| 90% |
In butan-1-ol for 18h; Heating; |
|
| 81% |
With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 150℃; for 15h; |
1
Example 1: Synthesis of Compound E14 (a); 2,3-Dichloropyridine (5) (5 g) and piperazine (6) (8 g, 94.5 mmol) (each commercially available from Sigma-Aldrich) was dissolved in 70 mL of DMF. To the resulting solution was added DIEA (12.21 g, 94.5 mmol) and the resulting reaction was mixture allowed to stir at a temperature of about 150°C for about 15 h. Water (100 mL) and ethyl acetate (150 mL) were added to the reaction mixture and the organic phase and aqueous phases were separated. The aqueous phase was extracted twice with ethyl acetate (about 100 mL/extraction) and the ethyl acetate layers were combined. The combined ethyl acetate layers were then washed with water (50 mL), washed with brine (50 mL), and dried (Na2S04). The solvent was removed under reduced pressure to provide a residue that was purified using column chromatography (silica gel eluted with 20% methanol in ethyl acetate) to provide the compound of formula 4 (5.2 g, 81% yield). |
| 72% |
In butan-1-ol for 72h; Heating / reflux; |
239A EXAMPLE 239A; 1-(3-chloropyridin-2-yl)piperazine
[1751] A solution of piperazine (29.1 g, 338 mmol), 2,3-dichloropyridine (5.00 g, 33.8 mmol), and n-butanol (220 mL) was refluxed for 3 days. The reaction mixture was cooled to 23° C. and concentrated under reduced pressure. The residue was slurried with ethyl acetate and water. The ethyl acetate layer was poured off and dried over sodium sulfate, filtered, and concentrated to afford 4.8 g (72% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δb2.83 (m, 4H), 3.15 (m, 4H), 6.97 (dd, 1H, J=4.5, 7.5 Hz), 7.77 (dd, 1H, J=1.5, 7.5 Hz), 8.21 (dd, 1H, J=1.5, 4.5 Hz)); MS (ESI) m/e 198 (M+H)+. |
| 52.4% |
In dimethyl sulfoxide at 20 - 85℃; for 6h; |
3
To a stirred solution of 2, 3-dichloropyridine (2 g, 13.5 mmol) in dimethyl sulphoxide (20 ml) was added anhydrous piperazine (1.4 g, 16.2 mmol) at room temperature and heated to 85 ° C. After 6 hours of stirring at 85 ° C, the reaction mass was cooled to room temperature and quenched with water (500 ml). The product was extracted into ethyl acetate (2 X 25 ml) and the combined organic layer was washed with water (4 X 250 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was subjected to column purification to yield the title product (1.4 g, yield 52.4%). 1H-NMR (300 MHz, CD3OD): δ 3.25 - 3.31 (m, 4H), 3.47 - 3.51 (m, 4H), 6.97 - 7.01 (m, IH)3 7.72 (dd, J= 1.6 Hz, J= 7.8 Hz, IH), 8.15 - 8.17 (m, IH). MS: 198.3 (M++.) |
| 39% |
In N,N-dimethyl-formamide at 240℃; for 0.0833333h; Microwave; |
8.1 General Procedure:
EXAMPLE 8 General Procedure: Microwave assisted Nucleophilic displacement of 2-Chloropyridine Piperazine (5 mmol) and 2,3 dichloropyridine (1 mmol) were dissolved in dimethylformamide (1 mL) in a microwave safe vial. The vial was sealed and the reaction was heated to 240° C. via a microwave for 5 min. The reaction mixture was then diluted with dichloromethane and washed with water. The organic phase was then washed a second time with water, then dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was then purified via flash chromatography with 10% methanol in dichloromethane to yield the desired product. In this manner the following compound was synthesized: Example Structure Name Yield 8.1 1-(3-Chloro-pyridin-2-yl)-piperazine 39%1H 1.65(s, broad, 1H); 3.07(m, 4H); 3.33(m, 4H); 6.85(m, 1H); 7.60(dd, J=7.8, 1.8 Hz, NMR 1H); 8.21(m, 1H). |
| 28% |
Stage #1: piperazine; 2,3-dichloro-pyridine In dimethyl sulfoxide at 110℃; for 60h;
Stage #2: With water; sodium hydrogencarbonate In dimethyl sulfoxide |
|
|
In butan-1-ol for 72h; Heating; |
|
|
In dimethyl sulfoxide at 100℃; for 6h; |
|
|
With N-ethyl-N,N-diisopropylamine In acetonitrile Heating; |
|
|
With triethylamine In dimethyl sulfoxide at 80℃; for 24h; |
1 Example 1: Synthesis of Compound AAA
2,3-Dichloropyridine (15.0 g, 101.6 mmol), piperazine (9. 78 g, 113.70 mmol), and triethylamine (14. [36] g, 141.95 mmol) were dissolved in [300 ML OFDMSO] and the resulting mixture was heated at about 80°C for about 24 h. The reaction mixture was then cooled to room temperature and extracted with a saturated aqueous sodium bicarbonate solution. The organic layer was dried, concentrated, and purified using a silica gel column eluted with a gradient elution from ethyl acetate to [2] : 1 ethyl acetate: methanol to provide N- [(3-CHLOROPYRIDIN-2-YL)-PIPERAZINE] (compound 1) as a yellow liquid. A solution diphenylcyanocarbodimidate (Commercially available from Sigma- Aldrich, St. Louis, MO (www. sigma-aldrich. com)) [(0.] [5] mmol) and 4-tert-butylaniline (0.5 [MMOL) IN 1. 5] mL [OF DCM WAS STIRRED] at room temperature for about [12] [H.] The mixture was concentrated under reduced pressure to provide compound 2, which was used directly in the [NEXT STEP'WITHOUT FURTHER PURIFICATION.] A solution of compound 2, prepared as described above, and compound 1 (0.5 mmol), prepared as described [ABOVE : IN 1.] 5 mL [OF2-METHOXYMETHYLETHCR WAS STIRRED] at about [75 5°C FOR ABOUT 12H. THE SOLUTION WAS COOLED TO ROOM TEMPERATURE AND PURIFIED USING DIRECT] [HASH CHROMATOGRAPHY] on a silica gel column eluted with a gradient elution from 1: [10 ETHYL] [ACETATE : BEXANE TO] 1: 1 ethyl acetate [:] hexane to provide Compound AAA (62 [%] yield). The identity of compound AAA was confirmed using'H NMR. Compound [AAA: 1H NMR (CDCL3) No. 9.19(DD, J=1.5, ] 4.7 Hz, 1H), 6.62 (dd, J=1.5, 7.8 Hz, 1H), 7.38 (d, J =8. 5 [HZ,] 2H), 7. [18 (B, 1H),] 7. 01 [(D,] J = 8. [5] Hz, 2H), 6.91 (dd, [J =] 4.7, 7. 8 Hz, 1H), 3.58 [(M,] 4H), 3.34 [(M,] [4H),] 1.33 (s, 9H) ppm |
|
In butan-1-ol |
R.2 REFERENCE EXAMPLE 2
REFERENCE EXAMPLE 2 A solution of 2,3-chloropyridine (13.1 g) and anhydrous piperazine (37.9 g) in n-butanol (350 ml) was heated under reflux for 16 hours. The solvent was removed by evaporation under reduced pressure, and the residue was diluted with aqueous sodium hydroxide solution and extracted with dichloromethane. From the extract, the solvent was removed by distillation under reduced pressure to give 1-(3-chloro-2-pyridyl)piperazine (15.7 g) as an oil. IR νmaxfilm (cm-1): 3280, 1575. M.P., 142°-144° C. (hydrochloride). |
|
In water |
210.1 Synthesis of 3-{(2S,4S)-4-[4-(3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride
(1) Piperazine (20.0 g) was melted by heating at 140°C and 2,3-dichloropyridine(3.42 g) was added thereto. The mixture was stirred at 120°C for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3-chloro-2-pyridyl)piperazine (4.68 g) as a dark-brown oil. |
|
at 120℃; |
|
|
In butan-1-ol for 20h; Reflux; |
|
|
at 110℃; for 0.5h; Microwave irradiation; |
2.2.13
2.13 Example 13 (Prepared according to Scheme 2); 4-(3-Chloropyridin-2-yl)-N-(4-(trimethylsilyl)phenyl)piperazine-l -carboxamide; A mixture of piperazine (25 mmol) and 2,3-dichloropyridine (5mmol) was heated in the microwave at 1 10 °C for 30 min. The resulting residue was purified by flash chromatography (0-5 % methanol in DCM on KPNH cartridge) yielding l-(3-chloropyridin-2-yl)piperazine (3.25mmol).1H NMR (400 MHz, CD3OD-d4) δ 7.95 (br. s., IH), 7.41 - 7.65 (m, IH), 6.59 - 6.86 (m, IH), 4.70 (br. s.,IH), 2.87 - 3.21 (m, 4H), 2.72 - 2.89 (m, 4H) l-(3-chloropyridin-2-yl)piperazine (1.58mmol), Intermediate 1 (1.58mmol) in THF (10 ml) was heated to reflux for 18 hr. The reaction was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (0-100 % ethyl acetate in petroleum ether) yielding the title compound (0.74mmol).MS ES+ 388.8. 1H NMR (400 MHz, DMSOd6) δ 8.40 (s, IH), 7.96 - 8.09 (m, IH), 7.57 - 7.72 (m, IH),7.21 - 7.33 (m, 2H), 7.11 - 7.21 (m, 2H), 6.75 - 6.91 (m, IH), 3.28 - 3.47 (m, 4H), 3.01 - 3.09 (m, 4H), -0.13 -0.09 (m, 9H). |
|
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 120℃; for 16h; |
1
1.1 Synthesis of 1-(3-substituted-2-pyridyl)-piperazine (Compound 3)The reaction mixture of 2-chloro-3-substituted pyridine (compound 1), 2-substituted piperazine (compound 2) (1.5 equivalent) and diisopropyl ethylamine in DMSO was heated to 120° C. overnight (1416 h). After cooled to room temperature, the mixture was diluted with five times of ethyl acetate, then washed twice with 5 times of water, washed once with brine, and dried with anhydrous sodium sulfate. The organic layer was evaporated and concentrated to give a crude product compound 3 (yield 80 to 90%). The crude product compound 3 was directly used for the next step. Example 1Synthesis of 4(3-chloropyridin-2-yl)-N-(4-(trimethylsilyl)phenyl)piperazine-1-carboxamide (Compound A-01) Compound A-01 can be synthesized according to method 1. Just R1, R2, and R3 of Scheme 1 are respectively -Cl, -H and p-SiMe3. More specifically, compound 1 is 2,3-dichloro-pyridine (2 g); compound 2 is piperazine; compound 3 is 1-(3-chloro-2-pyridyl)piperazine (2.3 g, yield 86.8%); compound 7 is compound 7a-p-(trimethylsilyl)phenyl isocynate. In this example, from 382 mg of compounds 7a, it gave about 500 mg of compound A-01. The yield is about 65%.Using 1H NMR to identify compound A-01: 1H NMR (300 MHz, CDCl3): δ8.18 (m, 1H), 7.63 (m, 1H), 7.45-7.34 (dd, 4H), 6.85 (m, 1H), 6.54 (s, 1H), 3.70-3.60 (m, 4H), 3.45-3.35 (m, 4H), 0.24 (s, 9H). |
|
In butan-1-ol Reflux; |
|
|
In butan-1-ol for 18h; Reflux; |
36.1 Step 1: l-(3-Chloropyridin-2-yl)piperazine
A mixture of 2,3-dichloropyridine (0.9 g, 6.1 mmol) and piperazine (5.5 g, 64.1mmol) in -butanol (25mL) was refluxed for 18 hrs. The mixture was then concentrated, poured into water (100 mL), and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to give crude l-(3-chloropyridin-2-yl)piperazine (1.1 g, 92%) as a yellow oil. ESI-MS (EI+, m/z): 198.2 [M+H]+. |
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