* 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.
With triethylamine In acetonitrile at 0 - 20℃; for 0.6 h;
To the stirred solution of tert-butyl piperazine-l-carboxylate (6.0 g, 33.0 mmol, 1.0 eq) in acetonitrile (60 niL), the reaction mixture was cooled at 0 °C, then added triethylamine (22 mL, 161 mmol, 5.0eq) and (bromomethyl)benzene (6.0 mL, 35.0 mmol, 1.1 eq) drop wise. The reaction mixture was stirred at room temperature for about 6 hours. The reaction mixture was diluted with water and extracted with CH2CI2. The combined organic extracts were dried over Na2S04, filtered and evaporated under reduced pressure to afford the desired product (6.5 g, yield: 76.0percent) as a white solid.
57%
With potassium carbonate In acetonitrile at 70℃; for 16 h;
Step 1 : tert-Butyl 4-benzylpiperazine-l-carboxylate (0754) [00268] To a solution of compound A3-1 (20.0 g, 107 mmol, 1.0 eq) and (0755) bromomethylbenzene (22.0 g, 129 mmol, 1.2 eq) in CH3CN (300 mL) was added K2CO3 (14.8 g, 107 mmol, 1.0 eq). The reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (50 mL) and the resultant mixture was extracted with EA (80 mL * 2). The combined organic layers were dried over NaiSO/t, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether: ethyl acetate = 1 :0 to 5: 1) to afford the title compound (16.8 g, 57percent yield) as a white solid. 'HNMR (400MHZ, CDCl3-i/) δ 7.34 - 7.23 (m, 5H), 3.50 (s, 2H), 3.46 - 3.38 (m, 4H), 2.43 - 2.33 (m, 4H), 1.45 (s, 9H)
Ca. 177 mg
With triethylamine In dichloromethane at 20℃; for 3 h;
To a 25 mL flask was added TEA (177 mg, 244 ).ll, 1.75 mmol), tert-butyl piperazine-1-carboxylate (240 mg, 1.29 mmol), (bromomethyl)benzene (200 mg, 139 ).ll, 1.17 mmol) andDCM (4 mL). The colorless solution was stirred at rt for 3 hrs. The reaction mixture wasconcentrated to give a white solid. Then it was purified by silica gel column chromatography(eluted with EA/PE=15- 30percent ), about 177 mg tert-butyl4-benzylpiperazine-1-carboxylate20 (Compound lOA) was obtained as a colorless oil. MS: calc'd 277 (M+Ht, measured 277(M+Ht
Reference：
[1] Synthetic Communications, 2009, vol. 39, # 13, p. 2297 - 2303
[2] Patent: WO2017/17630, 2017, A1, . Location in patent: Page/Page column 34-35
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 4, p. 1830 - 1842
[4] Patent: WO2017/58716, 2017, A1, . Location in patent: Paragraph 00268
[5] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 1, p. 54 - 62
[6] Patent: WO2017/202704, 2017, A1, . Location in patent: Page/Page column 43
3
[ 57260-71-6 ]
[ 57260-70-5 ]
Yield
Reaction Conditions
Operation in experiment
84%
With triethylamine In dichloromethane; water; acetonitrile
[Referential Example 158] 1-Benzyl-4-tert-butoxycarbonylpiperazine In acetonitrile (80 ml), tert-butyl 1-piperazine carboxylate (2.50 g) was dissolved. Under ice cooling,benzyl bromide (1.59 ml) and triethylamine (1.87 ml) were added dropwise to the resulting solution, followed by stirring at room temperature for 90 minutes. After the solvent was distilled off under reduced pressure, distilled water and dichloromethane were added to the residue to separate the organic layer. The organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (ethyl acetate: hexane = 1:20 to 1:5), whereby the title compound (3.12 g, 84percent) was obtained as colorless powder. 1H-NMR (CDCl3) δ: 1.45(9H,s), 2.38(4H,t,J=4.9Hz), 3.42(4H,t,J=4.8Hz), 3.51(2H,s), 7.25-7.29(1H,m), 7.30-7.33(4H,m). MS (EI) m/z: 276M+.
Reference：
[1] Patent: EP1104754, 2001, A1,
[2] European Journal of Medicinal Chemistry, 2013, vol. 64, p. 488 - 497
[3] Organic Letters, 2015, vol. 17, # 3, p. 446 - 449
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 6604 - 6614
6
[ 100-44-7 ]
[ 57260-71-6 ]
[ 57260-70-5 ]
Reference：
[1] Organic Letters, 2010, vol. 12, # 18, p. 4176 - 4179
[2] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 10, p. 1731 - 1743
7
[ 1131-01-7 ]
[ 57260-71-6 ]
[ 5294-61-1 ]
Reference：
[1] Green Chemistry, 2013, vol. 15, # 3, p. 756 - 767
8
[ 57260-71-6 ]
[ 111669-25-1 ]
Reference：
[1] Patent: US9226970, 2016, B2,
9
[ 110-85-0 ]
[ 24424-99-5 ]
[ 76535-75-6 ]
[ 57260-71-6 ]
Yield
Reaction Conditions
Operation in experiment
60%
at 0℃; for 1 h;
To a cold methylene chloride solution (10 ml) of piperazine (30.23 mmol, 2.60 g) was added methylene chloride solution (10 ml) of BOC anhydride (1.50 mmol) and the mixture was stirred at 0°C for 1 hour. After the reaction is complete, water is added and the aqueous K2CO3 solution is added to make the reaction mixture basic. All of the reaction mixture was extracted with methylene chloride and the product was isolated by column chromatography.
Reference：
[1] Green Chemistry, 2014, vol. 16, # 7, p. 3635 - 3642
[2] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1559 - 1563
[3] Russian Journal of Organic Chemistry, 2009, vol. 45, # 5, p. 788 - 791
[4] Patent: KR2015/111825, 2015, A, . Location in patent: Paragraph 0722-0734
[5] Journal of Medicinal Chemistry, 1992, vol. 35, # 21, p. 3845 - 3857
[6] Journal of Medicinal Chemistry, 1992, vol. 35, # 21, p. 3845 - 3857
[7] Tetrahedron Letters, 2006, vol. 47, # 46, p. 8039 - 8042
[8] Patent: KR2016/108281, 2016, A, . Location in patent: Paragraph 0721-0724
10
[ 24424-99-5 ]
[ 57260-71-6 ]
[ 76535-75-6 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8283 - 8286
11
[ 57260-71-6 ]
[ 53788-49-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 452 - 458
12
[ 35198-42-6 ]
[ 57260-71-6 ]
[ 112275-50-0 ]
Reference：
[1] Patent: US5380724, 1995, A,
13
[ 35198-42-6 ]
[ 57260-71-6 ]
[ 112275-50-0 ]
Reference：
[1] Patent: EP574906, 1993, A2,
14
[ 540-51-2 ]
[ 57260-71-6 ]
[ 77279-24-4 ]
Yield
Reaction Conditions
Operation in experiment
82.6%
With potassium carbonate In acetonitrile for 16 h; Reflux
Tert-Butyl piperazine-1-carboxylate 11a (3.72 g, 20 mmol),2-Bromoethanol (3 · Og, 24 mmol) and potassium carbonate(4.14 g, 30 mmol) was dissolved in 100 mL of acetonitrile and refluxed for 16 hours. Cool to room temperature, filter the reaction and concentrate under reduced pressureThe residue was added to 50 mL of ethyl acetate, filtered and the filtrate was concentrated under reduced pressure to give the title product 4- (2-hydroxyethyl) piperidineOxazine-1-carboxylate llb (3.8 g, yellow oil), yield: 82.6percent.
65%
With potassium carbonate In acetonitrile for 2.5 h; Reflux
A mixture of 4a (0.5g, 2.7mmol), 4b (0.34g, 2.7mmol) and K2C03 (0.74g, 5.36mmol) in CH3CN (25mL) was heated under reflux for 2.5h. The solid was filtered off and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to provide 4c (0.4g, 65percent).
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 18, p. 7278 - 7288
[2] Patent: CN103382206, 2016, B, . Location in patent: Paragraph 0365-0370
[3] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 11, p. 3923 - 3933
[4] Patent: WO2012/48259, 2012, A2, . Location in patent: Page/Page column 41
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 12, p. 5826 - 5840
[6] Patent: WO2015/92819, 2015, A2, . Location in patent: Paragraph 0250; 0251
15
[ 57260-71-6 ]
[ 77279-24-4 ]
Reference：
[1] Patent: KR101798840, 2017, B1,
16
[ 350-46-9 ]
[ 57260-71-6 ]
[ 182618-86-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate In N,N-dimethyl-formamide at 50℃;
To a solution of terf-butyl-piperazine (1 eq) and 4-fluoro-nitrobenzene (1.1 eq) in DMF (0.43 M), K2CO3 (1.1 eq) was added. The mixture was heated to 50 °C with stirring overnight. At this time the reaction was allowed to cool to RT and partitioned between EtOAc and IN aqueous HCl. The aqueous fraction was extracted with EtOAc and the combined organics washed with brine, before being dried over Na2SO4, filtered and evaporated in vacuo to afford the title compound as yellow solid (97 percent); MS (ES+) m/z 308 (M+H)+.
95%
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 18 h;
To a solution of 1-fluoro-4-nitrobenzene (5 g, 35.43 mmol) and tert-butyl piperazine-1- carboxylate (6.6 g, 35,43 mmol) in DMF (100 mL) was added potassium carbonate (14.7g, 106.36 mmol) and the mixture was stirred at 50 °C for 18 h, then allowed to cool to room temperature and concentrated under reduced pressure. The oily residue was washed with diethyl ether (3x) to give tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate as a yellow solid (8.2 g, 95percent). ‘HNMR(400 MFIz, Chloroform-d) ppm 1.48 (s, 9 H) 3.38- 3.45(m,4H)3.56-3.63 (m,4H)6.75 -6.86(m,2H)8.07-8.20(m,2H). C15H21N304MS m/z 308.1 (M+H)
85.3%
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
Compound 18 (10.0 g, 70.87 mmol) was added to the reaction flask, respectively,Compound 36 (15.84 g, 85.05 mmol)Dissolved in DMF,K2CO3 (15.67 g, 113.39 mmol) was added,80 ° C under the conditions of reaction,TLC tracking, to be completely complete,The reaction system is poured into ice water,There is a yellow solid precipitation,Filter the solid, beat with ether,18.58 g of compound 40 was dried,Yield: 85.3percent.
77%
With N-ethyl-N,N-diisopropylamine In ethyl acetate
4-(4-Nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in ethyl acetate (25 mL). Piperazine-1-carboxylic acid tert-butyl ester (6.7 g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were added and the mixture was stirred at 65° C. for five days and cooled to room temperature. Ether (100 mL) was added and the combined mixture was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid (8 g, 77percent).
77%
With N-ethyl-N,N-diisopropylamine In ethyl acetate
4-(4-Nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. 4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in ethyl acetate (25 mL). Piperazine-1-carboxylic acid tert-butyl ester (6.7 g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were added and the mixture was stirred at 65° C. for five days and cooled to room temperature. Ether (100 mL) was added and the combined mixture was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid (8 g, 77percent).
77%
With N-ethyl-N,N-diisopropylamine In ethyl acetate
4-(4-Nitro-phenyl)-piperazine-1-carboxylic acid Tert-butyl Ester 4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in ethyl acetate (25 mL). Piperazine-1-carboxylic acid tert-butyl ester (6.7 g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were added and the mixture was stirred at 65° C. for five days and cooled to room temperature. Ether (100 mL) was added and the combined mixture was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid (8 g, 77percent).
48%
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
Step: 5aSynthesis of 4-(4-Nitro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester.Procedure:K2C03 (2.7g, 0.0194mol) was added to 1 -Fluoro-4-nitro-benzene (2.5g, 0.0177mol) and Piperazine-1 -carboxylic acid tert-butyl ester (3.2g, 0.0177mol) in DMF (10ml) at 80°C. The reaction was monitored by the TLC (30percent EtOAc: hexane). The resultant was cooled to RT and precipitated by the addition of ice. The precipitate was collected and dried at reduced pressure to afford 2.6g (48percent yield) of 4-(4-Nitro-phenyl)-piperazine-l- carboxylic acid tert- buyl ester.
Reference：
[1] Patent: WO2006/38039, 2006, A1, . Location in patent: Page/Page column 17; 30
[2] Patent: WO2017/123542, 2017, A1, . Location in patent: Page/Page column 398; 399
[3] Patent: CN106905245, 2017, A, . Location in patent: Paragraph 0314; 0315; 0316; 0317; 0318
[4] Patent: US2003/13708, 2003, A1,
[5] Patent: US2004/87575, 2004, A1,
[6] Patent: US2004/110745, 2004, A1,
[7] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2179 - 2191
[8] Patent: WO2012/59932, 2012, A1, . Location in patent: Page/Page column 117
[9] Tetrahedron Letters, 1997, vol. 38, # 23, p. 4091 - 4094
[10] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[11] Tetrahedron Letters, 2006, vol. 47, # 15, p. 2549 - 2552
[12] Patent: US5556969, 1996, A,
[13] Patent: WO2005/14599, 2005, A1, . Location in patent: Page/Page column 51
[14] Patent: US2007/60577, 2007, A1, . Location in patent: Page/Page column 49
[15] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 3086 - 3090
[16] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5552 - 5556
[17] Patent: CN107245073, 2017, A, . Location in patent: Paragraph 0133; 0134; 0135
[18] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 303 - 315
[19] Patent: WO2006/122806, 2006, A2, . Location in patent: Page/Page column 70
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 135℃;
Step 1: To a solution containing compound 1 (3.9 g, 31 mmol) and Boc-piperazine (6.3 g, 34 mmol) in N-methyl-2-pyrrolidone (NMP) (30 ml) was added K2C03 (8.5 g, 62 mmol). The mixture was stirred overnight at 135 C. After completion of the reaction, the mixture was poured into ice water, and the precipitate was collected to afford the desired product as a yellow solid (6.4 g, 72percent).
39%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
Synthesis of 4-(4-formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1). A mixture of 4-(tert-butyl-l -piperazinecarboxylate (556 mg, 3.0 mmol), 4- fluoro-benzaldehyde (315 μl, 3.0 mmol) and K2CO3 (514 mg, 3.7 mmol) in DMF (5 ml) was stirred at ambient temperature overnight. Reaction was diluted with water (30 ml) and extracted with EtOAc (50 ml x 2). Organic layer was washed with water (20 ml), 1 M aq. HCl (20 ml), water (20 ml x 2) and brine (20 ml) and dried over MgSO4 (anh.). Solvent was evaporated in vacuum. Residue was triturated with hexane. Formed precipitate was filtrated and dried in vacuum overnight to provide target compound (1) (342 mg, 39percent) as off-white solid. LC-MS [M+H] 291.2 (C16H22N2O3+H, requires 291.38).
Reference：
[1] Patent: WO2016/57779, 2016, A2, . Location in patent: Page/Page column 68
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2747 - 2759
[3] Chemical Communications, 2016, vol. 52, # 67, p. 10289 - 10292
[4] Patent: WO2008/154642, 2008, A2, . Location in patent: Page/Page column 155-156
[5] Patent: US2003/13737, 2003, A1,
[6] Patent: EP1396487, 2004, A1, . Location in patent: Page 14
[7] Patent: EP1612204, 2006, A1, . Location in patent: Page/Page column 46
[8] New Journal of Chemistry, 2010, vol. 34, # 11, p. 2612 - 2621
21
[ 598-21-0 ]
[ 57260-71-6 ]
[ 112257-12-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium hydrogencarbonate In dichloromethane; water at 0 - 20℃; for 2 h;
To a solution of tert-butyl piperazine-1-carboxylate (2.00 g, 10.7 mmol) in 5 wt percent aq NaHCO3 (36 mL) and DCM (36 mL) was added 2-bromoacetyl bromide (1.40 mL, 16.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. and then at room temperature for 2 hours. After separation of phase, the organic layer was washed with water, 2 N aq. HCl, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residual solid was purified by recrystallization from EtOAc and hexanes to afford tert-butyl 4-(2-azidoacetyl)piperazine-1-carboxylate (2.92 g, 89percent) as a white solid. 1H-NMR (CDCl3, Varian, 400 MHz): δ 1.47 (9H, s), 3.42-3.44 (2H, m), 3.46-3.54 (4H, m), 3.58-3.60 (2H, m), 3.86 (2H, s).
78%
With triethylamine In dichloromethane at -78℃; for 3 h; Inert atmosphere
(q) tert-butyl4-(2-bromoacetyl)piperazine-1-carboxylate (6q) Under inert atmosphere and at -78°C, bromoacetylbromide (53.7 mmol, 1 eq.) was slowly added to a solution of Boc-piperazine(53.7 mmol, 1 eq.) and TEA (59.1 mmol, 1.1 eq.) in DCM (150 ml). The reactionmixture was stirred at -78°C for 3h, diluted with DCM (75 ml) and washed withwater. The recovered organic layer was dried over magnesium sulfate and thesolvent was evaporated under vacuum. The obtained crude product was furthertriturated with diethyl ether, filtered and dried under vacuum to conduct tothe desired acetylated compound. CnHi 9BrN 20 3; yield 78percent; white solid; m.p.243-244 °C; M = 307.18 g/mol; IR (KBr): v = 2965 (m), 1689 (s), 1632 (s), 1417(s), 1246 (s), 1167 (s), 1023 (m); cm - ; NMR (250 MHz, CDCI 3) δ 3.87 (s, 2H), 3.61-3.57 (m, 2H), 3.55-3.47 (m,4H), 3.46- 3.41 (m, 2H), 1.46 (s, 9H); C NMR (63 MHz, CDCI 3) δ 165.5 (C q), 154.5 (C q), 80.5 (C q), 46.6 (2CH2), 40.9 (2CH 2), 28.4 (3CH 3), 25.7 (CH 2);
65%
Stage #1: With sodium carbonate In dichloromethane; water at 0℃; for 0.333333 h; Stage #2: With dmap In dichloromethane; water at 0 - 25℃; for 1 h;
Boc-pyridazine (compound F-1, 0.558 g, 3 mmol) was weighed in 10 mL of anhydrous CH2Cl2 in a 25 mL beaker and anhydrous Na2CO3 (0.848 g, 8 mmol) was weighed into 7 mL of deionized water. Pour into a 100 mL single-mouth bottle and stir it in an ice bath for 20 min. Dissolve bromoacetyl bromide (0.568 mL, 6.6 mmol) in 10 mL of anhydrous CH2C12 and quickly drip into a single-mouth flask. Add DMAP (36.7 mg) after the addition. 0.3 mmol), stirring continued, TLC traces until starting material conversion, transfer to room temperature reaction 1 h. Extract with CH2C12 (3 X 30 mL). Combine the organic layers and dry over anhydrous Na2SO4. Chromatographic separation of CH2Cl2/MeOH=60:1, v/ ν) 598 mg (Compound G-1) was obtained as a milky white solid, yield 65percent.
54%
With triethylamine In dichloromethane at 20℃; for 4 h;
To a stirred solution of tert-butyl piperazine-l-carboxylate 4 (1 g, 5.38 mmol) in CH2C12 (15 mL) at 0 °C, were added 2-bromoacetyl bromide (864 mg, 4.3 mmol) and TEA (1 mL, 7.53 mmol). The reaction mixture was warmed to RT and stirred for 4 h. The mixture was quenched with water (50 mL) and extracted with CH2C12 (2 x 40 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2S04), filtered and concentrated under reduced pressure. The crude was purified (silica gel; eluting 25percent EtOAc/ hexanes) to afford compound 2 (900 mg, 54percent) as pale yellow solid. 1H MR (500 MHz, DMSO-i): δ 4.16 (s, 2H), 3.47-3.42 (m, 4H), 3.38-3.35 (m, 2H), 3.31-3.29 (m, 2H), 1.41 (s, 9H); LC-MS (ESI): m/z 328.1 (M+ + Na).
41%
With N-ethyl-N,N-diisopropylamine In dichloromethaneCooling with ice
Bromo acetyl bromide (4.86 ml, 21.47 mmol, 1 eq) was added dropwise to a stirred ice cold mixture of the piperazine-1-carboxylic acid tert butyl ester (4.0 g, 21.47 mmol, 1 eq) and diisopropyl ethyl amine (12.05 g, 92.5 mmol, 4.3 eq) in dichloromethane (108 ml). The resulting mixture was washed with water (2*50 mL) and saturated sodium chloride solution (100 mL), and dried over MgSO4. After filtration, the solvent was evaporated and the residue was purified with chromatography with (ethyl acetate/n-hexane 1/1) to give the product (2.72 g, 41percent) as a orange oil.
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 2, p. 556 - 565
[2] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1407 - 1413
[3] Patent: US2016/168156, 2016, A1, . Location in patent: Paragraph 0510; 0511
[4] Patent: WO2014/57266, 2014, A1, . Location in patent: Page/Page column 61
[5] Tetrahedron, 1998, vol. 54, # 16, p. 3999 - 4012
[6] Patent: US6329523, 2001, B1,
[7] Journal of the American Chemical Society, 2016, vol. 138, # 34, p. 10778 - 10781
[8] Patent: CN107619397, 2018, A, . Location in patent: Paragraph 0065; 0066; 0067
[9] Chemical Communications, 2018, vol. 54, # 97, p. 13698 - 13701
[10] Chemical Biology and Drug Design, 2011, vol. 77, # 1, p. 86 - 92
[11] Patent: WO2016/144703, 2016, A1, . Location in patent: Paragraph 00353
[12] Patent: US9133213, 2015, B2, . Location in patent: Page/Page column 33
[13] Patent: WO2006/109817, 2006, A1, . Location in patent: Page/Page column 56
22
[ 861359-74-2 ]
[ 598-21-0 ]
[ 57260-71-6 ]
[ 112257-12-2 ]
Reference：
[1] Patent: US6191273, 2001, B1,
23
[ 79-08-3 ]
[ 57260-71-6 ]
[ 112257-12-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4898 - 4908
24
[ 497-19-8 ]
[ 598-21-0 ]
[ 57260-71-6 ]
[ 112257-12-2 ]
Reference：
[1] Patent: US2002/137755, 2002, A1,
25
[ 79-22-1 ]
[ 57260-71-6 ]
[ 219509-79-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 21, p. 3229 - 3233
[2] Patent: US6335324, 2002, B1, . Location in patent: Page column 67
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2807 - 2810
[4] Organic and Biomolecular Chemistry, 2012, vol. 10, # 31, p. 6420 - 6431
26
[ 6160-65-2 ]
[ 57260-71-6 ]
[ 196811-66-2 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: at 20 - 50℃; for 3 h; Stage #2: With ammonia In tetrahydrofuran; methanol at 0 - 60℃; for 20 h;
To a solution of 1-boc piperazine (5.0 g, 26.88 mmol) in dry THF (50 mL), 1,1-thiocarbonylimidazole (5.48 g, 29.56 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was heated at 50°C for 1 h. It was cooled down to 0 °C and methanolic ammonia solution (50 mL, 7 N) was added. The mixture was stirred at 60°C for 20 h. It was then diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography to give the title compound. Yield: 92percent (4.0 g, white solid). 1H NMR (400 MHz, DMSO-d6): δ 9.2 (m, 2H), 3.16-3.14 (m, 2H), 2.49-2.48 (m, 6H), 1.30 (s, 9H). LCMS: (Method A) 246.2 (M+H), Rt. 2.93 min, 95.3percent (Max).
92%
Stage #1: at 20 - 50℃; for 2 h; Stage #2: With ammonia In tetrahydrofuran; methanol at 0 - 60℃; for 20 h;
To a solution of 1-boc piperazine (5.0 g, 26.88 mmol) in dry THE (50 mL), 1,1-thio carbonylimidazole (5.48 g, 29.56 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was heated at 50°C for I h. It was cooled down to 0 °C and methanolic ammonia solution (50 mL, 7 N) was added. The mixture was stirred at 60°C for 20 h. It was then diluted with water and extracted with EtOAc. The organic layerwas dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography to give the title compound. Yield: 92percent (4.0 g, white solid). 1H NMR (400 MHz, DMSO-d6): 6 9.2 (m, 2H), 3.16-3.14 (m, 2H), 2.49-2.48 (m, 6H), 1.30 (s, 9H). LCMS: (Method A) 246.2 (M+H), Rt. 2.93 mm, 95.3percent (Max).
72%
Stage #1: at 20℃; for 1 h; Stage #2: With ammonia In tetrahydrofuran; water at 20℃; for 12 h;
The production of compound No. 26 proceeds according to the sequence of reaction steps shown in the following schemes: The first sub-step shown above was performed at 20° C. during 2 hours with a molar excess of CH2N2 (about 2 molar equivalents) in dry ether, then in a second sub-step (shown below) performed at 5° C. HCl gas was bubbled into the reaction mixture for 15 minutes, and the desired intermediate was obtained in 71percent yield. For the conversion from 3 to 4, the first sub-step shown above was performed at 20° C. during 1 hour with a molar excess of thio-carbonyldiimidazole (about 2 molar equivalents) in THF, then in a second sub-step performed at 20° C. for 12 hours a 25percent aqueous NH3 solution was added, and the desired intermediate was obtained in 72percent yield. The conversion from 4 to 5 was performed during 6 hours with 1 molar equivalent NaHCO3 at reflux in methanol, and the desired intermediate was obtained in 92percent yield. The conversion from 5 to 6 was performed during 3 hours at 20° C., and the desired intermediate was obtained in 90percent yield. The conversion from 6 to the final compound was performed during 6 hours at 20° C. in 1,2-dichloroethane (DCE) in the presence of a molar excess of triethylamine (1.2 molar equivalents).
69%
Stage #1: at 20 - 55℃; for 3 h; Stage #2: With ammonia In tetrahydrofuran; methanol at 20℃; for 72 h;
To a solution of di(lH-imidazol-l- yl)methanethione 2 (2.14 g, 12 mmol) in anhydrous THF (30 mL) was added tert-butyl piperazine-l-carboxylate 1 (1.86 g, 10 mmol) at ambient temperature. The mixture was allowed to stir at ambient temperature for 2 h, then the mixture was heated at 55 °C for 1 h. The mixture was concentrated under vacuum to about half the volume. To the remaining reaction mixture was added 2 M solution of ammonia in methanol (20 mL) and allowed to stir at ambient temperature for 3 days. The solvent was removed and the residue was purified by chromatography eluting with 50: 1 DCM/MeOH to afford the title compound (1.7 g, 69percent) as white solid. MS (ESI): m/z = 246.1 [M + H]+.
With triethylamine In <i>N</i>-methyl-acetamide; methanol
a 4-(2-Amino-ethyl)-piperazine-1-carboxylic Acid Tert-butyl Ester A solution of N-tert-butoxycarbonyl-piperazin (5 g, 26.8 mmol), triethylamine (7.44 ml, 53.6 mmol), and chloroethylamine (3.11 g, 26.8 mmol) in dimethylformamide (50 ml) was stirred at room temperature for 72 hours. The reaction mixture was filtered, partitioned between H2O and ethyl acetate. The aqueous phase was lyophilized, the residue stirred with methanol and the precipitate collected by suction. The precipitate was purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia=9/1/0.1) to give 1.6 g (26percent) of the desired product. MS m/z: 230 ((M+H)+, 91percent).
Reference：
[1] Patent: US6395737, 2002, B1,
30
[ 57260-71-6 ]
[ 192130-34-0 ]
Reference：
[1] ChemMedChem, 2014, vol. 9, # 4, p. 752 - 761
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 7, p. 2251 - 2259
31
[ 540-37-4 ]
[ 57260-71-6 ]
[ 170911-92-9 ]
Yield
Reaction Conditions
Operation in experiment
43%
With potassium phosphate; copper(l) iodide In ethylene glycol; isopropyl alcohol at 80℃; for 30 h;
A mixture of 4-iodoaniline (0.654 g, 3 mmol), piperazine-1-carboxylic acid tert-bvyl ester (0.67 g, 3.6 mmol), potassium phosphate (1.272 g, 6 mmol), ethylene glycol (0.33 ml) and copper iodide (0.03 g, 0.15 mmol) in 2-propanol (3 ml) was placed under argon in a sealed-tube and heated to 8O0C for 30 hours. After being cooled to room temperature, the medium was washed with water (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane: acetone, 70:30) to yield 43a (0.36 g, 1.3 mmol, 43percent) as a yellow powder.
Reference：
[1] Patent: WO2006/124118, 2006, A1, . Location in patent: Page/Page column 59
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 7, p. 2779 - 2796
32
[ 62-53-3 ]
[ 57260-71-6 ]
[ 170911-92-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen In 1,2-dichloro-ethane for 10 h; Irradiation
Adding aniline, piperazine-1-carboxylic acid tert-butyl ester, acridine salt visible light catalyst, 2,2,6,6-tetramethylpiperidine-nitrogen-oxide to anhydrous dichloroethane,The reaction environment was then replaced with oxygen three times and irradiated with a blue LED for a reaction time of 10 h.After the reaction is completed, the filtrate is spun dry and separated by column chromatography.The title product was obtained as a colorless white solid, yield 95percent.
Reference：
[1] Patent: CN108440451, 2018, A, . Location in patent: Paragraph 0024; 0025; 0026; 0031-0040; 0045-0061
33
[ 57260-71-6 ]
[ 170911-92-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[2] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2179 - 2191
[3] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 43 - 56
[4] Patent: WO2017/123542, 2017, A1,
[5] Patent: CN107245073, 2017, A,
[6] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 303 - 315
34
[ 371-40-4 ]
[ 57260-71-6 ]
[ 170911-92-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 3086 - 3090
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 4 h;
tert-Butyl 4-(4-nitrobenzyl)-1-piperazinecarboxylate (3). To a solution of tert-butyl 1-piperazinecarboxylate, 1 (0.74 g, 4 mmol), and 4-nitrobenzyl bromide, 2 (0.86 g, 4 mmol), in N,N-dimethylformamide (DMF, 5 mL) was added potassium carbonate (3 g), and the reaction mixture was stirred at room temperature for 4 h. The product was extracted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL.x.3). The solution was dried with sodium sulfate, and solvent was removed in vacuo. The product was purified by column chromatography, eluting with ethyl acetate to afford 3 as a solid (1.22 g, 95percent yield), mp 99-100° C. 1H NMR (DMSO-d6): 8.21-8.19 (d, 2H, J=8.8 Hz, Ar-H), 7.61-7.59 (d, 2H, J=8.0 Hz, Ar-H), 3.63 (s, 2H, CH2), 3.34-3.30 (m, 4H, partially obscured, 2.x.CH2), 2.35-2.32 (m, 4H, 2.x.CH2), 1.39 (s, 9H, 3.x.CH3). Anal. (C16H23N3O4) C, H, N.
95%
With triethylamine In acetonitrile at 20℃; for 0.333333 h;
A solution of piperazine-1-carboxylic acid tert-butyl ester (1.90 g, 10.2 mmol) and triethylamine (1.55 mL, 11.1 mmol) in CH3CN (9 mL) was treated with 1-bromomethyl-4-nitro-benzene (2.00 g, 9.26 mmol) as a solution in CH3CN (15 mL) at RT for 20 min. The mixture was concentrated in vacuo. The residue was taken up in CH2Cl2 (20 mL) and washed with water (1.x.20 mL). The aqueous layer was extracted with CH2Cl2 (2.x.20 mL), and the combined organic layers were washed with water (1.x.40 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 10-25percent EtOAc-hexane afforded the title compound (2.82 g, 95percent) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C16H23N3O4, 322.2 (M+H), found 321.9.
95%
With sodium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;
1-(Bromomethyl)-4-nitrobenzene (1 .08 g, 5.00 mmol) was added to a vigorously stirred mixture of fert-butyl piperazine-1 -carboxylate (1 .02 g, 5.50 mmol) and sodium carbonate (0.583 g, 5.50 mmol) in DMF (5 mL) at room temperature and the resulting mixture stirred for two hours. Water (25 mL) was added, and the resulting suspension was allowed to stand for five minutes then filtered. The collected solid was washed with water (25 mL) and air-dried to give the title compound (192) (1 .523 g, 95percent yield); 1H NMR (400 MHz, CDCI3) δ 8.32 - 8.10 (m, 2H), 7.51 (d, J = 8.8 Hz, 2H), 3.59 (s, 2H), 3.52 - 3.39 (m, 4H), 2.43 - 2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 4.58 min, m/z 266.1 [M-tBu+2H]\\ 222.1 [M-Boc+2Hf.
95%
With sodium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;
1-(Bromomethyl)-4-nitrobenzene (1.08 g, 5.00 mmol) was added to a vigorously stirred mixture of ferf-butyi piperazine-1-carboxylate (1.02 g, 5.50 mmol) and sodium carbonate (0.583 g, 5.50 mmol) in DMF (5 mL) at room temperature and the resulting mixture stirred for two hours. Water (25 mL) was added, and the resulting suspension was allowed to stand for five minutes then filtered. The collected solid was washed with water (25 mL) and air-dried to give the title compound (192) (1.523 g, 95percent yield); 1H N R (400 MHz, CDCI3) δ 8.32 - 8.10 (m, 2H), 7.51 (d, J = 8.8 Hz, 2H), 3.59 (s, 2H), 3.52 - 3.39 (m, 4H), 2.43 - 2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 4.58 min, m/z 268, 1 [ -tBu+2H]+, 222.1 [M-Boc+2H]•.
73.9%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 5 h;
A solution of 1-(bromomethyl)-4-nitrobenzene (1.000 g, 4.629 mmol), N,N-diisopropylethylamine (1.209 mL, 6.943 mmol) and tert-butyl piperazine1-carboxylate (0.948 g, 5.092 mmol) in acetonitrile (50 mL) was stuffed at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 percent to 20 percent) to give tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate as yellow oil (1.100 g, 73.9 percent).
71%
With triethylamine In dichloromethane at 20℃; for 3 h;
1-(bromomethyl)-4-nitrobenzene (1 mmol) was added to a solution of tert-butyl piperazine-1 -carboxylate derivative (1.2 mmol) (Compound (ST) with suitable substitution) and triethylamine (2 mmol) in DCM. The reaction is slightly exothermic. The resulting mixture was left stirring 3 hours at RT. The reaction was diluted withDCM, washed with water and diluted citric acid, dried and evaporated to give the compounds of examples 1,2,3.
a. 4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene 10.6 g (57 mmol) of N-tert.butoxycarbonyl-piperazine are dissolved in 100 ml of dichloromethane and combined with 10.7 g (63 mmol) of 4-nitrobenzylchloride and 24 ml (171 mmol) of triethylamine. The mixture is refluxed for 12 hours. After cooling to ambient temperature the reaction solution is washed several times with water. The organic phase is dried over magnesium sulphate and then evaporated to dryness. Yield: 17 g (99percent) of theory Melting point: 83-84° C. Rf value: 0.7 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 21, p. 3793 - 3796
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4417 - 4423
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 27, p. 6821 - 6830
[4] Journal of Organic Chemistry, 2005, vol. 70, # 22, p. 8924 - 8931
[5] Synthesis, 2010, # 24, p. 4287 - 4299
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5605 - 5609
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 17, p. 4817 - 4822
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4599 - 4604
41
[ 19493-44-8 ]
[ 57260-71-6 ]
[ 205264-33-1 ]
Yield
Reaction Conditions
Operation in experiment
66%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In phthalic acid dimethyl ester at 105 - 110℃;
Example 14: General Arylation Procedure E (as referred to in Schemes I and 2) EPO <DP n="84"/>[00183] 1-Chloro-isoquinoline (176 mg, 1.07 mmol), piperazine-1-carboxylic acid tert-butyl ester (420 mg, 2.26 mmol) and DBU (0.25 mL, 1.61 mmol) were added into DMP (2 mL). The mixture was heated to 105-1100C for overnight. The residue was diluted with water and extracted with ether. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to dryness. The resulting residue was purified by column chromatography (5percent to 10percent ethyl acetate/hexane) to give 222 mg of the desired product 4-isoquinolin-l-yl-piperazine-l-carboxylic acid tert-butyl ester (yield: 66percent).
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 4910 - 4925
43
[ 106-93-4 ]
[ 57260-71-6 ]
[ 655225-01-7 ]
Yield
Reaction Conditions
Operation in experiment
36%
at 30℃; for 72 h; Inert atmosphere
Example 24 tert-Butyl 4-(2-bromoethyl)piperazine-1-carboxylate A mixture of tert-butyl piperazine-1-carboxylate (5.0 g, 26.9 mmol), 1,2-dibromoethane (25 mL), DIPEA (3.5 g, 26.9 mmol) was stirred at 30° C. under argon for 72 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (1-2percent methanol/dichloroethane) to afford the desired product (2.8 g, 36percent yield) as a solid. ESI-MS m/z: 293.1[M+1]+.
Reference：
[1] Patent: US2014/288045, 2014, A1, . Location in patent: Paragraph 0575
[2] Organic and Biomolecular Chemistry, 2007, vol. 5, # 1, p. 132 - 138
44
[ 57260-71-6 ]
[ 655225-01-7 ]
Reference：
[1] Patent: US5994356, 1999, A,
45
[ 624-28-2 ]
[ 57260-71-6 ]
[ 153747-97-8 ]
Yield
Reaction Conditions
Operation in experiment
82%
With tris-(dibenzylideneacetone)dipalladium(0); [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; sodium t-butanolate In toluene at 80℃; for 4 h; Sealed tube; Inert atmosphere
To a stirred solution of 2,5-dibromopyridine (2 g, 10.7 mmol), sodium tert-butoxide (1.6 g,16.6 mmol), xantphos (400 mg, 0.7 mmol) and toluene (100 mL) in sealed tube argon waspurged for 5 min. To the reaction mixture tert-butyl piperazine-1-carboxylate (3 .4 g, 14.30mmol) followed by Pd2(dba)3 (200 mg, 0.21 mmol) was added and heated at 80 °C for 4 h(TLC indicated complete consumption of starting material). The reaction mixture was dilutedwith EtOAc (200 mL), water (100 mL), filtered through Celite bed and washed with EtOAc(2 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried overNa2S04 and concentrated under reduced pressure to give the crude product which waspurified by column chromatography (100-200 silica gel, 50 g, 10-20percent EtOAc-hexanes) toafford tert-butyl4-(5-bromo-2-pyridyl)piperazine-1-carboxylate (3 g, 82percent) as a yellow solid.LCMS (ESI+ ): m/z: 342.57 [M+Ht.
With potassium carbonate In acetonitrile at 110℃; for 12 h;
General procedure: To 1,4-dioxane (30 mL) were added tert-butyl piperazine-1-carboxylate (2.89 g, 15.51 mmol), 5-bromo-2-chloropyrimidine (2.00 g, 10.34 mmol) and potassium carbonate (2.86 g, 20.68 mmol) sequentially. The mixture was heated to 110 °C, after stirring for 12 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (3.15 g, 88.7percent).; The title compound was prepared using tert-butyl piperazine-1-carboxylate (1.45 g, 7.79 mmol),5-bromo-2-chloropyridine (1.00 g, 5.20 mmol) and potassium carbonate (1.44 g, 10.39 mmol) in acetonitrile (30 mL) according to the process described in Step 4 of Example 1, and the crude product was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (1.45 g, 8 1.5percent).MS (ESI, pos. ion) m/z: 342.1 [M+H] and‘H NMR (600 MHz, CDC13): (ppm) 8.17 (d, J 2.4 Hz, 1H), 7.52 (dd, J 9.0, 2.5 Hz, 1H), 6.52 (d, J 9.0 Hz, 1H), 3.55 - 3.49 (m, 4H), 3.49 - 3.45 (m, 4H), 1.46 (s, 9H).
58.8%
at 80℃; for 14 h;
To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symax fine chemicals) in dryDMF (lOOmL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 52.08mmol, Oakwood chemicals) were added and the reaction mixture was stirred at 80°C for 14h. It was cooled down to rt and poured on iced water (100 mL). The resulting precipitatewas filtered and washed with hexane (50 mL) to afford the title compound. Yield: 58.8percent(10 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.60(s, IH), 8.13 (dd, J= 8.6, 2.4Hz, IH), 7.54 (dd, J = 8.4, 0.4 Hz, IH), 3.22-3.20 (m, 4H), 2.61-2.59 (m, 4H), 1.42 (5, 9H).LCMS: (Method A) 343.9 (M +2H), Rt. 5.58 mm, 98.9percent (Max).
58.8%
With triethylamine In N,N-dimethyl-formamide at 80℃; for 14 h;
To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symax fine chemicals) in dry DMF (100mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyridine (10 g, 52.08 mmol, Oakwood chemicals) were added and the reaction mixture was stirred at 80°C for 14 h. It was cooled down to rt and poured on iced water (100 mL). The resulting precipitate was filtered and washed with hexane (50 mL) to afford the title compound. Yield: 58.8percent (10 g, off white solid). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1 H), 8.13 (dd, J = 8.6, 2.4 Hz, 1 H), 7.54 (dd, J = 8.4, 0.4 Hz, 1 H), 3.22-3.20 (m, 4H), 2.61 -2.59 (m, 4H), 1.42 (s, 9H). LCMS: (Method A) 343.9 (M +2H), Rt. 5.58 min, 98.9percent (Max).
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 12 h;
Step 1: K2CO3 (2.76 g, 20 mmol) was added into a mixture of 270-2 (1.76 g, 10 mmol) and 270-1 (2.24 g, 12 mmol) in DMF (20 mL). The mixture was stirred at 110°C for 12h, poured into H2O (100 mL). The obtained mixture was extracted with EtOAc (150 mL×3). The organic phases were combined and washed with brines (150 mL), dried over anhydrous sodium sulfate, filtrated, and concentrated under vacuum. The residue was purified by column chromatography (PE/EtOAc=7:1) to deliver 270-3 (3 g, yield 87.66percent) as colorless oil. MS ESI calcd for C14H2OBrN3O2 [M+H]+ 342, found 342.
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2433 - 2446
[2] Tetrahedron Letters, 2011, vol. 52, # 45, p. 5905 - 5909
[3] Chinese Chemical Letters, 2013, vol. 24, # 4, p. 303 - 306
[4] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6410 - 6414
[5] Patent: EP2773638, 2015, B1,
52
[ 4548-45-2 ]
[ 1227862-58-9 ]
[ 57260-71-6 ]
[ 119285-07-3 ]
Reference：
[1] Patent: US2011/224137, 2011, A1,
53
[ 179897-89-3 ]
[ 57260-71-6 ]
[ 791846-40-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
With triethylamine In dimethyl sulfoxide at 100℃;
In a pressure tube, 5-bromo-2-fluorobenzonitrile (2500 mg, 12.5 mmol), tert-butyl piperazine-1-carboxylate (2444.45 mg, 13.12 mmol), triethylamine (5.23 ml, 37.5 mmol) in dimethylsulfoxide (10 ml) were combined and refluxed at 100 C for ovn. The mixture was cooled, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried using sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel 5-60percent ethyl acetate/hexane to provide a light brown oil, tert-butyl 4-(4-bromo-2-cyanophenyl)piperazine-1-carboxylate (3660 mg, 80percent).
44%
With caesium carbonate In dimethyl sulfoxide at 120℃; for 1 h;
A mixture of 1—15 (3.0 g, 14.99 mmcl), 1-Boc-piperizine(3.33 g, 17.99 mmcl) and Cs2003 (9.68 g, 29.98 mci) in DMSO(60 ml) was stirred at 12000 for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (100 ml x 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give thedesired product 1—16 (2.5 g, 44percent) as yellow solid which wasused in the next step without purification; LCMS: m/z 312 [MtBu+1]
Reference：
[1] Patent: KR2016/37198, 2016, A, . Location in patent: Paragraph 2392-2394
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 20, p. 5095 - 5098
[3] Patent: WO2017/38909, 2017, A1, . Location in patent: Paragraph 0290; 0291
[4] Patent: WO2009/79593, 2009, A1, . Location in patent: Page/Page column 120
54
[ 57260-71-6 ]
[ 764667-65-4 ]
Reference：
[1] Patent: CN108178761, 2018, A,
55
[ 93777-26-5 ]
[ 57260-71-6 ]
[ 628326-05-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2667 - 2677
[2] Synthesis, 2010, # 24, p. 4287 - 4299
56
[ 57260-71-6 ]
[ 154590-35-9 ]
Reference：
[1] Patent: US2011/306606, 2011, A1,
[2] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 43 - 56
[3] Patent: US2014/121200, 2014, A1,
[4] Chemical Papers, 2018, vol. 72, # 2, p. 457 - 468
[5] Patent: EP2394993, 2011, A2,
57
[ 369-34-6 ]
[ 57260-71-6 ]
[ 154590-35-9 ]
Reference：
[1] Patent: WO2011/37731, 2011, A1,
58
[ 504-29-0 ]
[ 57260-71-6 ]
[ 571188-59-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen In 1,2-dichloro-ethane for 10 h; Irradiation
2-aminopyridine, piperazine-1-carboxylic acid tert-butyl ester,The acridine salt visible light catalyst, 2,2,6,6-tetramethylpiperidine-nitrogen-oxide is added to anhydrous dichloroethane, and then the reaction environment is replaced with oxygen three times, and irradiated with a blue LED.The reaction time is 10h. After the reaction is completed, the filtrate is spun dry and separated by column chromatography.The title product was obtained as a colorless white solid, yield 95percent.
Reference：
[1] Patent: CN108558792, 2018, A, . Location in patent: Paragraph 0025; 0026; 0027; 0034; 0041; 0048; 0055; 0062
With triethylamine; lithium chloride In dimethyl sulfoxide at 60 - 65℃; for 12 h;
To a vessel was added 5-bromo-2-nitropyridine (10.0 g, 1.0 equiv.) along with DMSO (25 ml_, 2.5 vol). N-Boc piperazine (13.8 g, 1.5 equiv.) was added, followed by triethylamine (7.5 g, 1.5 equiv.) and LiCI (2.1 g, 1.0 equiv.). The mixture was warmed to 60-65°C for a minimum of 12 hours.Water (5 ml_, 0.5 vol) was added slowly to the vessel at 60-65°C. The mixture was kept at 60-65 °C for one hour, then cooled to room temperature. The slurry was kept at 20-25 °C for 1 hour and then filtered onto a 2 Whatman™ paper filter. The cake was rinsed with water (50 ml_, 5 vol.). The crude solids were collected and transferred back to a clean vessel. Water (100 mL, 10 vol.) was added to the vessel containing the solids and the mixture was warmed to 35-40°C for 2 hours, then filtered while warm onto a 2 Whatman paper™ filter. The solids were rinsed with water (40 mL, 4 vol.) and allowed to dry overnight in the vacuum oven at 50-55°C. The 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester was isolated as a yellow solid (14.1 g collected; -93percent yield).
90%
With triethylamine; lithium chloride In dimethyl sulfoxide at 60 - 65℃; for 12 h;
500 mL of the reaction flask was added to the starting material III20.3 g (0.1 mol) and IV27.9 g (0.15 mol) of starting material,200mL DMSO,15.2 g (0.15 mol) of triethylamine and 4.2 g (0.1 mol) of lithium chloride were added with stirring,System temperature to 60-65 incubation reaction 12h.65 ° C to the system slowly adding 200mL of water,Stir for 1 h. The system was cooled to room temperature and stirred for 1 h. The mixture was filtered and washed thoroughly with water at 50-55 ° C overnight to give 27.7 g of pure product as a pale yellow solid. Yield: 90.0percent
88.87%
With triethylamine In dimethyl sulfoxide at 60℃; for 18 h; Inert atmosphere
Step 1 tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate To a solution of 5-bromo-2-nitropyridine (20.00 g, 98.53 mmol, 1.00 equivalent) in dimethylsulfoxide (52 mL) were added tert-butyl piperazine-1-carboxylate (24.00 g, 128.86 mmol, 1.31 equivalentalents) and triethylamine (20.00 g, 197.65 mmol. 2.01 equivalents). The solution was heated to 60°C and stirred for 18 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed completion of the reaction. The solution was diluted with water (200 mL), stirred for 30 minutes, and then filtered. The filter cake was washed with water and dried in vacuo to give a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 50: 1 to 20: 1) to give the title compound (27.00 g, 87.57 mmol, 88.87percent yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 9.03 Hz, 1H), 8.13 (d, J = 2.89 Hz, 1H), 7.21 (dd, J = 9.10, 2.95 Hz, 1H), 3.69-3.59 (m, 4H), 3.51-3.40 (m, 4H), 1.49 (s, 9H).
84.1%
With potassium carbonate In water; dimethyl sulfoxide at 70℃; for 28 h; Inert atmosphere
Step a): synthesis of 1-Boc-4-(6-nitro-3-pyridyl)piperazine (formula 3)Step b): A 1 -L RBF, was charged with 50 g of 5-Bromo-2-nitro-pyridine (0.246 mol, 1 .00 eq.), 175 ml DMSO and 35 ml water. To the resulting mixture was added 37.45 g potassium carbonate (0.271 mol, 1 .1 eq.) followed by 59.64 g boc-piperazine (0.320 mol, 1 .3 eq.). The mixture was heated to 70^ and stirred under argon until completion (approx. 28 h). The reaction was diluted with 315 ml of water and allowed to cool down to RT. After 2 h stirring, the solid was collected by filtration, washed with water (2 x 250 ml) and left in air at RT overnight to give crude wet 1 -Boc-4-(6-nitro-3- pyridyl)piperazine as yellow solid. HPLC (Method 1 ): 6.49 min (96.4percent) (230 nm)Crude product was suspended in 250 ml toluene, followed by concentrated under reduced pressure. The residue was dissolved in 200 ml toluene, under reflux. Resulting orange solution was allowed to cool down slowly to RT without stirring. After 3 h, precipitated solid was filtered, washed with toluene (50 ml), TBME (2 x 100 ml) and dried at 50<C/20 mbar for 7 h to yield 63.88 g of 1 -Boc-4-(6-nitro-3-pyridyl)piperazine as yellow solid (84.1 percent yield). HPLC (Method 1 ): 6.49 min (99.1 percent) (230 nm).
82%
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 80℃;
To a solution of 5-bromo-2-nitropyridine (40.0 g,197 mmol) in DMSO (150 mL) were added 1-Bocpiperazine(47.4 g, 252 mmol) and DIPEA (38 mL,219 mmol) . The reaction mixture was heated at 80 °C for11 h. The reaction mixture was poured into ice-water andthen extracted with EtOAc. The combined extracts werewashed with water and brine. The organic layer was driedover Na2SO4, filtered, and concentrated under reducedpressure. Purification by column chromatography (1:9methanol/ dichloromethane) gave 1-Boc- 4-(6-nitro-pyridin-3-yl)-piperazine (49.9 g, 82percent) as yellow solid. 1H NMR(400 MHz, CDCl3): δ 8.11 (d, J = 9.1 Hz, 1H), 8.08 (d, J =2.7 Hz, 1H), 7.18 (dd, J = 9.1, 2.8 Hz, 1H), 3.65–3.56 (m,4H), 3.48–3.38 (m, 4H), 1.45 (s, 9H).
80%
With N-ethyl-N,N-diisopropylamine In acetonitrile for 72 h; Reflux
To a stirred solution of 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol) and piperazine-1-carboxylic acid tert-bλxtyl ester (4.97 g, 26.7 mmol) in CH3CN (60 ml) is added DIPEA (4.65 mL, 26.7 mmol). The mixture is heated at reflux for 72 hours then cooled to room temperature and the precipitated product collected by filtration. The filtrate is concentrated and purified by flash column chromatography eluting with 30percent EtO Ac/petrol. The combined products are re-crystallized from EtO Ac/petrol to give 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-huty\\ ester, (4.50 g, 80percent yield). MS(ESI) m/z 308 (M+H)+
80%
at 120℃; for 3 h;
A solution of 1-Boc-piperazine (15.0 mmol) and 5-bromo-2-nitropyridine (5.00 mmol) in N-methyl pyrrolidone (15 mL) was stirred at 120 °C for 3 h. The reaction mixture was diluted with water and the precipitate was collected by filtration to give 2 (80percent) as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ 8.10–8.08 (d, J = 9.2 Hz, 1H, ArH), 7.96–7.95 (d, J = 3.0 Hz, 1H, ArH), 7.33–7.30 (dd, J = 3.4 Hz, 1H, ArH), 3.66–3.63 (m, 4H, piperazine-CH2), 3.43–3.41 (m, 4H, piperazine-CH2), 1.47 (s, 9H, t-butyl-CH3).
80%
With N-ethyl-N,N-diisopropylamine In acetonitrile for 72 h; Reflux
Nitrile analogues can be made by the following. To a stirred solution of 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol) and piperazine-1-carboxylic acid tert-butyl ester (4.97 g, 26.7 mmol) in CH3CN (60 ml) is added DIPEA (4.65 mL, 26.7 mmol). The mixture is heated at reflux for 72 hours then cooled to room temperature and the precipitated product collected by filtration. The filtrate is concentrated and purified by flash column chromatography eluting with 30percent EtOAc/petrol. The combined products are re-crystallized from EtOAc/petrol to give 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester, (4.50 g, 80percent yield). MS(ESI) m/z 308 (M+H)+
79%
With triethylamine In dimethyl sulfoxide at 65 - 70℃; for 30 h;
EXAMPLE 2: Preparation of 4-(6-Nitro-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester; B Exampl e 2A: Preparation of 4-(6-Nitro-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester To 1.0 kg (5 mol) 5-bromo-2-nitropyridine was added 1.2 kg {6.4 mol) boc piperazine (tert-Butyl piperazine-1-carboxylate) in 2.6L DMSO and 0.5 kg triethylamine under nitrogen. The mixture was heated to 65-700C and held for 30~hours after which some solids precipitated. Water was added and the reaction cooled to 25°C over 2hrs. The resulting slurry was filtered, washed and dried at 45°C to give 1.2kg (79percent crude yield) of canary yellow solid intermediate (2A), which was used without further purification in the subsequent step.
79%
With tetra-(n-butyl)ammonium iodide; potassium carbonate In dimethyl sulfoxide at 120℃; for 16 h;
Synthesis of compound 107.1 To a solution of 78.4(1. Og, 4.92mmol, 1.0 eq) in DMSO (10 ml) was added Bu4NI (0.18g, 0.049 mmol, 0.1 eq), tert-butyl piperazine-1- carboxylate (1.37g, 7.38mmol, 1.5eq), and K2CO3 (1.36g, 9.85mmol, 2eq). Reaction mixture was heated at 120° C for 16 hours.Upon completion reaction mixture was poured into water and product was extracted with ethyl acetate. Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure. The crude was purified using column chromatography to provide 107.1 (1.2 g, 79percent). MS (ES): m/z 279.23 [M+H]+.
67%
for 72 h; Heating / reflux
Preparation XX <n="116"/>Synthesis of 4-r6-amino-pyridin-3-ylVpiperazine-l-carboxylic acid tert-butyl ester Step 1. Synthesis of 4-f6-nitro-pyridin-3-yl)-piperazine-l-carboxyric acid tert-butyl ester; A mixture of 5-bromo-2-nitropyridine (4.93g, 24.30 mmol) and tert-butyl piperazine-1-carboxylate (5.Og, 26.7 mmol) in acetonitrile (60ml) was heated at refluxed for 3 days. The solvent was evaporated and the solid residue purified by flash chromatography on silica eluting with EtO Ac/Petrol (1:3) and recrystallised from EtO Ac/Petrol to afford the title compound as an orange solid (5.Og, 67percent) (LCMS: Rt 2.8, [M+H]+ 309).
60%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 110℃; for 72 h;
To the reaction flask was added 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol), Piperazine-1-carboxylic acid tert-butyl ester (4.97 g, 26.7 mmol)Diisopropylethylamine (4.65 mL, 26.7 mmol) and acetonitrile (60 mL)The mixture was stirred at 110 ° C for 72 hours.Cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10/1)The resulting residue was purified to give the title compound (4.5 g, white solid) in 60percent yield.
60%
With potassium carbonate; potassium iodide In dimethyl sulfoxide at 120℃;
Compound 11a (13.7 g, 73.9 mmol), compound 11b (10 g, 49.3 mmol), potassium iodide (81.8 mg, 0.493 mmol)and potassium carbonate (13.6 g, 98.6 mmol) were added into DMSO (100 mL). The reaction solution was stirred at120 °C overnight and then cooled to room temperature, adjusted to pH 7 with hydrochloric acid (1 mol) and then extractedwith dichloromethane. The aqueous phase was alkalize by saturated solution of sodium carbonate, and then extractedwith dichloromethane again. The organic phase was combined and dried over anhydrous Na2SO4, concentrated andthen slurried by water to give compound 11c (9.2 g, 60percent). LCMS:309(M+H)+, RT=1.710min.
50%
With N-ethyl-N,N-diisopropylamine In acetonitrile for 2 h; Reflux
N,N-Diisopropylethylamine (4.77g, 36.94mmol) was added to a solution of 82 5-bromo-2-nitropyridine (5.00g, 24.63mmol) and 100 tert-butyl piperazine-1-carboxylate (5.10g, 27.09mol) in 101 acetonitrile ([ACN] 30mL). The mixture was refluxed for 2h, cooled to RT, concentrated under a vacuum, and purified by silica gel column chromatography (from 102 PE/86 EA=1:1 to 103 DCM/87 MeOH=20:1) to obtain 104 tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (3.80g; yield, 50percent) as a yellow solid. Pd/C (100.0mg) was added to a solution of tert-butyl 4-(6-nitropyridin-3-yl) piperazine-1-carboxylate (925.0mg, 3.0mmol) in EA/MeOH (10 mL/10mL). The mixture was degassed by flushing with H2, stirred at RT under a H2 atmosphere for 2h, and filtered and concentrated under a vacuum to obtain INT-3 (792.0mg; yield, 95percent) as an off-white solid. ESI-MS: m/z 279.2 [M+H]+.
45.2%
With triethylamine In dimethyl sulfoxide for 12 h; Heating
4.1.39 Tert-Butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (10a) A mixture of 5-bromo-2-nitropyridine (3.4 g, 16.9 mmol), tert-butyl piperazine-1-carboxylate (3.2 g, 16.9 mmol) and Et3N (3.4 g, 33.8 mmol) in DMSO (20 mL) was stirred at 75 °C for 12 h. The reaction mixture was cooled down to room temperature and diluted with water (10 mL), and then the product was extracted three times with EtOAc (25 mL). The combined organic layer was dried over Na2SO4, and the solvent was removed in vacuo. The residue product was purified on a silica gel column using petroleum ether/EtOAc (4:1, v/v) as eluent to afford 10a (2.19 g, 45.2percent) as a white solid. MS (ESI) m/z 309.2 [M+H]+; 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 9.10 Hz, 1H), 8.13 (d, J = 3.00 Hz, 1H), 7.22 (dd, J = 3.20 Hz, 9.20 Hz, 1H), 3.65 (t, J = 5.00 Hz, 4H), 3.46 (t, J = 5.00 Hz, 4H), 1.49 (s, 9H).
40.63%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃;
Compound 38 (10.2 g, 49.52 mmol) was added to the reaction flask, respectively,Compound 36 (10.40 g, 54.47 mmol)Dissolved in DMF,DIPEA (7.78 g, 59.42 mmol) was added.50 ° C under the conditions of reaction,TLC tracking, to be completely complete,The reaction system is poured into ice water,There is a yellow solid precipitation,Filter solids, beat with EA,Dried to obtain 6.20 g of compound 39,Yield: 40.63percent.
37%
With potassium carbonate In dimethyl sulfoxide at 65℃;
Into a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) were added K2CO3 (40 g, 296 mmol) and teri-butyl piperazine-l-carboxylate (28g, 148 mmol). The mixture was stirred at 65 degree for overnight. After cooling down, it was poured into water (2 L). The solid precipitated was collected and dried under vacuum. It was then further purified by flash column eluting with 20:1 petroleum ether/ethyl acetate and then with methylene chloride to give 188a as a yellow solid (17 g, 37percent). MS: [M+H]+ 309.
37%
With potassium carbonate In dimethyl sulfoxide at 65℃;
To a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) was added K2CO3 (40 g, 296 mmol) and tert-butyl piperazine-1-carboxylate (28 g, 148 mmol). The mixture was stirred at 65° C. overnight. After cooling down, it was poured into water (2 L). The precipitated solid was collected and dried under vacuum. It was then further purified by flash column eluting with 20:1 petroleum ether/ethyl acetate and then with methylene chloride to give 115a as a yellow solid (17 g, 37percent). MS: [M+H]+309.
37%
With potassium carbonate In dimethyl sulfoxide at 65℃;
Example 101g tert-Butyl 4-(6-Nitropyridin-3-yl)piperazine-1-carboxylate 101g Into a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) were added K2CO3 (40 g, 296 mmol) and tert-butyl piperazine-1-carboxylate (28g, 148 mmol). The mixture was stirred at 65 °C overnight. After cooling down, it was poured into water (2 L). The solid precipitated was collected and dried under vacuum. It was then further purified by flash column eluting with 20:1 petroleum ether/ethyl acetate and then with methylene chloride to give 101g as a yellow solid (17 g, 37percent). MS: [M+H]+ 309.
33%
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 36 h;
4-(6-nitro-3-pyridinyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester A solution is prepared of 1 g (4.9 mM) of 2-nitro-5-bromopyridine and 917 mg (4.9 mM) of N-Boc-piperazine in 10 ml of dimethylformamide and 1.02 g (7.4 mM) of potassium carbonate are added. The reaction mixture is agitated at 120° C. for 36 hours and then cooled. 50 ml of water are then added and extraction is carried out with ethyl acetate. The organic phase obtained is washed with water, dried and concentrated under reduced pressure. The crude product is purified by silica gel chromatography in eluding with the aid of a toluene/isopropanol mixture (98/2; v/v). The product sought after is thus obtained as a yellow solid (yield=33percent). 1H NMR (250 MHz, DMSO) δ: 8.24 (d, 1H); 8.17 (d, 1H); 7.46 (dd, 1H); 3.50 (m, 8H); 1.42 (s, 9H).
400 mg
at 120℃; for 18 h;
Dissolved 5-bromo-2-nitropyridine (1.0 g, 4.92 mmol) and tert-butyl piperazine-1- carboxylate (1.1 g, 5.91 mmol) in N-methylpyrrolidine and stirred at 120 C for 18 h. Thereafter the reaction mixture was cooled to 30 C and diluted with water and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was washed with brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give crude product. The crude product was purified by column chromatography to give 400 mg of the desired product. LC-MS: m/z calcd for C14H20N4O4, 308.33, no ionization 1H NMR (500 MHz, CDC13): δΗ 1.4 (9H, s, 0(CH3)3), 3.38 (4H, t, J = 5 Hz, NCH2CH2N), 3.58 (4H, t, J = 5 Hz, NCH2CH2N), 7.14 (1H, dd, Jl = 5 Hz, J2 = 10 HZ, ArCH), 8.06 (1H, d, J = 5 Hz, ArCH) and 8.11 (1H, d, J = 10 Hz, ArCH).
Reference：
[1] Patent: WO2014/128588, 2014, A1, . Location in patent: Page/Page column 32; 33
[2] Patent: CN105153149, 2017, B, . Location in patent: Page/Page column 2; 7
[3] Patent: EP3269715, 2018, A1, . Location in patent: Paragraph 0061; 0121; 0122
[4] Patent: WO2016/30439, 2016, A1, . Location in patent: Page/Page column 29; 38
[5] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 6, p. 3125 - 3140
[6] Medicinal Chemistry Research, 2018, vol. 27, # 6, p. 1666 - 1678
[7] Patent: WO2010/20675, 2010, A1, . Location in patent: Page/Page column 50
[8] European Journal of Medicinal Chemistry, 2014, vol. 81, p. 341 - 349
[9] Patent: US2016/8367, 2016, A1, . Location in patent: Paragraph 0204; 0205
[10] Patent: WO2008/32157, 2008, A2, . Location in patent: Page/Page column 25
[11] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00669; 00670
[12] Patent: WO2008/7123, 2008, A2, . Location in patent: Page/Page column 114-115
[13] Patent: CN106608879, 2017, A, . Location in patent: Paragraph 0154-0157
[14] Patent: EP3284746, 2018, A1, . Location in patent: Paragraph 0095
[15] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 1 - 28
[16] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 2, p. 348 - 364
[17] Patent: CN106905245, 2017, A, . Location in patent: Paragraph 0304; 0305; 0306; 0307; 0308
[18] Journal of Medicinal Chemistry, 2018, vol. 61, # 6, p. 2227 - 2245
[19] Patent: WO2011/140488, 2011, A1, . Location in patent: Page/Page column 270
[20] Patent: US2013/116262, 2013, A1, . Location in patent: Paragraph 0313; 0314
[21] Patent: EP2773638, 2015, B1, . Location in patent: Paragraph 0168; 0169; 1404
[22] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 6, p. 608 - 613
[23] Patent: US2006/178360, 2006, A1, . Location in patent: Page/Page column 27
[24] Patent: WO2010/101849, 2010, A1, . Location in patent: Page/Page column 61
[25] Patent: WO2013/90497, 2013, A1, . Location in patent: Page/Page column 50; 51
[26] Patent: WO2014/195274, 2014, A1, . Location in patent: Page/Page column 48-49
[27] Patent: CN106749259, 2017, A, . Location in patent: Paragraph 0011; 0046; 0110; 0122; 0134
[28] Patent: CN108586452, 2018, A, . Location in patent: Paragraph 0024-0035
64
[ 52092-47-4 ]
[ 57260-71-6 ]
[ 571189-16-7 ]
Yield
Reaction Conditions
Operation in experiment
63.81%
With potassium carbonate In dimethyl sulfoxide at 100 - 110℃; Microwave irradiation
A microwave vial was charged with 5-chloro-2-nitropyridine (1 g, 6.31 mmol), 1 -boc-piperazine (1 .29g, 6.94mmol) and potassium carbonate (3.3ml_, 18.92mmol), which was suspended in DMSO (15ml_). The resulting mixture was irradiated for 1 hour at 100°C. After this time, the mixture had solidified. LC-MS showed the reaction had not gone to completion. The solid mixture was then transferred to a flask along with DMSO (5ml_) and heated to 1 10°C, at which point the solid mixture had melted. This was left heating overnight, after which LC-MS showed product formation and no starting material. Reaction was allowed to cool. The reaction mixture was then added to water and extracted with EtOAc (x3). The organics were then combined, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness, affording an orange solid. Purification by flash column chromatography was then performed, (40g S1O2, eluting with 0-50percent EtOAc in heptane). The fractions containing product were combined and concentrated to dryness, affording tert-butyl 4-(6- nitro-3-pyridyl)piperazine-1 -carboxylate (1 .24g, 4.02mmol, 63.81 percent yield) as a bright orange/yellow solid. MS Method 2: RT: 1 .61 min, ES+ m/z 309.1 [M+H]+ H NMR (400MHz, CDC ) δ/ppm: 8.10-8.13 (d, J=9.1 Hz, 1 H), 8.06-8.07 (d, J=3.0Hz, 1 H), 7.12-7.16 (dd, J=9.2, 3.0Hz, 1 H), 3.55-3.59 (m, 4H), 3.36-3.41 (m, 4H), 1 .42 (s, 9H).
Stage #1: With sodium t-butanolate In toluene at 42℃; for 22 h; Inert atmosphere Stage #2: With acetic acid In water; toluene for 0.166667 h;
5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde Toluene (9.7 L) was introduced into a reactor and degassed using vacuum /nitrogen. Under nitrogen at 23°C was palladium acetate (11.0 g, 0.049 mol, 0.01 equiv.) was loaded and the mixture was stirred until complete dissolution of palladium. A solution of tri-tert-butyl-phosphine (10.0 g, 0.049 mol, 0.01 equiv.) in toluene (0.3 L) was then added, followed by the addition of 5-bromo-2-hydroxybenzaldehyde (1000 g, 4.97 mol, 1 equiv.), tert-butyl-1-piperazinecarboxylate (1065.4 g, 5.72 mol, 1.1 equiv.) and sodium-tert-butoxide (1052.4 g, 10.9 mol, 2.2 equiv.). The resulting yellow-orange solution was stirred for 22 h at 42°C. The red-brownish slurry was mixed with a mixture (pH around 5-6) of distilled water (8 L) and glacial acetic acid (800 mL), and stirred for 10 min. The organic phase was separated from the aqueous phase and washed twice with distilled water (2 x 8 L). The organic phase was then dried by addition of sodium sulphate (2.5 kg), stirred for 30 min. and filtered. The resulting dark-orange organic phase was weighed (9.65 kg) and an aliquot (100 g) was taken. The aliquot was concentrated in vacuo to yield a dark-orange oil which was purified by column chromatography (SiO2, h: 30 cm, d: 4 cm, eluant: MTBE/heptane 1:1). The named compound was obtained as yellow crystals (8.9 g). Calculation of the total yield from the aliquot gave 56percent. MS (ES+): 307 (M+H).
Reference：
[1] Patent: EP2110374, 2009, A1, . Location in patent: Page/Page column 30
[2] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 18, p. 4843 - 4852
69
[ 13716-12-6 ]
[ 1761-61-1 ]
[ 57260-71-6 ]
[ 343306-50-3 ]
Yield
Reaction Conditions
Operation in experiment
51%
With sodium t-butanolate In n-heptane; water; toluene
1) Synthesis of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde 0.58 g of bis(dibenzylideneacetone)palladium and 0.16 g of tri-tert-butylphosphine are added under nitrogen to 200 ml of toluene, and the resultant solution, which becomes dark red, is stirred at 20° for 30 minutes. 10 g of 5-bromo-2-hydroxybenzaldehyde, 10.2 g of tert-butyl 1-piperazinecarboxylate and 7.2 g of sodium tert-butoxide are then added. The mixture is stirred at 60° for 24 hours and cooled, 800 ml of water are added, and the mixture is extracted with 2*500 ml of ethyl acetate. The organic phases are combined and washed with 300 ml of water, and the solvent is removed at 30° under reduced pressure. The dark-orange oil which remains (11 g) is purified by chromatography (300 g of silica gel; MTB ether/heptane 5:1; 1.5 litres) leaving 7.8 g of pale-yellow crystals (51percent), m.p. 84-86°; MS 306 (M+), 250 (100percent), 233, 176, 164.
Reference：
[1] Patent: US2003/125558, 2003, A1,
70
[ 369-34-6 ]
[ 57260-71-6 ]
[ 154590-34-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate In N,N-dimethyl-formamide at 90 - 95℃; for 18 h;
Step A. 4-(2-Fluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. A mixture of piperazine-1 -carboxylic acid tert-butyl ester (10.0 g, 53.7 mmol), 3,4-difluoronitrobenzene (6.0 ml_, 54.2 mmol) and K2CO3 (22.0 g, 159 mmol) in DMF (60.00 mL) was heated to about 90-950C for 18 h. The resulting mixture was cooled to room temperature and diluted with ethyl acetate (700.0 mL) and water (200.0 mL). The organic phase was separated and washed with water (3x300 mL), dried (Na2SO4), filtered and concentrated to yield a yellow solid (17.0O g, 97 percent). 1H NMR (CDCI3): 8.01 -7.96 (m, 1 H), 7.95-7.88 (m, 1 H), 6.90 (t, J = 8.8, 1 H), 3.65-3.55 (m, 4H), 3.28-3.20 (m, 4H), 1.48 (s, 9H).
91%
With potassium carbonate In N,N-dimethyl-formamide at 5℃;
To an ice cold (5 °C) solution of piperazine-l -carboxylic acid tert-butyl ester (17.56 g, 94.28 mmol) in dry DMF (50 mL) was added K2CO3 (12.8 g, 94.28 mmol) and the slurry stirred for 15 minutes. 1 ,2-Difluoro-4-nitro-benzene (15.0 g, 94.28 mmol) was added to the slurry and the reaction mixture stirred vigorously for 2 h. The mixture was filtered and the insoluble material washed with DMF (25 mL). The combined filtrate was evaporated to dryness under reduced pressure, and the yellow solid that formed was re-crystallized from DCM to affording 30.1 g (91percent) of the title compound. 1H NMR (400 MHz, DMSO-i/6) δ (ppm): 8.04 - 7.99 (m, 2H), 7.17 (t, J= 9.0 Hz, 1H), 3.48 (t, J = 4.8 Hz, 4H), 3.25 (t, J= 5.2 Hz, 4H), 1.42 (s, 9H); l 9F NMR (376 MHz, DMSO-4 δ (ppm): - 1 19.79 (dd, J = 13.8, 9.0 Hz).
91%
With triethylamine In methanol at 50 - 60℃; for 17 h;
3-4-1: Preparation of [3-fluoro-4-BOC-piperazino)]nitrobenzene To 100 ml of methanol were sequentially added 5 g (31.4 mmol) of 3,4-difluoronitrobenzene, 5.3 ml (37.7 mmol) of triethylamine and 6.4 g (34.5 mmol) of Boc-piperazine, followed by reaction at a temperature of 50 to 60° for 17 hours. After the reaction was complete, the reaction liquid was cooled to room temperature and 20 ml of water was slowly added dropwise thereto, followed by stirring for 4 hours. The resulting solid was filtered, washed with a 1:1 (v/v) solution of water and methanol and then dried under vacuum at about 40° to afford 9.3 g (yield: 91percent) of the desired compound. 1H-NMR (DMSO-d6): 1.42(s, 9H), 3.25(m, 4H), 3.48(m, 4H), 7.18(3, 1H), 8.03(m, 2H).
91%
With triethylamine In methanol at 50 - 60℃; for 17 h;
Example 3-4-1 Preparation of [3-fluoro-4-(BOC-piperazino)]nitrobenzene To 100ml of methanol were sequentially added 5g (31.4mmol) of 3,4-difluoronitrobenzene, 5.3ml (37.7mmol) of triethylamine and 6.4g (34.5mmol) of BOC-piperazine, followed by reaction at a temperature of 50 to 60°C for 17 hours. After the reaction was complete, the reaction liquid was cooled to room temperature and 20ml of water was slowly added dropwise thereto, followed by stirring for 4 hours. The resulting solid was filtered, washed with a 1:1 (v/v) solution of water and methanol and then dried under vacuum at about 40°C to afford 9.3g (yield: 91percent) of the desired compound. 1H-NMR (DMSO-d6): 1.42(s, 9H), 3.25(m, 4H), 3.48(m, 4H), 7.18(3,1H), 8.03(m, 2H).
72%
for 16 h; Heating / reflux
Preparation 57; 4-(2-Fluoro-4-nitro-phenyl)-piperazine- 1 -carboxylic acid tert-bvXyl ester; Dissolve 3,4-difluoronitrobenzene (2.0 g, 12.6 mmol) in acetonitrile (35 mL) and add piperazine-1 -carboxylic acid tert-bvAyl ester (4.7 g, 25.2 mmol). Heat the mixture at reflux for 16 h. Cool the mixture to room temperature and concentrate in vacuo. Partition the residue between dichloromethane (75 mL) and water (75 mL), separate the organic portion and extract the aqueous portion with dichloromethane (2 x 25 mL).Combine the organics and dry (Na2SO4), filter, and concentrate in vacuo to give 2.83 g (72percent) of the title compound. MS/ES m/z 270.2 [M-tertBu+H]+.
Reference：
[1] Patent: WO2009/79597, 2009, A1, . Location in patent: Page/Page column 58-59
[2] Patent: WO2011/37731, 2011, A1, . Location in patent: Page/Page column 113-114
[3] Patent: US2011/306606, 2011, A1, . Location in patent: Page/Page column 15
[4] Patent: EP2394993, 2011, A2, . Location in patent: Page/Page column 23
[5] Patent: WO2007/146758, 2007, A2, . Location in patent: Page/Page column 53
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1302 - 1305
[7] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5552 - 5556
[8] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 43 - 56
[9] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0251; 0252
[10] Chemical Papers, 2018, vol. 72, # 2, p. 457 - 468
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; for 12 h;
(1) Preparation of tert-butyl 4-(pyrimidin-5-yl)piperazin-1-carboxylate To a 100 mL eggplant-shaped bottle were added 5-bromopyrimidine (3.16 g, 20 mmol), tert-butyl piperazin-1-carboxylate (3.72 g, 20 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.49 g, 4 mmol), cesium carbonate (13.0 g, 40 mmol) and tris(dibenzylideneacetone)dipalladium (1.83 g, 2 mmol); and toluene (80 mL) was added. The reaction was carried out at 90°Cunder the protection of nitrogen for 12 h. The mixture was filtrated under suction, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol=50:1) to get the title compound (3.1 g, yield: 58.7percent).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; butan-1-ol In DMF (N,N-dimethyl-formamide) at 20℃; for 22 h;
To a solution of 4-aminobenzoic acid (411 mg, 3.00 mmol) in DMF (3.0 mL) at room temperature was added EDC (862 mg, 4.50 mmol), HOBt (608 mg, 4.50 mmol), triethylamine (606 mg, 0.835 mL, 6.00 mmol) and tert-butyl piperazinecarboxylate (671 mg, 3.60 mmol). The mixture was stirred for 22 h, and then 2 N aq. NaOH was added to adjust the PH>10. The mixture was extracted with ethyl acetate, and the organic layer was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatograghy eluted with EtOAc:hexanes (50 to 90percent EtOAc) to give 4-(4-amino-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (796 mg, 87percent) as a colorless oil. MS (ES+): m/z = 306.2
Reference：
[1] Patent: WO2015/22663, 2015, A1,
[2] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 247 - 258
78
[ 4487-59-6 ]
[ 57260-71-6 ]
[ 193902-78-2 ]
Yield
Reaction Conditions
Operation in experiment
93%
With potassium carbonate In dimethyl sulfoxide at 50℃; for 3 h;
2-Bromo-5-nitro-pyridine (11.39 g, 56.1 mmol), tetrabutylammonium iodide (TBAI) (1.04 g, 0.05 mmol), potassium carbonate (8.53 g, 61.7 mmol) and piperazine-1-carboxylic acid tert-butyl ester (11.5 g, 61.7 mmol) were mixed together in DMSO (100 mL) and gently warmed to 50 C. for 3 hours and cooled to room temperature overnight. The reaction was diluted with EtOAc (200 mL), the salts were filtered and then the EtOAc was evaporated to leave the DMSO solution. This was diluted with water and a precipitate formed. This precipitate was filtered, washed with water, and then dried in an oven vacuum to give 4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (16.1 g, 93percent) as a light orange solid. 1H NMR (400 MHz, CDCl3) ppm 1.47 (s, 9H), 3.55 (m, 4H), 3.75 (m, 4H), 6.55 (d, J=9.3 Hz, 1H), 8.21 (dd, J=9.5, 2.7 Hz, 1H), 9.03 (d, J=2.7 Hz, 1H). 4-(5-Nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (16.0 g, 51.9 mmol) was dissolved in THF (400 mL), RaNi (4 g) added and placed under a H2 atmosphere at 50 psi for 5 h. The catalyst was removed by filtration through celite and the solvent evaporated in vacuo to give 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (14.5 g, 100percent). 1H NMR (400 MHz, CDCl3) ppm 1.46 (s, 9H), 3.31 (m, 6H), 3.53 (m, 4H), 6.56 (d, J=8.8 Hz, 1H), 6.98 (dd, J=8.8, 2.9 Hz, 1H), 7.78 (dd, J=2.9, 0.7 Hz, 1H). m/z 279.1 (M+1).
71%
With potassium carbonate In water at 150℃; for 0.25 h; Microwave irradiation
In a 5 mL glass microwave tube were placed 2-bromo-5-nitro pyridine 1 (1015 mg, 5 mmol), 1-Boc-piperazine 2a (930 mg, 5 mmol), K2CO3 (690 mg, 5 mmol), H2O (3 mL) and a magnetic stir bar. The vessel was sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 300 W initial was used, the temperature being ramped from rt to 150 °C. Once 150 °C was reached, the reaction mixture was held at this temperature for 15 min. Thereafter the mixture was allowed to cool to rt, extracted with ethyl acetate (15 mL) and washed with water (10 mL) then dried over MgSO4. After filtration, the solvent was evaporated to afford a yellow solid 1100 mg (71percent) yield. 1H NMR CDCl3 δ = 9.03 (1H, s), 8.18 (1H, d, J = 9.1 Hz), 6.53 (1H, d, J = 9.5 Hz), 3.77-3.52 (8H, m), 1.44 (9H, s). 13C NMR CDCl3 δ = 164.2, 154.7, 145.3, 135.0, 133.2, 105.0, 79.8, 52.9 (2C), 46.0 (2C), 28.4 (3C).
70%
With caesium carbonate In toluene at 20 - 80℃; for 1.25 - 2.25 h;
BINAP [[ (R)-2,] 2'-Bis [(DIPHENYLPHOSPHINO)-1,] [1APOS;-BINAPHTHYL]] (2.5 g, 3.94088 mmoles) and tris (dibenzylidene acetone) dipalladium (o) (7.2 g, 7.88177 mmoles) were taken in dry toluene (400 ml) and stirred under argon atmosphere at room temperature for 15 minutes. 2-Bromo-5-nitro-pyridine (40 g, 197.044 mmoles) was dissolved in toluene (200 ml) and added to the reaction mixture followed by N-t-butoxycarbonyl piperazine (44 g, 236.45 mmoles). To this cesium carbonate (90 g, [275,] 862 mmoles) was added at room temperature under argon atmosphere. The reaction mixture was heated to [80 °C] for 1-2 hours under argon atmosphere and was cooled to RT and filtered through celite. Washed the residue thoroughly with ethylacetate. The combined filtrates were washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel column using dichloromethane and methanol as eluent to yield the title compound (42.4 g, yield 70percent).
54%
for 2.5 h; Reflux
Example 197a tert-Butyl 4-(5-Nitropyridin-2-yl)piperazine-1-carboxylate 197a A mixture of 2-bromo-5-nitropyridine (5.0 g, 24.6 mmol), tert-butyl piperazine-1-carboxylate (13.8 g, 74.2 mmol), acetonitrile (150 mL) was stirred at reflux for 2.5 h. After the reaction was completed, the solvent was removed under reduced pressure to afford 197a as a yellow solid (4.1 g, 54percent). MS-ESI: [M+H]+ 309.
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 16 h;
Step 1 : t-Butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (B-2) To 5-nitro-2-chloropyridine (10.0 g, 0.0631 mol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 ml_) was added N1N- diisopropylethylamine (24.5 g, 31.3 ml_, 0.189 mol). The reaction mixture was heated at 100 0C for 16 h then cooled to RT and concentrated. Water (300 ml_) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 5percent EtOAc-CH2CI2) gave t-butyl 4-(5-nitropyridin-2-yl)piperazine-1 -carboxylate (B-2) as a yellow solid (19.45 g, 100percent yield). MS (M+1): 309.
100%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 16 h;
Intermediate B-54-(5-Aminopyridin-2-yl)-N-(2-fluorophenyl)piperazine- 1 -carboxamide (B-5) Step 1 : t-Butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (B-2)To 5-nitro-2-chloropyridine (10.0 g, 0.0631 raol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 mL) was added N,N-diisopropylethylamine (24.5 g, 31.3 mL, 0.189 mol). The reaction mixture was heated at 100 °C for 16 h then cooled to RT and concentrated. Water (300 mL) was added, and the aqueous solution was extracted with CH2G2. The combined organic extract was dried (MgS0 ), filtered, and concentrated.Purification by vacuum filtration through silica gel (eluant: 5percent EtOAc-CFkCL.) gave t-butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (B-2) as a yellow solid (19.45 g, 100percent yield). MS (M+l): 309.
95%
With potassium carbonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 4 h;
N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml). The resulting mixture was heated at 1200C for 4 hours.After cooling to room temperarure, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95percent.LCMS (ES+) 209.05 (MH+-BOC)
95%
With potassium carbonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 4 h;
N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml). The resulting mixture was heated at 1200C for 4 hours.After cooling to room temperarure, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95percent. LCMS (ES+) 209.05 (MH+-BOC).
88%
With potassium carbonate In 1,4-dioxane for 4 h; Heating / reflux
Potassium carbonate (1.7g, 12.31 mmol) was added to a solution of 2-Chloro- 5-nitropyridine (1.33g,8.38mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.57g, 8.42mmol) in dioxane (10ml) then stirred at reflux for 4hours. The reaction was cooled, and solvent evaporated. The residue was extracted with MeCI2 (100ml) washed with H2O (50ml), separated organic layer washed with brine (50ml) dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 10percent v/v EtOAc/hexanes yielding desired product as a pale yellow solid (2.3g,88percent)Partial 1H NMR (400MHz, CDCI3)σ 9.0 (s,1H) 8.20(d,1H)6.50 (d,1 H) .
87%
With potassium carbonate In acetonitrile for 4 h; Heating / reflux
A suspension of 2-chloro-5-nitropyridine (7.90 g), piperazine-1-carboxylic acid tert-butyl ester (11.2 g) and potassium carbonate (6.90 g) in acetonitrile (250 mL) was heated under reflux for four hours. The reaction mixture was concentrated and diluted with ethyl acetate and washed with water and saturated brine and dried over sodium sulfate and filtered and concentrated. The residue was vigorously stirred in ethyl acetate/isopropyl ether, collected by filtration and dried under reduced pressure, and 16.1 g (87percent) of the title compound was obtained as a yellow solid. MS(FAB) m/z:309 (M + H)+.
83%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 20 - 50℃; for 4 h;
To a solution of tert-butyl piperazine-1-carboxylate (64 g, 346 mmol) in 600 ml. of THF at O0C was added NaH (16.4 g, 409 mmol, 60percent in mineral oil) portionwise. The reaction mixture was stirred for 15 min and 2-chloro-5-nitropyridine (50 g, 314 mmol) was added. The reaction mixture was allowed to warm to rt and then heated to 5O0C for 4 h. The reaction was quenched by water (30 ml.) and extracted with DCM (1.5 Lx 3). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was subjected to wash with petroleum ether to give the desired product of Step A (80 g, yield 83percent). 1H NMR (CDCI3, 400 MHz) δ 8.95 (d, J = 2.4 Hz, 1 H), 8.24 (d, J = 12 Hz, 1 H), 6.92 (d, J = 6.0 Hz, 1 H), 3.75 (s, 4 H), 3.44 (s, 4H), and 1.41 (s, 9 H).
58%
With potassium carbonate In butan-1-ol at 120℃; for 17 h;
Place 2-chloro-5-nitro-pyridine (1.0 g, 6.31 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.76 g, 9.45 mmol), and triethylamine (1.76 mL, 12.6 mmol) in ra-butanol (20 mL). Heat to 120 °C for 17 hours. Cool to room temperature and add ethyl acetate and water. Separate organic layer and wash with water and saturated aq. sodium chloride. Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 20percent EtOAc:hexane to yield 1.14 g (58percent) of 4-(5-nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester. MS(ES): m/z = 309 [M+H].
50%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.333333 h; Stage #2: at 50℃;
To a solution containing 5.8 g (31.5 mmol) of tert-butyl 1-piperazinecarboxylate and 20 mL of THF at 00C was added 1.5 g (37 mmol) of a 60percent dispersion of NaH in mineral oil. The reaction mixture was allowed to stir for 20 min and 5.0 g (31.5 mmol) of 2-chloro-5-nitropyridine was added. The reaction mixture was heated at 500C <n="96"/>overnight, quenched by the addition of water, and extracted with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was subjected to silica gel chromatography to give 4.89 g (50percent) of tert-butyl 4-(5-nitro-2-pyridinyl)-1-piperazinecarboxylate as a yellow solid: 1H NMR (400 MHz, DMSOd6) δ 8.25 (dd, J = 9.5 and 2.9 Hz, 1 H), 6.93 (d, J = 9.5 Hz, 1 H), 3.76 -3.78 (m, 4 H), 3.41 - 3.48 (m, 4 H), and 1.42 (s, 9 H).
50%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333 h; Inert atmosphere Stage #2: at 50℃;
To a solution containing 5 8 g (31 5 mmol) of fert-butyl 1-pιperazιnecarboxylate and 20 mL of THF at 0 °C was added 1 5 g (37 mmol) of a 60percent dispersion of NaH in mineral oil The reaction mixture was allowed to stir for 20 mm and 5 0 g (31 5 mmol) of 2-chloro-5-nιtropyrιdιne was added The reaction mixture was heated at 50 °C overnight, quenched by the addition of H2O, and extracted with DCM The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure The residue was subjected to silica gel chromatography to give 4 89 g (50percent) of fert-butyl 4-(5-nιtro-2-pyrιdιnyl)-1-pιperazιnecarboxylate as a yellow solid 1H-NMR (400 MHz, DMSO-d6) δ 8 25 (dd, J =9 5 and 2 9 Hz, 1 H), 6 93 (d, J =9 5 Hz, 1 H), 3 76 -3 78 (m, 4 H), 341 - 3 48 (m, 4 H), and 1 42 (s, 9 H)
4.94 g
at 70℃; for 16 h;
To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert-butyl piperazine-l-carboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70°C for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgS04 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-l- carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 mlz 309.0 (M+H).
4.94 g
at 70℃; for 16 h;
Step 1 To a solution of 2-chloro-5-nitropyridine (LVII) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert-butyl piperazine-1-carboxylate (LXXII) (7.05 g, 37.9 mmol). The reaction was headed at 70° C. for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgSO4 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (LXXIII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 m/z 309.0 (M+H).
4.94 g
at 70℃; for 16 h;
To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added fert-butyl piperazine-l-carboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70°C for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgS04 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 mlz 309.0 (M+H).
Reference：
[1] Patent: WO2010/59606, 2010, A2, . Location in patent: Page/Page column 182
[2] Patent: WO2011/31628, 2011, A1, . Location in patent: Page/Page column 66-67
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 4, p. 985 - 988
[4] Patent: WO2006/94840, 2006, A1, . Location in patent: Page/Page column 43
[5] Patent: WO2006/94843, 2006, A1, . Location in patent: Page/Page column 53
[6] Chinese Chemical Letters, 2013, vol. 24, # 4, p. 303 - 306
[7] Patent: WO2007/97937, 2007, A1, . Location in patent: Page/Page column 195
[8] Patent: EP1764360, 2007, A1, . Location in patent: Page/Page column 105
[9] Patent: WO2009/32667, 2009, A1, . Location in patent: Page/Page column 149-150
[10] Patent: WO2007/53394, 2007, A1, . Location in patent: Page/Page column 14
[11] Patent: WO2009/32667, 2009, A1, . Location in patent: Page/Page column 94-95
[12] Patent: WO2010/104899, 2010, A1, . Location in patent: Page/Page column 115
[13] Patent: WO2006/131835, 2006, A2, . Location in patent: Page/Page column 50
[14] Patent: WO2008/29266, 2008, A1, . Location in patent: Page/Page column 26-27
[15] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2433 - 2446
[16] Patent: WO2012/24179, 2012, A1, . Location in patent: Page/Page column 62
[17] Patent: WO2013/40215, 2013, A1, . Location in patent: Paragraph 00319
[18] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6410 - 6414
[19] Patent: US2015/266825, 2015, A1, . Location in patent: Paragraph 1294; 1295
[20] Patent: WO2018/75858, 2018, A1, . Location in patent: Paragraph 0351; 0352
80
[ 4316-93-2 ]
[ 57260-71-6 ]
[ 147539-23-9 ]
Reference：
[1] Patent: EP1568699, 2005, A1, . Location in patent: Page/Page column 61
[2] Patent: US5599930, 1997, A,
[3] Patent: US5489593, 1996, A,
81
[ 1193-21-1 ]
[ 57260-71-6 ]
[ 203519-88-4 ]
Yield
Reaction Conditions
Operation in experiment
91%
With triethylamine In acetonitrile at 120℃; for 2 h; microwave irradiation
Step 1: tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine- 1-carboxylate:A solution of 4,6-dichloropyrimidine (0.5 g, 3.36 mmol), tert-butyl piperazine-1 - carboxylate (0.69 g, 3.69 mmol) and triethylamine (0.34 g, 3.36 mmol) in acetonitrile (10ml) was heated in a microwave vial at 120 °C for 2 h. The solution was then diluted with ethyl acetate, washed with a saturated solution of ammonium chloride, dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (0.82 g, 91 percent).1H NMR (500 MHz, CDCI3): 8.39 (s, 1 H), 6.50 (s, 1 H), 3.65 (m, 4H), 3.52 (m, 4H), 1 .48 (s, 9H).
83%
With triethylamine In methanol at 50℃; for 4 h;
4,6-dichloropyrimidine (A1) (12.75 mmol, 1.9 g)And 1-tert-butoxycarbonylpiperazine(16.13 mmol, 3.0 g) was dissolved in 20 ml of methanol, 2.3 ml of triethylamine (16.13 mmol) was added, and the mixture was heated to 50 ° C and refluxed for 4 hours. The solvent was distilled off under reduced pressure, 20 ml of water was added and the mixture was stirred. The cake was rinsed with water and dried in vacuo to give a white solid. Yield 83percent.
72%
With sodium t-butanolate In toluene at 100℃; for 6 h;
(1) Tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylate A mixture of 4,6-dichloropyrimidine (2.08 g, 14.0 mmol), tert-butyl piperazine-1-carboxylate (2.0 g, 10.7 mmol), trisdibenzylideneacetone dipalladium (197 mg, 0.215 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (373 mg, 0.644 mmol), sodium tert-butoxide (1.55 g, 16.1 mmol) and toluene (100 ml) was stirred at 100° C. for 6 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (2.31 g, 72percent) as a solid. 1H NMR (CDCl3) δ: 1.49 (9H, s), 3.50-3.57 (4H, m), 3.61-3.70 (4H, m), 6.50 (1H, s), 8.39 (1H, s).
64%
With triethylamine In 1,4-dioxane at 75℃; for 4 h;
A stirring solution of 4,6-dichloro-pyrimidine (2.2 g, 15 mmol) in dioxane (50 rnL) was treated with TEA (6.2 niL, 45 mmol) and piperazine-1-carboxylic acid tert-butyl ester (3.5 g, 18.8 mmol). This was then heated to 75 0C and stirred for 4 h. Solvents then cooled to room temperature and evaporated. Crude product purified by column chromatography (silica gel) to afford title intermediate as white powder (2.9 g, 64percent).
50%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 14 h;
(1) Tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylate To a solution of 4,6-dichloropyrimidine (15.0 g, 0.100 mol) in N,N-dimethylformamide (150 ml) was added tert-butyl piperazine-1-carboxylate (22.0 g, 0.12 mol) and triethylamine (12.0 g, 0.12 mol), and the mixture was stirred at room temperature for 14 hours. The reaction was poured into water and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethylether to obtain the title compound (15.0 g, 50percent) as a solid. 1H NMR (CDCl3) δ: 1.45 (9H, s), 3.41-3.53 (4H, m), 3.55-3.65 (4H, m), 6.47 (1H, s), 8.35 (1H, s).
With potassium carbonate In acetonitrile at 95℃; for 4 h;
Intermediate 121: tert-Butyl 4-(3-hvdroxypropyr)piperazine-l -carboxylate A mixture of tert-butyl piperazine-1 -carboxylate (2.75 g, 14.8 mmol), l-bromo-3- propanol (1.43 mL, 16.2 mmol) and potassium carbonate (2.25 mL, 27.5 mmol) in acetonitrile (75 mL) was heated at 950C for 4 hours. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (300 mL) and washed with water, brine, EPO <DP n="118"/>dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with methanol in dichloromethane (0-10percent) gave a tan solid 2.88 g (80percent yield). MS (ESV 245 (MH+) for C12H24N2O3,1H-NMR TCDCl1) δ: 1.44 (m, 9H); 1.70-1.82 (m, 2H); 2.40-2.53 (m, 2H); 2.62-2.65 (m, 2H); 3.43-3.50 (m, 4H); 2.77 (m, 2H); 3.73-3.82 (m, 2H).
With triethylamine In N,N-dimethyl-formamide at 20℃;
Weigh 2,4-dichloropyrimidine (2.0 g, 13.43 mmol),Dissolved in DMF (15 mL), followed by triethylamine (TEA) (2.72 g, 26.85 mmol).1-Boc piperazine (2.75 g, 14.77 mmol), stirred at room temperature overnight.A white solid precipitated in the reaction solution, and the reaction was completed by TLC.The reaction solution was poured into 200 mL of ice water, and a large amount of white solid precipitated.Filter and dry to give a white solid C-2 (3.8 g, 13.43 mmol)
90%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 4 h;
(1) Tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate A mixture of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol), tert-butyl piperazine-1-carboxylate (1.37 g, 7.38 mmol), triethylamine (1.40 ml, 10.1 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 4 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue was added diethylether and separated by filtration to obtain the title compound (1.80 g, 90percent) as a solid. 1H NMR (CDCl3) δ: 1.49 (9H, s), 3.47-3.58 (4H, m), 3.60-3.71 (4H, m), 6.40 (1H, d, J=6.2 Hz), 8.07 (1H, d, J=6.2 Hz).
90%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 4 h;
A mixture of 2,4-dichloropyrimidine (1.00g, 6.71mmol), N-Boc-piperazine (1.37g, 7.38mmol), triethylamine (1.40mL, 10.1mmol), and DMF (10mL) was stirred at room temperature for 4.0h. The mixture was diluted with water, and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was triturated with Et2O to give 7 (1.80 g, 90percent) as a colorless powder. 1H NMR (300MHz, CDCl3) δ: 1.49 (9H, s), 3.47–3.58 (4H, m), 3.60–3.71 (4H, m), 6.40 (1H, d, J=6.2Hz), 8.07 (1H, d, J=6.2Hz). MS (ESI): m/z 299 [M+H]+.
51%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 16 h;
A solution of 2,4-dichloropyrimidine (500 mg, 3.35 mmol) and tert-butyl piperazine-1-carboxylate (685 mg, 3.67 mmol) in DMF (5 mL) was charged with triethylamine (0.7 mL, 5.02 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction suspended in water, the solids formed were collected by filtration, washed with water, dried under reduced pressure. The crude material was purified by combi-flash companion (silica gel, CH3OH/CH2CI2) to provide tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate 417d (510 mg, 51percent) as a white solid. 1H NMR (400 MHz, CDC13): δ 8.06 (d, ./ 6.0 Hz, 1H), 6,40 (d, ./ 6.0 Hz, 1H), 3.65 (br s, 4H), 3.52 (br s, 4H), 1 .49 (s, 9H); ESI+APCI MS m/z 299 [M + Hf . A solution of 2-(5-chloro-2,4-dimethoxyphenyl)-7-(piperazin-1-yl)imidazo[l ,2-a]pyridine 301 (150 mg, 0.40 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.72 mmol) in DMF (3 mL) was charged with tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate 417d (243 mg, 0.81 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, suspended in water and stirred for 1 h. The precipitate was collected by filtration, washed with water, dried under reduced pressure. The solid obtained was purified by combi-fiash companion (silica gel, CH3OH/CH2Cl2) to provide tert-butyl 4-(2-(4-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ 1 ,2-a]pyridin-7-yl)piperazin-1-yl)pyrimidin-4-yl)piperazine-1-carboxylate 418d (70 mg, 39percent) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 6 8.34 (d,J = 7.6 Hz, 1H), 8.1 7 (s, i l l). 8.03 (s, IH), 7.93 (d. ./ 6.0 Hz, 1H), 6.87 (s, 1 H), 6.85 is. 1 H), 6.71 (s, 1 H), 6.12 (d. ./ 6.0 Hz, IH), 4.01 (s, 3H), 3.93 (s, 3H), 3.82 (br s, 4H), 3.56 (br s, 4H), 3.40 (br s, 4H), 3.27 (br s, 4H), 1.42 (s, 9H); ESI+APCI MS m/z 635 [M + H . A solution of ter -butyl 4-(2-(4-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[l ,2-a]pyridin-7-yl)piperazin-1-yl)pyrimidin-4-yl)piperazine-l-carboxylate 418d (90 mg, 0, 14 mmol) in 2,2,2-trifluoroethanol (3 mL) was charged with trimethylsilyl chloride (0.2 rnL) at 0 °C. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was evaporated to dryness to provide 2-(5-chloro-2,4-dimethoxyphenyl)-7-(4-(4-(piperazin-1-yl)pyrimidin-2-yi)piperazin-1-yl)imidazo| l,2-o]pyridine dihydrochloride 418e (80 mg, 93percent) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.97 (br s, IH), 9.55 (br s, 2H), 8,60 (d, ./ 10.0 Hz, IH), 8.30 (s, IH), 8.10 (s, IH), 8,01 (d, J= 9.2 Hz, IH), 7.35 (dd, J= 2,8 Hz, J= 10.4 Hz, IH), 6.98 (s, IH), 6.80 (d, J= 2.0 Hz, IH), 6,59 (s, IH), 4.06 (s, 3H), 3.99 (br s, 1 IH), 3.71 (br s, 4H), 3.21 (br s, 4H); HPLC (Method 1) 91.7percent (AUC), iR = 10.95 mm.; ESI+APCI MS m/z 535 [M + 1 1 ]
45%
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 0 - 10℃; for 15 h; Inert atmosphere
Method B: t-butyl 4-(2-chloropyhmidin-4-yl)piperazine-1 -carboxylate. To a mixture of 2,4-dichloropyrimidine (2Og, 0.135mol, 1 eq.) and DIPEA (26g, 0.203mol, 1.5eq) in /-PrOH (40OmL) was added tert-butyl piperazine-1- carboxylate (27g, 0.148mol, 1.1 eq) by portions at 0 0C, and the resulting reaction was stirred overnight (about 15 hrs) at 10 0C. A lot of white solid precipitated and TLC showed that there was still a little 2,4-dichloropyrimidine. The solid was filtered and recrystallized from DCM to afford the title product (18g, 45percent yield) as a white solid. 1H NMR (300 MHz, CDCI3): 8.08 (d, J = 6.2 Hz, 1 H), 6.41 (d, J = 6.2 Hz, 1 H), 3.67 (s, 4H), 3.56-3.41 (m, 4H), 1.48 (s, 9H). t-butyl 4-(2-(neopentylamino)pyhmidin-4-yl)piperazine-1 -carboxylate. A solution of tert-butyl 4-(2-chloropyhmidin-4-yl)piperazine-1 -carboxylate -->(300mg, 1 mmol) 2,2-dimethylpropan-1-amine (131 mg, 1.5mmol) and DIPEA (259mg, 2mmol) in pentan-1-ol (15mL) was stirred at reflux for 18 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (100percent ethyl acetate) to afford the desired product. 1H NMR (300 MHz, CDCI3): 7.88 (d, J = 5.7 Hz, 1 H), 5.84 (d, J = 6.3 Hz, 1 H), 4.97 (br s, 1 H), 3.58 (m, 4H), 3.50 (m, 4H), 3.21 (d, J = 6.3 Hz, 2H), 1.48 (s, 9H), 0.96 (s, 9H). N-neopentyl-4-(piperazin-1-yl)pyhmidin-2-amine dihydrochlohde. t-butyl 4-(2-(neopentylamino)pyhmidin-4-yl)piperazine-1 -carboxylate obtained from the previous stey was dissolved in MeOH (4ml_) and 7N HCI / Et2O solution (2OmL) was added. The resulting solution was stirred at ambient temperature for 18 hrs. The solvent was concentrated to give the desired product as a yellow solid (130mg, 40percent yield in two steps). 1H NMR (300 MHz, CD3OD): 7.84 (d, J = 7.2 Hz, 1 H), 6.56 (d, J = 7.2 Hz, 1 H), 4.27 (br s, 2H), 4.02 (br s, 2H), 3.40 (br s, 4H), 3.33 (br s, 2H), 1.01 (s, 9H); LC-MS, m/z = 250.2 [M+H]+, tR = 0.8 min; HPLC: 99percent (214 nm), 98percent (254 nm), tR = 4.7 min.
40%
With sodium hydrogencarbonate In ethanol for 1.5 h; Heating / reflux
(1) Tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate To a solution of 2,4-dichloropyrimidine (50.0 g, 0.338 mol) in ethanol (500 ml) was added tert-butyl piperazine-1-carboxylate (62.8 g, 0.338 mol) and sodium hydrogencarbonate (56.8 g, 0.676 mol) and heated under reflux for 1.5 hours. The reaction was filtered and the filtrate was concentrated. To the residue was added methylene chloride and water followed by extracted. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the title compound (40.0 g, 40percent). 1H NMR (CDCl3) δ: 1.49 (9H, s), 3.46-3.53 (4H, m), 3.62-3.69 (4H, m), 6.40 (1H, d, J=6.4 Hz), 8.06 (1H, d, J=6.4 Hz).
With triethylamine In isopropyl alcohol for 2 h; Heating; Reflux
Production Example 1062-{ 4- [2- (6~piperazin-l-ylpyrimidin-4- yl) ethyl] phenyl }acetohydrazide tetrahydrochloride step 1[0323] [0324]To a solution (60 ml) of 4, 6-dichloropyrimidine (2.00 g, 13.4 mmol) and tert-butyl piperazine-1-carboxylate (3.00 g, 16.1 mmol) in 2-propanol was added triethylamine (4.7 ml, 33.6 mmol), and the mixture was heated under reflux for 2 hrs . The mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 1:2) to give tert-butyl 4- ( 6-chloropyrimidin-2-yl) piperazine-1-carboxylate (3.80 g, yield 95percent) as a white solid.
With sodium hydrogencarbonate In ethanol for 1.5 h; Heating / reflux
(1) Tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate To a solution of 2,4-dichloropyrimidine (50.0 g, 0.338 mol) in ethanol (500 ml) was added tert-butyl piperazine-1-carboxylate (62.8 g, 0.338 mol) and sodium hydrogencarbonate (56.8 g, 0.676 mol) and heated under reflux for 1.5 hours. The reaction was filtered and the filtrate was concentrated. To the residue was added methylene chloride and water followed by extracted. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the title compound (6.30 g, 6percent). 1H NMR (CDCl3) δ: 1.49 (9H, s), 3.45-3.52 (4H, m), 3.75-3.83 (4H, m), 6.53 (1H, d, J=4.8 Hz), 8.16 (1H, d, J=4.8 Hz).
With caesium carbonate In acetonitrile at 20℃; for 17 h;
[19101 Step 1: Synthesis of tert-butyl 4-(2.2.2-trifluoroethyflpiperazine- 1 -carboxylate [19111 Tert-butyl piperazine-1-carboxylate (2.000 g, 10.738 mmol), 2,2,2-trifluoroethyl tnfluoromethanesulfonate (1.625 mL, 11.275 mmol) and Cs2CO3 (4. 198 g, 12.886 mmol) were dissolved in acetonitrile (100 mL) at room temperature, and the solution was stilTed at the same temperature for 17 hours. The reaction mixture was filtered through a glass filter to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (silicon dioxide, 12 g cartridge; ethyl acetate/hexane = from 0 percent to 20 percent) and concentrated to afford the desired compound (2.150 g, 74.7 percent) as a colorless oil.
Reference：
[1] Patent: WO2015/137750, 2015, A1, . Location in patent: Paragraph 1910; 1911
[2] Patent: WO2004/41829, 2004, A1, . Location in patent: Page 75
[3] Patent: CN108276382, 2018, A, . Location in patent: Paragraph 0462; 0464; 0465; 0466
94
[ 75-89-8 ]
[ 57260-71-6 ]
[ 692058-21-2 ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: With trifluoromethylsulfonic anhydride; triethylamine In dichloromethane at 0℃; for 0.5 h; Stage #2: at 20℃; for 16 h;
To a solution of trifluoroethanol (0.32 g, 3.22 mmol) in DCM (10 mL) was added a solution of triethylamine (0.65 g, 4.82 mmol) and trifluoromethanesulfonic anhydride (1.05 g, 3.75 mmol) at 0 °C and stirred at same temperature for 30 min. A solution of ieri-butyl piperazine-1- carboxylate (0.50 g, 2.68 mmol) in DCM (10 mL) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with H20 (20 mL). The organic layer was separated, washed with H20 (20 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The crude obtained was purified by column chromatography (silica 100- 200 mesh, 0.5 to 2percent MeOH in DCM) to afford tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-l- carboxylate (0.40 g, 55percent) as a white solid. 1H NMR (400 MHz, DMSO- 6) δ 1.46 (s, 9H), 2.64- 2.58 (m, 4H), 2.92-3.04 (m, 2H), 3.48-3.36 (m, 4H).
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 72 h;
Trifluoroiodoethane (0.794 mL, 8.05 mmol) was added to a stirred mixture of boc- piperazine (1.25 g, 6.71 mmol), DIPEA (6.25 mL, 33.6 mmol) and DMF (7 mL). The reaction mixture was stirred at rt for the 72 h. The reaction was filtered and the filtrate was evaporated. The crude product was purified by flash chromatography on silica gel (dry packing) using a solution of EtOAc in hexanes (20 to 100percent gradient) to give the title compound (253 mg, 0.943 mmol, 14percent) as yellow solid.
Reference：
[1] Patent: CN105461697, 2016, A,
[2] Patent: CN106187838, 2016, A,
[3] Patent: WO2005/110996, 2005, A1,
97
[ 141-30-0 ]
[ 57260-71-6 ]
[ 492431-11-5 ]
Yield
Reaction Conditions
Operation in experiment
88%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 80℃;
Synthesis of tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate To a solution of 3,6-dichloropyridazine (Sigma-Aldrich, St. Louis, Mo.) (57.3 g, 385 mmol) in 1,4-dioxane (250 mL) were added tert-butyl piperazine-1-carboxylate (Sigma-Aldrich) (71.6 g, 358 mmol) and N,N-diisopropylethylamine (66.9 mL, 385 mmol). The mixture was stirred overnight at 80° C. then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (3 L) and washed with 10percent citric acid, water, and brine. The organic layer was concentrated and the residue was re-crystallized in ethyl acetate to provide tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate as an off-white solid (101 g, 88percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (9H, s), 3.26-3.47 (8H, m), 6.67 (1H, d, J=9.6 Hz), 7.00 (1H, d, J=9.6 Hz); MS (ESI) m/z: 299.0 [M+H]+.
70%
With triethylamine In N,N-dimethyl-formamide at 80℃;
A solution of 3,6-dichloropyridazine (5.01 g, 33.6 mmol) and tert-butyl piperazine-1-carboxylate (6.88g, 37.0 mmol) in DMF (50 mL) was added triethylamine (11.7 mL, 50.4 mmol) and stirred at 80°C overnight. The resultant reaction mixture was cooled to room temperature, and water was added to the mixture. The mixture was extracted three times with a solvent mixture of dichloromethane and methanol (95:5) (50 mL). The resultant organic phases were combined together and dried over anhydrous magnesium sulfate. The resultant solid was separated by filtration, and the filtrate was then concentrated under reduced pressure. The resultant crude product was washed with diethyl ether to yield the title compound (7.0 g, 70percent).
63%
With triethylamine In toluene at 110℃; for 16 h;
Preparation of tert-Butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate 6-3: (1202) (1203) A stirred mixture of 3,6-dichloropyridazine 6-1 (2.0 g, 13.4 mmol), tert-butyl piperazine- 1-carboxylate 6-2 (3.72 g, 20.0 mmol) and triethylamine (2.78 mL, 20.0 mmol) in toluene (20mL) was heated at 110 °C for 16 h. After complete consumption of 6-1 as evident from TLC, the volatiles were stripped off, residue partitioned between ethyl acetate and water, combined organic extracts evaporated to afford a crude residue which was purified column chromatography (elution with 30percent ethyl acetate/Hexane) to afford tert-butyl 4-(6-chloropyridazin-3- yl)piperazine-1-carboxylate 6-3 (2.52 g, 8.46 mmol, 63.0 percent) as an off-white solid. LC MS: ES+ 299.2
With sodium carbonate In dichloromethane at 20℃; for 48 h;
2-Mercaptoethylpiperazine [0383] To a suspension of piperizaine (30.00 g, 348.27 mmol) and sodium carbonate (106 g, 348.27 mmol) in dichloromethane (200 ml) was added dropwise a solution of Di- tert-butyl dicarbonate (18.98 g, 87.07 mmol) in dichloromethane (30 ml) at room temperature for one hour. Then the mixture was stirred at room temperature overnight. The mixture was mixed with water (100 ml) and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in dichloromethane (150 ml). Sodium carbonate (15.55 g, 146.77 mmol) and 1- bromo-2-chloroethane (21.05 g, 146.77 mmol) were added. The mixture was stirred at room temperature for a weekend. The mixture was mixed with water (100 ml) and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using hexane and ethyl acetate as eluent to give 6.85 g of l-Boc-4-(2-chloroethyl)piperazine.
With triethylamine In dichloromethane at 0 - 20℃; for 3 h; Large scale
S1: N-Boc-piperazine (1.82 kg, 9.77 mol) was added to a 20 L four-necked flask with mechanical stirring and a thermometer.Triethylamine (1.48 kg, 14.66 mol), dichloromethane 5.46 Kg, cooled to 0 ° C,Cyclopropylcarbonyl chloride (1.12 kg, 10.75 mol) was slowly added dropwise, and the temperature was controlled from 0 ° C to 10 ° C.After the completion of the dropwise addition, the reaction was carried out for 3 hours at 10 ° C to 20 ° C.Add 5kg of water, add sodium carbonate to adjust pH=8-9, separate the liquid, collect the organic phase, add 1.50Kg of water phase, and extract once with dichloromethane.The methylene chloride phases were combined, washed once with 2 kg of 0.05 M diluted hydrochloric acid, and once with 2 kg of water.The dichloromethane was concentrated to remove 2.43 kg of 4-(cyclopropanecarbonyl)piperazine-1-carboxylic acid tert-butyl ester, yield 98percent.The nuclear magnetic warp alignment is consistent with the standard map.
73%
With potassium carbonate In dichloromethane at 0 - 20℃;
A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0° C., cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10percent citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate (3.7 g, yield 73percent) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
73%
With potassium carbonate In dichloromethane at 0 - 20℃;
Example 17Atert- Butyl 4-(cyclopropanecarbonyl)piperazine- 1 -carboxylate[00523] A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0 °C,cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10percent citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4- (cyclopropanecarbonyl)piperazine- 1 -carboxylate (3.7 g, yield 73percent) as a white solid. ^-NMR (400 MHz, CDCI3) δ (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
Reference：
[1] Patent: CN108341792, 2018, A, . Location in patent: Paragraph 0028; 0033
[2] Patent: US2010/35883, 2010, A1, . Location in patent: Page/Page column 56
[3] Patent: WO2011/130661, 2011, A1, . Location in patent: Page/Page column 102
[4] Patent: US2004/14770, 2004, A1, . Location in patent: Page/Page column 11
101
[ 57260-71-6 ]
[ 1759-53-1 ]
[ 414910-15-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 2, p. 462 - 466
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 16, p. 3739 - 3743
102
[ 100367-77-9 ]
[ 57260-71-6 ]
[ 867065-53-0 ]
Yield
Reaction Conditions
Operation in experiment
88%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃;
Tert-butyl piperazine-1-carboxylate (1.8 g, 10 mmol), ethyl 2-bromothiazole-4-carboxylate (2.36 g, 10 mmol) and DIPEA (2.02 g, 20 mmol) were added into 1 ,4-dioxane (15 ml). The mixture was stirred for overnight at 1000 C. When the reaction finished, it was extracted by EA and washed by brine. It was purified by flash column chromatography (PE/EA=5:1-3:1) to afford the yellow solid as product (3.0 g, 88percent).
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 2 h;
EXAMPLE 1; 1-[4-(4-Benzhydryl-piperazin-1-yl)-3-cyano-phenyl]-3-(3,5-dimethyl-isoxazol-4-yl)-urea; Step a: 4-(2-Cyano-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester; To a mixture of 1-Boc-piperazine (5.61 g, 30.1 mmol) and potassium carbonate (4.2 g, 1 eq) in DMF (50 mL), 2-fluoro-5-nitro-benzonitrile (5.0 g, 1.0 eq) was added. The resulting mixture was stirred at 50° C. for 2 hours. The mixture was poured into water and the resulting precipitate was filtered off and washed with water. After high-vacuum drying, 4-(2-cyano-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (8.66 g, 86.6percent yield) was obtained as a yellow solid which will be used without further purification.LC/MS: r.t. 6.22 min, 274.2 [M+H+CH3CN-Boc]
59%
With potassium carbonate In ethanol at 80℃; for 1 h;
A solution of 2-fluoro-5-nitrobenzonitrile (500 mg, 3.0 mmol) in ethanol (35 mL) was treated with potassium carbonate (420 mg, 3.0 mmol) and piperazine-1 -carboxylic acid tert-butyl ester (560 mg, 3.0 mmol). The reaction mixture was stirred at 80 0C for 1 h, then cooled and partitioned between ethyl acetate and water. The organic layer was then collected, dried over sodium sulfate, filtered and evaporated to a yellow residue.Purification using flash chromatography yielded 4-(2-cyano-4-nitro-phenyl)-piperazine- 1 -carboxylic acid tert-butyl ester (590 mg, 59percent yield) as a bright yellow solid. HRMS calcd for C16H20N4O4 (M+Na) 355.1377, obsd 355.1376.
With potassium carbonate In 1,4-dioxane at 110℃; for 12 h;
To 1,4-dioxane (30 mL) were added tert-butyl piperazine-1-carboxylate (2.89 g, 15.51 mmol), 5-bromo-2-chloropyrimidine (2.00 g, 10.34 mmol) and potassium carbonate (2.86 g, 20.68 mmol) sequentially. The mixture was heated to 110 °C, after stirring for 12 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (3.15 g, 88.7percent).MS (ESI, pos. ion)m/z: 343.1 [M+H] and‘HNMR(400IVIHz, CDC13): (ppm) 8.29 (s, 2H), 3.83-3.66 (m, 4H), 3.56-3.41 (m, 4H), 1.48 (s, 9H).
87.7%
With potassium carbonate In acetonitrile at 80℃;
To a solution of commercially available S-bromo-2-chloropyrimidin (9.75 g, 50 mmol) in CH3CN (100 mL) was added compound i-Boc-piperazine (9.25 g, 50 mmol) and K2003 (13.8 g, 100 mmol). The reaction mixture was stirred at 80 00 overnight. Then, the reaction mixture was concentrated under vacuo andextracted with EA and washed with water, dried by Na2SO4 and concentrated under vacuo to give the KR-7 (15 g 87.7percent yield). ESI-MS (Mi-i): 343, 345calc. for C13H19BrN4O2: 342.1.
87.7%
With potassium carbonate In acetonitrile at 80℃;
Preparation of reagents Preparation of reagent KR-1 : 1 - e/t-Butoxycarbonyl-4-(5-bromopyrimidin-2- vQpiperazine To a solution of commercially available 5-bromo-2-chloropyrimidin (9.75 g, 50 mmol) in CH3CN (100 mL) was added compound 1 -Boc-piperazine (9.25 g, 50 mmol) and K2CO3 (13.8 g, 100 mmol). The reaction mixture was stirred at 80 °C overnight. Then, the reaction mixture was concentrated under vacuo and extracted with EA and washed with water, dried by Na2SO4 and concentrated under vacuo to give the KR-1 (15 g 87.7percent yield). ESI-MS (M+1 ): 343, 345 calc. for Ci3H19BrN4O2: 342.1.
84.5%
With triethylamine In N,N-dimethyl-formamide at 80℃; for 14 h;
To a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g,51.69 mmol, Oakwood chemicals) were added at rt and the reaction mixture was stirred at80 °C for 14 h. The reaction mixture was cooled to rt and poured into water (100 mL). Theformed precipitate was filtered and washed with diethyl ether (50 mL) to afford the titleproduct. Yield: 84.5percent (15 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.49(s, 2H),3.69 (t, J = 5.2 Hz, 4H), 3.40 (t, J = 5.1 Hz, 4H), 1.42 (5, 9H). LCMS: (Method A) 345.23 (M+2), Rt. 4.92 mm, 99.6percent (Max).
84.5%
With triethylamine In N,N-dimethyl-formamide at 80℃; for 14 h;
To a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 51.69 mmol, Oakwood chemicals) were added at rt and the reaction mixture was stirred at 80 °C for 14 h. The reaction mixture was cooled to rt and poured into water (100 mL). The formed precipitate was filtered and washed with diethyl ether (50 mL) to afford the title product. Yield: 84.5percent (15 g, off white solid). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 2H), 3.69 (t, J = 5.2 Hz, 4H), 3.40 (t, J = 5.1 Hz, 4H), 1.42 (s, 9H). LCMS: (Method A) 345.23 (M +2), Rt. 4.92 min, 99.6percent (Max).
80%
With potassium carbonate In 1,4-dioxane for 1.5 h; Reflux
To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and 1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reflux for 1.5 h. The reaction was cooled to RT, quenched by water (500 mL) and extracted with diethyl ether (1000 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (petroleum ether:ethyl acetate=8:1-4:1) to give the title compound (70.5 g, 80percent) as a white solid. MS (ES+) C13H19BrN4O2 requires: 342. found: 243 [M+H−100]+.
80%
With potassium carbonate In 1,4-dioxane for 1.5 h; Reflux
Step 4: Synthesis of tert-butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and 1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reflux for 1.5 h. The mixture was diluted with water (500 mL) and extracted with diethyl ether (1000 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (elute: hexane:ethyl acetate=8:1 to 4:1) to give tert-butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (70.5 g, 80percent) as a white solid. MS (ES+) C13H19BrN4O2 requires: 342, found: 243 [M+H-100]+.
78%
With potassium carbonate In 1,4-dioxane at 20℃; for 4 h; Reflux
To a solution of 5-bromo-2-chloro-pyrimidine (0.5 g, 2.58 mmol) in 1,4-dioxane (20 mL),tert-butyl piperazine-1-carboxylate (0.722 g, 3.88 mmol) and K2C03 (0.713 g, 5.17 mmol)were added at RT. The reaction mixture was refluxed for 4 h (TLC indicated complete consumption of starting material). The reaction mixture was brought toRT, diluted withwater (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts werewashed with water (2 x 40 mL), brine (1 x 40 mL), dried over Na2S04 and concentratedunder reduced pressure to give the residue. The residue was further purified by columnchromatography (100-200 silica gel, 15 g, 10percent EtOAc-Hexane) to afford tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-l-carboxylate (0.7 g, 78percent) as a white solid.1H NMR [400 MHz, CDCh]: J 8.29 (s, 2H), 3.75 (t, J = 4.8 Hz, 4H), 3.47 (t, J = 5.2 Hz,4H), 1.47 (s, 9H).LCMS: m/z: 287.44 [M-tBut.
76%
With triethylamine In N,N-dimethyl-formamide at 90℃; for 8 h;
To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50 mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine (6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at 90 °C for 8 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added and the desired product was extracted with DCM (150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (10percent EtOAc in pet ether) to afford the title compound. Yield: 76percent (7 g, white). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 2H), 3.68-3.67 (m, 4H), 3.39-3,37 (m, 4H), 1.40 (s, 9H). LCMS: (Method A) 289.0 (M+H), Rt. 5.19 min, 99.05percent (Max).
76%
With triethylamine In N,N-dimethyl-formamide at 90℃; for 8 h;
To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50 mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine (6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at 90 °C for 8 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added and the desired product was extracted with DCM (150 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The crude product was purified by flash chromatography (10percent EtOAc in pet ether) to afford the title compound. Yield: 76percent (7 g, white). 1H NMR (400 MHz, DMSO-d6): 6 8.46 (s, 2H), 3.68-3.67 (m, 4H), 3.39-3,37 (m, 4H), 1.40 (s, 9H). LCMS: (Method A) 289.0 (M+H), Rt. 5.19 mm, 99.05percent (Max).
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4287 - 4299
113
[ 22276-95-5 ]
[ 57260-71-6 ]
[ 1072027-36-1 ]
Yield
Reaction Conditions
Operation in experiment
78.5%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 80℃; for 2 h; Microwave irradiation
Intermediate 2 (5 mmol),1-tert-butoxycarbonylpiperazine (6 mmol) and DIEA (7.5 mmol) were dissolved in 5 ml of dioxane, and microwaved at 80 °C for 2 h. The solvent was evaporated under reduced pressure, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, Recrystallization gave Intermediate 3. White solid, the yield is 78.5percent.
48%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 110℃; for 16 h;
General procedure: To a solution of 3a-3c (3.2mmol) and N, N-diisopropylethylamine (DIEA) (4.8mmol) in DMF (3mL) was added N-Boc-piperazine (3.6mmol), the resulting mixture was heated at 110°C for 16h. The reaction mixture was poured into ice water (30mL) and extracted with ethyl acetate (3×30mL), the combined organic layers were washed with brine (2×30mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography with petroleum ether/ethylacetate (1: 3) to obtain 4a-4c.
46%
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 100℃; for 16 h;
With potassium carbonate In dimethyl sulfoxide at 100℃; sealed tube
PREPARATION 24; {2-[4-(iert-Butoxycarbonyl)piperazin-1-yl]pyridin-4-yl}boronic acid; a) f erf-Butyl 4-(4-bromopyridin-2-yl)piperazine-1-carboxylate; A suspension of 4-bromo-2-fluoropyridine (1.55 g, 8.81 mmol), terf-butyl piperazine-1- carboxylate (2.46 g, 13.22 mmol) and potassium carbonate (3.65 g, 26.41 mmol) in dimethylsulphoxide (10 mL) was heated in a sealed tube at 100 °C with stirring. After stirring overnight the mixture was cooled and ethyl acetate and water were added. The organic layer was washed with brine, dried (MgS04) and evaporated. Purification of the residue by flash chromatography (100percent hexanes to 1 :4 hexanes /ethyl acetate) gave the title compound (2.33 g, 78percent) as a white solid.LRMS (m/z): 342/344 (M+1)+.
78%
With potassium carbonate In dimethyl sulfoxide at 100℃; Sealed tube
A suspension of 4-bromo-2-fluoropyridine (1.55 g, 8.81 mmol), tert-butyl piperazine-1-Carboxylate (2.46 g, 13.22 mmol) and potassium carbonate (3.65 g, 26.41 mmol) in dimethylsulphoxide (10 mL) was heated in a sealed tube at 100 ethyl acetate and water were added. The organic layer was washed with brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (100percent hexanes to 1:4 hexanes /ethyl acetate) gave the title compound (2.33 g, 78percent) as a white solid.LRMS (m/z): 342/344 (M+1)+.
78%
With potassium carbonate In dimethyl sulfoxide at 100℃; Sealed tube
4-bromo-2-fluoropyridine (1.55 g, 8.81 mmol), tert-butyl piperazine-1-carboxylate (2.46 g, 13.22 mmol) and potassium carbonate (3.65 g, 26.41 mmol) in dimethylsulphoxide (10 mL) was heated in a sealed tube at 100 ºC with stirring. After stirring overnight the mixture was cooled and ethyl acetate and water were added. The organic layer was washed with brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (100percent hexanes to 1:4 hexanes /ethyl acetate) gave the title compound (2.33 g, 78percent) as a white solid. LRMS (m/z): 342/344 (M+1)+. 1H NMR (300 MHz, , CDCl3) δ ppm 1.49 (s, 9 H), 2.49 (bs, 2 H), 3.63 (t, J=5.77 Hz, 2 H), 4.08 (d, J=2.75 Hz, 2 H), 6.05 (br s, 1 H), 7.21 (t, J=7.69 Hz, 1 H), 7.27 - 7.31 (m, 1 H), 7.36 - 7.40 (m, 1 H), 7.51 (t, J=1.79 Hz, 1 H)
Part 2: Preparation of tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-l- carboxylate [00579] A mixture of 4-fluoro-2-hydroxybenzaldehyde (10 g, 71.4 mmol), 1-boc-piperazine (15.3 g, 82.2 mmol), and DMSO (100 mL) was heated at 100 °C for 27 h. The reaction mixture was diluted in an aqueous K2CO3 solution and extracted with EtO Ac. The organic layer was washed with H20 and brine, dried over MgS04, filtered, and concentrated under vacuum. The residue was triturated with hexane/ether (1 : 1), yielding the title compound (18.8 g, 86percent) as a yellow solid. MS m/z 307.2 [M+H]+; 1H NMR (500 MHz, CDC13): δ 11.50 (1H, s), 9.60 (1H, s), 7.36 (1H, d, J= 9 Hz), 6.27 (1H, d, J= 2 Hz), 6.45 (1H, dd, J= 9 Hz, 2 Hz), 3.58 (4H, m), 3.42 (4H, m), 1.49 (9H, s).
86%
at 100℃; for 27 h;
Part 2: Preparation of tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate A mixture of 4-fluoro-2-hydroxybenzaldehyde (10 g, 71.4 mmol), 1-boc-piperazine (15.3 g, 82.2 mmol), and DMSO (100 mL) was heated at 100° C. for 27 h. The reaction mixture was diluted in an aqueous K2CO3 solution and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was triturated with hexane/ether (1:1), yielding the title compound (18.8 g, 86percent) as a yellow solid. MS m/z 307.2 [M+H]+; 1H NMR (500 MHz, CDCl3): δ 11.50 (1H, s), 9.60 (1H, s), 7.36 (1H, d, J=9 Hz), 6.27 (1H, d, J=2 Hz), 6.45 (1H, dd, J=9 Hz, 2 Hz), 3.58 (4H, m), 3.42 (4H, m), 1.49 (9H, s).
Reference：
[1] Patent: WO2013/101974, 2013, A1, . Location in patent: Paragraph 00578; 00579
[2] Patent: US9617268, 2017, B2, . Location in patent: Page/Page column 319; 320
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6070 - 6085
With N-ethyl-N,N-diisopropylamine; at 30℃; for 72h;Inert atmosphere;
Example 24 tert-Butyl 4-(2-bromoethyl)piperazine-1-carboxylate A mixture of tert-butyl piperazine-1-carboxylate (5.0 g, 26.9 mmol), 1,2-dibromoethane (25 mL), DIPEA (3.5 g, 26.9 mmol) was stirred at 30° C. under argon for 72 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (1-2percent methanol/dichloroethane) to afford the desired product (2.8 g, 36percent yield) as a solid. ESI-MS m/z: 293.1[M+1]+.
1-methyl-4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Preparation of 3:0.1 mol of I was stirred with 0.11 mol of CDI in 200 ml of chloroform at room temperature for 2 hours. Then 2 (0.1 mol) was added and reaction mixture was stirred at room temperature overnight. 200 ml of water were added, after that organic layer was separated and solvent removed under reduced pressure.
With potassium carbonate; In dimethyl sulfoxide; at 75℃;
A solution of <strong>[19745-07-4]2,5-dichloropyrazine</strong> (1.03 g, 6.91 mmol) in DMSO (10 mL) was treated sequentially with K2C03(s) (2.867 g, 20.74 mmol) and tert-butyl piperazine-1-carboxylate (1.288 g, 6.9 14 mmol), then stirred overnight at 75 °C. After cooling to ambient temperature, the mixture was partitioned between EtOAc (10 mL) and water (20 mL). After phase separation, the organic extracts were concentrated in vacuo to provide the title compound (1.928 g, 93percent yield). MS (apci) m/z = 199.1 (M-Boc). ?HNIVIR(CDC13) 8.07 (m, 1H), 7.86 (m, 1H), 3.56 (s, 8H), 1.48 (s, 9H).
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 1h;
To an NMP (7.5 ml) solution of 1.51 g of <strong>[19745-07-4]2,5-dichloropyrazine</strong> were added 2.00 g of 1-(t-butoxycarbonyl)piperazine and 2.00 g of potassium carbonate, followed by 1 hour of stirring under heating at 100°C. The mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 2.73 g of 2-chloro-5-(4-t-butoxycarbonylpiperazin-1-yl)pyrazine. Using this compound, 2-chloro-5-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrazine was obtained in a similar manner to Example 14 as colorless crystals.
4- 4-CYANO-2, 3-DIFLUORO-PHENYL)-PIPERAZINE-L-CARBOXYLIC ACID TERT-BUTYL ester To a solution OF N-BOC-PIPERAZINE (0.65 g) in DMA (20 mL) was slowly added a solution of 2, 3, 4-<strong>[143879-80-5]trifluorobenzonitrile</strong> (0.49 g) in DMA (10 mL). The reaction mixture was stirred for 2 hours at 80°C. After such time the solvent was removed in vacuo and purified by column chromatography (SIO2) to yield the title compound as white solid (0.76 g).
In ISOPROPYLAMIDE; at 80℃; for 2h;
To a solution of N-Boc-Piperazine (0.65 g) in DMA (20 mL) was slowly added a solution of <strong>[143879-80-5]2,3,4-<strong>[143879-80-5]trifluorobenzonitrile</strong></strong> (0.49 g) in DMA (10 mL). The reaction mixture was stirred for 2 hours at 80° C. After such time the solvent was removed in vacuo and purified by column chromatography (SiO2) to yield the title compound as white solid (0.76 g).
To a solution of piperazine-1-carboxylic acid ter-butyl ester (32.2 mmol) in tetrahydrofuran (60 ml) was added thiocarbonyldiimidazole (37.0 mmol). The reaction was stirred at RT for 2 h then heated at 55C for 1 h. The reaction was concentrated in vacuo to approximately half the volume and methanolic ammonia added (7N, 107.4 mmol). The reaction was heated at 55C for 16 h. The reaction was concentrated in vacuo to approximately half the volume and cooled to 0C at which point the product precipitated from solution. The product was collected by filtration to yield the title compound as a white solid (3.3 g). 1 H NMR (400MHz, d6-DMSO) 1.40 (9H, s), 3.32 (4H, s), 3.71 (4H, s), 7.42 (1 H, s).
With triethylamine; In dichloromethane; at 0 - 20℃; for 3.0h;Large scale;
S1: N-Boc-piperazine (1.82 kg, 9.77 mol) was added to a 20 L four-necked flask with mechanical stirring and a thermometer.Triethylamine (1.48 kg, 14.66 mol), dichloromethane 5.46 Kg, cooled to 0 C,Cyclopropylcarbonyl chloride (1.12 kg, 10.75 mol) was slowly added dropwise, and the temperature was controlled from 0 C to 10 C.After the completion of the dropwise addition, the reaction was carried out for 3 hours at 10 C to 20 C.Add 5kg of water, add sodium carbonate to adjust pH=8-9, separate the liquid, collect the organic phase, add 1.50Kg of water phase, and extract once with dichloromethane.The methylene chloride phases were combined, washed once with 2 kg of 0.05 M diluted hydrochloric acid, and once with 2 kg of water.The dichloromethane was concentrated to remove 2.43 kg of 4-(cyclopropanecarbonyl)piperazine-1-carboxylic acid tert-butyl ester, yield 98%.The nuclear magnetic warp alignment is consistent with the standard map.
73%
With potassium carbonate; In dichloromethane; at 0 - 20℃;
A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0 C., cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10% citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate (3.7 g, yield 73%) as a white solid. 1H-NMR (400 MHz, CDCl3) delta (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
73%
With potassium carbonate; In dichloromethane; at 0 - 20℃;
Example 17Atert- Butyl 4-(cyclopropanecarbonyl)piperazine- 1 -carboxylate[00523] A mixture of compound tert-butyl piperazine-1 carboxylate (3.725 g, 20 mmol) and potassium carbonate (5.53 g, 40 mmol) in anhydrous dichloromethane (30 mL) was cooled to 0 C,cyclopropanecarbonyl chloride (2.30 g, 22 mmol) was then added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 10% citric acid (50 mL), followed by saturated sodium bicarbonate (50 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4- (cyclopropanecarbonyl)piperazine- 1 -carboxylate (3.7 g, yield 73%) as a white solid. ^-NMR (400 MHz, CDCI3) delta (ppm): 0.76-0.81 (m, 2H), 0.98-1.03 (m, 2H), 1.49 (s, 9H), 1.69-1.75 (m, 1H), 3.46-3.48 (m, 4H), 3.63-3.65 (m, 4H); LC-MS (ESI) m/z: 255(M+1)+.
With potassium carbonate; In dichloromethane; at 20℃; for 18.0h;
Cyclopropanoyl chloride (112 muL) was added to a mixture of N-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassium carbonate in anhydrous DCM (10 mL) under a nitrogen atmosphere. The mixture was stirred at r.t. for 18 hours, then it was filtered off from inorganics. The organic phase was diluted with Et2O (20 mL) and washed with 1N hydrochloric acid solution (10 mL). The aqueous phase was made basic with 1N sodium hydroxide solution and extracted twice with DCM. The combined organic layers were dried and concentrated in vacuo to give the title compound (210 mg) as an oil. [0238] T.I.c.: AcOEt, Rf=0.45. [0239] NMR (d6-DMSO): 6 (ppm) 3.64-3.28 (m, 8H); 1.94 (m, 1H); 1.4 (s, 9H); 0.7 (m, 4H). [0240] MS (ES/+): m/z=255 [M+H]+.
tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; ethyl acetate;
Example 123A 4-(5-Bromo-pyridin-3-yl)-piperazine-1-carboxylic Acid Tert-Butyl Ester A solution of the 3,5-dibromo-pyridine (12.8 g, 68.8 mmol) and piperazine-1-carboxylic acid tert butyl ester (10 g, 42.4 mmol) in 200 mL of dioxane was treated with Pd2(dba)3 (5 g, 5.5 mmol), 2-(di-tbutyl-phosphino)biphenyl (4 g, 13.4 mmol), and sodium t-butoxide (7.2 g, 75 mmol). The reaction was heated to 95° C. for 8 h then cooled and filtered through celite. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel, eluding with a solvent gradient of 1:4 ethyl acetate/hexane to 100percent ethyl acetate. Recovered 2.9 g of product (20percent). MS (ESI) m/z 344 (M+H)+.
With triethylamine; In N-methyl-acetamide; methanol;
a 4-(2-Amino-ethyl)-piperazine-1-carboxylic Acid Tert-butyl Ester A solution of N-tert-butoxycarbonyl-piperazin (5 g, 26.8 mmol), triethylamine (7.44 ml, 53.6 mmol), and chloroethylamine (3.11 g, 26.8 mmol) in dimethylformamide (50 ml) was stirred at room temperature for 72 hours. The reaction mixture was filtered, partitioned between H2O and ethyl acetate. The aqueous phase was lyophilized, the residue stirred with methanol and the precipitate collected by suction. The precipitate was purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia=9/1/0.1) to give 1.6 g (26percent) of the desired product. MS m/z: 230 ((M+H)+, 91percent).
With N-ethyl-N,N-diisopropylamine; In methanol; 1,2-dibromomethane;
EXAMPLE X 2-(1-tert-Butyloxycarbonylpiperazin-4-yl)ethyl bromide A solution of 1.0 g of 1-tert-butyloxycarbonylpiperazine and 0.7 g (0.005 mol) of N-ethyldiisopropylamine in 5 ml of 1,2-dibromomethane is allowed to stand at room temperature for 3 days and then concentrated to dryness in vacuo. The residue is purified by means of chromatography on a silica gel column, methylene chloride which initially contains 1percent and then 2percent of methanol being used as eluent. Yield: 0.6 g (38percent of theory), Mass spectrum: (M+H)+ =293/295
2. Intermediate 2: 4-(4-tert-Butyloxycarbonyl)piperazin-1-yl Butanal Dimethyl Acetal A mixture of <strong>[29882-07-3]4-chlorobutanal dimethyl acetal</strong> (J. Chem. Soc., Perkin Trans. 1, 1981, 251-255; 4.1 g, 26.9 mmol), K2 CO3 (4.08 g, 29.6 mmol) and tert-butyl-1-piperazinecarboxylate (5.00 g, 26.9 mmol), in anhydrous DMF (100 ml) was heated at 100° C. for 24 h. The mixture was cooled to room temperature, water (75 ml) added and extracted with ethyl acetate (5*100 ml). The combined extracts were washed with water (*3), dried (Na2 SO4) and evaporated. The crude product was chromatographed on silica gel eluding with ethyl acetate to give the title-product (3.41 g, 42percent). delta (250 MHz, CDCl3) 1.46 (9H, s, OC(Me)3); 1.50-1.68 (4H, m, 2 of CH2); 2.32-2.42 (6H, m, 3 of CH2); 3.30 (6H, s, (OMe)2); 3.40-3.48 (4H, m, 2 of CH2); 4.38 (1H, t, J=6 Hz, CH).
With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 12h;
141a) tert-butyl 4-((2-amino-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate A solution of Boc-piperazine (4.67 g), 2-amino-4-chloromethylthiazole hydrochloride (WO 0190090; 5.1 g) and potassium carbonate (8.4 g) in DMF (100 ml) was mixed at 65°C for 12 hours. The precipitated insolubles were filtered off, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column to obtain the title compound as a brown solid (5.6 g, 74percent). NMR (CDCl3) delta: 1.45 (9H, s), 2.36-2.46 (4H, m), 3.42-3.49 (4H, m), 4.94 (2H, s), 6.32 (1H, s).
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 140.0℃; for 0.333333h;Microwave;
A solution of 3-Chloro-2-fluoroiodo-benzene (1.53 g, 6.0 mmol), piperazine- 1-carboxylic acid tert-butyl ester (1.39 g, 7.5 mmol), sodium tert-hutoxide (0.86 g, 9.0 mmol), BINAP (0.19 g, 0.30 mmol), Pd2(dba)3 (0.14 g, 0. 15 mmol) in toluene (12 mL) was heated at 14O0C for 20 minutes by microwave. The crude product mixture was filtered through celite, eluting with EtOAc(100 mL), concentrated and then purified by column chromatography (5-30percent EtOAc in hexanes, EPO <DP n="50"/>silica) to give U.9U g ol a white solid.
Synthetic Example 2 Synthesis of [4-(piperazin-1-yl)pyridin-3-yl]methanol hydrochloride 4-Chloro-3-hydroxymethylpyridine ( ) (143 mg, 1 mmol), 1- (tert-butoxycarbonyl)piperazine (186 mg, 1 mmol) and triethylamine (1 ml, 7 mmol) were dissolved in ethanol(3 ml), and the mixture was stirred overnight in a threaded test tube at 130°C. The solvent was evaporated and work-up according to a conventional method gave a crude product. The obtained crude product was dissolved in a dioxane solution (5 ml) containing 4 N hydrogen chloride, and the mixture was stirred for 2 hr. The solvent was evaporated to give the title compound, which was used for the synthesis of C-22 and C-37.
Mechanically stir mixture of <strong>[22280-60-0]6-chloro-2-methyl-3-nitro-pyridine</strong> (Asymchem, 25.00 g, 144.9 mmol), tert-butyl 1-piperazinecarboxylate (29.68 g, 159.4 mmol), and triethylamine (23.2 niL, 167 mmol) in K-BuOH (250 mL) at 50 C under nitrogen for 4 hours, at 65 C for 2 hours, then at room temperature overnight. Add additional tert-butyl 1-piperazinecarboxylate (1.5 g), and heat the reaction at 65 C for 4 hours. Cool the resulting slurry to 30 C then add hexanes (75 mL). Cool the slurry to room temperature over 1 hour, then add water (150 mL). Allow the slurry to stand for 45 min then filter. Wash the cake with water (4 x 100 mL) then hexanes (100 mL) and air-dry overnight to yield 4-(6-methyl-5-nitro-pyridin-2-yl)- rhoiperazine-1-carboxylic acid tert-butyl ester as bright yellow crystals (46.30 g, 99% yield, MS(ES): m/z = 267 [MH-H-C4H8]).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50℃; for 4h;
Step 1HLJNIG base (62.82 mL, 0.435 mol) is added to the solution of 6-chloro-3-nitro-2- methylpyridine SM-3 (50 g, 290 mmol) and N-Boc-piperazine SM-5b (53.95 g, 290 mmol) in dry AcCN (200 mL) and stirred for 4 h at 50 C. After the reaction is finished the reaction mixture is diluted with AcCN and water and stirred for 30 min. The precipitated product is collected by filtration, washed with water and the solid is dried in vacuo.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50℃; for 4h;
HUeNIG base (62.82 mL, 0.435 mol) is added to the solution of <strong>[22280-60-0]6-chloro-3-nitro-2-methylpyridine</strong> SM-3 (50 g, 290 mmol) and N-Boc-piperazine SM-5b (53.95 g, 290 mmol) in dry AcCN (200 mL) and stirred for 4 h at 50 C. After the reaction is finished the reaction mixture is diluted with AcCN and water and stirred for 30 min. The precipitated product is collected by filtration, washed with water and the solid is dried in vacuo.
With N-ethyl-N,N-diisopropylamine; for 4h;
DIPEA (62.82 mL, 0.435 mol) is added to the solution of 6-chloro-3-nitro-2- methylpyridine (1) (50 g, 290 mmol) and N-Boc-piperazine (2) (53.95 g, 290 mmol) in dry MeCN (200 mL) and stirred for 4 h at 50 C. After the reaction is finished the reaction mixture is diluted with MeCN and water and stirred for 30 min. The precipitated product is collected by filtration, washed with water and the solid is dried in vacuo.
With 6-chloro-1H-pyrazolo[4,3-c]pyridine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 2h;
(3) To a solution of the compound obtained in the above step (2) (0.72 g) in N-methylpyrrolidone (5.0 mL) was added N-tert-butoxycarbonylpiperazine (1.7 g) and the mixture was stirred at 140 °C for 2 hours. After cooling, to the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a flash column chromatography on NH-silica gel (Solvent; n-hexane/ethyl acetate = 1: 1) to give 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-1H-pyrazolo[4,3-c]pyridine (0.64 g) as colorless crystals. MS(APCI)m/z; 304 [M+H]+
4-(2,6-dichloro-phenyl)-piperazine-1-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 0.5h;Microwave irradiation;
EXAMPLE 20; Example 2OA. l^te-chlorophenvDsulfonyl'M-^.-dichlorophenvDpiperazine; Step 2OA; 2,6-dichlorobromobenzene (2.26g, 10 mmole), N-Boc-piperazine (2.05g, 11 mmole), Pd2(dba)3 (92mg, 1 molpercent), BINAP (187mg, 3 molpercent), and sodium tert-butoxide (1.15g, 12 mmole) were charged in a microwave vessel. The vessel was capped, purged with nitrogen, and 2OmL toluene added. The reaction mixture was heated to 1100C for 30 minutes in the microwave and then the mixture was filtered through celite, rinsing with EtOAc. The filtrate was evaporated and then filtered through a pad of silica gel, eluting with dichloromethane. Evaporation gave crude 4-(2,6-Dichloro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester as an orange oil that was taken on to the next step without further purification.
With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 15h;
5-[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}thiophene-2-carboxylic acid To a solution of 5-formylthiophene-2-carboxylic acid (0.505 g, 3.23 mmol) in MeOH (35 mL) and acetic acid (0.30 mL) was added tert-butyl piperazine-1-carboxylate (1.20 g, 6.47 mmol) and sodium cyanoborohydride (0.406 g, 6.47 mmol). The reaction mixture was allowed to stir at rt for 15 h and was then concentrated to give 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}thiophene-2-carboxylic acid (2.05 g, 6.27 mmol) as a white solid. LCMS: (FA) ES+327.3, ES-325.4.
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 70℃; for 1.5h;
In a sealed tube, <strong>[38573-88-5]1-<strong>[38573-88-5]bromo-2,3-difluorobenzene</strong></strong> (517 mg, 2.68 mmol) Pd2(dba)2 (2percent), BINAP (4percent), and sodium f-butoxide (386.4 mg, 4.02 mmol) were added to /V-Boc-piperazine (500 mg, 2.68 mmol) and the solids were dissolved in dry toluene (5 ml_). The mixture was stirred at 700C for 90 min., filtered over Celite.(R)., washing with etylacetate and the organic layer was evaporated under reduced pressure. The crude was purified by flash chromatography (40percent etylacetate in hexane) to give 7 as pail yellow solid (95percent yield): 1H NMR, 300MHz, (CDCI3) delta 1.38 (s, 9H), 2.91 (m, 4H),3.48 (m, 4H), 6.55 (m, 1 H), 6.66 (m, 1 H), 6.83 (m, 1 H). ESI-MS m/z 321 [M+Na+], 221 , 199. Anal (Ci5H20F2N2O2) C, H, N.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;
General procedure D. 4-(6-Fluoro~pyridine-2-carbonyI)-piperazine-l- carboxylic acid tert-butyl esterTo a stirred solution of 6-fluoro-2-pyridine carboxylic acid (leqv, 2.00 g, 14.2 mmol), N-boc-piperazine (1.15eqv, 3.04 g, 16.3 mmol) and DIPEA (2.5 eqv, 6.12 ml, 35.4 mmol) in DCM (100 ml) at room temperature was added portionwise EDC (1.2eqv, 3.09 g, 17.0 mmol) and HOBt (0.2eqv, 0.383 g, 2.83 mmol). The reaction mixture was stirred at room temperature for 16 hrs then concentrated at reduced pressure. The crude material was purified by chromatography [SiO2, EtOAc / heptane, 1 :1] to give pure product (4.40 g, 84percent, 11.93 mmol) as colourless oil. LC/MS: 95percent MH+, m/z 310, Rt = 0.97 mins.
With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 10h;
<strong>[10320-42-0]<strong>[10320-42-0]2-Chloro-5-nitropyrimidin</strong>e</strong> (2.5 g, 15.7 mmol) was dissolved in dry DMF 25 mL, and piperazinecarboxylic acid 1-tert-butyl ester (3.2 g, 17.2 mmol) was added, and triethylamine.5 mL was added with stirring. , 46.9mmol), heated to 90 ° C for 10 hours, the solvent was evaporated under reduced pressure, the residue was diluted with methylene chloride (50mL), washed with water, dried over anhydrous Na2SO4, filtered and evaporated. The ester/petroleum ether was recrystallized to give 57a, yield 75.0percent;
With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 12h;
To a stirred solution of <strong>[10320-42-0]2-chloro-5-nitro-pyrimidine</strong> (2.2 g, 13.7 mmol) in dry DMF (25mL,), triethylamine (5.7 mL,, 41.3 mmol, Spectrochem) followed by N-Boc piperazine (2.8 g, 15.7 mmol) were added and the resulting mixture was heated at 90 C for 12h. It was concentrated and the residue was diluted with DCM (50 mL,), washed with water (15 ml.) and dried over Na2SO4. After evaporation of the solvents, the crude product was washed with ACN with 5% methanol to afford the title compound (brown solid). 1H NMR (400 MHz, DMSO-d6): delta 9.12 (s, 2H), 3.92-3.88 (m, 4H), 3.45-3.42 (m, 4H), 1.4 (s, 9H).LCMS: (Method A) 254.0 (M-(t-butyl)+H), Rt. 4.43 min, 98.03% (Max).
With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 12h;
To a stirred solution of <strong>[10320-42-0]2-chloro-5-nitro-pyrimidine</strong> (2.2 g, 13.7 mmol) in dry DMF(25mL), triethylamine (5.7 mL, 41.3 mmol, Spectrochem) followed by N-Boc piperazine(2.8 g, 15.7 mmol) were added and the resulting mixture was heated at 90 C for 12h. Itwas concentrated and the residue was diluted with DCM (50 mL), washed with water(15 mL) and dried over Na2SO4. After evaporation of the solvents, the crude productwas washed with ACN with 5% methanol to afford the title compound (brown solid). 1HNMR (400 MHz, DMSO-d6): 69.12 (s, 2H), 3.92-3.88 (m, 4H), 3.45-3.42 (m, 4H), 1.4(s, 9H). LCMS: (Method A) 254.0 (M-(t-butyl)+H), Rt. 4.43 mm, 98.03% (Max).
To a solution of 4-(5-nitro-pyrimidin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester (927 mg, 3 mmol, prepared from <strong>[10320-42-0]2-chloro-5-nitropyrimidine</strong> and N-Boc-piperazine) in tetrahydrofuran (20 mL) and methanol (30 mL) was added 10% palladium on carbon (240 mg) and the mixture was hydrogenated at 50 psi for 1 hr. The mixture was filtered and the solvents were evaporated. The residue was dried in vacuum to give 4-(5-amino- pyrimidin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester.
2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid[ No CAS ]
[ 445-03-4 ]
[ 57260-71-6 ]
2-[7-chloro-2-oxo-4-phenyl-6-(piperazin-1-yl)methyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
A solution of 2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetic acid (0.28 g) in THF (7 ml) was combined with DMF (1 drop) and oxalyl chloride (120 ml), and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the residue, which was dissolved in THF (5 ml) and added dropwise to a suspension of 2-chloro-4-trifluoromethylaniline (101 ml) and sodium hydride (60percent, in oil) (32 mg) in THF (3 ml) at 0° C. After stirring at room temperature for 12 hours, the reaction solution was combined with water, and the product was extracted with ethyl acetate. The extract was washed with a 1 N solution of hydrochloric acid followed by a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and after drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The resultant residue was dissolved in THF (10 ml), combined with tert-butyl 1-piperidinecarboxylate (0.191 g) and triethylamine (0.14 ml), and heated under reflux for 5 hours. The reaction solution was combined with water and extracted with ethyl acetate. The extract was washed with a saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The resultant residue was dissolved in acetic acid (10 ml), combined with concentrated hydrochloric acid (10 ml), and then heated under reflux for 30 minutes. The reaction solution was combined with water and extracted with ethyl acetate. The extract was washed with a saturated sodium bicarbonate followed by a saturated brine, dried over magnesium sulfate, and then the extract was concentrated under reduced pressure. The resultant residue was recrystallized from ethyl acetate-diisopropyl ether to obtain the title compound as a colorless crystal (122 mg, 30percent). Melting point: 237-242° C.
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 24h;
Example 21 ferf-Butyl 4-((2-methylpyridin-4-yl)methyl)piperazine-1-carboxylate <n="38"/>To a mixture of 1-BOC-piperazine (0.615 g, 3.30 mmol) and 1 ,2 DCE (12 ml_) was added 2-methylpyridine-4-carboxaldehyde (0.363 g, 3.0 mmol) followed by the slow addition of sodium triacetoxyborohydride (0.885 g, 4.19 mmol). The reaction mixture was stirred at room temperature for 24 h, then partitioned between ethyl acetate (70 ml_) and saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL), and the combined extracts were dried (Na2SO4) and concentrated in vacuo. The residue was then absorbed on silica gel and placed on a 20 g isolute column. Elution of the column with ethyl acetate / dichloromethane (v/v; 1 :1 ), ethyl acetate, and finally 5percent methanol in ethyl acetate afforded the title compound as a colourless viscous oil (0.626 g, 72 percent). 1H-NMR (500 MHz, DMSO- d6) 1.39 (s, 9H, C(CH3)3), 2.31 (t, J = 5.0 Hz, 4H) and 3.32 (br t, J = 4.6 Hz, 4H) (2 x piperazine N(CH2J2), 2.44 (s, 3H, pyridine 2-CH3), 3.46 (s, 2H, NCH2-pyridyl), 7.11 (d, J = 5.5 Hz, 1 H, pyridine 5-H), 7.17 (s, 1 H, pyridine 3-H), 8.37 (d, J = 5.0 Hz, 1 H, pyridine 6-H);LC (Method B) - MS (ESI, m/z): Rt = 1.96 min - 292 [(M+H)+, 70percent], 236 [(M-1Bu)+, 100percent].
With sodium t-butanolate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In toluene; at 100℃; for 18h;Inert atmosphere;
Example A7; 4-(5-Chloro-pyridin-3-yl)-piperazine-l -carboxylic acid tert-butyi ester; Preparation of intermediate 7; JV-Boc-piperazine (0.52 g, 0.0028 mol) was added to a stirred solution of 3-bromo-5- chloro -pyridine (1 g, 0.0052 mol), tris(dibenzylideneacetone)dipalladium (0) chloroform adduct ( 0.269 g, 0.00026 mol), (R)-(+)-2,2'-bis(diphenylphosphino)-l,l'- binaphthyl (0.324 g, 0.00052 mol) and sodium tert-butoxide ( 1 g, 0.010 mol) in toluene (20 ml) under N2 flow. The mixture was heated at 100 0C for 18 h. and then filtered through a pad of diatomaceous earth. The filtrate was extracted with water. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica; ethyl acetate in heptane 25/75). The desired fractions were collected and evaporated in vacuo to yield A7 (1.3 g, 88percent). Ci4H20ClN3O2.
With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 12h;
To a stirred solution of <strong>[41731-83-3]ethyl 2-bromothiazole-5-carboxylate</strong> (4.0 g, 17.0 mmol) in dry DMF (40 mL), triethylamine (7.3 mL, 51 .0 mmol, Spectrochem), followed by N-Boc piperazine (3.6 g, 19.0 mmol, GLRscientific) were added. The resulting mixture was heated at 90 C for 12 h. It was then concentrated, diluted with DCM (200 mL,), washed with water (100 ml.) and dried over Na2SO4. After evaporation of the solvents, the crude product was purified by flash chromatography (3% methanol in DCM) to afford the title compound. Yield: 77% (4.5 g, white solid). LCMS: (Method A) 342.0 (M+H), Rt. 4.42 min, 99.5% (Max). 1H NMR (400 MHz, CDCl3): delta 7.88 (s, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.57 (s, 8H), 1.49 (s, 9H), 1.35 (t, J = 7.2 Hz, 3H).
77%
With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 12h;
To a stirred solution of <strong>[41731-83-3]ethyl 2-bromothiazole-5-carboxylate</strong> (4.0 g, 17.0 mmol) in dry DMF (40 mL), triethylamine (7.3 mL, 51.0 mmol, Spectrochem), followed by N-Boc piperazine (3.6 g, 19.0 mmol, GLRscientific) were added. The resulting mixture washeated at 90 C for 12 h. It was then concentrated, diluted with DCM (200 mL), washed with water (100 mL) and dried over Na2SO4. After evaporation of the solvents, the crude product was purified by flash chromatography (3% methanol in DCM) to afford the title compound. Yield: 77% (4.5 g, white solid). LCMS: (Method A) 342.0 (M+H), Rt. 4.42 mm, 99.5% (Max). 1H NMR (400 MHz, CDCI3): 6 7.88 (s, I H), 4.30 (q, J = 7.2 Hz,2H), 3.57 (s, 8H), 1.49 (s, 9H), 1.35 (t, J= 7.2 Hz, 3H).
With potassium carbonate; In 1,4-dioxane; at 90℃; for 16h;Sealed vial;
INTERMEDIATE 7; Ethyl { 5- [2-(piperazin- 1 -yl)- 1 ,3 -thiazol-5 -yl] -2//-tetrazol-2-yl } acetate hydrochloride; Step 1 : tert-Butyl 4-[5-(ethoxycarbonyl)-l,3-thiazol-2-yl]piperazine-l-carboxylate; Into a 100 mL pressure flask equipped with a magnetic stir bar was added ethyl 5- carboxylate 2-bromothiazole (6.00 g, 25.4 mmol), tert-bnty piperazine-1 -carboxylate (4.75 g, 25.4 mmol) and potassium carbonate (5.27 g, 38.1 mmol). The solids were suspended in dioxane (20 mL) and the vial was sealed and heated to 90 0C for 16 h. The resulting suspension was cooled to room temperature and diluted with water (75 mL). The mixture was stirred at room temperature for 15 min and filtered through filter paper on a Hirsch funnel, washing with water (5 mL). The title compound was obtained as a light yellow solid.
With potassium carbonate; In 1,4-dioxane; at 90℃; for 16h;
Step 1: tert-Butyl 4-[5-(ethoxycarbonyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate Into a 100 mL pressure flask equipped with a magnetic stir bar was added ethyl 5-carboxylate 2-bromothiazole (6.00 g, 25.4 mmol), tert-butyl piperazine-1-carboxylate (4.75 g, 25.4 mmol) and potassium carbonate (5.27 g, 38.1 mmol). The solids were suspended in dioxane (20 mL) and the vial was sealed and heated to 90 C. for 16 h. The resulting suspension was cooled to room temperature and diluted with water (75 mL). The mixture was stirred at room temperature for 15 min and filtered through filter paper on a Hirsch funnel, washing with water (5 mL). The title compound was obtained as a light yellow solid.
With triethylamine; In N,N-dimethyl-formamide; at 90℃;
To a solution of compound 1 (860 mg, 4.6 mmol) and <strong>[41731-83-3]ethyl 2-bromothiazole-5-carboxylate</strong> (1 g, 4.2 mmol), Et3N (1.27 g, 12.6 mmol) in DMF (20 ml) was stirred at 90 C. for overnight. The solvent was evaporated oil and extracted by EA (20 mlx2), washed with water, brine, concentrated in vacuo to afford compound 2 as a yellow solid (1.8 g, crude).
Example 1 Step 2. To solution of 1.0 eq IB in dry Et2O (0.06 M) at 00C was added dropwise a solution of diisobutyllithiumaluminum hydride (1.1 eq, 1.0 M in hexanes) by syringe. The resulting solution was kept at 00C overnight. The reaction mixture was added to a mixture of ice and glacial acetic acid. The reaction mixture was then diluted with ethyl acetate, and the aqueous layer was extracted with ethyl acetate two additional times. The combined organic layers were washed twice with saturated sodium bicarbonate, and once with brine. The organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. Purification over silica gel using 10percent EtOAc/hexanes as the eluant afforded a yellow solid (100percent) as an 80:20 mixture of 1C:1B. Example 1 Step 3. To cooled (00C) slurry of an 80:20 mixture of 1C:1B (1.0 eq) and boc-piperazine(about 2 eq) in a mixture of HOAc and DCM (4.8 M boc-piperazine in 1:1.4 v/v HOAc/DCM) was added sodium triacetoxyborohydride as a solid over about 5 minutes. The reaction was allowed to warm to RT and stirred for two hours. The reaction mixture was quenched with saturated sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the aqueous layer was washed three times with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by chromatography over silica gel using 50percent ethyl acetate/hexanes as the eluant provided ID (67.7percent) as a yellow oil.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
<strong>[65130-46-3]1-(1-bromoethyl)-4-fluorobenzene</strong> (1.2 equiv., 18 g) and K2CO3 (2 equiv., 22 g) were added at room temperature to a solution of tert.-butyl-piperazine-1-carboxylate (1 equiv., 15 g) in DMF (15 mL) and stirred for 2 h. After adding cold water (20 mL) the mixture was extracted with hexane (10.x.60 mL). The combined organic phases were dried over sodium sulphate and acidified with 10percent HCl. The precipitate was suction filtered, washed with hexane (3.x.100 mL), adjusted to pH9 with K2CO3 and re-extracted with hexane (5.x.100 mL). The combined organic phases were dried over sodium sulphate. The removal of the solvent in vacuo yielded a viscous product (tert-butyl 4-(1-(4-fluorophenyl)ethyl)piperazine-1-carboxylate) (12.5 g, 50percent yield).
Step C: Ethyl 2-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyrimidine-5-carboxylate Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (2 g, 8.6 mmol) was dissolved in 10 mL of DMSO. Boc protected piperazine (4.04 g, 21.7 mmol) was added to this and heated to 75-85 °C for an hour. The reaction mass was cooled to room temperature, quenched with water and extracted with DCM (2 x 100 mL). The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was further purified by column chromatography using DCM/MeOH solvent mixture to get the pure title product (2 g, Yield 68 percent).
With triethylamine; In N,N-dimethyl-formamide; at 60℃;
6.01.01.2 4-(6-methoxy-pyrimidin-4-yl)-piperazine- 1 -carboxylic acid tert-butyl ester 18.6 mL triethylamine and piperazine-1 -carboxylic acid tert-butyl ester were added to 9.7 g 4- chloro-6-methoxy-pyrimidine in 50 mL DMF. The reaction was sirred over night at 60°C. The reaction was cooled and the precipitate was filltered. The filtrate was evaporated. The residue was dissolved in DCM, extracted with water and washed with sodium chloride solution. The solvent was evaporated and the residue was crystallized with a mixture of petrolether and diethylether (8:2) to yield 8.7 g of the desired compound.Rt: 1.12min (method B)(M+H)+: 195
8.7 g
With triethylamine; In N,N-dimethyl-formamide; at 60℃;
6.01.01.2 4-(6-methoxy-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester 18.6 mL triethylamine and piperazine-1-carboxylic acid tert-butyl ester were added to 9.7 g <strong>[26452-81-3]4-chloro-6-methoxy-pyrimidine</strong> in 50 mL DMF. The reaction was stirred over night at 60° C. The reaction was cooled and the precipitate was filtered. The filtrate was evaporated. The residue was dissolved in DCM, extracted with water and washed with sodium chloride solution. The solvent was evaporated and the residue was crystallized with a mixture of petrolether and diethylether (8:2) to yield 8.7 g of the desired compound. Rt: 1.12 min (method B)
9.8 g
With triethylamine; In N,N-dimethyl-formamide; at 60℃;
4-(6-methoxy-pyrimidin-4-yl)-piperazine- 1 -carboxylic acid tert-butyl ester 10.8 g piperazine-1 -carboxylic acid tert-butyl ester was added to 8.3 g 4-chloro-6-methoxy- pyrimidine and 16 mL triethylamine in 40 mL DMF. The reaction was stirred over night at 60°C. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and evaporated. The residue was purified chromatography on silica gel (petrolether /ethyl acetate: 8/2) to yield 9.8 g of the desired compound. : 1.24 min (method B), (M+H) : 295
9.8 g
With triethylamine; In N,N-dimethyl-formamide; at 60℃;
10.8 g piperazine-1-carboxylic acid tert-butyl ester was added to 8.3 g <strong>[26452-81-3]4-chloro-6-methoxy-pyrimidine</strong> and 16 mL triethylamine in 40 mL DMF. The reaction was stirred over night at 60° C. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate and evaporated. The residue was purified chromatography on silica gel (petrolether/ethyl acetate: 8/2) to yield 9.8 g of the desired compound. Rt: 1.24 min (method B), (M+H)+: 295
With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 48h;Sealed tube;
To a stirred solution of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (1 g, 6.92 mmol) in DMF (20 mL) was added tert-butyl piperazine-1-carboxylate (1.2 g, 6.44 mmol) and TEA (3 mL, 21.52 mmol) in a sealed tube mixture was stirred at 60 °C for 48 h. The completion of the reaction was monitored by LCMS. The solvent was removed under reduced pressure to get cmde residue, which was dissolved in ethyl acetate (100 mL) and washed with water (2* 100 mL), the organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude (1.5 g) as brown liquid. The crude compound was purified by combi (24g silica gel column, eluted with 15percent ethyl acetate / Pet ether) to get tert-butyl 4-(5- methoxypyrimidin-2-yl)piperazine- 1 -carboxylate (550 mg, 1.738 mmol, 25.1 percentyield) as off white solid.LCMS: Column-Ascentis Express C18 (50X2.lmm-2.7iim), Mphase A: 10mM NH4COOH IN WATER:ACN(98:02), Mphase B: 10mM NH4COOH IN WATER:ACN(02:98), Flow = 1ML/MIN, Time: percentB:: 0.0 : 0.0:: 1.7: 100.0:: 3.0:100.0:: 3.2: 0.0, LCMS RT = 2.2 mm M(+1) -295.
957 mg
With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 144h;
6.01.02.01 4-(5-methoxy-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester 1.5 g piperazine-1-carboxylic acid tert-butyl ester was added to 1.2 g <strong>[22536-65-8]2-chlor-5-methoxy-pyrimidine</strong> and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60° C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodiumchloride-solution and evaporated. The residue was purified by HPLC to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295
957 mg
With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 144h;
6.01.02.01 4- 5-methoxy-pyrimidin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester 1.5 g piperazine-1 -carboxylic acid tert-butyl ester was added to 1.2 g 2-chlor-5-methoxy- pyrimidine and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60°C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodiumchloride-solution and evaporated. The residue was purified by HPLC to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295
957 mg
With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 144h;
6.02.08.01 4- 5-methoxy-pyrimidin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester 1.5 g piperazine-l-carboxylic acid tert-butyl ester was added to 1.2 g 2-chlor-5-methoxy- pyrimidine and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60°C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodium chloride solution and evaporated to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295
957 mg
With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 144h;
6.02.08.01 4-(5-methoxy-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester 1.5 g piperazine-1-carboxylic acid tert-butyl ester was added to 1.2 g <strong>[22536-65-8]2-chlor-5-methoxy-pyrimidine</strong> and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60° C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodium chloride solution and evaporated to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
General procedure: 1-Boc-piperazine (150 mg, 0.81 mmoles) was dissolved in anhydrous DMF (2 mL) and, under stirring, DIPEA (303 mL, 1.78 mmoles), PyBOP (461 mg, 0.89 mmoles) and 2-thiophenecarboxylic acid (114 mg, 0.89 mmoles) were added at room temperature. After complete conversion of 1-Boc-piperazine monitored by TLC analysis, the solution was diluted with DCM and washed with NaOH 0.5M, brine, HCl 0.1M and brine. Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatographic column (eluent DCM/MeOH = 96/4) to obtain 10e (188 mg, 79% yield).
[0211] Reference M [0212] Synthesis of (2-chloro-4-(methylsulfonyl)phenyl)(piperazin-l-yl)methanone, hydrogen chloride salt [0214] Step 1 : tert4outyl 4-(2-chloro-4-(methylsulfonyl)benzoyl)piperazine-l-carboxylate [0215] A solution of <strong>[53250-83-2]2-chloro-4-(methylsulfonyl)benzoic acid</strong> (550 mg, 2.344 mmol) in DCM (7813 mu) and DMF (2 drops) was treated with oxalyl chloride (41 1 mu, 4.69 mmol) at RT and the reaction mixture was stirred for 2 h. A solution of tert-butyl piperazine-1- carboxylate (960 mg, 5.16 mmol) and Ets (719 mu, 5.16 mmol) in DCM (4.6 mL) was cooled to 0 °C and the crude acid chloride solution was added dropwise. The reaction mixture was allowed to warm up to RTand stirred for 3 h. ISCO purification (75percent EtOAc/hexanes) afforded the title compound as a white solid.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 8h;Inert atmosphere;
To an oven-dried flask, 1-boc-piperazine (3.19 g, 17.1 mmol), Cs2CO3 (5.82 g, 17.86 mmol), Pd2(dba)3 (1.44 g, 1.57 mmol), rac-2,2?bis(diphenylphosphino)-1,1?-binaphthyl (0.89 g, 1.43 mmol), toluene (8 mL) and compound 7 (3.68 g, 14.26 mmol) were added. While stirring the reaction mixture at room temperature, the air in the flask was removed and replaced by N2. This process was repeated three times. The reaction temperature was brought to 110° C. and stirred for 8 h. Ethyl acetate (40 mL) was added to the mixture at room temperature, washed with H2O (15 mL) and brine (10 mL), dried over Na2SO4 and evaporated. The brown oily material was chromatographed on a silica column, eluting with hexanes:ethyl acetate (3:7), and then changing to (1:1) to obtain compound 18. Yield: 37percent, light red solid. IR (KBr, cm?1) 3310, 3168 (NH), 3176 (Ar?H), 1709, 1678 (CO), 1519, 1416 (C?C), 1210 (C?N), 1151 (C?O); 1H NMR (500 MHz, CDCl3) delta 1.49 (s, 9H, OC(CH3)3), 2.17 (s, 3H, COCH3), 3.15 (m, 4H, 2CH2), 3.60 (m, 4H, 2CH2), 7.22 (dd, J=2.5, 8.5 Hz, 1H, H-6), 7.62 (d, J=2.5 Hz, 1H, H-2), 7.57 (d, J=8.5 Hz, 1H, H-5), 9.98 (br. s, 1H, NH). 13C NMR (125.7 MHz, CDCl3) delta 25.59 (COCH3), 28.40 (OC(CH3)3), 48.92 (CH2), 52.31 (CH2), 79.94 (OC(CH3)3), 111.29 (C-2), 123.52 (C-5/C-6), 124.31 (C-5/C-6), 127.45 (C4), 137.45 (C-3), 147.11 (C-1), 154.63 (CO), 168.78 (CO). Anal. Calcd for C17H24N4O5: C, 56.03; H, 6.64; N, 15.38percent. Found: C, 55.96; H, 6.69; N, 15.30percent.
tert-butyl 4-(3,5-dichlorobenzyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere;
To a mixture of tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol) and potassium carbonate (1.34 g, 9.76 mmol) in anhydrous dimethylformamide (50 mL) was added 1, 3-dichloro-5-(chloromethyl) benzene (0.95 g, 4.88 mmol) under nitrogen. The resulting mixture was stirred at ambient temperature for 2 days. The reaction mixture was diluted with ethyl acetate (200 mL) , washed with water (100 mL) , saturated ammonium chloride (2 x 50 mL) , brine (2 x 40 mL) , dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (3:1 hexanes: ethyl acetate) to provide the title compound as a colorless oil (1.22 g, 73) :1H NMR (300 MHz, CDCl3) delta 7.25-7.17 (m, 3H) , 3.45-3.35 (m, 6H) , 2.39-2.30 (m, 4H) , 1.42 (s, 9H) MS (ES+) m/z 345.1, 347.1 (M + 1) .
With potassium carbonate; In acetonitrile; at 80℃; for 16h;
A mixed solution of compound 1-1 (1.96 g, 10.0 mmol), N-Boc-piperazine (1.95 g, 10.5 mmol), potassiumcarbonate (2.76 g, 20.0 mmol) in acetonitrile (20 ml) was stirred at 80°C for 16h. The reaction mixture was cooled toroom temperature, the solvent was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate (2*50 ml). The organic phase was washed with saturated brine (30 ml), dried and separated, and thefiltrate was concentrated under reduced pressure to give compound 1-2 (3.5 g) as a yellow oil, purity 90.26percent, yield100percent. MS m/z(ESI): 345.0[M+H]+.
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃;
Sodium triacetoxyborohydride (0.85 g, 4.01 mmol) was added to a solution of <strong>[131747-63-2]4-bromopicolinaldehyde</strong> (0.25 g, 1.34 mmol), tert-butyl piperazine-1-carboxylate (0.28 g,1.48 mmol) and acetic acid (0.02 mL, 0.4 mmol) in dichloromethane (5 mL) and the resulting mixture was stirred overnight at room temperature. The solvent was then evaporated and the residue was triturated with diethyl ether, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography to yield the titlecompound (363 mg, 68percent) as a solid. LRMS (m/z): 356/358 (M+1).1H-NMR (300 MHz, CDCI3): 1.46 (s, 9H), 2.46 (t, 4H), 3.46 (t, 4H), 3.64 (s, 2H), 7.62 (d, 1H), 8.37 (d, 1H).
tert-butyl 4-(2,6-dimethylpyridin-4-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 90℃;Schlenk technique; Inert atmosphere; Sealed tube;
A Schlenk tube was charged with tert-butyl piperazine-1-carboxylate (0.12 g, 0.62mmol), <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (0.15 g, 0.81 mmol), sodium tert-butoxide (0.09 g,0.94 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 g, 0.02 mmol) andtoluene (4 mL). The Schlenk tube was subjected to three cycles of evacuationbackfilling with argon and then tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 °C. After coolingto room temperature, the reaction mixture was filtered through diatomaceous earth (Celite®) and washed with water. The aqueous layer was extracted with ethyl acetate (x3) and the combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness to yield the title compound (198 mg, 100percent) as an oil.LRMS (mlz): 292 (M+1).1H-NMR (300 MHz, CDCI3): 1.48 (s, 9H), 2.43 (s, 6H), 3.25 - 3.32 (m, 4H),3.51 - 3.58 (m, 4H), 6.38 (s, 2H).
tert-butyl 4-(5-fluorobenzothiazol-2-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In N,N-dimethyl-formamide; at 100℃;
General procedure: GP4-1: A mixture of substituted2-chlorobenzothiazole (1.0eq), N-Bocpiperazine (1.05 eq) and Na2CO3 (1.2 eq) inDMF (10 volume) was heated up at 100 0C for hours, the process ofwhich was monitored by TLC. The mixture was diluted by EA and added by water.After extraction by EA (2 times), the collected organic layers were washed by10percent citric acid, and then brine, dried over Na2SO4 andconcentrated to give crude product, which could be used directly withoutfurther purification.GP4-2: N-Bocprotected amine in DCM (5 volume) was added by TFA (2.5 volume). The mixturewas stirred at rt for four hours and monitored by TLC. After consumption ofstarting material, volatile solvent was removed under reduced pressure and theresidue was neutralized by saturated Na2CO3 solution toobtain the slurry, which was extracted by 10percent methanol in DCM (3 times). Theorganic layers were collected, dried and concentrated to give the desired freeamine, for direct use for next step.GP4-3: Free amine (1.0 eq) suspendedin DCM (10 volume) was added by aldehyde (1.1 eq) under N2atmosphere. The mixture was stirred at rt 15 min. Then trimethylsilylazide (TMSN3, 1.1 eq) was added, and stirring was kept foranother 15 min, followed by addition of isonitrile (1.0 eq). The mixture wasstirred at for 12 h. After removal of solvent, the residue was purified bypreparative TLC (DCM/MeOH as eluent) to give the product, which could bere-purified by trituration with ether.
With potassium carbonate; In dimethyl sulfoxide; at 100 - 110℃;Microwave irradiation;
A microwave vial was charged with <strong>[52092-47-4]5-chloro-2-nitropyridine</strong> (1 g, 6.31 mmol), 1 -boc-piperazine (1 .29g, 6.94mmol) and potassium carbonate (3.3ml_, 18.92mmol), which was suspended in DMSO (15ml_). The resulting mixture was irradiated for 1 hour at 100°C. After this time, the mixture had solidified. LC-MS showed the reaction had not gone to completion. The solid mixture was then transferred to a flask along with DMSO (5ml_) and heated to 1 10°C, at which point the solid mixture had melted. This was left heating overnight, after which LC-MS showed product formation and no starting material. Reaction was allowed to cool. The reaction mixture was then added to water and extracted with EtOAc (x3). The organics were then combined, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness, affording an orange solid. Purification by flash column chromatography was then performed, (40g S1O2, eluting with 0-50percent EtOAc in heptane). The fractions containing product were combined and concentrated to dryness, affording tert-butyl 4-(6- nitro-3-pyridyl)piperazine-1 -carboxylate (1 .24g, 4.02mmol, 63.81 percent yield) as a bright orange/yellow solid. MS Method 2: RT: 1 .61 min, ES+ m/z 309.1 [M+H]+ H NMR (400MHz, CDC ) delta/ppm: 8.10-8.13 (d, J=9.1 Hz, 1 H), 8.06-8.07 (d, J=3.0Hz, 1 H), 7.12-7.16 (dd, J=9.2, 3.0Hz, 1 H), 3.55-3.59 (m, 4H), 3.36-3.41 (m, 4H), 1 .42 (s, 9H).
tert-butyl 4-(1-methylpyrazole-4-carbonyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;
GammaAlpha1 fe/t-Butyl 4-( 1 -methylpyrazole-4-carbonyl)piperazine- 1 -carboxylate To a stirred solution of iert-butyl piperazine-l-carboxylate (1 g, 5.3 mmol), EDCI (1.2 g, 6.4 mmol) and HOBT (864 mg, 6.4 mmol) in DCM (30 mL) was added 1-methylpyrazole- 4-carboxylic acid (668 mg, 5.3 mmol) and DIPEA (1.4 g, 10.7 mmol). The mixture was stirred at room temperature for 3 h before it was quenched with satd. aq. NH4C1 (40 mL), diluted with H20 (100 mL), and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (2 x 50 mL), dried over anhy. Na2S04, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography (PE: EA=2: 1) to afford the desired title compound as yellow oil (900 mg, 57percent). MS: 295.1 (M+H+).
4-benzothiazol-2-yl-piperazine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine; In N,N-dimethyl-formamide; at 120℃; for 16h;
Taking 100mL single-mouthed flask, was successively added <strong>[2516-40-7]2-bromobenzo[d]thiazole</strong> (200mg, 0.93mmol), tert-butyl piperazine-1-carboxylate (0.208g, 1.12mmol), TEA (0.4mL, 2.79mmol ), DMF (3mL), 120 deg. C reaction 16h, concentrated to dryness to give a crude product, after purification of the crude product by column chromatography to give pure product 0.3g, yield: 100percent.
tert-butyl 4-[(2-bromo-3-methylphenyl)methyl]piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
[00204] A flask was charged with <strong>[109179-31-9]2-bromo-3-methylbenzaldehyde</strong> (3.00 g, 15.1 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (3.40 g, 18.2 mmol, 1.20 equiv), and 1,2- dichloroethane (50 mL). The mixture was stirred for 30 min at rt. NaBH(OAc)3 (9.60 g, 45.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at rt and then diluted with H2O (20 mL). The resulting mixture was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column (20:80 EtOAc/petroleum ether) to provide tert-butyl 4-[(2-bromo-3-methylphenyl)methyl]piperazine-1- carboxylate (4.80 g, 86percent yield) as colorless oil. LCMS (ESI, m/z): 369 [M+H]+.
tert-butyl 4-(thiazole-2-carbonyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20.1 g
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 10 - 35℃; for 28h;
A) tert-Butyl 4-(thiazole-2-carbonyl)piperazine-1-carboxylate To a mixture of tert-butyl piperazine-1-carboxylate (15.87 g) and THF (310 mL) were added <strong>[14190-59-1]thiazole-2-carboxylic acid</strong> (10 g), triethylamine (16.19 mL), 1-hydroxybenzotriazole monohydrate (14.23 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.81 g) at room temperature. The reaction mixture was stirred at room temperature for 22 hr. To the reaction mixture were added tert-butyl piperazine-1-carboxylate (2.88 g), 1-hydroxybenzotriazole monohydrate (2.372 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.97 g) and THF (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with water, saturated brine and saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (20.10 g). MS, found: 242.1.
To a mixture of tert-butyl piperazine-1-carboxylate (31.7 g), 1,3-thiazole-4-carboxylic acid (20 g) and 1-hydroxybenzotriazole hydrate (28.5 g) in anhydrous DMF (500 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.6 g) at room temperature. The mixture was stirred at room temperature for 22 hr. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The solid was washed with diisopropyl ether. The solid was suspended with ethyl acetate (100 mL) and added hydrogen chloride (4 M in ethyl acetate, 171 mL). The mixture was stirred at 50° C. for 2 hr. The solid was collected by filtration. The residue was purified by column chromatography (NH silica gel, methanol/ethyl acetate) to give the title compound (16.00 g). MS: [M+H]+ 198.0.
tert-butyl 4-(6-chloro-2-methoxypyrimidin-4-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With triethylamine; In methanol; at 20.0℃; for 2.0h;
To a solution of <strong>[1074-40-4]4,6-dichloro-2-methoxy-pyrimidine</strong> (1.50 g, 8.38 mmol) and TEA (2.50 g, 25.1 mmol) in methanol (100 mL) was added a solution of piperazine-1-carboxylic acid tert30 butyl ester (1.55 g, 8.38 mmol), and the mixture was stirred at room temperature for 2 hrs.The reaction mixture was concentrated and the residue was washed with 5 mL of cold MeOH (5 mL) to get the title compound (2.4 g, yield 87percent) as a white solid.1H NMR (400 MHz, CDCI3): 66.19 (s, IH), 3.94 (s, 3H), 3.63-3.50 (m, 8H), 1.48 (s, 9H).LC-MS: [mobile phase: from 80percent water (0.02percent NH4OAc) and 20percent CH3CN to 5percent water(0.02percent NH4OAc) and 95percent CH3CN in 4 mm], Rt 2.418 mm, MS Calcd.:328, MS Found: 329[M+H].
tert-butyl 4-(6-chloro-4,5-dimethylpyridazin-3-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 7h;Inert atmosphere;
General procedure: Solid K2CO3 (2 equiv) was added to a solution of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> (1 equiv) and amine (1 equiv) in DMF(20 mL), and the resulting solution was stirred at 110 C for 7 h.The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography (ethyl acetate: hexane= 4:1) to yield pure product
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 16h;
A mixture of <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (1 g, 8.73 mmol), tert-butyl piperazine-1-carboxylate(1.626 g, 8.73 mmol), and K2C03 (2.413 g, 17.46 mmol) in NMP (10 mL) was stirred at 120 °C for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/20) to afford tertbutyl 4-(pyridazin-3-yl)piperazine-1-carboxylate (709 mg, 2.68 mmol, 31percent) as a yellow oil. ESIMS (EI+, m/z): 265.4 [M+H]t
With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 15h;
A mixture of compound 1.4 (soo mg, 1.89 mmol, 1 eq), tert-butyl piperazine-1- carboxylate (1.06 g, 5.67 mmol, 3 eq) and potassium carbonate (552 mg, 3.78 mmol, 2 eq) was stirred in DMF (18 mL) at 140°C for 15 hours. Upon completion (as monitored by LC-MS), the mixture was extracted with DCM (2 x 15 mL) and washed with water (10 mL) with the aqueous layer neutralized using a 1M solution of citric acid. Thecombined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The crude compound was recrystallized from DMF ( mL) to give pure compound 1.5 (285 mg, 35.0 percent yield) as a pale orange solid. JR (umax/cm1) 1729, 1687, 1627, 1502, 1462, 1417, 1383, 1340, 1286, 1246, 1217, 1168,1124, 1083, 1045, 1034, 940, 891, 86, 828, 8o, 782, 770, 746, 703, 667, 625; LC-MSRetention time 3.95 minutes, found 432.0 [M+H] calculated for C22H26FN305 432.46 [M+H]
With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 12h;
To a stirred solution of 538 <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (1.0 g, 5.843 mmol, 1.0 eq) and 539 tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g, 6.427 mmol, 1.1 eq) in 95 DMSO (20 mL) was added 64 K2CO3 (2.43 g, 17.53 mmol, 3.0 eq) at rt. The resulting mixture was stirred at 90 C. for 12 h. The progress of reaction was monitored by LCMS. The reaction mixture was poured into ice cold 7 water (100 mL), stirred for 5 min, formation of precipitates was observed, which was filtered and dried under vacuum to afford the desired compound 540 tert-butyl 4-(2-methoxy-4-nitrophenyl)piperazine-1-carboxylate (1.75 g, 88.83%) as a yellow solid. (0576) LCMS: 338.2 [M+1]+
With potassium carbonate; In dimethyl sulfoxide; at 0 - 80℃; for 8h;
General procedure: To a solution of 1-fluoro-4-nitrobenzene (5 g, 35.5 mmol) in DMSO(100 mL) was added K2CO3 (14.6 g, 106.4 mmol) at room temperature.And a solution of tert-butyl piperazine-1-carboxylate (3.5 g, 35.5 mmol)in DMSO (50 mL) was added dropwise to the mixture at 0 °C. The reactionmixture was stirred at 80 °C for 8 h. Water (500 mL) was added toquench the reaction. The precipitated solid was collected on a filter anddried under reduced pressure to give 1a (8.0 g, yield 73.5percent) withoutfurther purification. MS m/z: 308.2 [M+H]+. The crude product wasdelivered directly to the next step.
tert-butyl 1-[(6-methoxypyridin-2-yl)methyl]piperazine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.09%
With methanol; sodium cyanoborohydride; at 0 - 20℃; for 16h;
To a stirred mixture of <strong>[54221-96-4]6-methoxypyridine-2-carbaldehyde</strong>( 5 g, 36.46 mmol, 1 equiv.) and tert- butyl piperazine-1-carboxylate(8.1 g, 43.49 mmol, 1.19 equiv.) in MeOH(25 mL) was added NaBH3CN(4.6 g, 73.20 mmol, 2.01 equiv.) in portions at 0 degrees C. The resulting mixture was stirred for 16 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (40/1 to 1/1) to afford tert-butyl 1-[(6-methoxypyridin- 2-yl)methyl]piperidine-4-carboxylate(8.5 g, 76.09%) as a light yellow oil.
tert-butyl 4-(5-ethynyl-2-pyridyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With triethylamine; In acetonitrile; at 60℃; for 16h;
A solution of <strong>[853909-08-7]5-ethynyl-2-fluoro-pyridine</strong> (500 mg, 4.13 mmol), l-Boc-piperazine (923 mg, 4.95 mmol) and triethylamine (1.15 mL, 8.26 mmol) in MeCN (10 mL) was stirred at 60 C for 16 h. The reaction was poured into H20 (50 mL) and extracted with EtOAc (70 mL). The organic layer was separated, dried over Na2S04, filtered and concentrated under vacuum The residue was purified by silica gel chromatography (petroleum ehtenEtOAc, 10: 1 to 2: 1) to afford /e/ -butyl 4-(5-ethynyl-2-pyridyl)piperazine-l-carboxylate (630 mg, 79%) as white solid. lH NMR (CHLOROLORM-d, 400 MHz) d 8.24 (d, 1H, 7=2.2 Hz), 7.48 (dd, 1H, 7=2.3, 8.9 Hz), 6.48 (d, 1H, J= 8.8 Hz), 3.4-3.5 (m, 8H), 3.00 (s, 1H), 1.41 (s, 9H)
tert-butyl 4-(1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In toluene; at 90℃; for 16h;Sealed tube; Inert atmosphere;
A solution of 6-bromo- 1 -methyl- 1 //-indazole (500 mg, 2.37 mmol, 1.00 eq.), tert- butyl piperazine- 1 -carboxylate (443 mg, 2.38 mmol, 1.00 eq.), NaOtBu (343 mg, 1.50 eq.), DavePhos (9 mg, 0.01 eq.), and Pd2(dba)3 (22 mg, 0.02 mmol, 0.01 eq.) in toluene (10 mL) was stirred for 16 h in a 30-mL sealed tube under N2 at 90 C in an oil bath. The resulting solution was extracted with 2x30 mL EtOAc, and the organic layers were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / hexane (1/1), to afford 600 mg (80 %) of the title compound as white solid. LC-MS: (ES, m/z): 317
With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 10h;
Compound 11 (1 g, 2.54 mmol), compound 12 (0.568 g, 3.05 mmol), K2CO3 (0.527 g, 3.81 mmol) was dissolved in 15 mL DMSO and heated to 90 C. The reaction was stirred for 10 hours and detected by thin layer chromatography (dichloromethane: MeOH = 80:1). After the reaction solution was cooled to room temperature, 10 mL of water was added. Extracted three times with 15mL of dichloromethane and 3 times with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate to afford the product 1.35g, 97% yield.
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