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[ CAS No. 139290-70-3 ] {[proInfo.proName]}

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Chemical Structure| 139290-70-3
Chemical Structure| 139290-70-3
Structure of 139290-70-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 139290-70-3 ]

CAS No. :139290-70-3 MDL No. :MFCD07368262
Formula : C13H24N2O4 Boiling Point : -
Linear Structure Formula :- InChI Key :ITCQNWXLNZGEHP-UHFFFAOYSA-N
M.W : 272.34 Pubchem ID :11065582
Synonyms :

Calculated chemistry of [ 139290-70-3 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.85
Num. rotatable bonds : 6
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 75.19
TPSA : 59.08 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) : -7.17 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.24
Log Po/w (XLOGP3) : 1.11
Log Po/w (WLOGP) : 1.27
Log Po/w (MLOGP) : 1.18
Log Po/w (SILICOS-IT) : 0.23
Consensus Log Po/w : 1.4

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.83
Solubility : 4.01 mg/ml ; 0.0147 mol/l
Class : Very soluble
Log S (Ali) : -1.94
Solubility : 3.1 mg/ml ; 0.0114 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.07
Solubility : 23.0 mg/ml ; 0.0843 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.79

Safety of [ 139290-70-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 139290-70-3 ]

* 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 [ 139290-70-3 ]
  • Downstream synthetic route of [ 139290-70-3 ]

[ 139290-70-3 ] Synthesis Path-Upstream   1~31

  • 1
  • [ 139290-70-3 ]
  • [ 89895-06-7 ]
Reference: [1] Patent: WO2013/96744, 2013, A1,
[2] Patent: EP3255042, 2017, A2,
  • 2
  • [ 6638-79-5 ]
  • [ 84358-13-4 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 0.166667 h;
Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide)
Stage #3: With hydrogenchloride In water
To a stirring suspension of t-Boc-isonipecotic acid (19) (2.34 g, 10.2 mmol) and the Weinreb amine (1.5 g, 15 mmol) in DMF (50 mL), was added triethylamine (2.8 mL, 20 mmol) at room temperature. After stirring for 10 min, HOBt (1.62 g, 12 mmol) was added, followed by EDCI (2.3 g, 12 mmol). The resulting solution was stirred overnight and concentrated. The residue was taken up in 1 N HCl (100 mL) and extracted with EtOAc (3.x.100 mL). The combined organic extracts were washed with sat NaHCO3 (50 mL), brine (50 mL), dried (MgSO4) and concentrated to obtain a colorless oil (20) (2.79 g, >100percent). 1H NMR (500 MHz, CDCL3) δ4.14 (m, 2H), 3.71 (s, 3H), 3.19 (s, 3H), 2.78 (m, 3H), 1.68 (m, 4H), 1.46 (s, 9H); MS (ESI+) m/z 217.72 (M+H+-isobutylene).
99% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 48 h; PREPARATION 557erf-butyl 4-acetylpiperidine-1 -carboxylatea) Tert-butyl 4-[methoxy(methyl)amino]carbonyl}piperidine-1 -carboxylateTo a solution of N.O-dimethylhydroxylamine hydrochloride (894 mg, 9.17 mmol), 2- benzotriazol-1-yl-N,N,N',N'-tetramethyluronio hexafluorphosphate (HBTU) (3.48 g, 9.17 mmol) and diisopropylethylamine (DIPEξA) in N,N-dimethylformamide (40 mL) was carefully added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2 g, 8.73 mmol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with water (200 mL), extracted with ethyl acetate, washed with aqueous citric acid 5percent, aqueous sodium bicarbonate 4percent, water, and brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica flash, using ethyl acetate as eluent (isocratic), to yield the title compound (2.63 g, 99percent) as yellowish oil. <n="63"/>1H-NMR δ (CDCI3): 1.46 (s, 9H), 1.63-1.74 (m, 4H), 2.70-2.84 (m, 3H), 3.19 (s, 3H), 3.72 (s, 3H), 4.11-4.18 (m, 2H).
99% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; To a solution of compound 25 (40 g, 175 mmol) in DMF (250 mL) at 4°C was added N.O - dimethyl-OHamine, hydrochloride (34 g), EDCI (44 g, 0.228 mol), HOBT (2.4 g), and DIPEA (120 mL). The reaction was warmed to room temperature and stirred overnight. The reaction was then concentrated to half volume in vacuo and poured onto 1:1 ethyl acetate: water. The organic layer was separated and the aqueous layer extracted with additional ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, water, and brine, and dried. Concentration gave 26 as a light yellow oil (46.7 g, 99percent)
95% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 72 h; Intermediate 1; 1,1-dimethylethyl4-[methyl(methyloxy)amino]carbonyl}-1-piperidine-carboxylate; QN,O-Dimethylhydroxylamine hydrochloride (4.26 g, 43.7 mmols), di-isopropylethylamine (33.88 g, 45.66 ml, 262.2 mmols) and HATU (19.94 g, 52.4 mmols) were added to a solution of N-Boc-piperidine-4-carboxylic acid (11.03 g, 48.1 mmols) in dry DMF (250 ml_). The reaction mixture was stirred at room temperature for 72 hrs. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic phase was separated, washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL), and dried over MgSO4. Evaporation of the solvent afforded a dark oil (21.0 g) that was purified by flash chromatography (Silica, gradient elution with pentane/ethyl acetate 9:1 v/v to 3:2 v/v) to give the title compound 12.5 g (95percent) as a gum. LC/MS-M+H 273
95%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 25℃; for 1 h; Inert atmosphere
Stage #2: With triethylamine In dichloromethane at 25℃; for 0.5 h;
Stage #3: at 25℃; for 15 h;
3. Synthesis of intermediate D-1: C-1 D-1 To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2CI2 was added CDI (62.24 g, 0.38 mol) under N2 at 0°C. After the addition, the mixture was stirred at 25°C for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25°C for 30 min, then Ο,Ν-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25 °C for 15 hrs. The mixture was washed with water, aq. NaHC03 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2S04 and concentrated to get intermediate D-1 (80 g, 95percent) as a white solid.
95%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 25℃; for 1 h; Inert atmosphere
Stage #2: With triethylamine In dichloromethane at 25℃; for 0.5 h;
Stage #3: at 25℃; for 15 h;
To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2Cl2 was added CDI (62.24 g, 0.38 mol) under N2 at 0° C. After the addition, the mixture was stirred at 25° C. for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25° C. for 30 min, then O,N-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25° C. for 15 hrs. The mixture was washed with water, aq. NaHCO3 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to get intermediate D-1 (80 g, 95percent) as a white solid.
95% With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide Add N,O-dimethylhydroxylamine hydrochloride (2.52 g, 26 mmol), 1-hydroxybenzotriazole (HOBt) (2.8 g, 20.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl)(4 g, 20.8 mmol) and 4-methylmorpholine (5.28 g, 52 mmol) at 0° C. to the solution of N-Boc-piperidine-4-carboxylic acid (4 g, 17.4 mmol) in DMF (50 mL), stir the mixture overnight at room temperature. TLC (PE:EtOAc=1:1) shows the reaction is complete.
Partition between ethyl acetate and water, collect the organic layer and wash with brine, dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to give the crude product (4.5 g, 95percent) which is used in next step without further purification.
95%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 25℃; Inert atmosphere
Stage #2: With triethylamine In dichloromethane at 25℃; for 0.5 h;
Stage #3: at 25℃; for 15 h;
To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH2Cl2 was added CDI (62.24 g, 0.38 mol) under N2 at 0° C. After the addition, the mixture was stirred at 25° C. for 1 hour, gas formation was observed. Et3N (42.37 g, 42 mol) was added, the mixture was stirred at 25° C. for 30 min, then O,N-dimethylhydroxylamine hydrochloride (42.54 g, 0.44 mol) was added. After the addition, the mixture was stirred at 25° C. for 15 hrs. The mixture was washed with water, aq. NaHCO3 and aq. citric acid monohydrate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to get intermediate D-1 (80 g, 95percent) as a white solid.
95% With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 18 h; [0211] 1-(1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (6.51 g, 0.022 mol) was dissolved in dichloromethane (50 ml).
To the resulting solution were added 1,1'-carbonyldiimidazole (CDI) (6.31 g, 0.033 mol) and N,O-dimethylhydroxylamine hydrochloride (9.62 g, 0.67 mol) and the solution was stirred at room temperature for 18 hrs.
After completion of the reaction by addition of water, the solution was extracted with dichloromethane, washed with distilled water, and dried over magnesium sulfate (MgSO4) to concentrate.
The resulting residue was isolated and purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to give the white title compound (5.36 g, 95.0 percent).
1H NMR (400 MHz, CDCl3) δ 4.14 (m, 2H), 3.71 (s, 3H), 3.13 (s, 3H), 2.79 (m, 5H), 1.42 (s, 9H).
88%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.333333 h;
Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide
INTERMEDIATE B4 tert-Butyl 4-[methoxy(methyl)amino]carbonyl}piperidine-l-carboxylate A suspension of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.8 mmol), EDC (6.27 g, 32.7 mmol) and HOBT (2.95 g, 21.8 mmol) in DMF (10 mL) was stirred for20 min. To the mixture were then added 1 ,2-dimethylhydroxylamine hydrochloride (3.19 g, 32.7 mmol) and DIEA (13 mL, 76.3 mmol) and the stirring continued overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was concentrated and the residue was purified by flash chromatography on silica using EtOAc as eluent. Yield 5.22 g (88percent). Analytical HPLC: purity 100percent (System A and B);LRESIMS (ESI+) m/z = 217 (M+H-φu)+.
80% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19 h; Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid t-butyl ester
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylanine (1.5 eq, 32.7 mmol) were added.
The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 1.0 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h.
The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate.
The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered.
The solvent was removed and the residue as purified by distillation resulting in a yield of 80percent.
80% at 0 - 20℃; for 19.8333 h; Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-l-carboxylic acid t-butyl esterPiperidine-l,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl- hydroxylarnine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to O0C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq,21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at O0C for 1 h and at r.t. for 18 h.The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19.1667 h; Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethylhydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0°C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0°C for 1 h and at r.t. for 18 h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19.1667 h; Piperidine-l,4-dicarboxylic acid rnono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl- hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 00C, N-(3 -Dimethyl aminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0°C for 1 h and at r.t. for 18 h.The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19.1667 h; Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h.The solvent was removed under vacuum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
80% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 19 h; Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid t-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N, N- dimethylformamide, O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added.
The reaction mixture was cooled to 0°C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0°C for 1h and at r.t. for 18h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80percent.
77% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 16 h; To the mixture of 10 (47.0 g, 205 mmol) and N,O-dimethylhydroxylamine hydrochloride (20.8 g, 213 mmol) in CH2Cl2 (1 L) was added EDC (44.6 g, 232 mmol) in one portion followed by Et3N (32.4 mL, 232 mmol) dropwise at rt. The resulting solution was stirred at rt for 16 h. The solution was washed with brine (800 mL x 4) and a saturated NaHCO3 solution (500 mL), and then dried over Na2SO4. After evaporating the solvent, the residue was purified on silica gel using 60percentEtOAc/hexane to give 11 (43.2 g, 77percent) as an oil.
71%
Stage #1: With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.166667 h;
Stage #2: at 20℃; for 2 h;
To a stirred solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.0 g, 21.7 mmol) in DMF (20 mL) was added HATU (12.39 g, 32.60 mmol) and diisopropylethylamine (18.94 ml, 108.6 mmol). The solution was stirred for 10 min at 0 °C. After that Ν,Ο-dimethylhydroxylamine hydrochloride (2.12 g, 21.7 mmol) was added and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain a crude residue which was purified by column chromatography to afford tert-butyl 4- (methoxy(methyl)carbamoyl)piperidine-l-carboxylate (4.3 g, 71percent). LCMS: m/z = 173.05 (M-Boc)+.
61%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2 h;
Stage #2: at 20℃;
Example 5; Synthesis of 2-(4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin- 1 -yl)acetic acidStep lTo a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (11 g, 48 mmol) in DCM (120 mL) was added CDI (11 g). After stirring at rt for 2 h, N,O-dimethylhydroxyl- amine hydrochloride was added in portions. The mixture was stirred for 3 h at rt and was then left to stand overnight. The solvent was removed under vacuum, the residue was extracted with DCM, washed with brine and water, dried over anhydrous sodium sulfate and concentrated to give crude tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-l-carboxylate (8 g, 61percent yield) as a white solid which was used directly in the next step.
42% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; Reagents and conditions: (a) B0C2O, 1,4-dioxane, H2O, NaOH, overnight, rt, (yield 94percent); (b) HOBt, EDCl, TEA,DMF, NHMeOMe-HCl, overnight, rt, (yield 42percent); (c) BuLi, 2-bromobiphenyl, TMEDA, THF, 3h, -78°C, (yield 35percent) ; (d) TFA, DCM , lh, rt, (yield quant); (e) toluene, 2h, (yield 24percent), (f) NaBH4, THF, MeOH, overnight, rt, (yield 25percent). Compounds 8-9 were synthesized from isonipecotic acid. The amine function was first protected with tert-butyl carbamate group followed by the formation of the Weinreb amide using HOBt and EDCl. Then, the lithium anion of 2-bromobiphenyl reacted on the Weinreb amide and Boc deprotection to give compounds 8. Addition reaction on iso(thio)cyanate with the piperidine in toluene afforded (thio)urea 9a-9b, followed by a reduction of the ketone group give the alcohol derivatives lOa-lOb.
%
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;
Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;
N,Oτdimethylhydroxylamine hydrochloride (851 mg, 8.72 mmols) was, :,O suspended in dichloromethane (6 ml) and cooled to 0 C. N, N-diisopropylethylaminev (1.66 ml, 9.53 mmols) was added and the mixture was stirred at 0 C until a clear solution was obtained. The resulting solution was kept at 0 C for further use. Boc- isonipecotic acid (2 g, 8.72 mmol), 1-hydroxybenzotriazole (1.2 g, 8.88 mmols) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.83 g, 9.58 mmols) were dissolved in DMF (15 ml) and cooled to 0 C. The solution of N,O- dimethylhydroxylamine in dichloromethane was added with stirring, and the resulting reaction mixture was allowed to stir overnight at room temperature. DMF was removed under reduced pressure and residue was partitioned between ethyl acetate and 10percent citric acid. Organic layer was isolated, washed with water, saturated NaHCO3, water and brine and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified on silica gel eluting with ethyl acetate in hexanes (2:1 ) to provide the title compound (1.88 g, 79percent). LCMS m/e (295, M + Na).

Reference: [1] Patent: US2004/14763, 2004, A1, . Location in patent: Page 21
[2] Patent: WO2008/17461, 2008, A1, . Location in patent: Page/Page column 61-62
[3] Patent: WO2008/108957, 2008, A2, . Location in patent: Page/Page column 38
[4] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 4, p. 935 - 939
[5] Patent: WO2006/2434, 2006, A2, . Location in patent: Page/Page column 39
[6] Patent: WO2013/164337, 2013, A1, . Location in patent: Page/Page column 28
[7] Patent: US2015/87651, 2015, A1, . Location in patent: Paragraph 0104-0105
[8] Patent: US2015/197511, 2015, A1, . Location in patent: Paragraph 0213; 0214
[9] Patent: US2017/334880, 2017, A1, . Location in patent: Paragraph 0102-0103
[10] Patent: EP3255042, 2017, A2, . Location in patent: Paragraph 0209; 0211
[11] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6216 - 6233
[12] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 13, p. 2720 - 2725
[13] Journal of Medicinal Chemistry, 2009, vol. 52, # 19, p. 5826 - 5836
[14] Patent: WO2009/150144, 2009, A1, . Location in patent: Page/Page column 138
[15] Acta Chimica Slovenica, 2011, vol. 58, # 1, p. 95 - 109
[16] Chemistry of Heterocyclic Compounds, 2009, vol. 45, # 8, p. 957 - 964
[17] Patent: US2006/69102, 2006, A1, . Location in patent: Page/Page column 17
[18] Patent: WO2007/16979, 2007, A2, . Location in patent: Page/Page column 63
[19] Patent: EP1834954, 2007, A1, . Location in patent: Page/Page column 20
[20] Patent: WO2009/37357, 2009, A1, . Location in patent: Page/Page column 29
[21] Patent: US2008/241100, 2008, A1, . Location in patent: Page/Page column 11
[22] Patent: EP1977759, 2008, A1, . Location in patent: Page/Page column 15
[23] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1299 - 1305
[24] Patent: WO2016/40498, 2016, A1, . Location in patent: Paragraph 0268
[25] Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2492 - 2502
[26] Patent: WO2009/75857, 2009, A2, . Location in patent: Page/Page column 75
[27] Patent: WO2006/21449, 2006, A1, . Location in patent: Page/Page column 8; 9
[28] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9196 - 9213
[29] Patent: WO2014/116684, 2014, A1, . Location in patent: Page/Page column 251
[30] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 15, p. 4013 - 4017
[31] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 20, p. 5227 - 5232
[32] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 23, p. 5937 - 5941
[33] Patent: US6335341, 2002, B1, . Location in patent: Example 1
[34] Patent: US6391880, 2002, B1, . Location in patent: Page column 16
[35] Patent: WO2004/41777, 2004, A2, . Location in patent: Page 54
[36] Patent: US6028083, 2000, A,
[37] Patent: WO2008/58068, 2008, A1, . Location in patent: Page/Page column 20
[38] Patent: US2008/139615, 2008, A1, . Location in patent: Page/Page column 10
[39] Patent: WO2008/67120, 2008, A2, . Location in patent: Page/Page column 20
[40] Patent: WO2008/67121, 2008, A2, . Location in patent: Page/Page column 49; 50
[41] Patent: WO2009/45382, 2009, A1, . Location in patent: Page/Page column 32-33
[42] Patent: WO2004/41279, 2004, A1, . Location in patent: Page/Page column 69
[43] Patent: WO2010/57121, 2010, A1, . Location in patent: Page/Page column 64-65
[44] Patent: US2010/93668, 2010, A1, . Location in patent: Page/Page column 46; 47
[45] Patent: US2006/258672, 2006, A1, . Location in patent: Page/Page column 16
[46] Patent: WO2007/56170, 2007, A2, . Location in patent: Page/Page column 204-205
[47] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 38
[48] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 23
[49] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 28
[50] Patent: WO2004/20435, 2004, A1, . Location in patent: Page 87
[51] Patent: WO2011/143057, 2011, A1, . Location in patent: Page/Page column 47
[52] Patent: WO2014/418, 2014, A1, . Location in patent: Page/Page column 40; 41
[53] Patent: WO2015/14442, 2015, A1, . Location in patent: Page/Page column 47; 48
[54] Patent: WO2015/18475, 2015, A1, . Location in patent: Page/Page column 54; 55
[55] Patent: WO2018/33135, 2018, A1, . Location in patent: Paragraph 0102-0103
[56] Patent: TW2018/11794, 2018, A, . Location in patent: Paragraph 0055; 0091; 0095
[57] Patent: WO2018/137681, 2018, A1, . Location in patent: Paragraph 00137; 00138
[58] Patent: WO2008/156739, 2008, A1, . Location in patent: Page/Page column 220
  • 3
  • [ 84358-13-4 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;
Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;
λ/,O-dimethylhydroxylamine hydrochloride (851 mg, 8.72 mmols) was suspended in dichloromethane (6 ml) and cooled to 0 C. N, /V-diisopropylethylamine (1.66 ml, 9.53 mmols) was added and the mixture was stirred at 0 C until a clear solution was obtained. The resulting solution was kept at 0 C for further use. Boc- isonipecotic acid (2 g, 8.72 mmol), 1 -hydroxybenzotrazole (1.2 g, 8.88 mmols) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.83 g, 9.58 mmols) were dissolved in DMF (15 ml) and cooled to 0 C. The solution of MO- dimethylhydroxylamine in dichloromethane was added with stirring, and the resulting reaction mixture was allowed to stir overnight at room temperature. DMF was <n="258"/>removed under reduced pressure and residue was partitioned between ethyl acetate and-10-percent-citric-acid.-OrganiG-layer-was-isolated,-washed-with-wateFj r saturated . JSIaHCCh- water and brine and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified on silica gel eluting with ethyl acetate in hexanes (2:1 ) to provide the title compound (1.88 g, 79percent). LCMS m/e (295, M + Na).
Reference: [1] Patent: WO2007/70398, 2007, A1, . Location in patent: Page/Page column 255
[2] Organic Preparations and Procedures International, 2000, vol. 32, # 1, p. 96 - 99
[3] Patent: WO2008/42925, 2008, A1, . Location in patent: Page/Page column 95-96
[4] Chemical Communications, 2013, vol. 49, # 87, p. 10245 - 10247
[5] Patent: WO2008/42925, 2008, A1, . Location in patent: Page/Page column 95-96
  • 4
  • [ 6638-79-5 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.75 h;
Stage #2: at 20℃; for 1.5 h;
tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate. tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (640 mg, 2.8 mmol) and o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (1.0 g, 3.1 mmol) were combined and dissolved in N,N-dimethylformamide (12 mL). N,N-Diisopropylethylamine was added to the mixture. Reaction stirred at room temperature for 45 minutes. N,O-Dimethylhydroxylamine hydrochloride (450 mg, 4.6 mmol) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Mixture was diluted with diethyl ether and then washed 3.x. water, 1.x.1N hydrochloric acid. Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as clear colorless oil in 70percent yield. MS m/e (M-C4H8+H)+=217.1.
70%
Stage #1: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.75 h;
Stage #2: at 20℃; for 1.5 h;
tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate; tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (640 mg, 2.8 mmol) and o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (1.0 g, 3.1 mmol) were combined and dissolved in N,N-dimethylformamide (12 mL). N,N-Diisopropylethylamine was added to the mixture. Reaction stirred at room temperature for 45 minutes. N,O-Dimethylhydroxylamine hydrochloride (450 mg, 4.6 mmol) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Mixture was diluted with diethyl ether and then washed 3.x. water, 1.x. 1N hydrochloric acid. Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as clear colorless oil in 70percent yield. MS m/e (M-C4H8+H)+=217.1.
Reference: [1] Patent: US2006/94707, 2006, A1, . Location in patent: Page/Page column 40
[2] Patent: US2007/259850, 2007, A1, . Location in patent: Page/Page column 76-77
  • 5
  • [ 84358-13-4 ]
  • [ 1117-97-1 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
88.5% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 16 h; To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (20.0 g, 87.23 mmol) in DCM (200 mL) was added HATU (36.46 g, 95.95 mmol), TEA (17.62 g, 174.46 mmol) and N,O-dimethylhydroxylamine (8.93 g, 91.59 mmol). The mixture was stirred at 25 C for 16 h. The mixture was washed with H2O and the DCM layer was evaporated and the residue purified by silica column (PE/EA=1:1) to give the tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (21.0 g, yield: 88.5percent)
51% With triethylamine; HATU In dichloromethane at 20℃; N,0_Dimethylhydroxylamine (1.6 g, 26.2 mmol) in DCM (50 mL) was added HATU (9.9 g, 26.2 mmol) and Et3N (2.65 g, 26.2 mmol) at rt. The formed mixture was stirred at rt overnight. The mixture was washed with water, and purified by column chromatography to give the desired product (3 g, 51percent).
Reference: [1] Patent: KR2017/45749, 2017, A, . Location in patent: Paragraph 0614; 0617-0619
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 8, p. 1381 - 1385
[3] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 191
[4] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3419 - 3424
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2010, vol. 53, # 5-6, p. 394 - 397
[6] Patent: WO2011/103715, 2011, A1, . Location in patent: Page/Page column 46
[7] Patent: WO2011/106276, 2011, A1, . Location in patent: Page/Page column 46
[8] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1062 - 1066
[9] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5507 - 5520
  • 6
  • [ 142851-03-4 ]
  • [ 1117-97-1 ]
  • [ 139290-70-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 21, p. 3895 - 3905
[2] Journal of Organic Chemistry, 1994, vol. 59, # 19, p. 5828 - 5832
[3] RSC Advances, 2014, vol. 4, # 33, p. 17293 - 17299
  • 7
  • [ 6638-79-5 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
89% With sodium hydrogencarbonate In n-heptane; dichloromethane; water; toluene EXAMPLE 66
Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15)
Into a 250-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a 125-mL addition funnel with a stopper, and a thermowell with a thermocouple was placed 1,1'-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g).
The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g).
The solution was added to the reaction mixture over a 2 minute period, causing rapid CO2 evolution.
The reaction mixture was allowed to stir at 28° C. for 2 hours.
Into a 500-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a thermowell with a thermocouple, and a 125-mL addition funnel with a septum was placed N,O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g).
The imidazole amide intermediate/methylene chloride solution was added to the slurry of N,O-dimethylhydroxylamine hydrochloride and methylene chloride over a 20 minute period.
The resulting slurry was allowed to stir at 28° C. for 2 hours.
To the reaction mixture was added sodium bicarbonate (4.3 g) and water (75 g).
After stirring for 30 minutes at ambient temperature, the phases were allowed to stand and separate for 20 minutes.
The phases were separated and to the organic phase was added toluene (100 g).
The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath 60° C.) to afford the crude title compound as a thick oil.
The oil and heptane (25 g) were placed into a 100-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, a thermowell with a thermocouple, a nitrogen bubbler, and a stopper.
The slurry was warmed to 60° C. before allowing it to slowly cool to 10° C. over a 2 hour period.
The solution was maintained at 10° C. for 1 hour (nucleation temperature) before cooling to 3° C. and stirring overnight.
The title compoundcompound was collected by suction filtration and washed with cold heptane (7 g, ~0° C.).
The wet cake was allowed to air dry for 24 hours to afford the title compound (15) as a white crystalline material (10.5 g, 89percent); m.p. 69-71° C.
1H NMR (CDCl3) δ 4.08 (m, 2H, CHN's), 3.66 (s, 3H, -OCH3), 3.13 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H, CH2's), 1.40 (s, 9H, t-Bu);
13C NMR (CDCl3) δ 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36.1, 28.5, 28.0;
IR (KBr) 2973, 2935, 1694, 1663, 1421, 1367, 1289, 1133, 998, 870, 770 cm-1.
Reference: [1] Patent: US2005/261341, 2005, A1,
  • 8
  • [ 6638-79-5 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
89% With sodium chloride; sodium hydrogencarbonate In n-heptane; dichloromethane; water EXAMPLE 67
Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15)
A suitable reactor maintained under nitrogen was charged with 7.6 kg of 1,1'-carbonyldiimidazole and 15 L of methylene chloride.
A solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.5 kg, 45.8 mol) in 62 L of methylene chloride was added over 30 minutes while maintaining a reaction temperature of 20° C.
After stirring the reaction mixture at ambient temperature for 2 hours, 0.1 kg of 1,1'-carbonyldiimidazole was added.
A solution of 4.55 kg of N,O-dimethylhydroxylamine hydrochloride in 32 L of methylene chloride was added to the mixture with stirring.
The reaction mixture was stirred at 28° C. for 24 hours, followed by the addition of 0.52 kg of N,O-dimethylhydroxylamine hydrochloride and 0.7 kg of 1,1'-carbonyldiimidazole.
Stirring was continued at 28° C. for 48 hours.
The stirred reaction mixture was diluted with a solution of sodium bicarbonate (4.5 kg, 53.6 mol) in 50 L of water.
The organic phase was separated and washed with a solution of sodium chloride (7 kg) in 46 L of water.
The organic phase was separated and dried with sodium sulfate (4 kg).
Drying agent was filtered off and washed with 2*5 L of methylene chloride.
Solvent was removed below 50° C. at 500 torr.
The residue was diluted with 5 L of heptane and solvent was removed below 50° C. at 500 torr.
A total of 40 L of heptane was added and the stirred solution was heated to 70° C. to obtain solution.
The stirred solution was cooled to ambient temperature over 18 hours, then cooled to and maintained at 10C for 12 hours, then cooled to 0° C.
Solid which crystallized was filtered off, then dried at ambient temperature to give 11.1 kg (89percent yield).
Reference: [1] Patent: US2005/261341, 2005, A1,
  • 9
  • [ 478408-77-4 ]
  • [ 6638-79-5 ]
  • [ 84358-13-4 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
89% With sodium hydrogencarbonate In n-heptane; dichloromethane; water; toluene EXAMPLE 66
Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15)
Into a 250-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a 125-mL addition funnel with a stopper, and a thermowell with a thermocouple was placed 1,1 '-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g).
The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g).
The solution was added to the reaction mixture over a 2 minute period, causing rapid CO2 evolution.
The reaction mixture was allowed to stir at 28° C. for 2 hours.
Into a 500-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a thermowell with a thermocouple, and a 125-mL addition funnel with a septum was placed N,O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g).
The imidazole amide intermediate/methylene chloride solution was added to the slurry of N,O-dimethylhydroxylamine hydrochloride and methylene chloride over a 20 minute period.
The resulting slurry was allowed to stir at 28° C. for 2 hours.
To the reaction mixture was added sodium bicarbonate (4.3 g) and water (75 g).
After stirring for 30 minutes at ambient temperature, the phases were allowed to stand and separate for 20 minutes.
The phases were separated and to the organic phase was added toluene (100 g).
The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath 60° C.) to afford the crude title compound as a thick oil.
The oil and heptane (25 g) were placed into a 100-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, a thermowell with a thermocouple, a nitrogen bubbler, and a stopper.
The slurry was warmed to 60° C. before allowing it to slowly cool to 10° C. over a 2 hour period.
The solution was maintained at 10C for 1 hour (nucleation temperature) before cooling to 3° C. and stirring overnight.
The title compoundcompound was collected by suction filtration and washed with cold heptane (7 g, 0° C.).
The wet cake was allowed to air dry for 24 hours to afford the title compound (15) as a white crystalline material (10.5 g, 89percent); m.p. 69-71° C.
1H NMR (CDCl3) δ 4.08 (m, 2H, CHN's), 3.66 (s, 3H, -OCH3), 3.13 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H, CH2's), 1.40 (s, 9H, t-Bu);
13C NMR (CDCl3) δ 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36.1, 28.5, 28.0;
IR (KBr) 2973, 2935, 1694, 1663, 1421, 1367, 1289, 1133, 998, 870, 770 cm-1.
Reference: [1] Patent: US2002/151717, 2002, A1,
[2] Patent: US2002/151717, 2002, A1,
[3] Patent: US2002/151717, 2002, A1,
  • 10
  • [ 6163-66-2 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2002/151717, 2002, A1,
[2] Patent: US2002/151717, 2002, A1,
  • 11
  • [ 6638-79-5 ]
  • [ 84358-13-4 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
[2] Patent: US5371093, 1994, A,
  • 12
  • [ 124443-68-1 ]
  • [ 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
  • 13
  • [ 6638-79-5 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
  • 14
  • [ 498-94-2 ]
  • [ 139290-70-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 15, p. 4013 - 4017
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2492 - 2502
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2010, vol. 53, # 5-6, p. 394 - 397
[4] Patent: WO2011/103715, 2011, A1,
[5] Patent: WO2011/106276, 2011, A1,
[6] Chemical Communications, 2013, vol. 49, # 87, p. 10245 - 10247
[7] Patent: WO2014/418, 2014, A1,
[8] Patent: WO2014/116684, 2014, A1,
[9] Patent: WO2015/18475, 2015, A1,
[10] Patent: US2015/197511, 2015, A1,
[11] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9196 - 9213
[12] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5507 - 5520
[13] Patent: EP3255042, 2017, A2,
[14] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 8, p. 1381 - 1385
[15] Patent: WO2008/108957, 2008, A2,
  • 15
  • [ 1126-09-6 ]
  • [ 139290-70-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 21, p. 3895 - 3905
[2] Journal of Organic Chemistry, 1994, vol. 59, # 19, p. 5828 - 5832
[3] Patent: WO2013/164337, 2013, A1,
[4] RSC Advances, 2014, vol. 4, # 33, p. 17293 - 17299
[5] Patent: US2015/87651, 2015, A1,
[6] Patent: US2017/334880, 2017, A1,
  • 16
  • [ 24424-99-5 ]
  • [ 139290-70-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 21, p. 3895 - 3905
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2492 - 2502
[3] Journal of Organic Chemistry, 1994, vol. 59, # 19, p. 5828 - 5832
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2010, vol. 53, # 5-6, p. 394 - 397
[5] Patent: WO2011/103715, 2011, A1,
[6] Patent: WO2011/106276, 2011, A1,
[7] Chemical Communications, 2013, vol. 49, # 87, p. 10245 - 10247
[8] Patent: WO2013/164337, 2013, A1,
[9] Patent: WO2014/418, 2014, A1,
[10] Patent: WO2014/116684, 2014, A1,
[11] Patent: WO2015/18475, 2015, A1,
[12] Patent: US2015/87651, 2015, A1,
[13] Patent: US2015/197511, 2015, A1,
[14] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9196 - 9213
[15] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5507 - 5520
[16] Patent: US2017/334880, 2017, A1,
[17] Patent: EP3255042, 2017, A2,
[18] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 8, p. 1381 - 1385
[19] Patent: WO2008/108957, 2008, A2,
  • 17
  • [ 6638-79-5 ]
  • [ 280115-99-3 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: EP1734037, 2006, A2, . Location in patent: Page/Page column 58
[2] Chemical Communications, 2013, vol. 49, # 87, p. 10245 - 10247
  • 18
  • [ 6638-79-5 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US5618824, 1997, A,
  • 19
  • [ 478408-77-4 ]
  • [ 6638-79-5 ]
  • [ 84358-13-4 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2002/151717, 2002, A1,
  • 20
  • [ 6638-79-5 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
  • 21
  • [ 6638-79-5 ]
  • [ 293744-38-4 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: EP1734037, 2006, A2, . Location in patent: Page/Page column 55-58
  • 22
  • [ 142851-03-4 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: WO2013/164337, 2013, A1,
[2] Patent: US2015/87651, 2015, A1,
[3] Patent: US2017/334880, 2017, A1,
  • 23
  • [ 6638-79-5 ]
  • [ 139290-70-3 ]
Reference: [1] Organic Preparations and Procedures International, 2000, vol. 32, # 1, p. 96 - 99
  • 24
  • [ 6638-79-5 ]
  • [ 142851-03-4 ]
  • [ 139290-70-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 2989 - 3002
  • 25
  • [ 139290-70-3 ]
  • [ 162504-75-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2492 - 2502
  • 26
  • [ 75-16-1 ]
  • [ 139290-70-3 ]
  • [ 206989-61-9 ]
YieldReaction ConditionsOperation in experiment
96% at -78 - 0℃; To the solution of 11 (43.2, 158 mmol) in THF (1.3 L) at -78 °C was added methylmagnesium bromide (106 mL, 3 M, 317 mmol) dropwise. The solution was warmed to 0 °C for 1 h before it was quenched with a saturated ammonium chloride solution. To this mixture was added EtOAc (1000 mL) and the organic phase was washed with brine (500 mL x 2), dried over Na2SO4 to give 12 (34.8 g, 96percent) as an oil.
94% at -78 - 0℃; for 1 h; [0212] Tert-butyl-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (2.29 g, 8.32 mmol) was dissolved in 30 ml of tetrahydrofuran (THF) and the resulting solution was cooled to -78 °C.
To the solution was slowly added methylmagnesium bromide (3.0 M) (7.73 ml, 10.82 mmol) and the solution was stirred at 0 °C for 1 hr.
After completion of the reaction by 2 N hydrochloric acid aqueous solution, 6 N sodium hydroxide solution was added to adjust pH to 10 and then the solution was extracted with dichloromethane.
The organic layer was treated with magnesium sulfate (MgSO4) and filtered and the solution was concentrated.
The resulting residue was isolated and purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to give the white title compound (6.36 g, 94.0 percent).
1H NMR (400 MHz, CDCl3) δ 3.90 (m, 2H), 2.98 (s, 2H), 2.51 (s, 1H), 2.15(s, 3H), 1.67 (m, 4H), 1.49 (s, 9H).
82%
Stage #1: at 0℃; for 18 h;
Stage #2: With water In diethyl ether at 0℃; for 0.5 h;
b) f erf-butyl 4-acetylpiperidine-1-carboxylate Methyl magnesium bromide (3M in dietyhl ether, 2.45 ml_, 7.35 mmol) was dropwise added to an ice-cooled solution of the title compound of Preparation 55a (1g, 3.67 mmol) under argon and the mixture was stirred at that temperature for 18 hours. The reaction was quenched by the addition of ice and vigorously stirred for 30 minutes. The mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica flash, using hexane/ethyl acetate (1:1) as eluents, to yield the title compound (680 mg, 82percent) as colourless oil.1H-NMR δ (CDCI3): 1.46 (s, 9H)1 1.41-1.62 (m, 2H), 1.78-1.88 (m, 2H), 2.17 (m, 3H), 2.38-2.54 (m, 1 H)1 2.71-2.86 (m, 2H), 4.05-4.15 (m, 2H).
80%
Stage #1: at 0℃; for 0.833333 h; Cooling with acetone-dry ice
Stage #2: With hydrogenchloride In diethyl ether; water
[00191] Step 2: A 3- neck, 250 mL round bottom flask was charged with a solution of tert-bvXyl 4-(methoxy(methyl)carbamoyl)piperidine-l-carboxylate (9.9 g) in Et2O (120 mL). The flask was purged with nitrogen and then cooled in a CO2 / acetone bath. Methylmagnesium bromide (26.8 mL of a 3.0 M solution in Et2O, 80 mmol) was added dropwise over 10 min to the amide. The resulting thick mixture was warmed to 0 0C and then stirred for 40 min before being poured into 2 M HCl solution (50 mL). The mixture was diluted with Et2O (100 mL), washed with brine, dried (MgSO4) and concentrated on a rotary evaporator to give tert-bvAyl A- acetylpiperidine-1-carboxylate (7.3 g, 32.1 mmol, 80 percent yield) as a colorless oil. The product partly crystallized on standing at RT. 1H-NMR (400 MHz, CDCl3) δ ppm 4.06 (2 H, s), 2.74 (2 H, s), 2.42 (1 H, s), 2.12 (2 H, s), 1.78 (2 H, s), 1.49 (2 H, s), 1.41 (9 H, s).
80%
Stage #1: at 0℃; for 0.833333 h; Cooling with acetone-dry ice
Stage #2: With hydrogenchloride In diethyl ether; water
[00191] Step 2: A 3- neck, 250 mL round bottom flask was charged with a solution of tert-bvXyl 4-(methoxy(methyl)carbamoyl)piperidine-l-carboxylate (9.9 g) in Et2O (120 mL). The flask was purged with nitrogen and then cooled in a CO2 / acetone bath. Methylmagnesium bromide (26.8 mL of a 3.0 M solution in Et2O, 80 mmol) was added dropwise over 10 min to the amide. The resulting thick mixture was warmed to 0 0C and then stirred for 40 min before being poured into 2 M HCl solution (50 mL). The mixture was diluted with Et2O (100 mL), washed with brine, dried (MgSO4) and concentrated on a rotary evaporator to give tert-bvAyl A- acetylpiperidine-1-carboxylate (7.3 g, 32.1 mmol, 80 percent yield) as a colorless oil. The product partly crystallized on standing at RT. 1H-NMR (400 MHz, CDCl3) δ ppm 4.06 (2 H, s), 2.74 (2 H, s), 2.42 (1 H, s), 2.12 (2 H, s), 1.78 (2 H, s), 1.49 (2 H, s), 1.41 (9 H, s).
77% at 20℃; Cooling INTERMEDIATE B5 foert-ButyM-acetylpiperidine-l-carboxylateK>i A 3 M solution of bromo(methyl)magnesium in diethylether (13.8 niL, 41.4 mmol) was cooled in an ice-bath and a solution of tert-butyi 4-[methoxy(methyl)amino]carbonyl}- piperidine-1-carboxylate (Intermediate B4; 5.2 g 19.2 mmol) in Et2O (25 mL) was added dropwise. The ice-bath was removed and the mixture was stirred at r.t. for 2 h. The excess bromo(methyl)magnesium was quenched by dropwise addition of water, and the water phase was then extracted with ether. Yield 3.35 g (77percent). Analytical HPLC: purity 95percent (System A); LRESIMS (ESI+) m/z = 172 (M+H-?Bu)+.
72% at 0 - 20℃; To a solution of Compound 2 (500 mg, 1.84 mmol) in anhydrous THF (5 mL) was added CMgBr (0.8 mL, 2.4 mmol) at 0 °C . The formed mixture was allowed to warm to room temperature. The reaction was quenched with aqueous NH4CI solution. The organic layer was separated and extracted with EtOAc (10 mLx2). The combined organic layers were concentrated to give the crude product, which was purified by column chromatography to give the desired product (300 mg, 72percent). lH NMR (400 MHz, CDCI3): δ ppm: 4.04(br, 2H), 2.73(t, 2H), 2.43(m, 1H), 2.15(s, 3H), 1.82(m, 2H), 1.53(m, 2H), 1.45(s, 9H).
62% at -78 - 20℃; for 4 h; [0269] To a stirred solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-l- carboxylate (4.3 g, 15.8 mmol) in dry THF (20 mL) was added a solution of methyl magnesium bromide (20 mL, 23.71 mmol, 1.6 M in THF:toluene) at -78 °C and the reaction was stirred at -78 °C for 2 h and RT for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction was quenched with saturated NH4C1 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure to a crude residue which was purified by column chromatography to afford tert-butyl 4- acetylpiperidine-l-carboxylate (2.8 g, 62percent).

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 4, p. 935 - 939
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1299 - 1305
[3] Patent: EP3255042, 2017, A2, . Location in patent: Paragraph 0209; 0212
[4] Patent: WO2008/17461, 2008, A1, . Location in patent: Page/Page column 62
[5] Patent: WO2008/42925, 2008, A1, . Location in patent: Page/Page column 96
[6] Patent: WO2008/42925, 2008, A1, . Location in patent: Page/Page column 96
[7] Patent: WO2009/150144, 2009, A1, . Location in patent: Page/Page column 139
[8] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 191
[9] Patent: WO2016/40498, 2016, A1, . Location in patent: Paragraph 0269
[10] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 23; 38
[11] Angewandte Chemie - International Edition, 2017, vol. 56, # 23, p. 6646 - 6650[12] Angew. Chem., 2017, vol. 56, # 23, p. 6646 - 6650,5
[13] Patent: WO2018/33135, 2018, A1, . Location in patent: Paragraph 0102-0103
[14] Patent: TW2018/11794, 2018, A, . Location in patent: Paragraph 0055; 0091; 0095
[15] Patent: WO2018/137681, 2018, A1, . Location in patent: Paragraph 00137; 00138
  • 27
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YieldReaction ConditionsOperation in experiment
94.7% With methylmagnesium bromide In tetrahydrofuran at -78 - 25℃; for 16 h; To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1- carboxylate (10.0 g, 36.76 mmol) in THF (150 mL) was added MeMgBr (24.5 mL, 73.52 mmol) at -78 C. The mixture was stirred at 25 C for 16 h.. TLC showed the reaction worked well. The mixture was quenched with aq. NH4Cl and H2O (100 mL) was added. The mixture was extracted with DCM (100 mL x 3). The DCM layer was dried and evaporated to give the tert-butyl 4-acetylpiperidine-1-carboxylate (7.9 g, yield: 94.7 percent).
Reference: [1] Patent: KR2017/45749, 2017, A, . Location in patent: Paragraph 0614; 0620-0622
[2] Patent: WO2004/41777, 2004, A2, . Location in patent: Page 54-55
[3] Patent: US6140333, 2000, A,
  • 28
  • [ 676-58-4 ]
  • [ 139290-70-3 ]
  • [ 206989-61-9 ]
Reference: [1] Patent: WO2009/45382, 2009, A1, . Location in patent: Page/Page column 33
[2] Patent: WO2004/41279, 2004, A1, . Location in patent: Page/Page column 69
  • 29
  • [ 917-64-6 ]
  • [ 139290-70-3 ]
  • [ 206989-61-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3419 - 3424
  • 30
  • [ 139290-70-3 ]
  • [ 301221-79-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3419 - 3424
[2] Patent: WO2009/150144, 2009, A1,
[3] Patent: WO2008/42925, 2008, A1,
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  • [ 139290-70-3 ]
  • [ 887354-02-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5507 - 5520
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