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Product Details of [ 124443-68-1 ]

CAS No. :124443-68-1 MDL No. :MFCD02183584
Formula : C12H21NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :PTZNCCIULVXFIJ-UHFFFAOYSA-N
M.W : 243.30 Pubchem ID :392870
Synonyms :

Calculated chemistry of [ 124443-68-1 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 67.49
TPSA : 55.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.75 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.07
Log Po/w (XLOGP3) : 1.46
Log Po/w (WLOGP) : 1.43
Log Po/w (MLOGP) : 1.31
Log Po/w (SILICOS-IT) : 1.03
Consensus Log Po/w : 1.66

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.94
Solubility : 2.8 mg/ml ; 0.0115 mol/l
Class : Very soluble
Log S (Ali) : -2.24
Solubility : 1.4 mg/ml ; 0.00577 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.36
Solubility : 10.7 mg/ml ; 0.044 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.24

Safety of [ 124443-68-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 124443-68-1 ]

* 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 [ 124443-68-1 ]
  • Downstream synthetic route of [ 124443-68-1 ]

[ 124443-68-1 ] Synthesis Path-Upstream   1~27

  • 1
  • [ 67-56-1 ]
  • [ 84358-13-4 ]
  • [ 124443-68-1 ]
YieldReaction ConditionsOperation in experiment
90% With diazomethyl-trimethyl-silane In hexanes; acetonitrile at 0 - 20℃; for 3.5 h; A solution of trimethylsilyl diazomethane in hexanes (2.00 M, 52.9 mL, 106 mmol) was added dropwise to a suspension of l-fert-butoxycarbonyl-piperidine-4-carboxylic acid (12.14 g, 52.95 mmol) in acetonitrile (100 mL) and methanol (10 mL) at 0 °C. The mixture let stand for 30 minutes and then was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and product was purified from the residue by column chromatography [n-hex/EtOAc (4.5:1 v/v)] to give l-tert-butyl 4-methyl piperidine-1,4- dicarboxylate as an oil (11.5 g, 90percent). 1H NMR (400 MHz, d6-DMSO) δ 4.02 (dt, 2H, J= 3.5, 13.7 Hz), 3.69 (s, 3H), 2.82 (ddd, 2H5 J= 3, 11.5, 14.5 Hz), 2.45 (tt, 1H, J= 3.9, 11.5 Hz), 1.90-1.84 (m, 2H), 1.67-1.57 (m, 2H), 1.45 (s, 9H). MS(ES) m/z 265.8 (MNa+); MS cald: 243.1 (M).
Reference: [1] Patent: WO2006/86609, 2006, A2, . Location in patent: Page/Page column 160
[2] Tetrahedron Letters, 2004, vol. 45, # 12, p. 2663 - 2665
[3] Tetrahedron Letters, 2011, vol. 52, # 8, p. 849 - 852
  • 2
  • [ 67-56-1 ]
  • [ 498-94-2 ]
  • [ 24424-99-5 ]
  • [ 124443-68-1 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: at 20℃; for 1 h;
Stage #2: With triethylamine In dichloromethane at 0 - 20℃;
b. Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester; To a mixture of isonipecotic acid (39.0 g, 302 mmol) in MeOH (300 mL) was bubbled HCl gas. The flask was tightly capped and stirred at rt for 1.5 h, at which point the homogeneous solution was concentrated, taken up in DCM (2.x.125 mL), and repeatedly concentrated under reduced pressure to give a white solid largely free of MeOH. To this was added TEA (43.6 mL, 313 mmol) and DCM (80 mL), and this slurry was stirred on an ice bath while a solution of (Boc)2O (60.9 g, 279 mmol) in DCM (100 mL) was added dropwise with stirring over 10 min at 0° C. After 1 h stirring at 0° C., the ice bath was removed and the slurry was stirred at rt overnight. The slurry was then diluted with ether (700 mL), washed with 0.5M NaH2PO4 (1.x.400 mL), 4 M NaCl (1.x.450 mL), dried (Na2SO4), and concentrated under reduced pressure to provide the title compound as a clear light amber oil that crystallized upon standing (65.3 g, 96percent). 1H-NMR (300 MHz, CDCl3) δ 4.10-3.95 (br m, 2H), 3.69 (s, 3H), 2.92-2.75 (br m, 2H), 2.45 (m, 1H), 1.93-1.82 (m, 2H), 1.70-1.55 (m, 2H), 1.46 (s, 9H).
Reference: [1] Patent: US2006/281772, 2006, A1, . Location in patent: Page/Page column 51
[2] European Journal of Organic Chemistry, 2005, # 4, p. 673 - 682
  • 3
  • [ 2971-79-1 ]
  • [ 24424-99-5 ]
  • [ 124443-68-1 ]
YieldReaction ConditionsOperation in experiment
98% With triethylamine In dichloromethane at 25℃; for 12 h; Synthesis of 9-(Azetidin-1-yl)-9-phenyl-3-azaspiro[5.5]undecane Trifluoroacetate (A4); Step-1: 1-tert-Butyl 4-methyl piperidine-1,4-dicarboxylate; To a stirred solution of methyl isonipecotate (127.2 mmol, 1 eq) in dichloromethane (200 ml) were added di-tert-butyldicarbonate (190.8 mmol, 1.5 eq) and triethylamine (254.4 mmol, 2.0 eq). The reaction mixture was stirred for 12 h at 25° C. It was then diluted with dichloromethane (100 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was separated, dried over Na2SO4, concentrated and employed in the next step without further purification. Yield: 98percent
95.5% With triethylamine In dichloromethane at 20℃; for 8 h; The 1L round-bottom flask is added in piperidine-4-carboxylic acid methyl ester (30g, 0.21mol), dissolved in 500 ml of in DCM, constant voltage dropping funnel for dropping (Boc)2O (45.72g, 0 . 21mol), triethylamine (42.3g, 0 . 42mol), stirring the mixture at room temperature for, 8 hours after the completion of the reaction, the volume of water to wash DCM layer 3 times, and evaporation drying of colorless oily organic 97.5g, yield 95.5percent.
86% With triethylamine In dichloromethane at 20℃; for 1 h; A. Synthesis of l-fert-butyl-4-methyl piperidine-l,4-dicarboxylate; [0065] Methyl isonipecotate (5 mL, 33 mmol), di-tert-butyl-dicarbonate (7 g, 33 mmol) and TEA (6.3 mL, 49.5 mmol) were stirred in DCM (100 mL) under N2 at rt for 1 h. The reaction was diluted to twice its volume with DCM, washed twice with saturated sodium bicarbonate solution followed by one wash with H2O. The organic layer was separated, dried over MgSO4 and concentrated to yield crude product (6.9 g, 86percent) as a clear colorless oil that was sufficiently pure to use in subsequent reactions.
75% With triethylamine In dichloromethane at 20℃; for 16 h; To a solution of methyl piperidine-4-carboxylate (3.0 g, 21.0 mmol, 1.0 eq) in CH2C12 (70 mL) were added Et3N (3.18 g, 31.5 mmol, 1.5 eq) and (Boc)20 (5.04 g, 23.1 mmol, 1.1 eq). Then the reaction mixture was stirred at room temperature for 16 h. After concentration, the residue was purified by silica gel column (PE: EA = 3:1) to give 1-tert- butyl 4-methyl piperidine-l,4-dicarboxylate as colorless gum (3.8 g, Y: 75percent). ESTMS (M+H) +: 244.1. 1H NMR (400 MHz, CDC13) δ: 4.03-4.00 (m, 2H), 3.67 (s, 3H), 2.86- 2.79 (m, 2H), 2.48-2.42 (m, 1H), 1.89-1.85 (m, 2H), 1.67-1.57 (m, 2H), 1.45 (s, 9H).

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 18, p. 5036 - 5040
[2] Patent: US2010/113417, 2010, A1, . Location in patent: Page/Page column 36
[3] Patent: CN105541798, 2016, A, . Location in patent: Paragraph 0120; 0121
[4] Patent: WO2008/31227, 2008, A1, . Location in patent: Page/Page column 21
[5] Patent: WO2012/109108, 2012, A1, . Location in patent: Page/Page column 121
[6] Patent: WO2007/71035, 2007, A1, . Location in patent: Page/Page column 36-37
[7] Patent: WO2009/61676, 2009, A2, . Location in patent: Page/Page column 70-71
[8] European Journal of Medicinal Chemistry, 2010, vol. 45, # 7, p. 2827 - 2840
[9] Patent: US2006/63775, 2006, A1, . Location in patent: Page/Page column 18
[10] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 3085 - 3092
[11] Patent: WO2014/150132, 2014, A1, . Location in patent: Page/Page column 44
[12] Patent: WO2016/8064, 2016, A1, . Location in patent: Page/Page column 39
[13] Patent: WO2016/10801, 2016, A1, . Location in patent: Page/Page column 33
[14] Patent: WO2016/122994, 2016, A1, . Location in patent: Page/Page column 42
  • 4
  • [ 84358-13-4 ]
  • [ 74-88-4 ]
  • [ 124443-68-1 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 28, p. 4605 - 4607
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4453 - 4459
[3] Patent: WO2010/57121, 2010, A1, . Location in patent: Page/Page column 179-180
[4] Patent: WO2013/19621, 2013, A1, . Location in patent: Page/Page column 57
  • 5
  • [ 84358-13-4 ]
  • [ 18107-18-1 ]
  • [ 124443-68-1 ]
Reference: [1] Patent: US5576313, 1996, A,
[2] Patent: WO2007/8140, 2007, A1, . Location in patent: Page/Page column 107
[3] Patent: US2005/70609, 2005, A1, . Location in patent: Page/Page column 51; 57-58
[4] Patent: WO2007/3965, 2007, A1, . Location in patent: Page/Page column 27
[5] Patent: US5891889, 1999, A,
  • 6
  • [ 3236-56-4 ]
  • [ 124443-68-1 ]
Reference: [1] Patent: US2005/54850, 2005, A1,
  • 7
  • [ 7462-86-4 ]
  • [ 1538-75-6 ]
  • [ 124443-68-1 ]
Reference: [1] Journal of Organic Chemistry, 1990, vol. 55, # 4, p. 1399 - 1401
  • 8
  • [ 51300-90-4 ]
  • [ 7462-86-4 ]
  • [ 124443-68-1 ]
Reference: [1] Patent: US5656656, 1997, A,
  • 9
  • [ 498-94-2 ]
  • [ 124443-68-1 ]
Reference: [1] Patent: WO2014/150132, 2014, A1,
[2] Patent: WO2016/10801, 2016, A1,
[3] Patent: WO2016/8064, 2016, A1,
[4] Patent: WO2016/122994, 2016, A1,
[5] Patent: US5891889, 1999, A,
  • 10
  • [ 24424-99-5 ]
  • [ 124443-68-1 ]
Reference: [1] Patent: US5891889, 1999, A,
  • 11
  • [ 124443-68-1 ]
  • [ 7462-86-4 ]
YieldReaction ConditionsOperation in experiment
99% With hydrogenchloride In dichloromethane; ethyl acetate at 20℃; for 1.5 h; Inert atmosphere To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (2.16 g, 8.88 mmol) in DCM (3 mL) was added a HCl in EtOAcsolution (4 M, 6 mL) . The mixture was stirred at rt for 1.5 h and concentratedto give the title compound as a white solid (1.59 g, 99) . 1H NMR (400 MHz, CD3OD): δ ppm 3.73 (s, 3H) , 3.44-3.39 (m, 2H) , 3.15-3.09 (m, 2H) , 2.82-2.77 (m,1H) , 2.21-2.16 (m, 2H) , 1.99-1.89 (m, 2H) and MS-ESI: m/z 144.2 [M+H-HCl] +.
99% With hydrogenchloride In dichloromethane; ethyl acetate at 20℃; for 1.5 h; To N-Boc-4- methyl-piperidine (2.16g, 8.88mmol) in dichloromethane (3mL) was added a solution of HCl inethyl acetate solution (4M, 6mL), stirred at room temperature 1.5h, the solvent was removed to give 1.59g ofwhite solid: compound 4-methyl-piperidine hydrochloride, yield: 99.
Reference: [1] Patent: WO2016/34134, 2016, A1, . Location in patent: Paragraph 00373
[2] Patent: CN105399698, 2016, A, . Location in patent: Paragraph 0920-0923
  • 12
  • [ 124443-68-1 ]
  • [ 39674-99-2 ]
Reference: [1] Patent: CN105399698, 2016, A,
  • 13
  • [ 124443-68-1 ]
  • [ 91419-52-2 ]
Reference: [1] Synthesis (Germany), 2015, vol. 47, # 23, p. 3758 - 3766
  • 14
  • [ 124443-68-1 ]
  • [ 84358-13-4 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃;
Stage #2: With hydrogenchloride In water
A mixture of 1 -tert-butyl 4-methyl piperidine-1 ,4-dicarboxylate (4.84 g 20 mmol), and LiOH(2.52 g,60 mmol) in THF(90 mL) /MeOH (90 mL) /H2O(30 mL) was stirred at r.t overnight. Then the solvents were removed, and the pH of the residue was adjusted to 2 by using 2N HCI. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, and concentrated to give 1 -(tert-butoxycarbonyl)piperidine -4-carboxylic acid (4.6 g, yield 100.0percent).
100% With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; A mixture of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4.84 g 20 mmol), and LiOH (2.52 g, 60 mmol) in THF (90 mL)/MeOH (90 mL)/H2O (30 mL) was stirred at r.t overnight.
Then the solvents were removed, and the pH of the residue was adjusted to 2 by using 2N HCl.
The resulting mixture was extracted with EtOAc (3*20 mL).
The combined organic layers were dried over Na2SO4, and concentrated to give 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (4.6 g, yield 100.0percent).
96% at 50℃; for 24 h; (0031) (1) To compound 2 (24.33 g, 0.1 mol) was added dropwise 5M NaOH (60 mL, 0.3 mol), then stirred at 50° C. for 24 hours. 3M HCl was then added dropwise to the solution to adjust pH 3. The mixture was extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness to give a yellow oily liquid 4 (19.72 g, 96percent)
96% at 50℃; for 24 h; To a solution of compound 2 (24.33 g, 0.1 mol) was added dropwise 5 M NaoH (60 mL, 0.3 mol) and stirred at 50 ° C for 24 hours. Then 3 μ HC1 to ρ H 3 were added dropwise to the solution, Ethyl acetate (3 * 200 mL), dried over anhydrous sodium sulphate, filtered, and dried to give a yellow oily liquid 4 (19.72 g, 96percent)
91% With lithium hydroxide monohydrate; water In tetrahydrofuran at 45℃; for 1 h; Inert atmosphere A solution of 1-tert-butyl 4-methyl piperidine-1, 4-dicarboxylate (1.0 g, 4.1 mmol) and lithium hydroxide monohydrate (860 mg, 21 mmol) in a mixed solvent of THF (10 mL) and water (5 mL) was stirred at 45 for 1 h, and then adjusted with hydrochloric acid (1 M) to pH 1. The resulting mixture was extracted with EtOAc (20 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid as a white solid (860 mg, 91) .1H NMR (400 MHz, CD3OD) : δ ppm 3.97-4.02 (m, 2H) , 2.88-2.95 (m, 2H) , 2.48-2.55 (m, 1H) , 1.88-1.92 (m, 2H) , 1.54-1.61 (m, 2H) , 1.47 (s, 9H) and MS-ESI: m/z 174.20 [M-55] +.
91% With lithium hydroxide monohydrate; water In tetrahydrofuran at 45℃; for 1 h; Compound 4-methoxy carbonyl piperidine-1-carboxylic acid T-butyl ester (1.0g, 4 . 1mmol) and LiOH·H 2 O (860 mg, 21mmol) dissolved in tetrahydrofuran (10 ml) and water (5 ml) in the mixed solvent, 45 °C reaction 1h, plus 1.0mol/L adjusting pH=1 hydrochloric acid, extraction with ethyl acetate (10 ml × 3), the organic phase is dried with sodium sulfate, to remove the solvent, get 860 mg white solid, yield 91percent.
91% With lithium hydroxide monohydrate In tetrahydrofuran; water at 45℃; for 1 h; The compound N- tert-butoxycarbonyl-4-piperidine carboxylic acid methyl ester (1.0g, 4.1mmol) and lithiumhydroxide monohydrate (860mg, 21mmol) It was dissolved in tetrahydrofuran (10mL) and water (5mL) mixedsolvent, 45 ° C the reaction 1h, add hydrochloric acid (1M) adjusting the pH to 1, plus B Acetate (20mL × 3)was extracted, combined organic layers were dried over Na 2 SO 4, the solvent was removed to give a white solid860mg: 1- (tert Carbonyl) piperidine-4-carboxylic acid. Yield: 91percent.
84% With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 15 h; To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (1.19 g, 4.87 minol) in methanol (24 mL) and tetrahydrofuran (24 mL) were added a solution of LiOH (599 mg, 24.99 minol) in water (8 mL) at room temperature. The resultingminxture was stirred for 15 h at room temperature. When the reaction was done, the pH value of the reactionminxture was adJusted to 2 with hydrogen chloride solution (1 M). The resultingminxture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-[(tert-butoxy)carbonyljpiperidine-4-carboxylic acid as white solid (1.10 g, 84percent). MS: m/z = 128.0 [M-Hj.

Reference: [1] Patent: WO2012/34526, 2012, A1, . Location in patent: Page/Page column 56
[2] Patent: US2013/190307, 2013, A1, . Location in patent: Paragraph 0205; 0206
[3] Patent: US2016/102095, 2016, A1, . Location in patent: Paragraph 0131
[4] Patent: CN104292233, 2016, B, . Location in patent: Paragraph 0047
[5] Patent: WO2016/34134, 2016, A1, . Location in patent: Paragraph 00538
[6] Patent: CN105461693, 2016, A, . Location in patent: Paragraph 0389; 0390; 0391; 0392; 0393
[7] Patent: CN105399698, 2016, A, . Location in patent: Paragraph 1618-1620
[8] Patent: WO2017/106607, 2017, A1, . Location in patent: Paragraph 00446
[9] Patent: WO2007/71035, 2007, A1, . Location in patent: Page/Page column 37
[10] Patent: WO2009/61676, 2009, A2, . Location in patent: Page/Page column 71
[11] Patent: US2006/63775, 2006, A1, . Location in patent: Page/Page column 18
  • 15
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  • [ 91419-48-6 ]
YieldReaction ConditionsOperation in experiment
61% With sodium methylate; formamide In tetrahydrofuran; methanol at 20℃; for 24 h; General procedure: To a magnetically stirred solution of formamide (6.10 g, 130 mmol) inTHF (30 mL) was added MeONa (52 mmol, 12.8 mL of 4.05 M solutionin MeOH) at r.t. After 5 min, a solution of methyl cis/trans-1-phenethyl-4-(phenylamino)piperidine-3-carboxylate29 (4.60 g, 13 mmol) in THF (7 mL) was added in one portion and the stirring was continued at r.t. The initially clear solution became turbid after 1–3 h, followed by the gradual formation of a white precipitate. The reaction progress was monitored by TLC (reactant consumption; CH2Cl2–MeOH, 9:1). After 24 h, the mixture was concentrated (30 °C, 1 h, rotary evaporator) and the syrupy residue was partitioned between brine (75 mL) and CHCl3 (3 × 25 mL). The combined organic layers were concentrated by rotary evaporator, yielding the 1a/1b mixture (4.05 g, 96percent) as an off-white solid. The mixture was separated by flash column chromatography on silica gel (CH2Cl2–MeOH, 95:5).
Reference: [1] Synthesis (Germany), 2016, vol. 48, # 10, p. 1550 - 1560
[2] Synthesis (Germany), 2015, vol. 47, # 23, p. 3758 - 3766
[3] Patent: WO2016/34134, 2016, A1,
[4] Patent: CN105399698, 2016, A,
  • 16
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  • [ 1117-97-1 ]
  • [ 139290-70-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4837 - 4841
[2] Angewandte Chemie - International Edition, 2017, vol. 56, # 23, p. 6646 - 6650[3] Angew. Chem., 2017, vol. 56, # 23, p. 6646 - 6650,5
  • 17
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  • [ 189321-63-9 ]
Reference: [1] Patent: WO2013/19621, 2013, A1,
  • 18
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  • [ 206989-61-9 ]
Reference: [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 23, p. 6646 - 6650[2] Angew. Chem., 2017, vol. 56, # 23, p. 6646 - 6650,5
  • 19
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  • [ 479630-08-5 ]
Reference: [1] Patent: US2016/102095, 2016, A1,
  • 20
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  • [ 187834-88-4 ]
YieldReaction ConditionsOperation in experiment
95% With hydrazine hydrate In ethanol at 20℃; N- t-butoxycarbonyl-4-piperidine carboxylic acid methyl ester 2g (7.77mmol) was dissolved in ethanol and hydrazine hydrate (1: 1) mixed solvent (30 mL), and stirred at room temperature overnight. Ethanol was concentrated to dryness, added water (50mL) in dichloromethane (50mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid 1.8g, 95percent yield.
83% With hydrazine In methanol at 20℃; for 16 h; To a stirred solution of 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate (1.2 g, 0.49 mmol) in methanol (20 mL) was added hydrazine (2 mL) at room temperature. The reaction was stirred for 16 h at same temperature. The reaction was worked up via standard methods to afford tert-butyl 4- (hydrazinecarbonyl)piperidine-1-carboxylate (1.0 g, 83percent) as an off white gummy solid.
Reference: [1] MedChemComm, 2015, vol. 6, # 4, p. 653 - 664
[2] Patent: CN105384734, 2016, A, . Location in patent: Paragraph 0102; 0103
[3] Patent: WO2016/89977, 2016, A1, . Location in patent: Paragraph 00174
[4] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 3085 - 3092
  • 21
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  • [ 188792-67-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 14, p. 3675 - 3678
  • 22
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  • [ 741687-09-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 14, p. 3675 - 3678
  • 23
  • [ 124443-68-1 ]
  • [ 189442-92-0 ]
Reference: [1] Patent: WO2018/68295, 2018, A1,
[2] Patent: WO2018/68297, 2018, A1,
  • 24
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  • [ 75-05-8 ]
  • [ 660406-84-8 ]
YieldReaction ConditionsOperation in experiment
77% With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1 h; Cooling with ice To an ice-cooled solution of 1-ieri-butyl 4-methyl piperi dine- 1,4-dicarboxy late (50 g, 206 mmol) in tetrahydrofuran (1 L) and acetonitrile (53 mL, 1027 mmol) was added potassium tert-butoxide (69 g, 616 mmol) portion-wise. The resulting mixture was warmed to room temperature. After 1 h, the reaction mixture was added to saturated aqueous ammonium chloride solution (2 L). The solution was extracted with ethyl acetate (3 x 500 mL). The combined organic was washed with saturated aqueous sodium chloride solution. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated to afford a pale yellow oil (40 g, 77percent). TLC (Rf = 0.5 in 2: 1 petroleum ether / ethyl acetate).
42%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 4 h;
Stage #2: at -78 - 20℃; for 2 h;
Anhydrous acetonitrile (1.18 g, 28.81 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and thereaction solution was cooled to -78 °C. And then n-butyllithium (11.5 mL, 28.75 mmol, 2.5 M solution in n-hexane) wasadded dropwise to the above solution, and after the addition, the stirring was continued for 4 hours. A solution of N-Bocpiperidine-4-carboxylic acid methyl ester (7.0 g, 28.81 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwiseto the above reaction mixture. The reaction mixture was stirred at -78°C for 30 minutes and slowly warmed to roomtemperature. And the stirring was continued for 2 hours. Then the reaction mixture was diluted with saturated aqueousammonium chloride solution (100 mL). The mixed solution was extracted with ethyl acetate (50 mL 3 3). The combinedorganic phases were washed successively with water (50 mL 3 3) and brine (50 mL), dried over anhydrous sodiumsulfate, filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel columnchromatography (petroleum ether: ethyl acetate = 5: 1) to deliver a pale yellow solid 25-c (3.1 g, yield: 42percent).LC-MS(ESI): m/z = 197 [M+H-t-Bu]+.
Reference: [1] Patent: WO2014/111496, 2014, A1, . Location in patent: Page/Page column 153
[2] Patent: EP3287463, 2018, A1, . Location in patent: Paragraph 0225; 0226
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8182 - 8199
[4] Patent: WO2016/138532, 2016, A1, . Location in patent: Paragraph 0251
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Reference: [1] Patent: WO2014/15495, 2014, A1,
[2] Patent: WO2014/18764, 2014, A1,
[3] Patent: WO2014/150132, 2014, A1,
[4] Patent: WO2015/17305, 2015, A1,
[5] Patent: WO2016/8064, 2016, A1,
[6] Patent: WO2016/10801, 2016, A1,
[7] Patent: WO2016/65582, 2016, A1,
[8] Patent: WO2016/122994, 2016, A1,
[9] Patent: WO2016/60941, 2016, A1,
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Reference: [1] Patent: WO2016/138532, 2016, A1,
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Reference: [1] Patent: WO2014/15495, 2014, A1,
[2] Patent: WO2015/17305, 2015, A1,
[3] Patent: WO2016/60941, 2016, A1,
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