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[ CAS No. 148214-90-8 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 148214-90-8
Chemical Structure| 148214-90-8
Chemical Structure| 148214-90-8
Structure of 148214-90-8 * Storage: {[proInfo.prStorage]}
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Product Details of [ 148214-90-8 ]

CAS No. :148214-90-8 MDL No. :MFCD06858457
Formula : C9H18N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :MOZOQDNRVPHFOO-RNFRBKRXSA-N
M.W : 202.25 Pubchem ID :11275699
Synonyms :

Calculated chemistry of [ 148214-90-8 ]

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.89
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 55.66
TPSA : 75.79 Ų

Pharmacokinetics

GI absorption : High
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) : -7.97 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.93
Log Po/w (XLOGP3) : -0.61
Log Po/w (WLOGP) : -0.46
Log Po/w (MLOGP) : -0.27
Log Po/w (SILICOS-IT) : -0.83
Consensus Log Po/w : -0.05

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.51
Solubility : 62.3 mg/ml ; 0.308 mol/l
Class : Very soluble
Log S (Ali) : -0.51
Solubility : 62.5 mg/ml ; 0.309 mol/l
Class : Very soluble
Log S (SILICOS-IT) : 0.16
Solubility : 295.0 mg/ml ; 1.46 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.13

Safety of [ 148214-90-8 ]

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 [ 148214-90-8 ]

* 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.

  • Downstream synthetic route of [ 148214-90-8 ]

[ 148214-90-8 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 407-25-0 ]
  • [ 190792-74-6 ]
  • (3R,4S)-3-Hydroxy-4-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 2
  • [ 203434-45-1 ]
  • [ 190792-74-6 ]
  • 3
  • [ 24424-99-5 ]
  • [ 190792-74-6 ]
  • [ 252574-05-3 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydroxide; In 1,4-dioxane; for 18h; INTERMEDIATE 13(3.S'.4.Sr)-3-(fert-ButoxycarbonylaminoV4-hydroxypyrrolidine-l -carboxylic acid tert-buty esterTo a solution of Intermediate 12 (700 mg, 5.0 mmol) in 1,4-dioxane (30 mL) was added sodium hydroxide (300 mg, 7.5 mmol) and di-tert-butyl dicarbonate (1.6 g, 7.5 mmol) and the mixture stirred for 18 h. After this time the reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (25 mL), dried (Na2SO4) and evaporated in vacuo to give the title compound as a colourless oil (1.4 g, 93%). 5H (DMSO-d6) 7.02 (IH, s), 5.18 (IH, m), 3.96 (IH, m), 3.57 (IH, m), 3.42 (2H, m), 3.08 (2H, m), 1.40 (18H, s).
  • 4
  • [ 252574-03-1 ]
  • [ 190792-74-6 ]
  • 9
  • (±)-trans-tert-butyl 3-bromo-4-hydroxypyrrolidine-1-carboxylate [ No CAS ]
  • [ 190792-74-6 ]
  • 10
  • tert-butyl (+/-)-trans-3-(benzylamino)-4-hydroxypyrrolidine-1-carboxylate [ No CAS ]
  • [ 190792-74-6 ]
YieldReaction ConditionsOperation in experiment
99% With hydrogen;palladium 10% on activated carbon; In butan-1-ol; under 2585.81 Torr; for 10h; PREPARATION 58 (3S,4S)-3-Amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of (3S,4S)-3-benzylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.054 mol, 16.0 g) in n-butanol (225 mL) add 10% Pd/C (5.0 g) and hydrogenate the mixture at 50 psi for 10 h. Filter the reaction mixture thorough a plug of diatomaceous earth and wash with ethanol. Evaporate the filtrate to obtain the title compound as a white solid (11.10 g, 99%). APCI MS m/z 203 [M+H]+; [alpha]23D+7.8 (c, 0.50, MeOH).
  • 11
  • [ 190792-74-6 ]
  • (3R,4S)-4-amino-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine [ No CAS ]
  • 12
  • [ 98-09-9 ]
  • [ 190792-74-6 ]
  • C15H22N2O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 20℃; for 4h; [0173] To a stirred solution of the azide (39) (86 mg, 1 equiv.) in MeOH/CHCl3 (2 mL each) was added 10% palladium on carbon (10 mg, 9%). The solution was evacuated, placed under a H2 atmosphere (1 atm) and stirred for 48 h. The suspension was then filtered through celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford the desired amine. Following general procedure 11, to a stirred solution of this amine (76 mg, 1 equiv.) and Et3N (73 uL, 1.4 equiv.) in CH2Cl2 (4 mL) was added benzenesulfonyl chloride (58 uL, 1.2 equiv.). The resultant mixture was stirred at rt for 4 h. The mixture was then diluted with EtOAc and washed successively with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 50% EtOAc in hexane to 100% EtOAc) to afford the desired coupled product (40).
  • 13
  • [ 190792-84-8 ]
  • [ 190792-74-6 ]
YieldReaction ConditionsOperation in experiment
Pd on carbon; In methanol; d trans-3-amino-1-tert-butoxycarbonyl-4-hydroxypyrrolidine To a solution of the compound of Example 2(c) (210 mg, 0.92 mmol) in CH3OH (10 mL) was added 10% Pd on carbon. This mixture was stirred under an atmosphere of hydrogen until TLC analysis indicated the complete disappearence of the starting material. The reaction was filtered through a pad of celite with CH2Cl2 and concentrated to give 202 mg of the title compound which was used directly in the next step.
With hydrogen;palladium 10% on activated carbon; In methanol; chloroform; under 760.051 Torr; for 48h; [0173] To a stirred solution of the azide (39) (86 mg, 1 equiv.) in MeOH/CHCl3 (2 mL each) was added 10% palladium on carbon (10 mg, 9%). The solution was evacuated, placed under a H2 atmosphere (1 atm) and stirred for 48 h. The suspension was then filtered through celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford the desired amine. Following general procedure 11, to a stirred solution of this amine (76 mg, 1 equiv.) and Et3N (73 uL, 1.4 equiv.) in CH2Cl2 (4 mL) was added benzenesulfonyl chloride (58 uL, 1.2 equiv.). The resultant mixture was stirred at rt for 4 h. The mixture was then diluted with EtOAc and washed successively with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 50% EtOAc in hexane to 100% EtOAc) to afford the desired coupled product (40).
With hydrogen;platinum(IV) oxide; In methanol; 22.3 A solution of 2.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 25 MeOH was treated under an argon atmosphere with 100 mg PtO2. The reaction mixture was stirred over night under a hydrogen atmosphere. The catalyst was filtered off and washed with methanol. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 4:1) to give 1.5 g (3S,4S)-3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as off-white solid. MS 202.9 ([M+H]+)
  • 14
  • [ 24065-33-6 ]
  • [ 190792-74-6 ]
  • [ 913742-79-7 ]
  • 15
  • [ 1118-02-1 ]
  • [ 190792-74-6 ]
  • [ 1202067-62-6 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; at 20℃; for 18h; INTERMEDIATE 53(35',41Sf)-3-Hydroxy-4-ureidopyrrolidine-l-carboxylic acid fert-butyl ester To a solution of Intermediate 12 (300 mg, 1.49 mmol) in DCM (50 mL) was added trimethylsilyl isocyanate (189 mg, 1.64 mmol) and the mixture was stirred at room temperature for 18 hours. After this time hexane (5 mL) was added to the reaction mixture and a pale precipitate formed. This was filtered and taken on to the next step as crude product (255 mg, 75%).
  • 16
  • [ 109-90-0 ]
  • [ 190792-74-6 ]
  • [ 1202067-91-1 ]
YieldReaction ConditionsOperation in experiment
99% In dichloromethane; for 18h; INTERMEDIATE 83(3£4lS)-3-(3-EthylureidoV4-hydroxypyrrolidine-l-carboxylic acid tert-butgamma esterIntermediate 12 (500 mg, 2.49 mmol) in DCM (50 mL) was treated with ethyl isocyanate (177 mg, 2.49 mmol) and the reaction mixture was stirred for 18 h. The solvent was evaporated to afford the title compound (670 mg, 99%) as brown gum. 5H (CDCl3) 6.01 (IH, d, J 7.7 Hz), 5.66 (IH, m), 5.21 (IH, d, J 3.7 Hz), 3.88 (IH, m), 3.77 (IH, m), 3.43 (IH, m), 3.32 (IH, m), 3.07 (4H, m), 1.38 (9H, s), 0.96 (3H, t, J 7.2 Hz).
  • 17
  • [ 98-88-4 ]
  • [ 190792-74-6 ]
  • [ 1202067-40-0 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; INTERMEDIATE 26(3£45)-3-Benzoylammo-4-hydroxypyrrolidme-l-carboxylic acid tert-butyl esterIntermediate 12 (2.1 g, 10.4 mmol) was dissolved in DCM (20 mL) and triethylamine (1.26 g, 1.75 mL, 12.5 mmol), cooled to O0C and treated with benzoyl chloride (1.6 mL, 11.4 mmol). The reaction was stirred at 00C for 30 minutes then allowed to warm to room temperature. After concentration in vacuo the residual oil was chromatographed (SiO2; ethyl acetate) to yield the title compound (2 g). 5H (DMSO-d6) 8.45 (IH, d, J 6.6 Hz), 7.82-7.88 (2H, m), 7.42-7.56 (3H, m), 5.32 (IH, d, J 4.0 Hz), 4.16- 4.25 (IH, m), 4.10-4.16 (IH, m), 3.54-3.67 (IH, m), 3.50 (IH, dd, J 11.3, 4.9 Hz), 3.29- 3.19 (IH, m), 3.18-3.13 (IH, m), 1.42 (9H, s). LCMS RT 1.54 minutes, (ES+) 307 (M+H)+.
  • 18
  • [ 24424-99-5 ]
  • [ 190792-74-6 ]
  • [ 1202067-96-6 ]
YieldReaction ConditionsOperation in experiment
81% INTERMEDIATE 89(35'.45r)-3-(fert-Butoxycarbonylamino)-4-(tert-butoxycarbonyloxy)pyrrolidine-l- carboxylic acid fert-butyl ester Intermediate 12 (1.14 g, 5.7 mmol) in THF (20 mL) was cooled in an ice-bath and treated with sodium hydride (0.80 g, 19.9 mmol) and the reaction mixture was stirred for 20 minutes. Di-tert-butyl dicarbonate (4.35 g, 19.9 mmol) was then added and the reaction mixture stirred for 18 h. After this time the reaction mixture was quenched with water (2 mL), diluted with ethyl acetate (50 mL), washed with brine (2 x 50 mL), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (SiO2; 20% EtOAc in hexanes) to afford the title compound as a colourless oil (1.86 g, 81%). deltaH (DMSO-Cl6) 7.40-7.29 (IH, m), 4.81(1H, s), 3.98-3.86 (IH, m), 3.66-3.55 (IH, m), 3.52-3.42 (IH, m), 3.28-3-18 (2H, m), 1.43 (9H, m), 1.40 (9H, s), 1.39 (9H, s).
  • 19
  • [ 190792-74-6 ]
  • [ 199915-38-3 ]
  • [ 1202067-55-7 ]
YieldReaction ConditionsOperation in experiment
100% In dichloromethane; at 20℃; for 3h; INTERMEDIATE 47(35',45r)-3-Hydroxy-4-[3-(9H-fluoren-9-ylmethoxycarbonyl)thioureido1pyrrolidine-l- carboxylic acid fert-butyl esterTo a solution of Intermediate 12 (550 mg, 2.26 mmol) in DCM (20 mL) was added 9H-fluoren-9-ylmethoxycarbonyl isothiocyanate (699 mg, 2.49 mmol) and the mixture was stirred at room temperature for three hours. After this time the solvent was removed in vacuo to yield the title compound as a yellow solid (1.2 g, quant.). 6Eta (DMSOd6) 11.51 (1Eta, s), 9.85 (1Eta, m), 7.90 (2Eta, m), 7.82 (2H, m), 7.46 (2H, m), 7.36 (2H, m), 5.51 (IH, m), 4.48 (IH, m), 4.35 (2H, m), 4.27 (2H, m), 3.66 (IH, m), 3.39 (IH, m), 3.24 (2H, m), 1.39 (9H, s). LCMS RT 2.99 minutes, (ES+) 485 (M+H).
  • 20
  • [ 190792-74-6 ]
  • (3S,4S)-3-amino-4-hydroxypyrrolidine dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride; In 1,4-dioxane; for 4h; INTERMEDIATE 86(3£4,SV3-Amino-4-hydroxypyrrolidineIntermediate 12 (100 mg, 0.50 mmol) was treated with 4M HCl in 1,4-dioxane (5 mL) and stirred for 4 h. After this time the solvent was evaporated to afford the title compound as a white solid (86 mg, quantitative). deltaH (DMSOd6) 9.70-8.30 (4H, m), 6.10 (IH, m), 4.64 (IH, m), 3.62 (IH, m), 3.28 (2H, m), 3.11 (2H, m).
  • 21
  • [ 56601-42-4 ]
  • [ 190792-74-6 ]
  • [ 1202067-59-1 ]
YieldReaction ConditionsOperation in experiment
100% In dichloromethane; at 20℃; for 3h; INTERMEDIATE 50(3£45V3-?-CyclopropylthioureidoV4-hydroxypyrrolidine- 1 -carboxylic acid fert-butyl esterTo a solution of Intermediate 12 (500 mg, 2.5 mmol) in DCM (50 mL) was added cyclopropyl isothiocyanate (267 mg, 2.7 mmol) and the mixture was stirred at room temperature for three hours. After this time the solvent was removed in vacuo to yield the title compound as a yellow solid (748 mg, quant.). deltaH (DMSO-d6) 7.80 (IH, s), 7.35 (IH, d, J 7.6 Hz), 5.29 (IH, d, J4.2 Hz), 4.42 (IH, m), 4.12 (IH, m), 3.57 (IH, m), 3.43 (IH, m), 3.13 (2H, m), 2.73 (IH, m), 1.40 (9H5 s), 0.68 (2H, m), 0.46 (2H, m). LCMS RT 1.59 minutes, (ES+) 302 (M+H).
  • 22
  • [ 1202067-33-1 ]
  • [ 190792-74-6 ]
YieldReaction ConditionsOperation in experiment
71% INTERMEDIATE 12(35l.4.y)-3-Amino-4-hydroxypyrrolidine-l-carboxylic acid tert-butl esterTo a solution of Intermediate 11 (5.1 g, 17.1 mmol) in MeOH (50 mL) was added TFA (3 drops) and the mixture stirred for 2 h. After this time the mixture was treated with platinum oxide (100 mg, 0.44 mmol) and stirred under a hydrogen atmosphere for 18 h. The mixture was then filtered through celite and the solvent evaporated in vacuo. The crude solid was recrystallised from DCM to afford the title compound as a white solid (2.42 g, 71%). deltaH (CDCl3) 3.99 (IH, m), 3.70 (2H, m), 3.34 (2H, m), 3.12 (IH, m), 1.48 (9H, s).
  • 23
  • meso-N-trifluoroacetyl-3-pyrroline oxide [ No CAS ]
  • [ 190792-74-6 ]
  • 24
  • [ 358-23-6 ]
  • [ 190792-74-6 ]
  • [ 1333413-99-2 ]
  • 25
  • [ 183184-52-3 ]
  • [ 190792-74-6 ]
  • 26
  • [ 190792-74-6 ]
  • [ 1333414-01-9 ]
  • 27
  • [ 190792-74-6 ]
  • [ 1333414-02-0 ]
  • 28
  • [ 926913-20-4 ]
  • [ 190792-74-6 ]
  • 29
  • C30H34N4O5 [ No CAS ]
  • [ 190792-74-6 ]
  • 30
  • [ 55583-59-0 ]
  • [ 190792-74-6 ]
  • C13H21ClN6O3 [ No CAS ]
  • 31
  • [ 190792-74-6 ]
  • C14H20N6O4 [ No CAS ]
  • 32
  • [ 18162-48-6 ]
  • [ 190792-74-6 ]
  • tert-butyl (3R,4S)-3-amino-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1H-imidazole; In dichloromethane; at 20℃; To a solution of (3R,4S)-tert-butyl 3 -amino-4-hydroxypyrrolidine- 1-carboxylate (250 mg, 1.24 mmol) and imidazole (210 mg, 3.09 mmol) in DCM (i2ml) wasadded TBDMS-Cl (224 mg, 1.48 mmol) at rt. The reaction was stirred at rt overnight, thenpartitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated and purified on silica gel column (40g) using 10-10% MeOH/DCM to give the title compound.
  • 33
  • [ 100-39-0 ]
  • [ 190792-74-6 ]
  • tert-butyl (3S,4S)-3-amino-4-(benzyloxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a mixture of <strong>[190792-74-6]tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate</strong> (1 mol) in tetrahydrofuran (30 mL) was added KOtBu ( 1M in tetrahydrofuran, 4 mol). The mixture was stirred for 30 min at 50 C. To a stirred mixture was added benzyl bromide (1.1 mol) and stirred for 2 hrs at 50 C. The mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was used for the next step without further purification
  • 34
  • [ 108-12-3 ]
  • [ 190792-74-6 ]
  • tert-butyl (3S,4S)-3-hydroxy-4-(3-methylbutanamido)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% A solution of tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (355.5 mg, 1.758 mmol) in DCM (2 mL) was treated with DIEA (921.0 jiL, 5.273 mmol) then stirred for 30 min at 0 C. The 0 C mixture was treated dropwise with isovaleryl chloride (235.7 mu^, 1.933 mmol). The resulting mixture was stirred for 20 min, over which time the temperature was allowed to gradually reach ambient temperature. The reaction mixture was diluted with DCM, and washed with saturated NaHC03(aq). The organic extracts were directly purified by silica chromatography (using 20-100% EtOAc in Hexanes as the gradient eluent) to cleanly provide the title compound (487.2 mg, 97% yield). MS (apci) m/z = 187.2 ([M - boc]+H).
  • 35
  • [ 190792-74-6 ]
  • [ 1202067-34-2 ]
  • 36
  • [ 190792-74-6 ]
  • [ 1202067-63-7 ]
  • 37
  • [ 190792-74-6 ]
  • [ 1202067-41-1 ]
  • 38
  • [ 190792-74-6 ]
  • [ 1202067-60-4 ]
  • 39
  • [ 190792-74-6 ]
  • [ 1202067-98-8 ]
  • 40
  • [ 190792-74-6 ]
  • [ 1202067-56-8 ]
  • 41
  • 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran [ No CAS ]
  • [ 190792-74-6 ]
  • trans-tert-butyl-3-amino-4-((2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With sodium hydride; In dimethyl sulfoxide; mineral oil; at 20℃; for 16h; A mixture of 6-chloro-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran (Intermediate A) (200mg, 0.88 mmol) and <strong>[190792-74-6]trans-tert-butyl-3-amino-4-hydroxy-pyrrolidine-1-carboxylate</strong> (355 mg,1.76 mmol) were dissolved in dimethylsulfoxide (6.8 mL) and treated with sodium hydride(60% wt in mineral oil, 70.3 mg, 1.76 mmol) at room temperature. After 16 h, the reactionmixture was diluted with isopropyl acetate and washed with water. The layers were separatedand the aqueous layer was extracted with isopropyl acetate (3x). The combined organicphases were dried over sodium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (eluting gradient 0-100% isopropyl acetate in heptane) to afford trans-tert-butyl-3 -amino-4-((2,2-dimethyl-5 -nitro-2,3 -dihydrobenzofuran6-yl)oxy)pyrrolidine-1-carboxylate (244 mg, 0.620 mmol, 70% yield) as a solid. ?H NMR (400 MHz, DMSO-d6) oe 7.82 (s, 1H), 6.85 (s, 1H), 4.67 (d, J =3.9 Hz, 1H), 3.77 - 3.64 (m,1H), 3.49 -3.40 (m, 2H), 3.40- 3.31 (m, 2H), 3.15 - 3.08 (m, 1H), 3.01 (s, 2H), 1.46 (s, 6H),1.40 (s, 9H).
  • 42
  • [ 50-00-0 ]
  • [ 190792-74-6 ]
  • [ 859213-33-5 ]
YieldReaction ConditionsOperation in experiment
84% With hydrogen; palladium(II) hydroxide; In methanol; at 25℃; for 16h; To a degassed mixture of tert-butyl (3R, 4S) -3-amino-4-hydroxypyrrolidine-1-carboxylate (1g, 4.95mmol) and paraformaldehyde (1.49 g, 49.5 mmol) in MeOH (25mL) was added Pd (OH) 2 (500mg, 10%wt) and the mixture was degassed under N 2 atmosphere for three times and stirred under a H 2 balloon at 25 for 16 hrs. The mixture was filtered and the filtrate was concentrated to dryness to give desired product (950 mg, 84%yield) as colorless oil. MS (ESI) m/z: 231 (M+H) + .
  • 43
  • [ CAS Unavailable ]
  • [ 530-62-1 ]
  • [ 148214-90-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
53% Stage #1: 1,1'-carbonyldiimidazole; (3S,4S)-4-amino-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine In N,N-dimethyl-formamide for 0.416667h; Stage #2: N-[4-[[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chlorophenyl]-5-[1-[(1S)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)-pyrazol-4-yl]-1-methylimidazole-2-carboxamide hydrochloride In N,N-dimethyl-formamide at 20℃; 183.1 Step 1) tert-butyl (3S,4S)-3-[[(lS,5R)-6-[[2-chloro-4-[[5-[l-[(lS)-2,2-difluorocyclopropyl]-3-(1660) (trifluoromethyl)pyrazol-4-yl]-l-methylimidazole-2-carbonyl]amino]benzoyl]amino]-3- azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-l-carboxylate tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (13.5 mg,66.8 pmol, Eq: 1.3) and CDI (10.8 mg,66.8 pmol, Eq: 1.3) were dissolved in DMF (1 ml). The mixture was stirred for 25 min, then N-(4-(((lR,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)- 5-( 1-((S)-2,2-difluorocyclopropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-methyl-1H- imidazole-2-carboxamide hydrochloride (35 mg, 51.4 pmol, Eq: 1) (Example 182 step 3), dissolved in 250 ul DMF, was added. The reaction mixture was stirred at room temperature overnight. 10 mL of ethyl acetate were added. The organic phase was washed three times with water (added a bit brine for better separation), dried with magnESIum sulfate and concentrated. The rESIdue was purified by to yield the title compound as a wH-ite solid (24 mg, 53%). MS (ESI, m/z): 798.5
  • 44
  • [ CAS Unavailable ]
  • [ 530-62-1 ]
  • [ 148214-90-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1,1'-carbonyldiimidazole; (3S,4S)-4-amino-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: N-[4-[[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]carbamoyl]-3-chlorophenyl]-5-[1-[(1R)-2,2-difluorocyclopropyl]-3-(trifluoromethyl)-pyrazol-4-yl]-1-methylimidazole-2-carboxamide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1.5h; 3.1 Step 1) tert-butyl (3S,4S)-3-[[(lS,5R)-6-[[2-chloro-4-[[5-[l-[(lR)-2,2-difluorocyclopropyl]-3-(1640) (trifluoromethyl)pyrazol-4-yl]-l-methylimidazole-2-carbonyl]amino]benzoyl]amino]-3- azabicyclo[3.1.0]hexane-3-carbonyl]amino]-4-hydroxy-pyrrolidine-l-carboxylate tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (6.42 mg, 31.7 mH-io. Eq: 1.3) and CDI (5.14 mg, 31.7 miho, Eq: 1.3) were dissolved in DMF (0.5 ml). The clear solution was stirred at room temperature. After 20 minutes N-(4-(((lR,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamoyl)-3-chlorophenyl)-5-(l-((R)-2,2-difluorocyclopropyl)-3-(trifluoromethyl)-lH- pyrazol-4-yl)-l-methyl-lH-imidazole-2-carboxamide hydrochloride (18.5 mg, 24.4 mH-io. Eq: 1) ( Example 181step 3) dissolved in 250 ul DMF was added. The mixture was stirred at room temperature for 90 min. 5 mL ethyl acetate were added. The organic phase was washed three times with water, dried with magnESIum sulfate and concentrated to yield the crude title product as a wH-ite solid (11 mg), that was used as is. MS (ESI, m/z): 798.6
  • 45
  • [ 2562327-44-8 ]
  • [ 148214-90-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 6h; 72 To a solution of 4-((R)-1-((S)-6-(tert-butyl)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2- carboxamido)-3-morpholinopropyl)benzoic acid (I-32, 25 mg, 0.047 mmol) in anhydrous DMF (1.5 mL) was added tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (9.5 mg, 0.047 mmol), TBTU (14.98 mg, 0.047 mmol) and DIEA (8.14 µl, 0.047 mmol). The resulting reaction was stirred at ambient temperature for 6 hrs. (0803) The reaction mixture was partitioned between EtOAc (6 mL) and water (2 mL). The organic phase was washed with brine and concentrated in vacuum. The crude product was dissolved in DCM (0.5 ml) and treated with TFA (0.5 mL) at ambient temperature for 1 hr. The reaction mixture was concentrated in vacuum. The crude product was purified by reverse-phase HPLC (MeCN / water with 0.1% ammonium hydroxide modifier) to afford the desired product
  • 46
  • [ 85-44-9 ]
  • [ 148214-90-8 ]
  • [ 2715210-64-1 ]
YieldReaction ConditionsOperation in experiment
36.5% With dmap; triethylamine In tetrahydrofuran at 70℃; 449.1 (3S,4S)-3-(1,3-dioxoisoindoline-2-yl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester Combine (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 1.20 mmol), phthalic anhydride (0.18 g, 1.20 mmol), triethylamine (0.36 g , 3.60 mmol) and N,N-4-dimethylaminopyridine (12 mg, 0.10 mmol) were added to tetrahydrofuran (10 mL), and the temperature was raised to 70 to react overnight. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a silica gel column (30-50% ethyl acetate/petroleum ether) to obtain the target product (3S,4S)-1-(5-(7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthalazine-5-yl)pyridin-2-yl)- 4-(Pyridin-2-oxy)pyrrolidin-3-amine (0.15 g, yellow solid). Yield: 36.5%;
  • 47
  • [ 629-04-9 ]
  • [ 148214-90-8 ]
  • [ 2750435-61-9 ]
YieldReaction ConditionsOperation in experiment
56.5% Stage #1: (3S,4S)-4-amino-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.0833333h; Stage #2: 1-Bromoheptane In N,N-dimethyl-formamide; mineral oil at 20℃; for 16h; 42.1 Step-1: Preparation of tert-butyl (3S,4S)-3-(heptylamino)-4- (heptyloxy)pyrrolidine-l-carboxylate. tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (0.5 g, 2.472 mmol) was dissolved in dry DMF (10 mL). Sodium hydride (60% in mineral oil) (0.346 g, 8.652 mmol) was added at 0°C. After 5 min, 1-bromoheptane (1.54 g, 8.652 mmol) was added and the reaction mixture was stirred at room temperature for 16 hr. The mixture was extracted with ethyl acetate (2 X 50 mL), washed with ice-water (50 mL), dried and concentrated. The crude product was purified using flash chromatography, eluting with 1% MeOH in DCM, to give tert-butyl (3S,4S)- 3-(heptylamino)-4-(heptyloxy)pyrrolidine-l-carboxylate. (0.74 g, 56.5%). LCMS (Method-J): 64.96% (RT 4.726, 202.0 nm) (MS: ESI +ve 399.4 [M+l]).
56.5% Stage #1: (3S,4S)-4-amino-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.0833333h; Stage #2: 1-Bromoheptane In N,N-dimethyl-formamide; mineral oil at 20℃; for 16h; 42.1 Step-1: Preparation of tert-butyl (3S,4S)-3-(heptylamino)-4- (heptyloxy)pyrrolidine-l-carboxylate. tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (0.5 g, 2.472 mmol) was dissolved in dry DMF (10 mL). Sodium hydride (60% in mineral oil) (0.346 g, 8.652 mmol) was added at 0°C. After 5 min, 1-bromoheptane (1.54 g, 8.652 mmol) was added and the reaction mixture was stirred at room temperature for 16 hr. The mixture was extracted with ethyl acetate (2 X 50 mL), washed with ice-water (50 mL), dried and concentrated. The crude product was purified using flash chromatography, eluting with 1% MeOH in DCM, to give tert-butyl (3S,4S)- 3-(heptylamino)-4-(heptyloxy)pyrrolidine-l-carboxylate. (0.74 g, 56.5%). LCMS (Method-J): 64.96% (RT 4.726, 202.0 nm) (MS: ESI +ve 399.4 [M+l]).
  • 48
  • [ 3954-13-0 ]
  • [ 148214-90-8 ]
  • [ 2750435-26-6 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane at 0 - 20℃; for 16h; 31.1 Step-1: Preparation tert-butyl (3S,4S)-3-hydroxy-4-(3- pentylureido)pyrrolidine-l-carboxylate. Tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (0.700 g, 3.461 mmol) was dissolved in DCM (5 mL) and cooled to 0°C. Pentyl isocyanate (0.391 g, 3.461 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs. The mixture was concentrated to give tert-butyl (3S,4S)-3- hydroxy-4-(3-pentylureido)pyrrolidine-l-carboxylate (1.1 g, crude). LCMS (Method-H): 98.2% (RT: 2.663, 202.0 nm) (MS: ESI +ve 314.2 [M-l]).
In dichloromethane at 0 - 20℃; for 16h; 31.1 Step-1: Preparation tert-butyl (3S,4S)-3-hydroxy-4-(3- pentylureido)pyrrolidine-l-carboxylate. Tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (0.700 g, 3.461 mmol) was dissolved in DCM (5 mL) and cooled to 0°C. Pentyl isocyanate (0.391 g, 3.461 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs. The mixture was concentrated to give tert-butyl (3S,4S)-3- hydroxy-4-(3-pentylureido)pyrrolidine-l-carboxylate (1.1 g, crude). LCMS (Method-H): 98.2% (RT: 2.663, 202.0 nm) (MS: ESI +ve 314.2 [M-l]).
  • 49
  • [ 2765-11-9 ]
  • [ 190792-74-6 ]
  • tert-butyl (3S,4S)-3-hydroxy-4-(pentadecylamino)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73.52% With palladium on activated charcoal; hydrogen In methanol for 16h; 42.1 Step-1: Preparation of tert-butyl (3S,4S)-3-hydroxy-4- (pentadecylamino)pyrrolidine-l-carboxylate. tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (0.1 g, 0.495 mmol) and pentadecanal (0.111 g, 0.495) were dissolved in MeOH (10 mL). Palladium on carbon (50% moisture) (0.1 g) was added, and the mixture was stirred for 16 hr under hydrogen (balloon). The reaction mixture was filtered through a pad of celite and concentrated to give tert-butyl (3S,4S)-3-hydroxy-4- (pentadecylamino)pyrrolidine-l-carboxylate (0.15 g, 73.52%). LCMS (Method- X): 77.10% (RT 1.123, 202.0 nm) (MS: ESI +ve 413.6 [M+l]).
73.52% With palladium on activated charcoal; hydrogen In methanol for 16h; 42.1 Step-1: Preparation of tert-butyl (3S,4S)-3-hydroxy-4- (pentadecylamino)pyrrolidine-l-carboxylate. tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (0.1 g, 0.495 mmol) and pentadecanal (0.111 g, 0.495) were dissolved in MeOH (10 mL). Palladium on carbon (50% moisture) (0.1 g) was added, and the mixture was stirred for 16 hr under hydrogen (balloon). The reaction mixture was filtered through a pad of celite and concentrated to give tert-butyl (3S,4S)-3-hydroxy-4- (pentadecylamino)pyrrolidine-l-carboxylate (0.15 g, 73.52%). LCMS (Method- X): 77.10% (RT 1.123, 202.0 nm) (MS: ESI +ve 413.6 [M+l]).
  • 50
  • [ 870693-09-7 ]
  • [ 148214-90-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
75% With triethylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In dimethyl sulfoxide at 20℃; for 12h; 1.1 Step 1. Synthesis of tert-butyl (3S,4S)-3-[3-[5-fluoro-2-(4-fluorophenyl)-1H-indol-3- yl ]propanoylamino ]-4-hydroxy-pyrrolidine-1-carhoxylate ( C22 ) To a solution of tert-butyl (3S,4S)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate C21 (20 mg, 0.099 mmol) in DMSO (1 mL) was added 3-[5-fluoro-2-(4-fluorophenyl)-1H-indol-3- yl]propanoic acid S7 (20 mg, 0.066 mmol), HATU (40 mg, 0.11 mmol), and NEt3 (50 μL, 0.36 mmol). The mixture was allowed to stir at room temperature for 12 hours. The mixture was then purified by reversed-phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid) to afford the product (25 mg, 75%). 1H NMR (400 MHz, Methanol-d4) δ 7.64 (ddd, J = 8.8, 5.2, 2.2 Hz, 2H), 7.30 (td, J = 6.2, 5.7, 2.9 Hz, 2H), 7.25 - 7.18 (m, 2H), 6.87 (tt, J = 8.8, 2.2 Hz, 1H), 4.02 (ddt, J = 11.1, 5.5, 2.3 Hz, 1H), 3.89 (ddt, J = 9.0, 4.4, 2.4 Hz, 1H), 3.55 (ddd, J = 11.5, 5.9, 4.2 Hz, 1H), 3.45 (m, 1H), 3.25 - 3.08 (m, 4H), 2.60 - 2.43 (m, 2H), 1.43 (d, J= 1.0 Hz, 9H). LCMS m/z 486.2 [M+H]+.
75% With triethylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In dimethyl sulfoxide at 20℃; for 12h; 1.1 Step 1. Synthesis of tert-butyl (3S,4S)-3-[3-[5-fluoro-2-(4-fluorophenyl)-1H-indol-3- yl ]propanoylamino ]-4-hydroxy-pyrrolidine-1-carhoxylate ( C22 ) To a solution of tert-butyl (3S,4S)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate C21 (20 mg, 0.099 mmol) in DMSO (1 mL) was added 3-[5-fluoro-2-(4-fluorophenyl)-1H-indol-3- yl]propanoic acid S7 (20 mg, 0.066 mmol), HATU (40 mg, 0.11 mmol), and NEt3 (50 μL, 0.36 mmol). The mixture was allowed to stir at room temperature for 12 hours. The mixture was then purified by reversed-phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid) to afford the product (25 mg, 75%). 1H NMR (400 MHz, Methanol-d4) δ 7.64 (ddd, J = 8.8, 5.2, 2.2 Hz, 2H), 7.30 (td, J = 6.2, 5.7, 2.9 Hz, 2H), 7.25 - 7.18 (m, 2H), 6.87 (tt, J = 8.8, 2.2 Hz, 1H), 4.02 (ddt, J = 11.1, 5.5, 2.3 Hz, 1H), 3.89 (ddt, J = 9.0, 4.4, 2.4 Hz, 1H), 3.55 (ddd, J = 11.5, 5.9, 4.2 Hz, 1H), 3.45 (m, 1H), 3.25 - 3.08 (m, 4H), 2.60 - 2.43 (m, 2H), 1.43 (d, J= 1.0 Hz, 9H). LCMS m/z 486.2 [M+H]+.
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