=4 Hz, 4H), 3.21 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.38 (d, J=6 Hz, 2H), 7.54 (t, J=6 Hz, 1H), 7.70 (d, J=6 Hz, 2H), 8.12 (d, J=5 Hz, 1H), 9.90 (s, 1H); MS (ESI/APCI+) m/e 331 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium carbonate; In DMF (N,N-dimethyl-formamide); water; at 20℃; for 18h; | [1578] A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2-methyl-phenyl)-2-chloroacetamide (37 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 29.3 mg (63%) of the desired product. 1H NMR (500 MHz, DMSO-d6) delta2.23 (s, 3H), 2.62 (t, J=4 Hz, 4H), 3.20 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.05 (t, J=6 Hz, 1H), 7.10 (m, 2H), 7.58 (t, J=5 Hz, 1H), 7.78 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 9.40 (s, 1H); MS (ESI/APCI+) m/e 311 (M+H)+ |
29.3 mg (63%) | With sodium carbonate; In water; N,N-dimethyl-formamide; | EXAMPLE 184 N-(2-methylphenyl)-2-[4-(2-pyridinyl)-1-piperazinyl]acetamide A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2-methyl-phenyl)-2-chloroacetamide (37 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 29.3 mg (63%) of the desired product. 1H NMR (500 MHz, DMSO-d6) delta2.23 (s, 3H), 2.62 (t, J=4 Hz, 4H), 3.20 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.05 (t, J=6 Hz, 1H), 7.10 (m, 2H), 7.58 (t, J=5 Hz, 1H), 7.78 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 9.40 (s, 1H); MS (ESI/APCI+) m/e 311 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate; In DMF (N,N-dimethyl-formamide); water; at 20℃; for 18h; | [1588] A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2-trifluoromethylphenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 41 mg (75%) of the desired product. 1H NMR (500 MHz, DMSO-d6) delta2.65 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.65 (t, J=5 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.73 (m, 2H), 8.15 (d, J=5 Hz, 1H), 8.22 (d, J=6 Hz, 1H), 9.95 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+. |
41 mg (75%) | With sodium carbonate; In water; N,N-dimethyl-formamide; | EXAMPLE 189 2-[4-(2-pyridinyl)-1-piperazinyl]-N-[2-(trifluoromethyl)phenyl]acetamide A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2-trifluoromethylphenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 41 mg (75%) of the desired product. 1H NMR (500 MHz, DMSO-d6) delta2.65 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.65 (t, J=5 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.73 (m, 2H), 8.15 (d, J=5 Hz, 1H), 8.22 (d, J=6 Hz, 1H), 9.95 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 24.3333h; | A solution [CONTAINING-50%] of propylphosphonic anhydride in [N, N-DIMETHYLFORMAMIDE (FLUKA,] Buchs, Switzerland ; [674muL, No. 1 MMOL) ] is added within 20 minutes to a stirred mixture of 4- [METHYL-3- [ [4- (3-PYRIDINYL)-2-PYRIMIDINYL]] amino] -benzoic acid (214.4 mg, 0.7 [MMOL),] [1- (2-] pyridyl) piperazine (Aldrich, Buchs, Switzerland; 114.3 mg, 0.7 [MMOL)] and triethylamine [(7761LL,] 5.6 [MMOL)] in 2 mL [N, N-DIMETHYLFORMAMIDE.] After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is purified by column chromatography on silica gel, eluent 5-10% methanol in dichloromethane, to give the title compound as a solid.'H-NMR (400 MHz, [DMSO-D6,] [6)] : 2.31 (s, 3H); 3.35-3. 74 (m, 8H); 6.65 (ddd, [1 H)] ; 6.79 (d, [1 H)] ; 7.13 (dd, [1 H)] ; 7.32 (d, [1 H)] ; 7.44 [(D,] [1 H)] ; 7.49-7. 56 (m, 2H); 7.69 (m, [1 H)] ; 8.11 (m, [1 H)] ; 8.40 (m, [1 H)] ; 8.52 (d, [1 H)] ; 8.66 (dd, [1 H)] ; 9.06 (s, [1 H)] ; 9.24 (m, [1 H).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); biphenyl-4-yl(di-tert-butylphosphine); In ethyleneglycol dimethyl ether; for 4h;Heating / reflux; | A mixture of <strong>[477312-85-9](S)-[1-(3-bromophenyl)ethyl]carbamic acid tert-butyl ester</strong> (5.0 g, 16.7 mmol), 1-pyridin-2-ylpiperazine (10.9 g, 67 mmol), Pd2(dba)3 (1.55 g, 10 mol %), di-t-butyl-biphenylphosphine (0.51 g, 10 mol %), potassium phosphate (7.2 g, 34 mmol) in ethyleneglycol dimethyl ether (40 mL) was refluxed for 4 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (100 mL) and the precipitate was filtered off. The filtrate was concentrated under vacuum. The crude product was purified by flash chromatography over silica with ethyl acetate/hexanes (1:2) to provide the title compound as an oil (4.1 g, 64% yield). MS (M+H)+ 383. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; at 20.0℃; for 40.0h;Combinatorial reaction / High throughput screening (HTS); | Second Step: N-Alkylation Reaction [0434] 1.2 ml of a corresponding piperazine solution (1.2 mmol, 10 eq) previously prepared is distributed into each reactor. The piperazines used and the amounts added to the reaction are listed below: [TABLE-US-00008] Structure MW Quantity (g) [CHEMMOL-00071] 162.24 0.417 [CHEMMOL-00072] 192.26 0.494 [CHEMMOL-00073] 192.26 0.494 [CHEMMOL-00074] 192.26 0.494 [CHEMMOL-00075] 196.68 0.506 [CHEMMOL-00076] 196.68 0.506 [CHEMMOL-00077] 196.68 0.506 [CHEMMOL-00078] 176.26 0.453 [CHEMMOL-00079] 176.26 0.453 [CHEMMOL-00080] 176.26 0.453 [CHEMMOL-00081] 180.23 0.463 [CHEMMOL-00082] 180.23 0.463 [CHEMMOL-00083] 230.23 0.592 [CHEMMOL-00084] 163.22 0.420 [CHEMMOL-00085] 163.22 0.420 [CHEMMOL-00086] 176.26 0.453 [CHEMMOL-00087] 164.21 0.422 [CHEMMOL-00088] 164.21 0.422 [CHEMMOL-00089] 164.21 0.422 [CHEMMOL-00090] 198.66 0.511 [CHEMMOL-00091] 198.66 0.511 [CHEMMOL-00092] 190.29 0.489 [0435] Next, 75 mul (3.5 eq) of DIEA is added to each well and shaken at room temperature for 40 hours. The resins are filtered and rinsed three times each with three successive solvents: DMF, MeOH, CH2Cl2 (4 ml/reactor per rinse). The resin is allowed to dry in air. [0436] Cleavage [0437] Cleavage is carried out in 2 ml of TFA per reactor at room temperature for 2 hours. The resins are filtered and rinsed with 2×2 ml of CH2Cl2, then the filtrates are concentrated. Each filtrate is taken up in 1 ml of MeOH, the pH is adjusted to 9 with an aqueous 1 M NaOH solution. The mixtures are then purified on cation exchange resins according to the protocol described hereinabove. The 44 filtrates collected into previously tared tubes are vacuum concentrated (Genevac) and analyzed by HPLC/MS before being weighed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; at 20.0℃; for 40.0h;Combinatorial reaction / High throughput screening (HTS); | Second Step: N-Alkylation Reaction [0434] 1.2 ml of a corresponding piperazine solution (1.2 mmol, 10 eq) previously prepared is distributed into each reactor. The piperazines used and the amounts added to the reaction are listed below: [TABLE-US-00008] Structure MW Quantity (g) [CHEMMOL-00071] 162.24 0.417 [CHEMMOL-00072] 192.26 0.494 [CHEMMOL-00073] 192.26 0.494 [CHEMMOL-00074] 192.26 0.494 [CHEMMOL-00075] 196.68 0.506 [CHEMMOL-00076] 196.68 0.506 [CHEMMOL-00077] 196.68 0.506 [CHEMMOL-00078] 176.26 0.453 [CHEMMOL-00079] 176.26 0.453 [CHEMMOL-00080] 176.26 0.453 [CHEMMOL-00081] 180.23 0.463 [CHEMMOL-00082] 180.23 0.463 [CHEMMOL-00083] 230.23 0.592 [CHEMMOL-00084] 163.22 0.420 [CHEMMOL-00085] 163.22 0.420 [CHEMMOL-00086] 176.26 0.453 [CHEMMOL-00087] 164.21 0.422 [CHEMMOL-00088] 164.21 0.422 [CHEMMOL-00089] 164.21 0.422 [CHEMMOL-00090] 198.66 0.511 [CHEMMOL-00091] 198.66 0.511 [CHEMMOL-00092] 190.29 0.489 [0435] Next, 75 mul (3.5 eq) of DIEA is added to each well and shaken at room temperature for 40 hours. The resins are filtered and rinsed three times each with three successive solvents: DMF, MeOH, CH2Cl2 (4 ml/reactor per rinse). The resin is allowed to dry in air. [0436] Cleavage [0437] Cleavage is carried out in 2 ml of TFA per reactor at room temperature for 2 hours. The resins are filtered and rinsed with 2×2 ml of CH2Cl2, then the filtrates are concentrated. Each filtrate is taken up in 1 ml of MeOH, the pH is adjusted to 9 with an aqueous 1 M NaOH solution. The mixtures are then purified on cation exchange resins according to the protocol described hereinabove. The 44 filtrates collected into previously tared tubes are vacuum concentrated (Genevac) and analyzed by HPLC/MS before being weighed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20.0℃; for 40.0h;Combinatorial reaction / High throughput screening (HTS); | Second Step: N-alkylation Reaction [0155] 1.5 ml of a corresponding piperazine solution (1.6 mmol, 10 eq) previously prepared by dissolving the quantity to be weighed in 3.3 ml of CH2Cl2 is distributed into each reactor. A slight excess of each solution is prepared. The piperazines used and the amounts added in the reaction are listed below: [TABLE-US-00007] Structure MW Quantity (g) [CHEMMOL-00012] 162.24 0.578 [CHEMMOL-00013] 192.26 0.685 [CHEMMOL-00014] 192.26 0.685 [CHEMMOL-00015] 192.26 0.685 [CHEMMOL-00016] 196.68 0.700 [CHEMMOL-00017] 196.68 0.700 [CHEMMOL-00018] 196.68 0.700 [CHEMMOL-00019] 176.26 0.628 [CHEMMOL-00020] 176.26 0.628 [CHEMMOL-00021] 176.26 0.628 [CHEMMOL-00022] 180.23 0.642 [CHEMMOL-00023] 180.23 0.642 [CHEMMOL-00024] 230.23 0.820 [CHEMMOL-00025] 163.22 0.581 [CHEMMOL-00026] 163.22 0.581 [CHEMMOL-00027] 176.26 0.628 [CHEMMOL-00028] 164.21 0.585 [CHEMMOL-00029] 164.21 0.585 [CHEMMOL-00030] 164.21 0.585 [CHEMMOL-00031] 164.21 0.585 [CHEMMOL-00032] 198.66 0.708 [CHEMMOL-00033] 198.66 0.708 [CHEMMOL-00034] 190.29 0.678 [CHEMMOL-00035] 178.24 0.635 [0156] Next, 125 mul (4.5 eq) of DIEA to each reactor and shake the mixture at room temperature for 40 hours is added. The resins are filtered and rinsed three times each with three successive solvents: DMF, MeOH, CH2Cl2 (4 ml/reactor per rinse). The resin is allowed to dry in air. [0157] Cleavage [0158] Cleavage is carried out in 2 ml of TFA per reactor at room temperature for 2 hours. The resins are filtered and rinsed with 2×2 ml of CH2Cl2, and the filtrates are concentrated under vacuum. [0159] Extraction in Alkaline Medium [0160] The 48 mixtures are individually taken up in 8 ml of a 1:1 mixture of CH2Cl2/H2O in Whatman 12 ml cartridges equipped with a PTFE filter. The organic phase (=Organic phase A) is filtered, the aqueous phase is washed with 4 ml of CH2Cl2. The pH of the aqueous phase is adjusted to alkaline pH range by adding a saturated aqueous Na2CO3 solution. Then the aqueous phase is extracted with CH2Cl2 (1×4 ml then 1×2 ml). The 48 filtrates (=48 organic phase B) are vacuum concentrated. [0161] Purification on Cation Exchange Resin [0162] The cation exchange resin is a BCX resin packaged by Bodhan (Mettler-Toledo) in the form of 1 g SPE cartridges. The resin is first washed with 2×3 ml of MeOH (conditioning). The crude mixture, dissolved in 1 ml of MeOH and adjusted to pH 9 with a 1 M aqueous NaOH solution, is then deposited on the small resin column (loading). The column is then washed with 2×3 ml of MeOH (wash). The piperazine derivative is then released by elution with 3 ml of a 2 M solution of NH4OH/MeOH (elution). The filtrate is concentrated under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20.0℃; for 40.0h;Combinatorial reaction / High throughput screening (HTS); | Second Step: N-alkylation Reaction [0155] 1.5 ml of a corresponding piperazine solution (1.6 mmol, 10 eq) previously prepared by dissolving the quantity to be weighed in 3.3 ml of CH2Cl2 is distributed into each reactor. A slight excess of each solution is prepared. The piperazines used and the amounts added in the reaction are listed below: [TABLE-US-00007] Structure MW Quantity (g) [CHEMMOL-00012] 162.24 0.578 [CHEMMOL-00013] 192.26 0.685 [CHEMMOL-00014] 192.26 0.685 [CHEMMOL-00015] 192.26 0.685 [CHEMMOL-00016] 196.68 0.700 [CHEMMOL-00017] 196.68 0.700 [CHEMMOL-00018] 196.68 0.700 [CHEMMOL-00019] 176.26 0.628 [CHEMMOL-00020] 176.26 0.628 [CHEMMOL-00021] 176.26 0.628 [CHEMMOL-00022] 180.23 0.642 [CHEMMOL-00023] 180.23 0.642 [CHEMMOL-00024] 230.23 0.820 [CHEMMOL-00025] 163.22 0.581 [CHEMMOL-00026] 163.22 0.581 [CHEMMOL-00027] 176.26 0.628 [CHEMMOL-00028] 164.21 0.585 [CHEMMOL-00029] 164.21 0.585 [CHEMMOL-00030] 164.21 0.585 [CHEMMOL-00031] 164.21 0.585 [CHEMMOL-00032] 198.66 0.708 [CHEMMOL-00033] 198.66 0.708 [CHEMMOL-00034] 190.29 0.678 [CHEMMOL-00035] 178.24 0.635 [0156] Next, 125 mul (4.5 eq) of DIEA to each reactor and shake the mixture at room temperature for 40 hours is added. The resins are filtered and rinsed three times each with three successive solvents: DMF, MeOH, CH2Cl2 (4 ml/reactor per rinse). The resin is allowed to dry in air. [0157] Cleavage [0158] Cleavage is carried out in 2 ml of TFA per reactor at room temperature for 2 hours. The resins are filtered and rinsed with 2×2 ml of CH2Cl2, and the filtrates are concentrated under vacuum. [0159] Extraction in Alkaline Medium [0160] The 48 mixtures are individually taken up in 8 ml of a 1:1 mixture of CH2Cl2/H2O in Whatman 12 ml cartridges equipped with a PTFE filter. The organic phase (=Organic phase A) is filtered, the aqueous phase is washed with 4 ml of CH2Cl2. The pH of the aqueous phase is adjusted to alkaline pH range by adding a saturated aqueous Na2CO3 solution. Then the aqueous phase is extracted with CH2Cl2 (1×4 ml then 1×2 ml). The 48 filtrates (=48 organic phase B) are vacuum concentrated. [0161] Purification on Cation Exchange Resin [0162] The cation exchange resin is a BCX resin packaged by Bodhan (Mettler-Toledo) in the form of 1 g SPE cartridges. The resin is first washed with 2×3 ml of MeOH (conditioning). The crude mixture, dissolved in 1 ml of MeOH and adjusted to pH 9 with a 1 M aqueous NaOH solution, is then deposited on the small resin column (loading). The column is then washed with 2×3 ml of MeOH (wash). The piperazine derivative is then released by elution with 3 ml of a 2 M solution of NH4OH/MeOH (elution). The filtrate is concentrated under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; In 1,4-dioxane; water; at 90℃; for 24h; | To a rubber-septum-capped vial containing 4, 6-dichloro-2-morpholinopyrimidine (0. 2 M in dioxane, 0. 25 mL) and L-PYRIDIN-2-YL-PIPERAZINE (0. 2 M in dioxane, 0. 28 mL) add aqueous K3P04 (0. 5 M, 0. 125 mL). Heat the mixture at 90C for 24 hours. Cool the mixture and concentrate under reduced pressure. Partition between ethyl acetate and water, dry (NA2S04) the organic layer and concentrate under reduced pressure. Filter the crude product through a pad of silica gel (1 : 1 ethyl acetate/hexanes) and remove the solvent under reduced pressure to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In toluene; at 80℃; for 6h; | EXAMPLE 49B 1-phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)acetone The product from Example 49A (2.60 g, 15.4 mmol) and diisopropylethylamine (6 mL) were combined in toluene (100 mL), treated with 1-(2-pyridinyl)piperazine (2.80 mL, 18.3 mmol), and heated at 80 C. After 6 hours, the mixture was cooled, washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; elution with 4:1 hexanes:ethyl acetate then 1:1 hexanes:ethyl acetate) to provide the title. 1H NMR (300 MHz, CDCl3) delta 2.56 (t, J=5.4 Hz, 4H), 3.26 (s, 2H), 3.58 (t, J=5.1 Hz, 4H), 3.77 (s, 2H), 6.62 (m, 2H), 7.28 (m, 5H), 7.47 (m, 1H), 8.18 (m, 1H); MS (DCI/NH3) m/z 296 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 20h;Combinatorial reaction / High throughput screening (HTS); | Each resin from Step 3 was distributed into 24 fritted syringes (Torvig, 50 mg each, 50 mumol), for a total of 96 syringes, and was swelled in NMP (1 mL) for 30 min. The solvent was removed by filtration. Twenty-four solutions of the building blocks listed below (10 mmol each) and DIBA (3.5 mL, 20 mmol) in NMP (10 mL) were prepared. 3 mL of the 24 solutions was added to the 24 syringes for each resin from Step 3, accordingly. The suspensions were then shaken for 20 h on a Titer Plate Shaker. The reaction mixture was filtered and washed 5 times with methylene chloride (5 mL), 3 times with THF (5 mL), 3 times THF/H2O (3/1 v/v, 5 mL), and 3 times with THF (5 mL). The resins were then dried overnight under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 20h;Combinatorial reaction / High throughput screening (HTS); | Each resin from Step 3 was distributed into 24 fritted syringes (Torvig, 50 mg each, 50 mumol), for a total of 96 syringes, and was swelled in NMP (1 mL) for 30 min. The solvent was removed by filtration. Twenty-four solutions of the building blocks listed below (10 mmol each) and DIBA (3.5 mL, 20 mmol) in NMP (10 mL) were prepared. 3 mL of the 24 solutions was added to the 24 syringes for each resin from Step 3, accordingly. The suspensions were then shaken for 20 h on a Titer Plate Shaker. The reaction mixture was filtered and washed 5 times with methylene chloride (5 mL), 3 times with THF (5 mL), 3 times THF/H2O (3/1 v/v, 5 mL), and 3 times with THF (5 mL). The resins were then dried overnight under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 20h;Combinatorial reaction / High throughput screening (HTS); | Each resin from Step 3 was distributed into 24 fritted syringes (Torvig, 50 mg each, 50 mumol), for a total of 96 syringes, and was swelled in NMP (1 mL) for 30 min. The solvent was removed by filtration. Twenty-four solutions of the building blocks listed below (10 mmol each) and DIBA (3.5 mL, 20 mmol) in NMP (10 mL) were prepared. 3 mL of the 24 solutions was added to the 24 syringes for each resin from Step 3, accordingly. The suspensions were then shaken for 20 h on a Titer Plate Shaker. The reaction mixture was filtered and washed 5 times with methylene chloride (5 mL), 3 times with THF (5 mL), 3 times THF/H2O (3/1 v/v, 5 mL), and 3 times with THF (5 mL). The resins were then dried overnight under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 20h;Combinatorial reaction / High throughput screening (HTS); | Each resin from Step 3 was distributed into 24 fritted syringes (Torvig, 50 mg each, 50 mumol), for a total of 96 syringes, and was swelled in NMP (1 mL) for 30 min. The solvent was removed by filtration. Twenty-four solutions of the building blocks listed below (10 mmol each) and DIBA (3.5 mL, 20 mmol) in NMP (10 mL) were prepared. 3 mL of the 24 solutions was added to the 24 syringes for each resin from Step 3, accordingly. The suspensions were then shaken for 20 h on a Titer Plate Shaker. The reaction mixture was filtered and washed 5 times with methylene chloride (5 mL), 3 times with THF (5 mL), 3 times THF/H2O (3/1 v/v, 5 mL), and 3 times with THF (5 mL). The resins were then dried overnight under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In 2-chloromethyl-1H-benzimidazole; water; N,N-dimethyl-formamide | 1.A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole EXAMPLE 1A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole To a rapidly stirred solution of 1-(2-pyridyl)piperazine (5.9 g, 36 mmol) in DMF (15 mL) in a large round bottom flask in a water bath at 20° C. was added 2-chloromethylbenzimidazole powder (6 g, 36 mmol) over 2 minutes. Triethylamine (7.5 mL, 1.5 eq) was added, and the reaction was stirred for 16 hours, until TLC indicated complete consumption of starting material. The reaction was then treated with 5 mL of triethylamine followed by the slow dropwise addition of water (70 mL). After one hour, the precipitate was collected by suction filtration and washed with 400 mL of water and dried to give 9 grams of product. The solid was recrystallized twice from boiling n butanol to give 7.6 grams (72% yield purified) of the title compound as a huff powder. mp 220-221° C. 1H NMR (d6-DMSO, 300 MHz)δ2.55 (4H, J=4.5 Hz), 3.52 (4H, J=4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J=6.6, 4.5 Hz), 6.81 (1H, J=8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J=4.5, 1.8 Hz). MS (DCI/NH3) m/z 294 [M+H]+. Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6.58; N, 23.87. |
72% | With triethylamine In 2-chloromethyl-1H-benzimidazole; water; N,N-dimethyl-formamide | 1.A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole Example 1A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole To a rapidly stirred solution of 1-(2-pyridyl)piperazine (5.9 g, 36 mmol) in DMF (15 mL) in a large round bottom flask in a water bath at 20° C. was added 2-chloromethylbenzimidazole powder (6 g, 36 mmol) over 2 minutes. Triethylamine (7.5 mL, 1.5 eq) was added, and the reaction was stirred for 16 hours, until TLC indicated complete consumption of starting material. The reaction was then treated with 5 mL of triethylamine followed by the slow dropwise addition of water (70 mL). After one hour, the precipitate was collected by suction filtration and washed with 400 mL of water and dried to give 9 grams of product. The solid was recrystallized twice from boiling n-butanol to give 7.6 grams (72% yield purified) of the title compound as a buff powder. mp 220-221° C. 1H NMR (d6-DMSO, 300 MHz) δ2.55 (4H, J=4.5 Hz), 3.52 (4H, J=4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J=6.6, 4.5 Hz), 6.81 (1H, J=8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J=4.5, 1.8 Hz). MS (DCI/NH3) m/z 294 (M+H)+. Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6.58; N, 23.87. |
72% | With triethylamine In 2-chloromethyl-1H-benzimidazole; water; N,N-dimethyl-formamide | 1.A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole Example 1A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole To a rapidly stirred solution of 1-(2-pyridyl)piperazine (5.9 g, 36 mmol) in DMF (15 mL) in a large round bottom flask in a water bath at 20° C. was added 2-chloromethylbenzimidazole powder (6 g, 36 mmol) over 2 minutes. Triethylamine (7.5 mL, 1.5 eq) was added, and the reaction was stirred for 16 hours, until TLC indicated complete consumption of starting material. The reaction was then treated with 5 mL of triethylamine followed by the slow dropwise addition of water (70 mL). After one hour, the precipitate was collected by suction filtration and washed with 400 mL of water and dried to give 9 grams of product. The solid was recrystallized twice from boiling n-butanol to give 7.6 grams (72% yield purified) of the title compound as a buff powder. mp 220-221° C. 1H NMR (d6-DMSO, 300 MHz) δ 2.55 (4H, J=4.5 Hz), 3.52 (4H, J=4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J=6.6, 4.5 Hz), 6.81 (1H, J=8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J=4.5, 1.8 Hz) MS (DCI/NH3) m/z 294 (M+H)+. Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6.58; N, 23.87. |
72% | With triethylamine In 2-chloromethyl-1H-benzimidazole; water; N,N-dimethyl-formamide | 1.A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole EXAMPLE 1A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole To a rapidly stirred solution of 1-(2-pyridyl)piperazine (5.9 g, 36 mmol) in DMF (15 mL) in a large round bottom flask in a water bath at 20° C. was added 2-chloromethylbenzimidazole powder (6 g, 36 mmol) over 2 minutes. Triethylamine (7.5 mL, 1.5 eq) was added, and the reaction was stirred for 16 hours, until TLC indicated complete consumption of starting material. The reaction was then treated with 5 mL of triethylamine followed by the slow dropwise addition of water (70 mL). After one hour, the precipitate was collected by suction filtration and washed with 400 mL of water and dried to give 9 grams of product. The solid was recrystallized twice from boiling n-butanol to give 7.6 grams (72% yield purified) of the title compound as a buff powder. mp 220-221° C. 1H NMR (d6-DMSO, 300 MHz) δ2.55 (4H, J=4.5 Hz), 3.52 (4H, J=4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J=6.6, 4.5 Hz), 6.81 (1H, J=8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J=4.5, 1.8 Hz), MS (DCI/NH3) m/z 294 (M+H)+. Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6.58; N, 23.87. |
72% | With triethylamine In 2-chloromethyl-1H-benzimidazole; water; N,N-dimethyl-formamide | 1.A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole EXAMPLE 1A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole To a rapidly stirred solution of 1-(2-pyridyl)piperazine (5.9 g, 36 mmol) in DMF (15 mL) in a large round bottom flask in a water bath at 20° C. was added 2-chloromethylbenzimidazole powder (6 g, 36 mmol) over 2 minutes. Triethylamine (7.5 mL, 1.5 eq) was added, and the reaction was stirred for 16 hours, until TLC indicated complete consumption of starting material. The reaction was then treated with 5 mL of triethylamine followed by the slow dropwise addition of water (70 mL). After one hour, the precipitate was collected by suction filtration and washed with 400 mL of water and dried to give 9 grams of product. The solid was recrystallized twice from boiling n-butanol to give 7.6 grams (72% yield purified) of the title compound as a buff powder. mp 220-221° C. 1H NMR (d6-DMSO, 300 MHz) δ 2.55 (4H, J=4.5 Hz), 3.52 (4H, J=4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J=6.6, 4.5 Hz), 6.81 (1H, J=8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J=4.5, 1.8 Hz). MS (DCI/NH3) m/z 294 (M+H)+. Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6.58; N, 23.87. |
72% | With triethylamine In 2-chloromethyl-1H-benzimidazole; water; N,N-dimethyl-formamide | 1.A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole Example 1A 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole To a rapidly stirred solution of 1-(2-pyridyl)piperazine (5.9 g, 36 mmol) in DMF (15 mL) in a large round bottom flask in a water bath at 20° C. was added 2-chloromethylbenzimidazole powder (6 g, 36 mmol) over 2 minutes. Triethylamine (7.5 mL, 1.5 eq) was added, and the reaction was stirred for 16 hours, until TLC indicated complete consumption of starting material. The reaction was then treated with 5 mL of triethylamine followed by the slow dropwise addition of water (70 mL). After one hour, the precipitate was collected by suction filtration and washed with 400 mL of water and dried to give 9 grams of product. The solid was recrystallized twice from boiling n-butanol to give 7.6 grams (72% yield purified) of the title compound as a buff powder. mp 220-221° C. 1H NMR (d6-DMSO, 300 MHz) δ 2.55 (4H, J=4.5 Hz), 3.52 (4H, J=4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J=6.6, 4.5 Hz), 6.81 (1H, J=8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J=4.5, 1.8 Hz). MS (DCI/NH3) m/z 294 (M+H)+. Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6.58; N, 23.87. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(General Procedure 16)4-Pyridin-2-yl-piperazine-1-carboxylic Acid pyrazol-1-yl Ester The title compound was prepared from <strong>[81945-73-5]1-<strong>[81945-73-5]hydroxypyrazole</strong></strong> and 1-(2-pyridyl)piperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (59%, crystals). 1H NMR (300 MHz; CDCl3): delta 3.62-3.85 (m, 8H), 6.32 (t, 1H), 6.66-6.72 (m, 2H), 7.39 (dd, 1H), 7.42 (dd, 1H), 7.53 (dt, 1H), 8.21 (d, 1H); HPLC-MS: m/z=274.1 (M+1); Rt=0.63 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.7% | With triethylamine In methanol; dichloromethane; N,N-dimethyl-formamide | 9 Preparation of N-{3-[1-[4-(2-pyridyl)piperazinyl]-methyl]-[1,2,4]thiadiazol-5-yl}-L-leucyl-L-proline methyl ester. EXAMPLE 9 Preparation of N-{3-[1-[4-(2-pyridyl)piperazinyl]-methyl]-[1,2,4]thiadiazol-5-yl}-L-leucyl-L-proline methyl ester. A mixture of N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester (0.45 g, 1.2 mmol), 1-(2-pyridyl)piperazine (0.62 mL, 4 mmol), triethylamine (1.2 mL, 8 mmol) and tetra-butylammonium bromide (100 mg) in DMF (20 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was collected, washed with water, dried (sodium sulfate), filtered and concentrated in vacuo to give a light yellow oil. Purification by column chromatography on silica gel using a solvent mixture of 5% methanol in dichloromethane afforded N-{3-[1-[4-(2-pyridyl)piperazinyl]-methyl]-[1,2,4]thiadiazol-5-yl}-L-leucyl-L-proline methyl ester as a white foam (0.55g, 91.7 %). 1H-NMR (CDCl3) δ 8.19 (m, 1H), 7.48-7.52 (m, 1H), 7.14 (br. m, 1H, NH), 6.64-6.67 (m, 2H), 4.67 (m, 1H, CHCO), 4.57 (dd, J=8.4 and 4.6 Hz, 1H, CHCO2), 3.92 (m, 1H, NCHpro), 3.62-3.78 (m, 10OH, OMe, NCHpro, N=CCH2, 2NCH2), 2.83 (m, 4H, 2NCH2), 1.62-2.30 (m, 6H, 2CH2pro and CH2), 0.90-1.03 (2d, J=6.5 and 6.6 Hz, 7H, 2Me and 1CH); MS (m/z) 502 (M++1), 459, 408, 382, 300, 253, 225, 176, 147, 121, 95. |
91.7% | With triethylamine In methanol; dichloromethane; N,N-dimethyl-formamide | 9 Preparation of N-{3-[1-[4-(2-pyridyl)piperazinyl]-methyl]-[1,2,4]thiadiazol-5-yl}-L-leucyl-L-proline methyl ester. EXAMPLE 9 Preparation of N-{3-[1-[4-(2-pyridyl)piperazinyl]-methyl]-[1,2,4]thiadiazol-5-yl}-L-leucyl-L-proline methyl ester. A mixture of N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester (0.45 g, 1.2 mmol), 1-(2-pyridyl)piperazine (0.62 mL, 4 mmol), triethylamine (1.2 mL, 8 mmol) and tetra-butylammonium bromide (100 mg) in DMF (20 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was collected, washed with water, dried (sodium sulfate), filtered and concentrated in vacuo to give a light yellow oil. Purification by column chromatography on silica gel using a solvent mixture of 5% methanol in dichloromethane afforded N-{3-[1-[4-(2-pyridyl)piperazinyl]-methyl]-[1,2,4]thiadiazol-5-yl}-L-leucyl-L-proline methyl ester as a white foam (0.55 g, 91.7 %). 1 H-NMR (CDCl3) δ8.19 (m, 1H), 7.48-7.52 (m, 1H), 7.14 (br. m, 1H, NH), 6.64-6.67 (m, 2H), 4.67 (m, 1H, CHCO), 4.57 (dd, J=8.4 and 4.6 Hz, 1H, CHCO2), 3.92 (m, 1H, NCHpro), 3.62-3.78 (m, 1OH, OMe, NCHpro, N=CCH2, 2NCH2), 2.83 (m, 4H, 2NCH2), 1.62-2.30 (m, 6H, 2CH2 pro and CH2), 0.90-1.03 (2d, J=6.5 and 6.6 Hz, 7H, 2Me and 1CH); MS (m/z) 502 (M+ +1), 459, 408, 382, 300, 253, 225, 176, 147, 121, 95. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In toluene | 1.b (a) (b) 3-[4-(pyridin-2-yl)-piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine To a solution of 3-(N,N-dimethylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (258 mg, 1.39 mmol) (prepared in Example 1(a)) in toluene (10 mL) was added 1-(pyridin-2-yl)piperazine (233 mL, 250 mg, 1.53 mmol). The mixture was heated at reflux over night. Heating was discontinued and when the reaction temperature had reached room temperature the solid was filtered off and dried in vacuo to give 3-[4-(pyridin-2-yl)-piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine as a colourless solid (395 mg, 93%). δH (300 MHz, CDCl3) 2.50 (4H, m, piperazinyl), 3.46 (4H, m, piperazinyl), 3.68 (2H, s), 6.61 (1H, dd, J=5.1 and 6.9), 6.78 (1H, d, J=8.6), 7.06 (1H, dd, J=4.7 and 7.8), 7.39 (1H, s), 7.51 (1H, dd, 6.9 and 8.6), 8.10 (1H, d, J=8.1), 8.12(1H, d, J=7.8), 8.22(1H, d, J=4.6),11.49(1H, br s); ESMS 294 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | EXAMPLE 10 1-(1-benzothien-2-ylmethyl)-4-(2-pyridinyl)piperazine The product from Example 8A (300 mg 1.8 mmol), methane sulfonic anhydride (313 mg, 1.8 mmol), DIEA (200 muL 5.4 mmol) and 1-(2-pyridinyl)piperazine (328 mg, 2.9 mmol) in 4 ml DCM were processed as described in Example 8B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) delta2.57 (m, 4H) 3.50 (m, 4H) 3.84 (s, 2H) 6.63 (m, 2H) 6.81 (d, J=8.48 Hz, 1H) 7.32 (m, 2H) 7.52 (m, 2H) 7.77 (m, 1H) 7.90 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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26 mg (52%) | With potassium carbonate; paraformaldehyde In ethanol | 194 3-chloro-N-[4-(2-pyridinyl)-1-piperazinyl]methyl}benzamide EXAMPLE 194 3-chloro-N-[4-(2-pyridinyl)-1-piperazinyl]methyl}benzamide A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), 3-chlorobenzamide (78 mg, 0.5 mmol, Maybridge), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 26 mg (52%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ2.58 (t, J=4 Hz, 4H), 3.50 (t, J=4 Hz, 4H), 4.19 (d, J=5 Hz, 1H), 6.62 (t, J=5 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.51 (m, 2H), 7.61 (m, 1H), 7.82 (d, J=6 Hz, 1H), 7.92 (s, 1H), 8.12 (d, J=5 Hz, 1H), 8.93 (t, J=5 Hz, 1H); MS (ESI/APCI-) m/e 329 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25 mg (51%) | With potassium carbonate; paraformaldehyde In ethanol | 195 4-fluoro-3-methyl-N-[4-(2-pyridinyl)-1-piperazinyl]methyl}benzamide EXAMPLE 195 4-fluoro-3-methyl-N-[4-(2-pyridinyl)-1-piperazinyl]methyl}benzamide A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), 4-fluoro-3-methylbenzamide (77 mg, 0.5 mmol, Oakwood), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 25 mg (51%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ2.25 (s, 3H), 2.58 (t, J=4 Hz, 4H), 3.52 (t, J=4 Hz, 4H), 4.18 (d, J=5 Hz, 1H), 6.61 (t, J=5 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.21 (t, J=6 Hz, 1H), 7.51 (t, J=5 Hz, 1H), 7.75 (t, J=5 Hz, 1H), 7.82 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.76 (t, J=5 Hz, 1H); MS (ESI/APCI-) m/e 327 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg (55%) | With potassium carbonate; paraformaldehyde; In ethanol; | EXAMPLE 178 N-[4-(2-pyridinyl)-1-piperazinyl]methyl}-<strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), <strong>[1801-10-1]3-trifluoromethylbenzamide</strong> (95 mg, 0.5 mmol), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 30 mg (55%) pure compound. 1H NMR (500 MHz, DMSO-d6) delta2.60 (t, J=4 Hz, 4H), 3.52 (t, J=4 Hz, 4H), 4.22 (d, J=5 Hz, 1H), 6.62 (t, J=5 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.51 (t, J=6 Hz, 1H), 7.75 (d, J=6 Hz, 1H), 7.92 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.10 (m, 2H), 9.05 (t, J=5 Hz, 1H); MS (ESI/APCI-) m/e 363 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-(pyiotadin-2-yl)piperazine (13 mmol) was added to a solution of 3-bromo-4- methoxybenzoic acid (8.7 mmol) in DMF (100 ml.) and DIEA (17.4 mmol). The solution was allowed to stir at room temperature for 10 minutes, and then HOBt (13 mmol) and 1-(3- (dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (WSCDI) (13 mmol) were added. The reaction was allowed to stir at room temperature for 16 hours, at which time Liquid Chromatography - Mass Spectrophotometry (LCMS) analysis indicated the reaction was complete. The solution was diluted with 100 mL ethyl acetate (EtOAc) and washed with 100 mL water. The organic layer was dried over MgSO4, and concentrated in vacuo. Purification via silica column chromatography (Hex:EtOAc as eluent) produced the intermediate compound (3- bromo-4-methoxyphenyl)(4-(pyridin-2-yl)piperazin-1 -yl)methanone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In methanol; at 20℃; for 48h; | General procedure: To a suspension of <strong>[33263-43-3]4-chloro-3-pyridinesulfonamide</strong> 1 (0.77 g, 4 mmol) in dry methanol (10 ml) the appropriate 4-substituted-piperazine (8 mmol) was added and reaction mixture was stirred at room temperature for 48 h. The resulting precipitate was collected by filtration, washed with water (3ml) and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Synthesis of Aj; Step 9: Dissolve 1-(2-pyridinyl)piperazine (1 eq) dry DMF and added CsCO3 (3 eq), stirred the reaction mixture for 10 minutes at 15 C, added 4-ethoxy-3- (1 -methyl-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene- 1- sulfonyl chloride (1 eq) and stirred the reaction for 4 hours at 35 C. After completion of the reaction, added 30 ml EtOAc, 30 ml water organic layer was separated. Waterlayer was re-extracted with 20 ml EtOAc and the combined organic layer are washedwith brine solution, concentrated under vacuum. The residue was purified by columnchromatography on silica the desired product Aj as a white solid; yield 91%. ?H NMR(400 MHz, CDC13) 8 10.80 (s, 1H), 8.85 (d, J= 2.3 Hz, lH), 8.14 (d, J 3.6 Hz, 1H),7.86 (dd, J= 8.7, 2.3 Hz, lH), 7.46 (m, 1H), 7.15 (d, J= 8.7 Hz, 1H), 6.64-6.58 (m,2H), 4.37 (q, J= 7.0 Hz, 2H), 4.27 (s, 3H), 3.67 (t, J= 4.8 Hz 4H), 3.18 (t, J= 4.8 Hz4H), 2.94 (t, J= 7.5 Hz, 2H), 1.87 (m, 2H), 1.64(t, J= 7.0 Hz 3H), 1.04 (t, J= 7.4 Hz,3H). MASS: ES [M + H] + : 538.10; Elemental anal. calcd. for C26H31N704S; C, 58.08; H, 5.81; N, 18.24; 0,11.90; S, 5.96; found C, 58.12; H, 5.80; N, 18.23; 0, 11.86; S, 5.98. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In tetrahydrofuran Reflux; | Synthesis of Novel Acetylated Piperazine-containing Nglucosides 8a-8h General procedure: To a solution of 4-substituted piperazine 3a-g, or 4-methylpiperazin-1-amine (1 mmol) in THF (10 mL), isothiocyanateintermediate 7 (1 mmol) was added and the resultingsolution was stirred at refluxing temperature until TLCshowed that the reaction is completed (0.5 ~ 1 h). After removingthe solvent under reduced pressure, the residue wasrecrystallized with acetone-diethyl ether or purified by silicagel chromatography with petroleum ether and ethyl acetateas solvents (1:3), or recrystallization with acetone-diethylether (10:1) or diethyl ether to give the product 8a-h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; | 100 mL round bottom flask, 1.84 g (10 mmol) of compound II was added, 1.62 g (10 mmol) of compound III and 20 mL of dry THF, The resulting mixture was stirred under ice-water bath cooling, After adding 2.48 g (12 mmol) of DCC, Stirring was continued at room temperature overnight. TLC shows the completion of the reaction.The reaction mixture was poured into ice water, stirred, extracted with 50 mL of X3 in dichloromethane, the combined organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated on a rotary evaporator. The resulting residue was subjected to column chromatography To give the product I as a white solid, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.8% | With potassium carbonate; In acetonitrile; at 60 - 65℃;Inert atmosphere; | General procedure: To a mixture of the corresponding secondary amines 4a?4k(0.6 mmol), anhydrous K2CO3 (89.7 mg, 0.65 mmol) in anhydrousCH3CN (7 mL) were added the appropriate intermediates 10?13(0.5 mmol). The reaction mixture was warmed to 60?65 C andstirred for 6?10 h under an argon atmosphere. After complete reaction,the solvent was evaporated under reduced pressure. The residuewas dissolved in water (30 mL) and the mixture was extractedwith dichloromethane (20 mL 3). The combined organic phaseswere washed with saturated aqueous sodium chloride (30 mL),dried over sodium sulfate, and filtered. The solvent was evaporatedto dryness under reduced pressure. The residue was purified on asilica gel chromatography using mixtures of dichloromethane/acetone(30:1) as eluent to afford the corresponding 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives TM1?TM31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.19 mg | In dimethyl sulfoxide; at 140℃; for 2h; | (S)-9,lo-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-lj]quinolone-6- carboxylic acid (A1.4, 5.1; 100 mg, 0.36 mmol, 1 eq) and 1-(pyridin-2-yl)piperazine (108 iL, 0.71 mmol, 2 eq) were added to DMSO (3 mL) and stirred at 140 oC for 2hours. The mixture was allowed to cool, then DMSO removed using a 1 g SCX-2 catch and release cartridge (see Solid Phase Extraction method). Trace solvent was subsequently removed by extraction with dichloromethane (20 mL) and washing with saturated brine ( x 100 mL). Combined organic fractions were dried over MgSO4, filtered and concentrated in vacuo. Purification was achieved via automated flash column chromatography (see Flash Column Chromatography method; o%-5%-1o%-2o%-o% DCM/Acetone) to afford compound 5.8 (69.19 mg, 45.8 % yield) as a yellow solid. 1H NMR (400 MHz, CDC13) 6 14.99 (s, 1H), 8.64 (s, 1H), 8.23 (dd, J = 1.64, 4.91 Hz, 1H),7.74 (d, J = 12.09 Hz, 1H), 7.52 - 7.58 (m, 1H), 6.73 (d, J = 8.81 Hz, 1H), 6.69 (dd, J =5.04, 6.80 Hz, 1H), 4.51 - 4.57 (m, 1H), 4.48 (dd, J = 2.14, 11.46 Hz, 1H), 4.39 (dd, J =2.39, 11.46 Hz, 1H), 3.72 (br. 5., 4H), 3.43 - 3.56 (m, 4H), 1.64 (d, J = 6.80 Hz, 3H); 1FNMR (400 MHz, CDC13) 6 -107.0, -134.8; LC-MS Retention time 5.43 minutes, found425.0 [M+H] calculated for C22H21FN404 425.43 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | General procedure: 3-Formyl-rifamycin SV (RAL)was purchased from LKT Laboratories Inc. (>98%). RAL (250.0mg, 0.34 mmol) was dissolved in 50 ml CH2Cl2 and afterthe addition of catalyst (0.025 mmol HCl/EtOH) respective mixtures wereprepared with each of the following compounds taken separately: 1-adamantylamine,1-methylpiperazine,1-(2-pyridyl)piperazine,1-(4-fluorobenzyl)piperazine,1-(2,4,6-trimethylbenzyl)piperazine, 1-bis(4-fluorophenyl)methylpiperazine, 1-(ethanesulfonyl)piperazine, 1-(methylsulfonyl)piperidin-4-amine, 4-(dimethylamino)-piperidine,1-(4-pyridyl)piperazine, 1-(2-pyrimidyl)piperazinedihydrochloride, 1,9-dimethyl-1,4,9-triazaspiro[5.5]undecanetrihydrochloride, 3,4-dihydro-2H-spiro[isoquinoline-1,4?-piperidine],n-piperidin-4-yl-methanesulfonamide,1-[3-(trifluoromethyl)pyrid-2-yl]piperazine,1-(cyclohexylmethyl)-4-piperidinamine,1,4?-bipiperidine-4-carboxylic acid dihydrochloride, (4-amino-1-piperidinyl)acetic acid dihydrochloride, 2-oxo-2-(1-piperidinyl)ethanamine,1-(2-amino-ethyl)-pyrrolidin-2-one,4-amino-1-Boc-piperidine, 3-amino-2-piperidinonehydrochloride, 1-acetyl-4-aminopiperidine hydrochloride in1 ml of CH3OH. Amines containinghydrochloride were neutralized with an equivalent amount of KOH/EtOH (0.06 mmolor 0.12 mmol or 0.18 mmol) solution. The mixtures were stirred at 40C for halfan hour and after that 3/4 of the solvent volume was distilled off. To thecooled reaction mixture (room temperature) the reductant NaBH3CN (13mg, 0.15 mmol) was added portionwise over 1 min. The reaction mixture wasstirred for one hour. Next the reaction mixture was evaporated to dryness,dissolved in 50 ml of CH2Cl2 and extracted twice with 50ml of water and brine (theses stages were omitted for reactions with1,4?-bipiperidine-4-carboxylic acid dihydrochloride,(4-amino-1-piperidinyl)acetic acid dihydrochloride). The separated organiclayer was evaporated and the synthesized derivatives of <strong>[13292-22-3]<strong>[13292-22-3]3-formylrifamycin</strong> SV</strong>(compounds 1-23) were next purified by column chromatography with silicagel (25 cm × 1 cm, silica gel 60, 0.040-0.063 mm/230-400 mesh ASTM, Fluka) withdichloromethane/methanol (from 200:1 to 3:1) as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In methanol; at 20℃; for 12h; | General procedure: Lactone (1 mmol) in MeOH (5 mL) wasstirred, treated with a solution of piperazine (1 mmol) in MeOH (2 mL), and left at room temperature. The course of thereaction was monitored by TLC. If the product did not precipitate, the solvent was evaporated in vacuo after the reaction wascomplete. The residue was recrystallized from a suitable solvent (usually C6H6-hexane mixtures). Compounds 5a-e, 6a-d,and 7a,d,e were prepared by this method. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In methanol; at 20℃; for 4h; | General procedure: Lactone (1 mmol) in MeOH (5 mL) wasstirred, treated with a solution of piperazine (1 mmol) in MeOH (2 mL), and left at room temperature. The course of thereaction was monitored by TLC. If the product did not precipitate, the solvent was evaporated in vacuo after the reaction wascomplete. The residue was recrystallized from a suitable solvent (usually C6H6-hexane mixtures). Compounds 5a-e, 6a-d,and 7a,d,e were prepared by this method. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With potassium phosphate; copper(l) iodide; 4R-4-hydroxyproline; In dimethyl sulfoxide; at 100℃; for 16h; | To a solution of l-(pyridin-2-yl)piperazine (600 mg, 3.68 mmol) in DMSO (10 ml) was added <strong>[187973-60-0]6-iodopyridazin-3-amine</strong> (813 mg, 3.68 mmol) and the reaction mixture was degassed by passing through it N2 for 15 min. K3PO4 (1.17 g, 5.51 mmol), L-hydroxyproline (193 mg, 1.48 mmol) and Cul (140 mg, 0.74 mmol) were added to the reaction mixture. After degas sing with a N2 steam for 15 min, the reaction mixture was stirred at 100 C for 16 h. The re action mixture was poured into H20 (50 ml) and extracted with a mixture of 15% IPA/CHCb (3 x lOOml). The combined organic layers were washed with brine, dried over Na2S04 and solvents were evaporated. The resulting crude was purified by column chromatography (amine modified silica, 10% MeOH/DCM) to get 6-[4-(pyridin-2-yl)piperazin- l-yl]pyridazin- 3-amine (160 mg, 26%) as grey solid. LC-MS: m/z = 257.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 2h; | 5-Fluoro-2-nitropyridine (500 mg, 3.52 mmol) was combined with DMSO (5 ml) to give a yellow solution. K2CO3 (730 mg, 5.28 mmol) and l-(pyridin-2-yl)piperazine (862 mg, 804 m) were added and the reaction mixture was stirred at 90 C for 2 hours. The reaction mixture was diluted with H20 (20 ml) and washed with DCM (3 x 20 ml). The combined or ganic layers were washed with brine (1 x 20 ml), dried over MgS04 and evaporated under re duced pressure to get the crude material as an orange solid. This crude product was used without further purification in the next step. LC-MS: m/z = 286.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With caesium carbonate; In N,N-dimethyl-formamide; at 55℃; for 17h; | l-(Pyridin-2-yl)piperazine (1.64 g, 1.53 ml, 10.1 mmol), <strong>[19745-07-4]2,5-dichloropyrazine</strong> (1.5 g, 10.1 mmol) and CS2CO3 (5.25 g, 16.1 mmol) were dissolved in DMF (40 ml). The solution was stirred 17 h at 55 C. The solution was diluted with H20, then extracted with DCM (4 x) The combined organic layers were washed with brine, dried over MgS04, filtered and con centrated under vacuum. The crude material was purified by flash chromatography (DCM to DCM/0.6%MeOH) to yield 2-chloro-5-(4-(pyridin-2-yl)piperazin-l-yl)pyrazine (1.57 g, 55%). Light yellow solid. LC-MS: m/z = 276.l.[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | In tetrahydrofuran; | <strong>[10320-42-0]<strong>[10320-42-0]2-Chloro-5-nitropyrimidin</strong>e</strong> (2.0 g, 12 mmol) was dissolved in THF (60 ml). l-(Pyridin- 2-yl)piperazine (2.2 g, 2.1 ml, 14 mmol) was added. After completion of the reaction as mon itored by TLC, the mixture was concentrated under vacuum. The crude was diluted with H20 and extracted with EtOAc and additional portions of DCM. The combined organic layers were dried with MgS04 and concentrated under vacuum. The product was purified by flash chromatography (silica gel, 120 g, 0% to 5% MeOH in DCM) to yield 5-nitro-2-(4-(pyridin- 2-yl)piperazin-l-yl)pyrimidine (1.07 g, 30%) as an orange solid. LC-MS: m/z = 287.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 20 - 95℃; | The following reaction pathway was employed. Methyl 2-nitro-5-(4-(pyridin-2-yl)piperazin-1 -yl)benzoate was synthesized. A solution of 1 -(pyridin-2-yl)piperazine (1 g, 6.1 mmol), <strong>[393-85-1]methyl 5-fluoro-2-nitrobenzoate</strong> (1 .28 g, 6.4 mmol), and triethylamine (1 .71 mL, 12.3 mmol) in 1 ,4-dioxane (20 mL) was stirred at room temperature for 5 min. followed by heating at 95 C overnight. LCMS of aliquot showed complete conversion of starting material. The solvent was evaporated in vacuo and residue partitioned between water and ethyl acetate. The water layer was discarded and organic layer evaporated in vacuo to afford methyl 2-nitro-5-(4-(pyridin-2- yl)piperazin-1 -yl)benzoate as an orange solid (2.05 g, 98%). 1H NMR (500 MHz, Chloroform-d) d 8.24 (dd, J = 5.0, 2.1 Hz, 1 H), 8.12 - 8.01 (m, 1 H), 7.56 (t, J = 7.8 Hz, 1 H), 6.95 - 6.85 (m, 2H), 6.77 - 6.65 (m, 2H), 3.96 (d, J = 1.7 Hz, 3H), 3.80 - 3.75 (m, 4H), 3.64 - 3.60 (m, 4H); LRMS (ESI+ve): Calculated for C17H18N4O4, [M+H] = 343.14, observed [M+H] = 343.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In isopropyl alcohol; for 5h;Inert atmosphere; Reflux; | General procedure: Corresponding 2-(aryloxymethyl)oxiranes (5 mmol, 1 equiv) and amines (7.5 mmol, 1.5 equiv) were dissolved in 30 mL i-PrOH. The reaction was purged with argon 3 times and stirred at reflux for 5 h, andthen the mixture was cooled to room temperature and added AcOEt.After washing with brine 3 times, the organic layer was dried overanhydrous Na2SO4, filtered, and evaporated in vacuo. Purification ofthe crude residue by column chromatography on silica gel yielded target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With caesium carbonate In dimethyl sulfoxide at 110℃; for 5h; | 7-(4-(Pyridin-2-yl)piperazin-1-yl)indolo[2,1-b]quinazoline-6,12-dione General procedure: To a solution of 1a (1.0 mmol) in DMSO (5.0 mL) was added secondary amines (1.0 mmol) and Cs2CO3 (2.0 mmol) at 110 C. The reaction mixture was stirred at 110 C for 5 h and cooled to room temperature. To the reaction mixture was added MeOH to precipitate red solids. The precipitate was filtered and dried to afford the target compounds 1a-1e, 2a-2e, 3a, 3b, 4a and 5a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In tetrahydrofuran at 60℃; | 2.2.1. General procedure for the synthesis of compounds(2a-j) General procedure: To a stirred solution of 2-pyridyl piperazine (1) in dryTetrahydrofuran (THF) (10 ml), various isocynates and isothiocynates(2) were added at 10-15 °C in the presence of TEA.After completion of the addition, the reaction mixture was stirred for 2-3 h at 60 °C. The reaction progress was monitored by TLC. After completion of the reaction, Et3N.HCl was removed by filtration and the solvent in a Rota-evaporator toobtain crude product. It was purified by silica gel column chromatography eluting with hexane: ethyl acetate (10-30%)to afford the title compounds 2(a-j). |
82% | With triethylamine In tetrahydrofuran at 60℃; | 2.2.1. General procedure for the synthesis of compounds(2a-j) General procedure: To a stirred solution of 2-pyridyl piperazine (1) in dryTetrahydrofuran (THF) (10 ml), various isocynates and isothiocynates(2) were added at 10-15 °C in the presence of TEA.After completion of the addition, the reaction mixture was stirred for 2-3 h at 60 °C. The reaction progress was monitored by TLC. After completion of the reaction, Et3N.HCl was removed by filtration and the solvent in a Rota-evaporator toobtain crude product. It was purified by silica gel column chromatography eluting with hexane: ethyl acetate (10-30%)to afford the title compounds 2(a-j). |
[ 74764-17-3 ]
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1-(4-Chloropyridin-2-yl)piperazine
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H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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