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[ CAS No. 5625-67-2 ] {[proInfo.proName]}

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Chemical Structure| 5625-67-2
Chemical Structure| 5625-67-2
Structure of 5625-67-2 * Storage: {[proInfo.prStorage]}
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Product Details of [ 5625-67-2 ]

CAS No. :5625-67-2 MDL No. :MFCD01318687
Formula : C4H8N2O Boiling Point : -
Linear Structure Formula :- InChI Key :IWELDVXSEVIIGI-UHFFFAOYSA-N
M.W :100.12 Pubchem ID :231360
Synonyms :

Calculated chemistry of [ 5625-67-2 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.75
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 32.86
TPSA : 41.13 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) : -7.68 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.95
Log Po/w (XLOGP3) : -1.08
Log Po/w (WLOGP) : -2.06
Log Po/w (MLOGP) : -1.19
Log Po/w (SILICOS-IT) : 0.52
Consensus Log Po/w : -0.57

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 0.22
Solubility : 166.0 mg/ml ; 1.66 mol/l
Class : Highly soluble
Log S (Ali) : 0.71
Solubility : 509.0 mg/ml ; 5.08 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.9
Solubility : 12.5 mg/ml ; 0.125 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.07

Safety of [ 5625-67-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P271-P272-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362+P364-P403+P233-P501 UN#:N/A
Hazard Statements:H315-H317-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5625-67-2 ]

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

  • Upstream synthesis route of [ 5625-67-2 ]
  • Downstream synthetic route of [ 5625-67-2 ]

[ 5625-67-2 ] Synthesis Path-Upstream   1~27

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Reference: [1] Patent: WO2006/55951, 2006, A2, . Location in patent: Page/Page column 66
[2] Patent: WO2006/63113, 2006, A2, . Location in patent: Page/Page column 126-127
[3] Patent: US2787617, 1955, ,
  • 2
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YieldReaction ConditionsOperation in experiment
82%
Stage #1: at 20℃; for 5.5 h;
Stage #2: With sodium ethanolate In ethanol
Stage #3: With N,N-dimethyl-formamide In ethanol at 20 - 70℃; for 24 h;
2-(Oxo-piperazine: A solution of ethyl chloroacetate (4.9 g, 40 mmol) in 40 mL of absolute ethanol was slowly added dropwise over a period of 3.5 h at ambient temperature to ethylenediamine (24 g, 400 mmol) in 100 mL of absolute ethanol. The reaction mixture was allowed to stand for 2 h after addition was completed. Sodium ethoxide (15 mL, 40 mmol, 21 wt. percent solution in denatured ethylalcohol) was added. The precipitated sodium chloride was filtered off, the solvent was removed by evaporation and 40 mL of DMF was added to the resultant red oil. The reaction mixture was allowed to stir for 24 h at ambient temperature and then heated at about 60° to 70° C. while removing the volatile materials with N2 gas. The resultant yellow solid was applied to silica gel column for separation. The crude product (3.3 g, 33 mmol, 82percent) was obtained by elution with a solvent mixture (CHCl3:MeOH:NH4OH/9:1:0.1). This crude yellow solid was used for next synthesis without further purification. Recrystalization three times from acetone gave well-defined, pure-white crystals. 1H NMR (CDCl3): δ 1.70 (1H, br s), 3.03 (2H, t, J=5.4), 3.37 (2H, td, J=2.3, 5.4), 3.52 (2H, s), 6.54 (1H, br s). 13C NMR (CDCl3): δ 42.31, 43.05, 49.83, 170.00. mp: 132°-134° (uncorr.) [lit.]mp:136° (corr.) (American Chemical Society Journal, 62 (1940) 1202-1204.)
Reference: [1] Patent: US2005/222166, 2005, A1, . Location in patent: Page/Page column 13
[2] Tetrahedron Letters, 1994, vol. 35, # 51, p. 9545 - 9548
[3] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 80
[4] Journal of the American Chemical Society, 1940, vol. 62, p. 1202
  • 3
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YieldReaction ConditionsOperation in experiment
80% With [2-(4-hydroxymethyl)phenyl-4,4-(dimethyloxazole)Ru(CH3CN)4]PF6 In diethyl ether; water at 20℃; General procedure: A solution of amine (0.3 mmol in 4.0 mL Et2O) was added to a solution of Ru(II)-hm-pheox 3 ( 0.0075 mmol, 2.5 molpercent) in water ( 1.0 mL), then EDA (0.3 mmol, 1.0 equiv.) was injected and the biphasic reaction mixture was stirred at room temperature. At the end of reaction, the ether layer was removed by decantation and the water-soluble catalyst washed three times with ether (3 x 5.0 mL). The collected ether phase which contain the aminoester product was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The products in most cases were pure enough and there is no need for further purification. The water phase which contain the catalyst was recycled several times. The 2-piperazinone product was purified by using column chromatography on silica gel (by using CH3OH only as eluent).
Reference: [1] Journal of Porphyrins and Phthalocyanines, 2010, vol. 14, # 3, p. 284 - 292
[2] Tetrahedron Letters, 2017, vol. 58, # 51, p. 4750 - 4754
  • 4
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YieldReaction ConditionsOperation in experiment
79.84%
Stage #1: at 20℃; for 2 h;
Stage #2: at 20℃;
To a solution of ethyl 2-bromoacetate (1.67 g, 10 mmol) in ethanol (10 mL) was slowly added dropwise a solution of 1,2-ethanediamine (6.01 g, 100 mmol) in ethanol (25 mL) at room temperature The reaction mixture was stirred at room temperature for 2 hours,Sodium ethoxide (680.5 mg, 10 mmol) was added and stirring was continued at room temperature overnight. The crude product was purified by column chromatography (dichloromethane / methanol / aqueous ammonia (v / v / v) = 9/1/1) and recrystallized from acetone to give a yellow solid (0.8 g, 79.84percent ).
Reference: [1] Patent: CN104277040, 2016, B, . Location in patent: Paragraph 0159-0160
[2] Angewandte Chemie, International Edition, 2015, vol. 54, # 1, p. 179 - 183[3] Angewandte Chemie, 2015, vol. 127, # 1, p. 181 - 185,5
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YieldReaction ConditionsOperation in experiment
82%
Stage #1: With sodium ethanolate In ethanol at 20℃; for 5.5 h;
Stage #2: at 20 - 70℃; for 24 h;
A solution of ethyl chloroacetate (4.9g, 40 mmol) in 40 mL of absolute ethanol was slowly added dropwise over a period of 3.5 h at ambient temperature to ethylenediamine (24g, 400 mmol) in 100 mL of absolute ethanol. The reaction mixture was allowed to stand for 2 h after addition was completed. Sodium ethoxide (15 mL, 40 mmol, 21WT. percent solution in denatured ethylalcohol) was added. The precipitated sodium chloride was filtered off, the solvent was removed by evaporation and 40 mL of DMF was added to the resultant red oil. The reaction mixture was allowed to stir for 24 h at ambient temperature and then heated at about 60 to 70C while removing the volatile materials with N2 gas. The resultant yellow solid was applied to silica gel column for separation. The crude product (3.3g, 33 mmol, 82percent) was obtained by elution with a solvent mixture (CHCL3 : MeOH: NH40H/9 : 1: 0.1). This crude yellow solid was used for next synthesis without further purification. Recrystalization three times from acetone gave well-defined, pure-white CRYSTALS. IH NMR (CDC13) : 8 1.70 (1H, br s), 3.03 (2H, t, J=5.4), 3. 37 (2H, td, J=2.3, 5.4), 3.52 (2H, s), 6.54 (1H, br s). 13C NMR (CDC13) : 8 42. 31, 43.05, 49.83, 170.00. mp: 132-134 (uncorr. ) [lit. ] mp: 136 (CORR.) (American Chemical Society Journal, 62 (1940) 12Q2-1204.)
Reference: [1] Patent: WO2004/63150, 2004, A2, . Location in patent: Page 27-28
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YieldReaction ConditionsOperation in experiment
45% With ammonium hydroxide; sodium ethanolate; ethylenediamine In methanol; ethanol; dichloromethane; N,N-dimethyl-formamide A.
Synthesis of 2-ketopiperazine
A solution of bromoethylacetate (10 g, 59.8 mmol) in absolute ethanol (80 ml) is slowly added at room temperature to a solution of ethylenediamine (36 g, 598 mmol) in absolute ethanol (140 ml).
The addition requires about three hours and the mixture is allowed to stand for an additional two hours.
Sodium ethoxide (21percent wt, 22 ml, 59.8 mmol) was added dropwise.
The mixture was stirred at room temperature overnight and solvent was then evaporated. DMF (40 ml) was added to residue and stirred at 60-70° C. for 24 hours.
The salt was filtered and the solvent was evaporated.
The residue was purified by column chromatography using CH2Cl2: MeOH: NH4OH (90:10:0.1) to give a yellow solid in 45percent yield.
45% With ammonium hydroxide; sodium ethanolate; ethylenediamine In methanol; ethanol; dichloromethane; N,N-dimethyl-formamide A.
Synthesis of 2-ketopiperazine
A solution of bromoethylacetate (10 g, 59.8 mmol) in absolute ethanol (80 ml) is slowly added at room temperature to a solution of ethylenediamine (36 g, 598 mmol) in absolute ethanol (140 ml).
The addition requires about three hours and the mixture is allowed to stand for an additional two hours.
Sodium ethoxide (21percent wt, 22 ml, 59.8 mmol) was added dropwise.
The mixture was stirred at room temperature overnight and solvent was then evaporated. DMF (40 ml) was added to residue and stirred at 60-70 C° for 24 hours.
The salt was filtered and the solvent was evaporated.
The residue was purified by column chromatography using CH2Cl2: MeOH: NH4OH (90:10:0.1) to give a yellow solid in 45percent yield.
45% With ammonium hydroxide; sodium ethanolate; ethylenediamine In methanol; ethanol; dichloromethane; N,N-dimethyl-formamide A.
Synthesis of 2-ketopiperazine
A solution of bromoethylacetate (10 g, 59.8 mmol) in absolute ethanol (80 ml) is slowly added at room temperature to a solution of ethylenediamine (36 g, 598 mmol) in absolute ethanol (140 ml).
The addition requires about three hours and the mixture is allowed to stand for an additional two hours.
Sodium ethoxide (21percent wt, 22 ml, 59.8 mmol) was added dropwise.
The mixture was stirred at room temperature overnight and solvent was then evaporated. DMF (40 ml) was added to residue and stirred at 60-70° C. for 24 hours.
The salt was filtered and the solvent was evaporated.
The residue was purified by column chromatography using CH2Cl2: MeOH:NH4OH (90:10:0.1) to give a yellow solid in 45percent yield.
Reference: [1] Patent: US2004/44004, 2004, A1,
[2] Patent: US2004/266784, 2004, A1,
[3] Patent: US6943168, 2005, B2,
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YieldReaction ConditionsOperation in experiment
45% With ammonium hydroxide; sodium ethanolate; ethylenediamine In ethanol; N,N-dimethyl-formamide A.
Synthesis of 2-ketopiperazine
A solution of bromoethylacetate (10 g, 59.8 mmol) in absolute ethanol (80 ml) is slowly added at room temperature to a solution of ethylenediamine (36 g, 598 mmol) in absolute ethanol (140 ml).
The addition requires about three hours and the mixture is allowed to stand for an additional two hours.
Sodium ethoxide (21percent wt, 22 ml, 59.8 mmol) was added dropwise.
The mixture was stirred at room temperature overnight and solvent was then evaporated. DMF (40 ml) was added to residue and stirred at 60-70 C.° for 24 hours.
The salt was filtered and the solvent was evaporated.
The residue was purified by column chromatography using CH2Cl2:MeOH:NH4OH (90:10:0.1) to give a yellow solid in 45percent yield.
45% With ammonium hydroxide; sodium ethanolate; ethylenediamine In ethanol; N,N-dimethyl-formamide A.
Synthesis of 2-ketopiperazine
A solution of bromoethylacetate (10 g, 59.8 mmol) in absolute ethanol (80 ml) is slowly added at room temperature to a solution of ethylenediamine (36 g, 598 mmol) in absolute ethanol (140 ml).
The addition requires about three hours and the mixture is allowed to stand for an additional two hours.
Sodium ethoxide (21percent wt, 22 ml, 59.8 mmol) was added dropwise.
The mixture was stirred at room temperature overnight and solvent was then evaporated. DMF (40 ml) was added to residue and stirred at 60-70° C. for 24 hours.
The salt was filtered and the solvent was evaporated.
The residue was purified by column chromatography using CH2Cl2:MeOH: NH4OH (90:10:0.1) to give a yellow solid in 45percent yield.
45% With ammonium hydroxide; sodium ethanolate; ethylenediamine In ethanol; N,N-dimethyl-formamide A.
Synthesis of 2-ketopiperazine
A solution of bromoethylacetate (10 g, 59.8 mmol) in absolute ethanol (80 ml) is slowly added at room temperature to a solution of ethylenediamine (36 g, 598 mmol) in absolute ethanol (140 ml).
The addition requires about three hours and the mixture is allowed to stand for an additional two hours.
Sodium ethoxide (21percent wt, 22 ml, 59.8 mmol) was added dropwise.
The mixture was stirred at room temperature overnight and solvent was then evaporated. DMF (40 ml) was added to residue and stirred at 60-70 C.° for 24 hours.
The salt was filtered and the solvent was evaporated.
The residue was purified by column chromatography using CH2Cl2:MeOH:NH4OH (90:10:0.1) to give a yellow solid in 45percent yield.
Reference: [1] Patent: US2004/34035, 2004, A1,
[2] Patent: US2004/259866, 2004, A1,
[3] Patent: US6951862, 2005, B2,
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Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3647 - 3656
[2] Patent: WO2005/115146, 2005, A1, . Location in patent: Page/Page column 96-97
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YieldReaction ConditionsOperation in experiment
75% With trifluoroacetic acid In ethanol Step 3:
1-(2-Phenylpropyl)piperazin-2-one
In the same way as that described in Example 2, Step 3, using 2-[(bromoacetyl)(2-phenylpropyl)amino]ethyl carbamic acid tert-butyl ester (1.64 g, 4.11 mmol), trifluoroacetic acid (4 mL) and CH2 Cl2 (40 mL), followed by K2 CO3 (1.1 g, 8.2 mmol) and EtOH (100 mL).
The piperazinone (668 mg, 75percent) was isolated as a colourless oil. 1 H NMR (250 MHz, CDCl3) δ1.28 (3H, d, J=6.8 Hz), 2.72-2.93 (3H, m), 3.04-3.26 (3H, m), 3.28 (1H, d, J=17.3 Hz), 3.52 (1H, d, J=17.3 Hz), 3.85-3.93 (1H, m), 7.19-7.35 (5H, m).
Reference: [1] Patent: US5998415, 1999, A,
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Reference: [1] Patent: US2002/55631, 2002, A1,
[2] Patent: US2002/86887, 2002, A1,
[3] Patent: US6433134, 2002, B1,
[4] Patent: US5629322, 1997, A,
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YieldReaction ConditionsOperation in experiment
34.5% With sodium ethanolate; ethylenediamine In ethanol Reference Example 94
An anhydrous ethanol solution (10 mL) of ethyl chloroacetate (2.1 g, 17.1 mmol) was added dropwise to an anhydrous ethanol solution (30 mL) of ethylenediamine (6 g, 99.8 mmol) at room temperature over 2.5 hours.
The mixture was stirred at room temperature for 2 hours, and sodium ethoxide (sodium 0.4 g/ethanol 20 mL) solution was added thereto dropwise, gradually.
The mixture was stirred at room temperature for 14 hours; the precipitated sodium chloride was separated by filtration; and the filtrate was concentrated under reduced pressure.
The crude compound obtained was heated at 200 °C for 5 minutes, and the reaction product was purified by NH-silica gel column chromatography (ethyl acetate/chloroform, 10:240), to obtain a red solid, which was further purified by recrystallization (acetone-water), to obtain 2-piperazinone (0.59 g, 34.5percent) as orange solid.
1H-NMR(CDCl3)δ:1.50-2.05(1H,m),3.01-3.08(2H,m),3.34-3.42 (2H,m),3.53(2H,s),6.60(1H,brs)ppm
FABMS:101 (M+1)
Reference: [1] Patent: EP1820799, 2007, A1,
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Reference: [1] Patent: US6492553, 2002, B1,
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Reference: [1] Patent: US6069145, 2000, A,
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Reference: [1] Synthetic Communications, 2012, vol. 42, # 23, p. 3513 - 3523
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Reference: [1] Pharmazie, 1997, vol. 52, # 3, p. 198 - 202
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Reference: [1] Journal of the American Chemical Society, 1940, vol. 62, p. 1202
[2] Journal of the American Chemical Society, 1940, vol. 62, p. 1202
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Reference: [1] Patent: US2700668, 1952, ,
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  • [ 5625-67-2 ]
Reference: [1] Patent: US2700668, 1952, ,
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  • [ 103-63-9 ]
  • [ 23099-72-1 ]
YieldReaction ConditionsOperation in experiment
74%
Stage #1: With potassium carbonate In dimethyl sulfoxide at 80℃; for 5 h;
Stage #2: With hydrogenchloride In water
Stage #3: With sodium hydroxide In water
A suspension of (2-bromoethyl)benzene (4.10 mL, 30.0 mmol), piperazin-2-one (3.00 g, 30.0 mmol) and K2CO3 (4.90 g, 36.0 mmol) in DMSO (60.0 mL) was stirred at 80° C. for 5 h.
The reaction mixture was cooled to room temperature and filtered.
The filtrate was then washed with water (200 mL) and extracted with methylene chloride (2*).
The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated.
The result yellow solid was then dissolved in 1 N HCl (120 mL) and washed with methylene chloride.
The aqueous layer was separated, basified with 6 N NaOH, and extracted with methylene chloride (3*).
The combined organic layers were dried over MgSO4, filtered, and concentrated.
The residue was titrated with hexanes and filtered.
The filtered solid was dried under reduced pressure to give the title compound (4.50 g, 74percent) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 7.23-7.19 (m, 3H), 6.17 (br s, 1H), 3.40-3.37 (m, 2H), 3.23 (s, 2H), 2.83-2.79 (m, 2H), 2.73-2.67 (m, 4H).
74% With potassium carbonate In dimethyl sulfoxide at 80℃; for 5 h; A suspension of (2-bromoethyl)benzene (4.10 mL, 30.0 mmol), piperazin-2-one (3.00 g, 30.0 mmol) and K2CO3 (4.90 g, 36.0 mmol) in DMSO (60.0 mL) was stirred at 80° C. for 5 h.
The reaction mixture was cooled to room temperature and filtered.
The filtrate was then washed with water (200 mL) and extracted with methylene chloride (2*).
The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated.
The result yellow solid was then dissolved in 1 N HCl (120 mL) and washed with methylene chloride.
The aqueous layer was separated, basified with 6 N NaOH, and extracted with methylene chloride (3*).
The combined organic layers were dried over MgSO4, filtered, and concentrated.
The residue was titrated with hexanes and filtered.
The filtered solid was dried under reduced pressure to give the title compound (4.50 g, 74percent) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 7.23-7.19 (m, 3H), 6.17 (brs, 1H), 3.40-3.37 (m, 2H), 3.23 (s, 2H), 2.83-2.79 (m, 2H), 2.73-2.67 (m, 4H).
Reference: [1] Patent: US2012/157460, 2012, A1, . Location in patent: Page/Page column 24
[2] Patent: US2012/157469, 2012, A1, . Location in patent: Page/Page column 18
[3] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3647 - 3656
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Reference: [1] Journal of Medicinal Chemistry, 1970, vol. 13, p. 846 - 848
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YieldReaction ConditionsOperation in experiment
84.93% With sodium carbonate In water; ethyl acetate at 0 - 30℃; for 16 h; Step 2
benzyl 3-oxopiperazine-1-carboxylate
At 0°C, to a mixture solution of sodium carbonate (24.77 g, 233.73 mmol, 3.00 equivalents) and piperazine-2-one (7.80 g, 77.91 mmol, 1.00 equivalent) in ethyl acetate (70.00 mL) and water (70.00 mL) was added benzyl chloroformate (16.79 g, 93.49 mmol, 13.99 mL, 95percent purity, 1.20 equivalents).
The reaction mixture was stirred at 30°C for 16 hours. TLC showed completiton of the reaction.
The mixture was subjected to extraction using ethyl acetate (80 mL*3).
The combined organic layers was washed with a saturated aqueous solution of sodium chloride (80 mL*3), dried over sodium sulfate and concentrated in vacuo to give a crude product.
The crude product was beaten in (petroleum ether: ethyl acetate = 20: I, 80 mL).
The resulting mixture was stirred at 30°C for 15 minutes and filtered.
The solid was dried in vacuo to give the title compound (15.50 g, 66.17 mmol, 84.93percent yield) as a white solid.
82.6% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; General procedure: To a solution of 3-aminopyrrolidine-1-carboxylate (744 mg, 4 mmol) in DCM (10 mL) , DIEA(1.04 mL, 6 mmol) and benzyl chloroformate (0.72 mL, 5 mmol) were added at 0. The reactionmixture was stirred at room temperature until TLC monitoring showed that the reaction wascomplete. The mixture was diluted with DCM and washed with water and brine. The organic layerwas dried over anhydrous MgSO4andevaporated, and column chromatography (petroleum ether /ethyl acetate =8:1 to 5:1) to give the corresponding product I-4 as light yellow oil (1.05 g, 82percent).
59.8% With potassium carbonate In water; ethyl acetate at 20℃; Piperazine-2-one (1 g, 10 mmol) is added to ethyl acetate (40 mL),In the solution of 20 ml ,K2CO3 is added at the room temperature followed by Benzyloxycarbonyl chloride (2.1 mL, 15 mmol) is added dropwise to the reaction flask,and reaction is stirred at room temperature . The reaction stopped next day, and the organic layer is washed with 20 mL of X saturated NaCl solution, dried over anhydrous magnesium sulfate,Column chromatography (D: Μ = 75: 1) to obtain a white solid 1.48, 59.8percent.yield.
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 11, p. 3715 - 3719
[2] Tetrahedron, 2010, vol. 66, # 18, p. 3370 - 3377
[3] Patent: EP3269715, 2018, A1, . Location in patent: Paragraph 0238; 0239
[4] European Journal of Medicinal Chemistry, 2017, vol. 132, p. 26 - 41
[5] European Journal of Medicinal Chemistry, 1981, vol. 16, # 3, p. 229 - 232
[6] Patent: CN107098886, 2017, A, . Location in patent: Paragraph 0151-0153
[7] Patent: US6403595, 2002, B1,
[8] Patent: WO2007/11809, 2007, A1, . Location in patent: Page/Page column 102-103
[9] Patent: US2011/46105, 2011, A1, . Location in patent: Page/Page column 67
[10] Patent: WO2012/27261, 2012, A1, . Location in patent: Page/Page column 535-537
[11] Patent: WO2013/123444, 2013, A1, . Location in patent: Page/Page column 72; 73
[12] Journal of Medicinal Chemistry, 2014, vol. 57, # 2, p. 325 - 338
[13] Patent: WO2014/35872, 2014, A1, . Location in patent: Page/Page column 79-80
[14] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3094 - 3116
[15] Nature, 2013, vol. 504, # 7480, p. 437 - 440
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YieldReaction ConditionsOperation in experiment
100% for 3 h; To a mixture of piperazine-2-one (1.037 g, 10.4 mmol) in 52 mL of CH2Cl2, was added BOC20 (2.5 g, 11.4 mmol). The reaction became homogeneous after 3 hours when the starting material was completely consumed. The reaction was diluted with CH2Cl2 and the organic layer was washed with water. The solvent was removed in vacuo to yield quantitative amount of product 33 as a white solid. 1H NMR (300 MHz, CDCl3) 8 1.48 (s, 9H), 3.35-3.44 (m, 2H), 3.64 (t, 2H, J= 5 Hz), 4.10 (s, 2H), 6.41 (br s, 1H).
100% at 20℃; for 5 h; Di-tert-butyl dicarbonate (3.92 g, 17.98 mmol) was added to a suspension of 2-piperazinone (1.50 g, 14.98 mmol) in dichloromethane (15 mL). The mixture was stirred at room temperature for 5 hours. The solvent was evaporated to afford 1 ,1- dimethylethyl 3-oxo-1-piperazinecarboxylate (2.99 g, quantitative) as an off-white solid.
100% at 20℃; Cooling with ice Boc2O (2.0 mmol, 436mg, 1.0 eq) was added in portions under stirring and cooling on an ice bath to a suspension of piperazin-2-one (2.0 mmol, 200 mg, 1.0 eq) in anhydrous dichloromethane (10.0 mL). The reaction mixture was stirred overnight at room temperature, during which a homogeneous solutionformed. The solvent was evaporated and the solid residue was vacuum-dried tofurnish a yellow solid (300.0 mg, 100percent). 1H NMR (300 MHz, CDCl3) δ (ppm): 1.51(s, 9 H); 3.37-3.46 (m, 2 H); 3.66 (t, J= 5.2 Hz, 2 H); 4.12 (s, 2 H); 6.39 (bs, 1 H). 13C NMR (75 MHz, CDCl3) δ (ppm):27.4 (CH2); 28.3 (3 x CH3); 41.2 (CH2); 77.1(CH2); 80.9 (C); 153.9 (C); 168.0 (C). MS (DCI/NH3) m/z: 201.1 [M+H+]; 218.1 [M + NH4+].
99% for 16 h; Preparation Example 1-25-13-Oxo-piperazine-1-carboxylic acid tert-butyl ester piperazin-2-one (500 mg, 5.0 mmol) was dissolved in methanol (15 mL), and di t-butyl dicarbonate (1.09 g, 5.0 mmol) was added thereto and the mixture was stirred for 16 hours. The mixture was distilled under reduced pressure to remove the solvent, and purified by column chromatography using 5:95 mixture solvent of methanol and dichloromethane to obtain the title compound (0.99 g, 99percent).1H NMR (500 MHz, CDCl3); δ 6.01 (1H, br s), 4.09 (2H, s), 3.63 (2H, t), 3.38 (2H, br s), 1.47 (9H, s)
92% With triethylamine In tetrahydrofuran; methanol at 20℃; for 4 h; 1)
3-Oxopiperazine-1-carboxylic acid tert-butyl ester
Piperazin-2-one (5.07 g) was dissolved in tetrahydrofuran (50 mL) and methanol (50 mL), and, at room temperature, triethylamine (7.76 mL) and di-tert-butyl dicarbonate (12.17 g) were added to the solution, followed by stirring for 4 hours.
The reaction solvent was evaporated under reduced pressure, and diethyl ether was added to the residue.
The precipitated solid was collected through filtration, to thereby give 3-oxopiperazine-1-carboxylic acid tert-butyl ester as a solid product (9.36 g, 92percent).
1H-NMR(400MHz,DMSO-d6)δ:1.40(9H,s), 3.15(2H,br), 3.45(2H,br), 3.81(2H,br), 8.03(1H,br).
ESI-MS m/z:201(M+H)+.
90% With dmap; triethylamine In dichloromethane at 20℃; for 16 h; STEP 1 Piperazin-2-one (1 g, 10 mmol) was dissolved in CH2C12 (40 ML), and BOC20 (2.4 g, 11 mmol, 1.1 eq), Et3N (2.02 g, 20 mmol, 2 eq) and DMAP (0.024 g, 0.2 mmol, 2 molpercent) were added. After the mixture was stirred at RT for 16 h, it was acidified with 1 N HCI. The organic layer was separated, washed with saturated NAHC03, brine, dried (Na2SO4), and concentrated in vacuo to give the product (1.8 g, 90percent) as a white SOLID. H NMR (CDCI3, 300 MHz) No. 6. 70 (1 H, bs), 4.08 (2H, s), 3.62 (2H, t, J = 6. 0 Hz), 3.37 (2H, m), 1.46 (9H, s).
90% With dmap; triethylamine In dichloromethane at 0 - 20℃; for 5.5 h; To a solution of piperazinone (10.0 g, 100 mmol), triethylamine (20.2 g, 200mmol), and DMAP (50 mg) in CH2CI2 (250 ml) in an ice-water bath was added(Boc)2O (22.9 g, 105 mmol) slowly. The mixture was stirred in the ice-water bath for 1h and at RT for 4.5 h. The mixture was diluted with CH2CI2 (250 ml), washed withwater (200 ml), 5percent citric acid (200 ml), 1N HCI (200 ml), saturated sodiumbicarbonate (20 ml) and brine. The organic layer was dried (MgSCU) andconcentrated to give the product (18.0 g, 90percent). MS m/e 201 (M+H)+
90% With triethylamine In dichloromethane at 0 - 20℃; for 5.5 h; To a solution of piperazinone (10.0 g, 100 mmol), Triethylamine (20.2 g, 200mmol), and DMAP (50 mg) in CHaCIa (250 ml) in an ice water bath was added(Boc)2O (22.9 g, 105 mmol) slowly. The mixture was stirred in the ice-water bath for 1h and at RT for 4.5 h. The mixture was diluted with CH2CI2 (250 ml), washed withwater (200 ml), 5percent citric acid (200 ml), 1N HCI (200 ml), saturated sodiumbicarbonate (20 ml) and brine. The organic layer was dried (MgSO4) andconcentrated to give the product (18.0 g, 90percent). MS m/e 201 (M+H)"1"
90.91% With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 16 h; Step 1:
tert-Butyl-3-oxopiperazine-1-carboxylate
To a solution of piperazin-2-one (22.00 g, 219.7 mmol) in THF (300 mL) was added a mixture of NaHCO3 (29.53 g, 307.6 mmol) in H2O (100 mL), (Boc)2O (43.16 g, 197.8 mmol), then the reaction solution was stirred at rt for 16 h.
The mixture was concentrated, poured into water (100 mL) and extracted with EtOAc (100 mL*2).
The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain tert-butyl-3-oxopiperazine-1-carboxylate (40.00 g, 90.91percent) as white solid. ESI-MS (EI+, m/z): 145.2[M+H-56]+. 1H NMR (500 MHz, CDCl3) δ 4.08 (s, 2H), 3.62 (t, J=5.2 Hz, 2H), 3.37 (s, 2H), 1.47 (s, 9H).
90%
Stage #1: With dmap; triethylamine In dichloromethane at 20℃; for 16 h;
Stage #2: With hydrogenchloride In dichloromethane
Example 29 Step 1: Piperazin-2-one (1 g, 10 mmol) was dissolved in CH2CI2 (40 ML), and BOC20 (2.4 g, 11 MMOL, 1.1 eq), ET3N (2.02 g, 20 mmol, 2 eq) and DMAP (0.024 g, 0.2 mmol, 2 molpercent) were added. After the mixture was stirred at RT for 16 h, it was acidified with 1 N HCI. The organic layer was separated, washed with saturated NAHC03, brine, dried (NA2SO4), and concentrated in vacuo to give the product (1.8 g, 90percent) as a white solid.'H NMR (CDC13, 300 MHz) 8 6. 70 (1 H, bs), 4.08 (2H, s), 3.62 (2H, t, J = 6. 0 Hz), 3.37 (2H, m), 1.46 (9H, s).
87% With triethylamine In tetrahydrofuran; methanol at 20℃; for 3 h; [Referential Example 90]; 4-Methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester; 1) 3-Oxopiperazine-1-carboxylic acid tert-butyl ester ; Triethylamine (3.9 mL) and di-tert-butyl dicarbonate (6.31 g) were added to 2-oxopiperazine (2.61 g) in a mixture of tetrahydrofuran (40 mL) and methanol (50 mL) at room temperature, followed by stirring for 3 hours. The solvent was evaporated under reduced pressure. To the residue, diethyl ether was added, and the precipitated solid was recovered by filtration, to thereby give 3-oxopiperazine-1-carboxylic acid tert-butyl ester (4.54 g, 87percent).1H-NMR(400MHz,DMSO-d6)δ: 1.40(9H,s), 3.15(2H,br), 3.45(2H,br), 3.81(2H,br), 8.03(1H,br). LC-MSm/z: 201(M+H)+.
72% With triethylamine In tetrahydrofuran; methanol at 20℃; for 3 - 4 h; 1)
3-Oxopiperazine-1-carboxylic acid tert-butyl ester
Triethylamine (3.83 mL) and di-tert-butoxydicarbonate (6.32 mL) were added to a solution of piperazin-2-one (2.5 g) in a mixture of tetrahydrofuran (50 mL) and methanol (50 mL) at room temperature, and the mixture was stirred for 4 hours.
The reaction solvent was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate.
The organic layer was sequentially washed with water and saturated brine, and the aqueous layers obtained through washing were combined and then extracted with ethyl acetate.
The organic layers were combined and then dried over magnesium sulfate anhydrate.
After a filtration step, the solvent was removed under reduced pressure, and ethyl acetate - hexane was added to the residue for solidification, to thereby give 3-oxopiperazine-1-carboxylic acid tert-butyl ester (3.6 g, 72percent).
1H-NMR(400MHz,CDCl3)δ:1.48(9H,s), 3.37-3.40(2H,m), 3.62-3.65(2H,m), 4.01(2H,s), 6.32(1H,br s).
1) 3-Oxopiperazine-1-carboxylic acid tert-butyl ester Triethylamine (3.9 mL) and di-tert-butyl dicarbonate (6.31 g) were added to a solution of 2-oxopiperazine (2.61 g) in a mixture of tetrahydrofuran (40 mL) and methanol (50 mL) at room temperature, and the mixture was stirred for 3 hours. The reaction solvent was removed under reduced pressure, and diethyl ether was added to the residue. The solid that precipitated was collected through filtration, to thereby give 3-oxopiperazine-1-carboxylic acid tert-butyl ester (4.54 g, 87percent). 1H-NMR(400MHz,DMSO-d6)δ:1.40 (9H,s), 3.15(2H,br), 3.45(2H,br), 3.81 (2H,br) , 8.03 (1H,br) . LC-MSm/z:201(M+H)+.
72% With triethylamine In tetrahydrofuran; methanol at 20℃; for 4 h; 1)
3-Oxopiperazine-1-carboxylic acid tert-butyl ester
Triethylamine (3.83 mL) and di-tert-butoxydicarbonate (6.32 mL) were added at room temperature to piperazin-2-one (2.5 g) in a mixture of tetrahydrofuran (50 mL) and methanol (50 mL), followed by stirring for 4 hours.
The reaction solvent was evaporated under reduced pressure.
The residue was partitioned between water and ethyl acetate.
The organic layer was sequentially washed with water and saturated brine.
The aqueous layers obtained through washing were combined, and the combined layer was extracted with ethyl acetate.
The organic layers were combined, followed by drying over magnesium sulfate anhydrate.
After a filtration step, the solvent was evaporated under reduced pressure.
Subsequently, ethyl acetate-hexane was added to the residue, followed by drying to solid, to thereby give 3-oxopiperazine-1-carboxylic acid tert-butyl ester (3.6 g, 72percent).
1H-NMR(400MHz,CDCl3)δ:1.48(9H,s), 3.37-3.40(2H,m), 3.62-3.65(2H,m), 4.01(2H,s), 6.32(1H,br s).
[Referential Example 40] 1-Ethyl-2-oxopiperazine hydrochloride [Show Image] 1) 3-Oxopiperazine-1-carboxylic acid tert-butyl ester Piperazin-2-one (5.07 g) was dissolved in tetrahydrofuran (50 mL) and methanol (50 mL), and, at room temperature, triethylamine (7.76 mL) and di-tert-butyl dicarbonate (12.17 g) were added to the solution, followed by stirring for 4 hours. The reaction solvent was evaporated under reduced pressure, and diethyl ether was added to the residue. The precipitated solid was collected through filtration, to thereby give 3-oxopiperazine-1-carboxylic acid tert-butyl ester as a solid product (9.36 g, 92percent). 1H-NMR(400MHz,DMSO-d6)δ:1.40(9H,s), 3.15(2H,br), 3.45(2H,br), 3.81(2H,br), 8.03(1H,br). ESI-MS m/z:201(M+H)+.
72% With triethylamine In tetrahydrofuran; methanol at 20℃; for 4 h; 1) 3-Oxopiperazine-1-carboxylic acid tert-butyl ester Triethylamine (3.83 mL) and di-tert-butoxydicarbonate (6.32 mL) were added to a mixed solution of piperazin-2-one (2.5 g) in tetrahydrofuran (50 mL) and methanol (50 mL) at room temperature, and the resultant mixture was stirred for 4 hours. The reaction solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue thus obtained, and the mixture was partitioned. The organic layer was washed with water and saturated saline in this order, and then the washing water layer was combined for further extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was solidified using ethyl acetate-hexane, thus to obtain 3-oxopiperazine-1-carboxylic acid tert-butyl ester (3.6 g, 72percent). 1H-NMR(400MHz, CDCl3)δ: 1.48(9H, s), 3.37-3.40(2H, m), 3.62-3.65(2H, m), 4.01(2H, s), 6.32(1H, br s).1) 3-Oxopiperazine-1-carboxylic acid tert-butyl ester To a mixed solution of piperazin-2-one (5.07 g) in tetrahydrofuran (50 mL) and methanol (50 mL), triethylamine (7.76 mL) and di-tert-butyl dicarbonate ester (12.17 g) were added at room temperature, and the resultant mixture was stirred for 4 hours. The solvent of the reaction solution was evaporated under reduced pressure, diethyl ether was added to a residue thus obtained, and the precipitated solid was filtered, to obtain 3-oxopiperazine-1-carboxylic acid tert-butyl ester (9.36 g, 92percent). 1H-NMR(400MHz, DMSO-d6)δ: 1.40(9H, s), 3.15(2H, br), 3.45(2H, br), 3.81(2H, br), 8.03(1H, br). ESI-MSm/z: 201(M+H)+.
72% With triethylamine In tetrahydrofuran; methanol at 20℃; for 4 h; 1) 3-oxopiperazine-1-carboxylic acid tert-butyl ester Triethylamine (3.83 ml) and di-tert-butoxydicarbonate (6.32 ml) were added to a mixed solution of piperazin-2-one (2.5 g) in tetrahydrofuran (50 ml) and methanol (50 ml) at room temperature, and the resultant mixture was stirred for 4 hours. The reaction solvent was evaporated under reduced pressure, then water and ethyl acetate were added to the residue thus obtained, and the mixture was partitioned. The organic layer was washed sequentially with water and saturated brine, and then the washing water layers were combined and extracted again with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. After separating the organic layer by filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was solidified from ethyl acetate-hexane, to obtain 3-oxopiperazine-1-carboxylic acid tert-butyl ester (3.6 g, 72percent). 1H-NMR (400MHz, CDCl3) δ: 1.48 (9H, s), 3.37-3.40 (2H, m), 3.62-3.65 (2H, m), 4.01 (2H, s), 6.32 (1H, br s).
70% With triethylamine In dichloromethane at 0 - 20℃; for 3 h; Inert atmosphere Piperazine -2-one( 2g, 20 mmol) is added to DCM (30 mL) ,and under the protection of argon Et3N (3.46 mL, 24 mmol) is added ,after cooling down the room temperature to 0 , add BOC anhydride (4.79g, 22mmol) in one reaction flask and raise the room temperature . After 3 h, reaction is stopped and DCM (100 mL) is added, washed with saturated NaCl solution (30 mL x 2), dried over anhydrous magnesium sulfate, concentrated, and recrystallized from DCM and petroleum ether to give a white solid 2.8 g, yield 70percent.
68% With sodium hydroxide In 1,4-dioxane; water at 20℃; for 8 h; To a solution of piperadine-2-one (2.01 g) in dioxane (20 mL) and water (10 mL), an aqueous solution of two normal sodium hydroxide (10 mL) was added at room temperature and stirred. Then, a solution of tert-butyl dicarbonate (5.45 g) in dioxane (5 mL) was slowly added dropwise, and stirred as it is at room temperature for eight hours. Water was poured to the reaction mixture, and extracted twice with 50 mL of ethyl acetate. After the organic layers were combined and washed in saturated saline, it was dried on anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, dried under vacuum to obtain a title compound (3.41 g, yield 68percent) as a white solid compound. The product thus obtained was used in the subsequent reaction without further purification. ESI/MS m/e: 201.2 (M++H, C9H16N2O3)
66% With triethylamine In dichloromethane at 0 - 20℃; for 16 h; Inert atmosphere To a stirred solution of piperazin-2-one CK (3 g, 30 inmol) in CHjCfe (50 mL) under argon atmosphere were added tiiethylamine (8.65 mL. 60 mmol) and di-t-buryi dicarbonate (Boc anhydride, 8.2 mL, 36 niniol) at 0 °C. The reaction was wanned to RT and stirred for 16 h. The reaction was diluted with water (100 mL) and the product was extracted with CC (2 x 100 mL). The combined organic layers were dried over anhydrous Na S< and concentrated under reduced pressure to obtain Compound CO (4 g, 20 mmol, 66 percent) as a white solid, which was used in the next step without further purification. H NMR (400 MHz, CDCi3): δ 6.90 (br s. IH), 4.08 (s, 2H), 3.63-3.59 (m, 2H), 3.35-3.31 (m, 2H), 1.44 (s. 9H).
45% With triethylamine In dichloromethane at 0 - 20℃; for 18 h; Inert atmosphere To a stirring solution of piperazin-2-one 16 (500 mg, 5.00 mmol) in CH2C12 (5 mL) under argon atmosphere were added triethylamine (1.5 mL, 10.00 mmol) and Boc- anhydride (1.3 mL, 6.00 mmol) at 0 °C; warmed to RT and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was purified through silica gel flash column chromatography using 2percent MeOH/ CH2C12 to afford compound 17 (450 mg, 45percent) as pale yellow solid. TLC: 10percent MeOH/ CH2C12 (R/. 0.6); 1H-NMR (DMSO-i/tf, 400 MHz): δ 8.02 (br s, IH), 3.81 (s, 2H), 3.48-3.45 (m, 2H), 3.19-3.14 (m, 2H), 1.41 (s, 9H).
5.1 g at 20℃; for 4 h; 2-Piperazinone (2.5 g; 24.97 mmol) was dissolved in DCM ( 55 ml ). A solution of tert- butyloxycarbonyl anhydride (5.45g, 24.97mmol) in DCM (20 ml) was added dropwise. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated to dryness and dried under high vacuum, at room temperature. The residue containing Int. 177 (5.1 g) was used as such in the next reaction step.

Reference: [1] Patent: WO2005/117904, 2005, A2, . Location in patent: Page/Page column 407
[2] Patent: WO2011/41713, 2011, A2, . Location in patent: Page/Page column 147-148
[3] European Journal of Medicinal Chemistry, 2015, vol. 101, p. 218 - 235
[4] Patent: WO2006/72350, 2006, A1, . Location in patent: Page/Page column 37
[5] Patent: WO2006/72353, 2006, A1, . Location in patent: Page/Page column 30
[6] Patent: US2011/166121, 2011, A1, . Location in patent: Page/Page column 32
[7] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 57
[8] Patent: WO2005/14540, 2005, A1, . Location in patent: Page/Page column 59
[9] Patent: WO2006/14762, 2006, A1, . Location in patent: Page/Page column 37
[10] Patent: WO2006/14944, 2006, A1, . Location in patent: Page/Page column 29
[11] Patent: US2018/127370, 2018, A1, . Location in patent: Paragraph 0735; 0733
[12] Patent: WO2005/16876, 2005, A2, . Location in patent: Page/Page column 75-76
[13] Patent: EP1591443, 2005, A1, . Location in patent: Page/Page column 63
[14] Patent: US6235731, 2001, B1,
[15] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 47; 51-52
[16] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 36-37; 57
[17] Patent: EP1785418, 2007, A1, . Location in patent: Page/Page column 43; 72
[18] Patent: EP1803719, 2007, A1, . Location in patent: Page/Page column 39
[19] Patent: CN107098886, 2017, A, . Location in patent: Paragraph 0147-0149
[20] Patent: EP1477490, 2004, A1, . Location in patent: Page 109
[21] Patent: WO2017/117393, 2017, A1, . Location in patent: Page/Page column 148
[22] Patent: WO2016/168619, 2016, A1, . Location in patent: Paragraph 00291
[23] Tetrahedron Letters, 1980, vol. 21, # 32, p. 3019 - 3020
[24] Patent: WO2004/35576, 2004, A2, . Location in patent: Page 172;173
[25] Patent: US2003/109559, 2003, A1,
[26] Patent: US6403595, 2002, B1,
[27] Patent: US5629322, 1997, A,
[28] Patent: US4341698, 1982, A,
[29] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 11, p. 3236 - 3241
[30] Patent: EP1188755, 2002, A1, . Location in patent: Page 42
[31] Patent: WO2013/134226, 2013, A1, . Location in patent: Page/Page column 94
[32] Patent: US2013/236468, 2013, A1, . Location in patent: Paragraph 0333
[33] Patent: WO2014/100716, 2014, A1, . Location in patent: Paragraph 00222
[34] Patent: WO2015/150555, 2015, A1, . Location in patent: Page/Page column 151
[35] Patent: WO2007/8144, 2007, A1, . Location in patent: Page/Page column 27
[36] Patent: CN108610332, 2018, A, . Location in patent: Paragraph 0133; 0135; 0136; 0168
  • 23
  • [ 5625-67-2 ]
  • [ 75-65-0 ]
  • [ 76003-29-7 ]
Reference: [1] Patent: US5556977, 1996, A,
[2] Patent: US5652242, 1997, A,
[3] Patent: US5753659, 1998, A,
  • 24
  • [ 5625-67-2 ]
  • [ 24424-99-5 ]
  • [ 107-06-2 ]
  • [ 76003-29-7 ]
Reference: [1] Patent: JP2005/504737, 2005, A, . Location in patent: Page/Page column 129-130
  • 25
  • [ 5625-67-2 ]
  • [ 179051-25-3 ]
  • [ 24424-99-5 ]
  • [ 76003-29-7 ]
Reference: [1] Patent: US5965559, 1999, A,
  • 26
  • [ 5625-67-2 ]
  • [ 24424-99-5 ]
  • [ 100-39-0 ]
  • [ 78551-60-7 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: at 20℃; for 16 h;
Stage #2: With N,N-dimethyl acetamide; sodium hydride In dichloromethane for 1.5 h; Inert atmosphere
Step 1tert-butyl 4-benzyl-3-oxopiperazine-1-carboxylateDi-tert-butyl dicarbonate (750 mg, 3.44 mmol) was added to a solution of piperazine-2-one (344 mg, 3.44 mmol) in CH2C12 (13 mL). The solution was stirred at room temperature for 16 hours, then concentrated under vacuum. The residue was dissolved in N,Ndimethylformamide (10 mL) and stirred under nitrogen as sodium hydride (60percent dispersion in oil, 0.25 g, 6.25 mmol) was added at room temperature. The mixture was stirred for 30 minutes, then benzyl bromide (0.532 mL, 4.47 mmol) was added. The mixture was stirred under nitrogen for 1 hour, and the reaction was quenched by cautious addition of water (3 mL). Finally, the mixture was diluted with water (50 mL) and stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and washed with water (40 mL), then dried under vacuum to the titled compound (0.82 g, 82percent). ‘H NMR (400 MHz, methanol-d4) ppm 1.46 (s, 9H), 3.30 - 3.33 (m, 2H), 3.60 (t, J = 5.2 Hz, 2H), 4.11 (s, 2H), 4.62 (s, 2H), 7.25 - 7.37 (m, 5H); MS (ESI) m/z 291 (M+H).
82%
Stage #1: at 20℃; for 16 h;
Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5 h;
Stage #3: for 1 h; Inert atmosphere
Step 1
tert-butyl 4-benzyl-3-oxopiperazine-1-carboxylate
Di-tert-butyl dicarbonate (750 mg, 3.44 mmol) was added to a solution of piperazine-2-one (344 mg, 3.44 mmol) in CH2Cl2 (13 mL).
The solution was stirred at room temperature for 16 hours, then concentrated under vacuum.
The residue was dissolved in N,N-dimethylformamide (10 mL) and stirred under nitrogen as sodium hydride (60percent dispersion in oil, 0.25 g, 6.25 mmol) was added at room temperature.
The mixture was stirred for 30 minutes, then benzyl bromide (0.532 mL, 4.47 mmol) was added.
The mixture was stirred under nitrogen for 1 hour, and the reaction was quenched by cautious addition of water (3 mL).
Finally, the mixture was diluted with water (50 mL) and stirred at room temperature for 2 hours.
The resulting precipitate was collected by filtration and washed with water (40 mL), then dried under vacuum to the titled compound (0.82 g, 82percent).
1H NMR (400 MHz, methanol-d4) δ ppm 1.46 (s, 9H), 3.30-3.33 (m, 2H), 3.60 (t, J=5.2 Hz, 2H), 4.11 (s, 2H), 4.62 (s, 2H), 7.25-7.37 (m, 5H); MS (ESI) m/z 291 (M+H)+.
Reference: [1] Patent: WO2015/112445, 2015, A1, . Location in patent: Page/Page column 150; 151
[2] Patent: US2016/376240, 2016, A1, . Location in patent: Paragraph 0650
  • 27
  • [ 5625-67-2 ]
  • [ 352-34-1 ]
  • [ 780753-89-1 ]
Reference: [1] Patent: WO2009/53459, 2009, A1, . Location in patent: Page/Page column 42
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