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Chemical Structure| 103-76-4
Chemical Structure| 103-76-4
Structure of 103-76-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 103-76-4 ]

CAS No. :103-76-4 MDL No. :MFCD00005970
Formula : C6H14N2O Boiling Point : -
Linear Structure Formula :- InChI Key :WFCSWCVEJLETKA-UHFFFAOYSA-N
M.W : 130.19 Pubchem ID :7677
Synonyms :

Calculated chemistry of [ 103-76-4 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 43.53
TPSA : 35.5 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.86 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.59
Log Po/w (XLOGP3) : -1.08
Log Po/w (WLOGP) : -1.88
Log Po/w (MLOGP) : -0.67
Log Po/w (SILICOS-IT) : 0.19
Consensus Log Po/w : -0.37

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 0.17
Solubility : 190.0 mg/ml ; 1.46 mol/l
Class : Highly soluble
Log S (Ali) : 0.82
Solubility : 868.0 mg/ml ; 6.67 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.57
Solubility : 34.6 mg/ml ; 0.266 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.42

Safety of [ 103-76-4 ]

Signal Word:Danger Class:N/A
Precautionary Statements:P264-P280-P302+P352-P305+P351+P338-P332+P313-P362+P364 UN#:N/A
Hazard Statements:H315-H318 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 103-76-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 103-76-4 ]
  • Downstream synthetic route of [ 103-76-4 ]

[ 103-76-4 ] Synthesis Path-Upstream   1~27

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Reference: [1] Patent: US2860138, 1956, ,
  • 2
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  • [ 50-00-0 ]
  • [ 5464-12-0 ]
YieldReaction ConditionsOperation in experiment
67% With sodium cyanoborohydride In tetrahydrofuran at 50℃; In THF (30 ml) were added N-(2-hydroxyethyl)piperazine (500 mg, 3.84 mmol), a solution of formaldehyde (3117 mg, 38.41 mmol) and sodium cyanoborohydride (1207 mg, 19.20 mmol). The mixture was heated up to 50° C. overnight under stirring. After cooling some water was added and the mixture was extracted with DCM (3.x.). The organic layers were dried over MgSO4 and evaporated. The residue was purified over a silica plug with DCM/MeOH 9:1 as eluant to afford an oil (370 mg, Y=67percent). 1H NMR (DMSO-d6) δ 4.45 (t, J=5.3 Hz, 1H), 3.51-3.45 (m, 2H), 3.02-2.84 (m, 4H), 2.71-2.64 (m, 2H), 2.61 (s, 3H), 2.58-2.53 (m, 2H), 2.47-2.43 (m, 2H).
44% With formic acid In water at 20 - 100℃; 2-(4-Methylpiperazin-l-yl)ethyl 4-nitrophenyl carbonate To a stirred solution of l-(2-hydroxyethyl)piperazine (26.0 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water) The reaction mixture was cautiously heated at 100 0C for 2 hours and then stirred overnight at room temperature. The solvent was removed in vacuo. This procedure was repeated 3 further times to give -100 g of product. The crude products were combined and distilled under vacuum to give, at ~74 0C, 2-(4-methylpiperazin-l-yl)ethanol (51 g, 44percent) as a colourless liquid. Analytical LCMS: (System B, Rτ = 0.70 min), ES+: 145.1 (100percent) [MH]+.
44% With formic acid In water; N,N-dimethyl-formamide at 20 - 100℃; To a stirred solution of 1-(2-hydroxyethyl)piperazine (26 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water). The reaction mixture was cautiously heated at 100° C. for 2 hours then stirred overnight at room temperature. The solvent was removed in vacuo. This procedure was repeated 3 further times to give 100 g of product. The crude products were combined and distilled under vacuum to give, at 74° C., 2-(4-methylpiperazin-1-yl)ethanol (51 g, 44percent) as a colourless liquid.Analytical LCMS: (System B, RT=0.70 min), ES+: 145.1 [MH]+.
44% With formic acid In water; N,N-dimethyl-formamide at 20 - 100℃; 2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate
To a stirred solution of 1-(2-hydroxyethyl)piperazine (26.0 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water) The reaction mixture was cautiously heated at 100° C. for 2 hours then stirred overnight at room temperature.
The solvent was removed in vacuo.
This procedure was repeated 3 further times to give ~100 g of product.
The crude products were combined and distilled under vacuum to give, at 74° C., 2-(4-methylpiperazin-1-yl)ethanol (51 g, 44percent) as a colourless liquid.
Analytical LCMS: (System C, RT=0.70 min), ES+: 145.1 [MH]+.

Reference: [1] Patent: US2008/51397, 2008, A1, . Location in patent: Page/Page column 10; 26
[2] Synthesis, 2008, # 7, p. 1049 - 1060
[3] Patent: WO2009/71677, 2009, A1, . Location in patent: Page/Page column 23
[4] Patent: US2009/203695, 2009, A1, . Location in patent: Page/Page column 9
[5] Patent: US2009/281087, 2009, A1, . Location in patent: Page/Page column 10
[6] Journal of the American Chemical Society, 1948, vol. 70, p. 3098
[7] Australian Journal of Chemistry, 1956, vol. 9, p. 89,92
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YieldReaction ConditionsOperation in experiment
84% With hydrogenchloride; sodium hydroxide; formaldehyd In methanol (1)
1-(2-Hydroxyethyl)-4-methylpiperazine
A mixture of 1-(2-hydroxyethyl)piperazine (10.0 g, 76.8 mmol), 37percent aqueous formaldehyde solution (11.5 ml, 154 mmol), 10percent palladium carbon catalyst (1.0 g) and methanol (100 ml) was stirred for 13 hr at room temperature in a hydrogen atmosphere.
The reaction mixture was filtrated and the filtrate was concentrated.
To the obtained residue was added 2N hydrochloric acid, and the mixture was washed with diethyl ether (200 ml).
Sodium hydroxide (16 g) was added to the aqueous layer to make the layer alkaline, and the mixture was extracted with chloroform (4*200 ml).
The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (9.3 g, 84percent) as a pale-yellow liquid.
1H-NMR (300 MHz, CDCl3) δ 3.61 (t, J=5.4 Hz, 2H), 2.90-2.30 (m, 8H), 2.55 (t, J=5.4 Hz, 2H), 2.29 (s, 3H).
Reference: [1] Patent: US6610729, 2003, B1,
  • 4
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  • [ 67-56-1 ]
  • [ 5464-12-0 ]
Reference: [1] Organic Process Research and Development, 2015, vol. 19, # 10, p. 1400 - 1410
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  • [ 36228-61-2 ]
  • [ 626-64-2 ]
  • [ 56227-56-6 ]
Reference: [1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
[2] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
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Reference: [1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
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  • [ 122-96-3 ]
YieldReaction ConditionsOperation in experiment
86.2% With hydrogenchloride In methanol; water for 2.5 h; Inert atmosphere Under a nitrogen atmosphere, the reactor 100 ml, piperazine 8.6 g (0.1 mol) g of methanol 10.4 g, was added while stirring 35percent hydrochloric acid 10.4 g (0.1 mol), internal temperature It was referred to as 80 ° C. There, while maintaining the internal temperature below 80 ° C, 2- bromoethanol 8.7g of (0.07 mol) was added dropwise over 0.5 hours and then further continued for 2 hours and stirring remains the same temperature conditions. Since the reaction liquid was 4.2 where pH was measured, and added of 25percent NaOH aqueous solution 7.6 g, and the pH was adjusted to 8.5. Furthermore, maintaining the internal temperature at 80 ° C, stirring was continued for 2 hours to obtain a reaction solution 36.2g of colorless and transparent. Results The product was analyzed by gas chromatography, is 86.2percent for a yield of N-(2-hydroxyethyl) piperazine, the selectivity, N-(2-hydroxyethyl) piperazine, 91.9percent, N, N'- bis (2-hydroxyethyl) piperazine is 6.7percent, unknown content was 1.4percent. Along with other examples showing the results of Example 8 shown in Table 1.
Reference: [1] Patent: JP5838628, 2016, B2, . Location in patent: Paragraph 0056; 0062; 0065
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Reference: [1] European Journal of Organic Chemistry, 2012, # 34, p. 6752 - 6759
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Reference: [1] Journal of the American Chemical Society, 1954, vol. 76, p. 1126,1129
[2] Yakugaku Zasshi, 1955, vol. 75, p. 1367[3] Chem.Abstr., 1956, p. 10106
[4] Journal of Organic Chemistry, 1943, vol. 8, p. 342
[5] Patent: US2541260, 1949, ,
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  • [ 140-31-8 ]
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  • [ 107-15-3 ]
  • [ 111-40-0 ]
  • [ 112-24-3 ]
Reference: [1] Patent: US2014/213823, 2014, A1, . Location in patent: Paragraph 0044-0049
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  • [ 350-46-9 ]
  • [ 5521-38-0 ]
YieldReaction ConditionsOperation in experiment
97% With potassium carbonate In dimethyl sulfoxide at 80℃; for 16 h; To a stirred suspension of 1—fluoro—4—nitrobenzene (2 g,14.17 mmol) and potassium carbonate (3.92 g, 28.3 mmol) in anhydrous dimethyl sulfoxide (10 mL) was added 2— (piperazin—1—yl)ethanol (2.089 mL, 17.01 mmol) and the mixture was heated at 80 °C for 16 hours. After coolingthe mixture was partitioned between water (100 mL) and ethyl acetate (30 mL) . The aqueous layer was separated and extracted with ethyl acetate (2 x 30 mL) . The combined organic fractions were reduced in vacuo. The residue was triturated in water (100 mL) . The solid wascollected by filtration under vacuum and dried for 16 hours under vacuum and flowing nitrogen to give the title compound (3.45 g, 97 percent) . ‘H NMR (400 MHz, CDC13) : 3 8.11 (d, 2H), 6.82 (d, 2H), 3.68 (t, 2H), 3.44 (t, 4H), 2.67 (t, 4H), 2.62 (t, 2H), 2.55 (br s, 1H) . LCMS (Method C):RT = 0.45 mi m/z = 252 [M+H].
95.6% With triethylamine In dimethyl sulfoxide at 90℃; To a solution of l-fluoro-4-nitrobenzene (4.23 g, 30 mmol, 1.0 eq.) in DMSO (40 mL) was added TEA (9.1 g, 90 mmol, 3.0 eq.) followed by 2-(piperazin-l-yl)ethanol (3.9 g, 30 mmol, 1.0 eq.) and the mixture was stirred at 90 °C overnight. The mixture was poured into ice-water (400 mL), filtered and dried in vacum to afford 2-(4-(4-nitrophenyl)piperazin- l-yl)ethanol as a yellow solid (7.2 g, 95.6percent).
86% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5 h; Step: 3A-lSynthesis of 2-[4-(4-Nitro-phenyI)-piperazin-l-yl]-ethanol. Procedure:K2C03 (3.912g, 0.02834mol) followed by 1 -Fluoro-4-nitro-benzene (2g, 0.01417mol) was added to a solution of 2-Piperazin-l-yl-ethanol (5.21ml, 0.0425 lmol) in DMF (10ml) and the reaction flask was maintained at 80°C for 5hrs. The reaction was monitored by the TLC (10percent MeOH: CHC13). The resultant was quenched with ice to afford 3g (86percent yield) of 2-[4-(4-Nitro-phenyl)-piperazin-l-yl]-ethanol as a yellow solid.
72% With N-ethyl-N,N-diisopropylamine In acetonitrile for 15 h; Reflux; Sealed tube; Inert atmosphere [00212] Step 1 : To a solution of 4-fluoronitrobenzene (2.0g, 14.16 mmol) in AcN (15 mL), 2-(piperazin-l-yl)ethanol (1.85 g, 14.17mmol) and DIEA (2.97 mL, 17.01 mmol) were added. The mixture was refluxed for 15 h (in a sealed tube). After cooling, the resulting mixture was poured to water (300 ml). The mixture was stirred at room temperature for 30 min. The solids were collected by filtration and washed with water to afford the the desired product as off white solids (2.74g, 72percent yield). ESI-MS calcd for (C12H17N303) 251, found 252 [M+H]+.

Reference: [1] Patent: WO2015/92431, 2015, A1, . Location in patent: Page/Page column 236
[2] Patent: WO2015/27222, 2015, A2, . Location in patent: Paragraph 0322
[3] Patent: WO2012/59932, 2012, A1, . Location in patent: Page/Page column 112-113
[4] Patent: WO2016/138527, 2016, A1, . Location in patent: Paragraph 00212
[5] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2371 - 2387
[6] Patent: US2003/13708, 2003, A1,
[7] Patent: US2004/87575, 2004, A1,
[8] Patent: US2004/110745, 2004, A1,
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Reference: [1] Patent: WO2012/59932, 2012, A1,
[2] Patent: WO2015/27222, 2015, A2,
[3] Patent: WO2016/138527, 2016, A1,
[4] European Journal of Medicinal Chemistry, 2019, p. 690 - 709
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  • [ 5521-39-1 ]
Reference: [1] Patent: WO2015/92431, 2015, A1,
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  • [ 1562-00-1 ]
  • [ 7365-45-9 ]
YieldReaction ConditionsOperation in experiment
85.6%
Stage #1: at 50℃; for 5.5 h;
Stage #2: With 5percent by weight of raffinate In water
0.5 mol of N-hydroxyethylpiperazine, 0.565 mol of sodium 2-hydroxyethanesulfonate and 500 mL of methanol were charged into a 1000 mL four-necked flask equipped with a reflux tube and subjected to a condensation reaction with sufficient stirring;First reacted at 50 for 2.5 hours, then gradually heated to reflux and continued to react for 3.0 hours;And then cooled to obtain a reaction mother liquor containing 4-hydroxyethylpiperazineethanesulfonate.The yield of sodium 4-hydroxyethylpiperazineethanesulfonate was calculated to be 93.6percent by high performance liquid chromatography. 20 L of 4-hydroxyethylpiperazineethanesulfonate,Mass concentration of 15wtpercent raffinate, in the stirring effect,Diluted with deionized water to a concentration of 5 wtpercent by dialysis dialysis to remove sodium chloride,And finally concentrated by evaporation, cooling crystallization, filtration to get pure HEPES products,And finally washed once with anhydrous methanol, and dried by vacuum to obtain purified HEPES. The purified HEPES sample was formulated as a solution and then tested for purity:The purified HEPES sample was prepared as a solution and then tested for purity, 99.9percent, yield 85.6percent, pH = 6.46, Cl- concentration 6.8 μg / g.
Reference: [1] Patent: CN106905262, 2017, A, . Location in patent: Paragraph 0034; 0035; 0047
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Reference: [1] Patent: CN104803949, 2017, B, . Location in patent: Paragraph 0055; 0056; 0070; 0071
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Reference: [1] Patent: CN104803949, 2017, B, . Location in patent: Paragraph 0047; 0048; 0060; 0061
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Reference: [1] Patent: CN104803949, 2017, B, . Location in patent: Paragraph 0053; 0054; 0064; 0065
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Reference: [1] Patent: CN104803949, 2017, B, . Location in patent: Paragraph 0051; 0052; 0060; 0061
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  • [ 24424-99-5 ]
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YieldReaction ConditionsOperation in experiment
100% for 2 h; tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (57):
To 1-(2-hydroxyethyl)piperazine (3.0 g, 23.0 mmol) in THF was added di-tert-butyl dicarbonate (5.5 g, 25.3 mmol).
The mixture was stirred for 2 hours.
The solvent was evaporated under vacuum to half the initial volume and the mixture was poured in water, extracted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated to give a pale yellow oil (5.3 g, quant.).
1H NMR (400 MHz, CDCl3) δ1.46 (s, 9H), 2.44-2.46 (m, 4H), 2.54-2.57 (m, 2H), 2.66 (m, J=5.3, 1H), 3.42-3.45 (m, 4H), 3.62 (q, J=5.3, 2H).
100% at 0 - 20℃; for 14 h; Example 9. l-(4-{2-[[l-(3,5-Dichloro-benzyl)-lH-imidazol-2-ylmethyl]-(3-fluoro- benzyl)-amino]-ethyl}-piperazin-l-yl)-ethanone EPO <DP n="67"/>(BoC)2O (2.29 g, 10.5 mmol) was added to a solution l-(2-hydroxyethyl)piperizine (1.30 g, 10 mmol) in THF (10 mL) at 0 0C. The mixture was stirred at ambient temperature for 14 h. The volatiles were removed in vacuo to afford 4-(2-hydroxy-ethyl)-piperazine-l- carboxylic acid tert-butyl ester (2.3Og, 100percent) as a colorless oil which solidified on standing: ESI MS m/z 231 [CnH22N2O3 + H]+.
98.9% at 20℃; for 18 h; A solution of 2-(piperazin-1-yl)ethan-1-ol (0.943 mL, 7.681 mmol) and di-tert-butyl dicarbonate (1.760 g, 8.065 mmol) in tetrahydrofuran (5 mL) was stirred at the room temperature for 18 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 MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (SiO2, 24 g cartridge; methanol / dichloromethane = 0 percent to 10 percent) to give tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate as colorless oil (1.750 g, 98.9 percent).
96% at 20℃; for 1 h; To a ice-cooled solution of N-(2-hydroxyethyl)-piperazine (2.51 g, 19.3 mmol) in 10 ml DCM, a solution of Boc2O (4.21 g, 19.3 mmol), solved in 20 ml DCM was added dropwise. The resulting mixture was stirred for 1 h at room temperature. The solvent was removed under reduced pressure. 20 ml water was added to the remaining oil and the aqueous phase was extracted three times with diethyl ether (3 x 20 ml). The combined organic phases were dried (Na2SO4). The solvent was removed under reduced pressure and the product was obtained as colourless oil (4.28 g, 96 percent yield). (Synthesis according to Radan, G.; Gebel, J.; Rauh, D. Archiv der Pharmazie 2003, 336, 372). 1H-NMR (300MHz, CDCl3): δ 3.64 - 3.60 (m, 2H), 3.45 - 3.41 (m, 4H), 2.69 (bs, 1H), 2.56 - 2.53 (m, 2H), 2.46 - 2.43 (m, 4H), 1.45 (s, 9H). CI-MS: m/z (percent): 231 (100) [MH+].
96% at 20℃; 2—(piperazin—1—yl)ethan—1—ol (5 g, 38.41 mmol, 1.00 equiv) was dissolved inDCM (100 mL), and a solution of di—tert—butyl dicarbonate (8.38 g,38.40 mmol, 1.00 equiv) in DCM (20 mL) was added drop—wise. The reaction was left under agitation overnight at ambient temperature. The reaction was evaporated to dryness and the residue dissolved in 200 mL of AcOEt, washed 5 times with NaC1 (sat.), dried over sodium sulfate, filtered and concentrated under reduced pressure toyield 8.5 g (96 percent) of compound 45A in the form of a white solid.
96% at 20℃; 2—(piperazin—1—yl)ethan—1—ol (5 g, 38.41 mmol, 1.00 equiv) was dissolved inDCM (100 mL), and a solution of di—tert—butyl dicarbonate (8.38 g,38.40 mmol, 1.00 equiv) in DCM (20 mL) was added drop—wise. The reaction was left under agitation overnight at ambient temperature. The reaction was evaporated to dryness and the residue dissolved in 200 mL of AcOEt, washed 5 times with NaC1 (sat.), dried over sodium sulfate, filtered and concentrated under reduced pressure toyield 8.5 g (96 percent) of compound 45A in the form of a white solid.
96% at 20℃; Compound 45A: tert-but l 4-(2-hydroxyethyl)piperazine-l-carboxylate 2-(piperazin-l-yl)ethan-l-ol (5 g, 38.41 mmol, 1.00 equiv) was dissolved in DCM (100 mL), and a solution of di-tert-butyl dicarbonate (8.38 g, 38.40 mmol, 1.00 equiv) in DCM (20 mL) was added drop-wise. The reaction was left under agitation overnight at ambient temperature. The reaction was evaporated to dryness and the residue dissolved in 200 mL of AcOEt, washed 5 times with NaCl (sat.), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 8.5 g (96 percent) of compound 45 A in the form of a white solid.
90% With triethylamine In 1,4-dioxane; methanol; ethyl acetate a
N-(tert-Butoxycarbonyl)-1-(2-hydroxyethyl)piperazine
To a solution of 1-(2-hydroxyethyl)piperazine (5.20 g, 40 mmol) and triethylamine (6 mL 43 mmol), in 1,4-dioxane (100 mL) was added slowly di-tert-butyl dicarbonate (8.72 g, 40 mmol).
The reaction mixture was stirred at room temperature for 2 h.
The solvent was removed in vacuo and the residue was purified by flash column chromatography (ethyl acetate to 2percent methanol in ethyl acetate) to give the title compound as colorless oil (8.32 g, 90percent).
1 H-NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 2.46 (t, 4H), 2.55 (t, 2H), 2.75 (br s, 1H), 3.44 (t, 4H), and 3.63 (t, 2H).
90% With triethylamine In 1,4-dioxane; methanol; ethyl acetate a
N-(tert-Butoxycarbonyl)-1-(2-hydroxyethyl)piperazine
To a solution of 1-(2-hydroxyethyl)piperazine (5.20 g, 40 mmol) and triethylamine (6 mL) in 1,4-dioxane (100 mL) was added slowly di-tert-butyl dicarbonate (8.72 g, 40 mmol).
The reaction mixture was stirred at room temperature for 2 h.
The solvent was removed in vacuo and the residue was purified by flash column chromatography (ethyl acetate to 2percent methanol in ethyl acetate) to give the title compound as a colorless oil (8.32 g, 90percent).
1 H-NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 2.46 (t, 4H), 2.55 (t, 2H), 2.75 (bs, 1H), 3.44 (t, 4H), 3.63 (t, 2H).
90% With triethylamine In dichloromethane at 20℃; for 12 h; To a solution of 1-(2-hydroxyethyl) piperazine (1.0g, 7.686mmol) in dichloromethane (25mL) were added di-tert butyl dicarbonate (2.013g, 9.223mmol) and triethylamine (TEA, 2.130g, 15.372mmol). The reaction mixture was stirred at room temperature for 12h, then washed with 3percent HCl aqueous (2×50mL), saturated NaHCO3 aqueous (2×50mL), brine (2×50mL). The resulting organic layer wasdried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (40:1) to form 1-Boc-4-(2-hydroxyethyl)-piperazine a colorlessoil (1.592g, 90percent yield).
87% With triethylamine In methanol at 20℃; for 3 h; To a solution of 2-(piperazin-l-yl)ethanol (1. 3g, 0.01 mol) and (Boc)20 (2.4 g, 0.01 1 mol) in MeOH (15 mL) was added Et3N (1.52 g, 0.015 mol). The mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo. The residue was diluted with water and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine then dried over MgSC^. After filtration and concentration, the product (2 g, 87 percent) was obtained as an oil. 1H NMR (300 MHz, CDC13): δ 3.74 (t, 2H, J = 5.3 Hz), 3.56 (t, 4 h, J = 5.0 Hz), 2.72 (t, 2H, J = 5.1 Hz), 2.66 (t, 4 h, J = 5.0 Hz), 1.44 s, 9H). LCMS: No molecular ion observed for desired mass.
78%
Stage #1: With C12H24KO6(1+)*Br3H(1-) In ethanol at 20℃; for 0.0166667 h;
Stage #2: at 20℃; for 0.0333333 h;
For the N-boc protection of amines, to solution of diboc (1 mmol) in ethanol (5 ml) was added {K*18-crown-6]Br3}n (0.001 mmol). The solution was stirred at room temperature for 1 min. The amine (1 mmol) was then added and solution as stirred at room temperature for an appropriate time (table 1). After completion of the reaction, the solvent was removed by water bath distillation. To the residue was added ethyl acetate (5 ml) and the mixture was filtered (the catalyst is insoluble in n-hexane and ethyl acetate). The solid was washed with ethyl acetate ()10 ml*2) amd combined filtrates were reduced to dryness to yield the pure products.
77.7% at 0 - 20℃; for 3 h; To a stirred solution of 1-(2-Hydroxyethyl)piperazine (8.0 g, 61.45 mmol, 1.0 eq) in 1,4-dioxane (80 ml) di-tert-butyldicarbonate (15.93 g, 73.7 mmol, 1.2eq) was added at 0°C. The reaction mixture was allowed to stir at room temperature for 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure to get the desired compound (11.0 g, 77.7percent yield) as light green color syrup solid. This was used directly for next step without further purification. 1H NMR (300 MHz, CDCl3): δ ppm 3.65-3.61 (m, 2H), 3.46-3.43 (m, 4H), 2.55 (t, J = 5.4 Hz, 2H), 2.47-2.44 (m, 4H), 1.45 (s, 9H); ES Mass: [M+Na]+253.09 (100percent).
72% With triethylamine In DCM To a solution of 1-(2-hydroxyethyl)piperazine (51.7 g, 398 mmol) in DCM (500 mL) was added NEt3 (70.0 mL, 526 mmol) and di-tert-butyl dicarbonate (80.0 g, 367 mmol). The reaction mixture was stirred overnight at room temperature and then washed with 1M aq Na2CO3 solution (2.x.300 mL), dried (MgSO4) and concentrated in vacuo to give tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (66.0 g, 72percent) as a colourless oil.Analytical LCMS: (System B, RT=1.54 min), ES+: 231.4 [MH]+.
72% With triethylamine In DCM at 20℃; Example 30
2-piperazin-1-ylethyl 4-phenylpiperazine-1-carboxylate trihydrochloride
To a solution of 1-(2-hydroxyethyl)piperazine (51.7 g, 398 mmol) in DCM (500 mL) was added NEt3 (70.0 mL, 526 mmol) and di-tert-butyl dicarbonate (80.0 g, 367 mmol).
The reaction mixture was stirred overnight at room temperature then washed with 1 M aq Na2CO3 solution (2*300 mL), dried (MgSO4) and concentrated in vacuo to give tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (66.0 g, 72percent) as a colourless oil.
Analytical LCMS: (System D RT=1.54 min), ES+: 231.4 [MH]-4.
72% With triethylamine In dichloromethane To a solution of l-(2-hydroxyethyl)piperazine (51.7 g, 398 mmol) in DCM (500 mL) was added NEt3 (70.0 mL, 526 mmol) and dicarbonate (80.0 g, 367 mmol). The reaction mixture was stirred overnight at r.t. and then washed with IM aq Na2CO3 solution (2 x 300 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give tert-bvXy\\ 4-(2-hydroxyethyl)piperazine-l-carboxylate (66.0 g, 72percent) as a colourless oil.
23 g at 20℃; for 1 h; Compound 9 (13.0 g, 100 mmol) was weighed in 100 mL of anhydrous tetrahydrofuran (THF)Adding di-tert-butyl dicarbonate(Boc) 20) (21.8g, lOOmmol), room temperature stirring lh; TLC detection, iodine cylinder color; raw materials disappeared after the solvent was recovered l0 (23g).

Reference: [1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 4, p. 693 - 705
[2] Farmaco, 2004, vol. 59, # 12, p. 971 - 980
[3] Patent: US2011/263534, 2011, A1, . Location in patent: Page/Page column 89
[4] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 8, p. 1098 - 1108
[5] Patent: WO2006/107923, 2006, A1, . Location in patent: Page/Page column 66
[6] Patent: WO2017/18805, 2017, A1, . Location in patent: Paragraph 714-716
[7] Archiv der Pharmazie, 2003, vol. 336, # 8, p. 372 - 380
[8] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6274 - 6280
[9] Patent: WO2014/174060, 2014, A1, . Location in patent: Page/Page column 101
[10] Patent: WO2014/174062, 2014, A1, . Location in patent: Page/Page column 74
[11] Patent: WO2015/162293, 2015, A1, . Location in patent: Page/Page column 198
[12] Journal of Medicinal Chemistry, 2009, vol. 52, # 19, p. 5974 - 5989
[13] Journal of Medicinal Chemistry, 2007, vol. 50, # 14, p. 3242 - 3255
[14] Patent: US6034127, 2000, A,
[15] Patent: US5792769, 1998, A,
[16] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 23-24, p. 6035 - 6049
[17] Patent: WO2013/64445, 2013, A1, . Location in patent: Page/Page column 169
[18] Journal of the Chinese Chemical Society, 2011, vol. 58, # 4, p. 538 - 543
[19] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 6129 - 6152
[20] Chinese Journal of Catalysis, 2013, vol. 34, # 9, p. 1730 - 1733
[21] Patent: WO2013/160810, 2013, A2, . Location in patent: Paragraph 0277
[22] Patent: US2009/203695, 2009, A1, . Location in patent: Page/Page column 8
[23] Patent: US2009/281087, 2009, A1, . Location in patent: Page/Page column 20
[24] Patent: WO2009/147221, 2009, A1, . Location in patent: Page/Page column 25
[25] Journal of the American Chemical Society, 2002, vol. 124, # 41, p. 12182 - 12191
[26] Patent: US5969138, 1999, A,
[27] Chemical Communications, 2013, vol. 49, # 80, p. 9173 - 9175
[28] Dyes and Pigments, 2013, vol. 99, # 1, p. 185 - 191
[29] European Journal of Medicinal Chemistry, 2014, vol. 84, p. 505 - 515
[30] Patent: CN104250246, 2017, B, . Location in patent: Paragraph 0151-0153
[31] Patent: CN107286098, 2017, A, . Location in patent: Paragraph 0209-0210
  • 20
  • [ 103-76-4 ]
  • [ 34619-03-9 ]
  • [ 77279-24-4 ]
YieldReaction ConditionsOperation in experiment
87% With triethylamine In methanol at 20℃; for 3 h; Procedure: To a solution of 2-(piperazin-1-yl)ethanol (1.3 g, 0.01 mol) and (Boc)2O (2.4 g, 0.011 mol) in MeOH (15 mL) was added Et3N (1.52 g, 0.015 mol). The mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo. The residue was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine then dried over MgSO4. After filtration and concentration, the product (2 g, 87percent) was obtained as an oil. 1H NMR (300 MHz, CDCl3): δ 3.74 (t, 2H, J=5.3 Hz), 3.56 (t, 4 h, J=5.0 Hz), 2.72 (t, 2H, J=5.1 Hz), 2.66 (t, 4 h, J=5.0 Hz), 1.44 (s, 9H). LCMS: No molecular ion observed for desired mass.
Reference: [1] Patent: US2013/109661, 2013, A1, . Location in patent: Paragraph 0620-0621
  • 21
  • [ 103-76-4 ]
  • [ 77279-24-4 ]
Reference: [1] Patent: US2018/125821, 2018, A1,
  • 22
  • [ 103-76-4 ]
  • [ 89985-91-1 ]
  • [ 77279-24-4 ]
Reference: [1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 5, p. 1547 - 1550
[2] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 4, p. 1115 - 1119
  • 23
  • [ 103-76-4 ]
  • [ 1426682-55-4 ]
  • [ 77279-24-4 ]
Reference: [1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 9, p. 2971 - 2975
  • 24
  • [ 103-76-4 ]
  • [ 208167-83-3 ]
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 84, p. 505 - 515
[2] Patent: CN104250246, 2017, B,
[3] Patent: CN107286098, 2017, A,
[4] Patent: WO2006/107923, 2006, A1,
  • 25
  • [ 103-76-4 ]
  • [ 302964-08-5 ]
  • [ 863127-77-9 ]
YieldReaction ConditionsOperation in experiment
83.2%
Stage #1: With N-ethyl-N,N-diisopropylamine In butan-1-ol at 118℃; for 4.5 h;
Stage #2: With water In ethanol
To a mixture of compound 5D (4.00 g, 10.14 mmol) and hydroxyethylpiperazine (6.60 g, 50.69 mmol) in n-butanol (40 mL) was added DIPEA (3.53 mL, 20.26 mmol). The slurry was heated at 118°C for 4.5h, then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with n- butanol (5 mL), and dried. The product (5.11 g) was dissolved in hot 80percent EtOH-H2O (80 mL), and the solution was clarified by filtration. The hot solution was slowly diluted with water (15 mL) and cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with 50percent ethanol-water (5 mL) and dried affording 4.27 g (83.2 percent yield) of N- (2-chloro-6-methylphenyl)-2- (6- (4- (3- hydroxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide as monohydrate. 1H NMR (400 MHz, DMSO-d6) # 2.23 (s, 3H), 2.40 (s, 3H), 2.42 (t, 2H, J=6), 2.48 (t, 4H, J=6.3), 3.50 (m, 4H), 3.53 (q, 2H, J=6), 4.45 (t, 1H, J=5.3), 6.04 (s, 1H), 7.25 (t, 1H, J=7.6), 7.27 (dd, 1H, J=7.6, 1.7), 7.40 (dd, 1H, J=7.6, 1.7), 8.21 (s, 1H), 9. 87 (s, 1H), 11.47.
Reference: [1] Patent: WO2005/77945, 2005, A2, . Location in patent: Page/Page column 52
[2] Patent: US2009/118297, 2009, A1, . Location in patent: Page/Page column 32-33
  • 26
  • [ 103-76-4 ]
  • [ 1562-00-1 ]
  • [ 75277-39-3 ]
YieldReaction ConditionsOperation in experiment
94.6% at 204℃; for 2.25 h; Autoclave A magnetically-stirred 70-mL fluoropolymer-lined steel autoclave was fitted with an internal thermocouple capable of determining the temperature of the liquid phase contained in the vessel, a pressure gauge, a pressure-relief valve, and a vent valve. The amine starting material, anhydrous or aqueous sodium 2-hydroxyethanesulfonate, and anhydrous or aqueous sodium hydroxide were charged to the open autoclave, which was then assembled and immersed in an electrically heated oil bath. With the vent valve closed, the stirred reaction mixture was rapidly heated to the reaction temperature and held at that temperature for the times specified in Examples 9, 10, and 13 below. The reaction mixture was then cooled to ambient temperature, the reactor opened, and the reaction product taken up in sufficient water to dissolve all solids.
6% at 140 - 200℃; for 2 - 72 h; Autoclave An electrically-heated, mechanically stirred 1 liter autoclave was fitted with an vent valve connected in turn to a condenser and receiver assembly, a bottom valve, a thermowell, a pressure gauge, an inlet line for feeding of reagents, and a pressure-relief valve. The receiver was placed on a balance to facilitate continuous determination of the amount of distillate collected in the receiver. The amine starting material, aqueous sodium 2-hydroxyethanesulfonate, and aqueous 50 percent sodium hydroxide were charged to the autoclave. With the isolation valve open, the reaction mixture was rapidly heated with stirring until condensate was detected in the condenser/receiver. The mixture was further heated with continuous removal of water until the targeted amount of distillate had been removed. An analysis of the collected aqueous distillate was performed by UV spectroscopy to determine the amount of amine which co-distilled with the water. The isolation valve was then closed and the reaction mixture further heated to a target temperature in the range of 140-200° C. for 2-17 hours as specified in Examples 1-8. The reaction mixture was then cooled until the pressure dropped to 0 psig (ca. 110° C.) whereupon dilution water was added to dilute the concentrated reaction product. The resulting solution was then cooled to room temperature and drained from the reactor. Analysis of the product mixture was then performed by various chromatographic and spectroscopic procedures as indicated in the specific examples.; Procedure C A magnetically-stirred 70-mL fluoropolymer-lined steel autoclave was fitted with an internal thermocouple capable of determining the temperature of the liquid phase contained in the vessel, a pressure gauge, a pressure-relief valve, and a vent valve. The amine starting material, anhydrous or aqueous sodium 2-hydroxyethanesulfonate, and anhydrous or aqueous sodium hydroxide were charged to the open autoclave, which was then assembled and immersed in an electrically heated oil bath. With the vent valve closed, the stirred reaction mixture was rapidly heated to the reaction temperature and held at that temperature for the times specified in Examples 9, 10, and 13 below. The reaction mixture was then cooled to ambient temperature, the reactor opened, and the reaction product taken up in sufficient water to dissolve all solids.
Reference: [1] Patent: US2006/89509, 2006, A1, . Location in patent: Page/Page column 4-6
[2] Patent: US2006/89509, 2006, A1, . Location in patent: Page/Page column 4-6
  • 27
  • [ 103-76-4 ]
  • [ 1749-68-4 ]
  • [ 914347-48-1 ]
YieldReaction ConditionsOperation in experiment
26.5% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane for 12 h; Reflux 6-Chloro-2-methyl-pyrimidin-4-ylamine (500 mg, 3.49 mmol), 2-piperazinyl-ethanol (500 mg, 3.84 mmol) and DIPEA (541 mg, 4.19 mmol) were added to Dioxane (5 mL). The reaction mixture was refluxed for 12 h. TLC showed the reaction was completed. The reaction mixture was concentrated. The residue was washed with MeCN, recrystallized from MeOH to yield 2-[4-(6-amino-2-methyl-pyrimidin-4-yl)-piperazin-l-yl]-ethanol (220 mg, yield: 26.5percent) as a white solid. 1H NMR (400 MHz, MeOD): δ 5.61 (s, 1H, ArH), 3.74 (t, J = 6.0 Hz, 2H, OCH2), 3.64-3.61 (m, 4H, 2CH2), 2.67-2.62 (m, 6H, 3CH2), 2.31 (s, 3H, ArCH3).
Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 41, p. 5729 - 5732
[2] Patent: WO2014/52365, 2014, A1, . Location in patent: Page/Page column 174-175
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