[ CAS No. 330681-18-0 ] {[proInfo.proName]}

Name: 330681-18-0|(3R,4R)-tert-Butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate|98%
Brand: Ambeed
SKU: A673464
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Quality Control of [ 330681-18-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 330681-18-0 ]

SDS Specification

Alternatived Products of [ 330681-18-0 ]

Product Details of [ 330681-18-0 ]

CAS No. :	330681-18-0	MDL No. :	MFCD11111251
Formula :	C₉H₁₈N₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MOZOQDNRVPHFOO-RNFRBKRXSA-N
M.W :	202.25	Pubchem ID :	11275699
Synonyms :

Calculated chemistry of [ 330681-18-0 ]

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 Å²

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 [ 330681-18-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 330681-18-0 ]

* 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 [ 330681-18-0 ]
Downstream synthetic route of [ 330681-18-0 ]

[ 330681-18-0 ] Synthesis Path-Upstream 1~5

1
[ 1202067-36-4 ]
[ 330681-18-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: for 2 h; Stage #2: for 18 h;	INTERMEDIATE 20r3i?.4i?V3-Amino-4-hydroxypyrrolidine-l-carboxylic acid tert-butyl esterTo a solution of Intermediate 19 (2.5 g, 8.4 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 (1.5 g, 89percent). δ_H (CDCl₃) 3.99 (IH, m), 3.70 (2H, m), 3.34 (2H, m), 3.12 (IH, m), 1.48 (9H, s).

Reference： [1] Patent: WO2009/153554, 2009, A1, . Location in patent: Page/Page column 43

2
[ 73286-70-1 ]
[ 330681-18-0 ]

Reference： [1] Patent: WO2009/153554, 2009, A1,

3
[ 926912-99-4 ]
[ 330681-18-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1612 - 1621

4
[ 1214272-52-2 ]
[ 330681-18-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1612 - 1621

5
[ 114214-49-2 ]
[ 330681-18-0 ]

Reference： [1] Patent: WO2009/153554, 2009, A1,

[ 330681-18-0 ] Synthesis Path-Downstream 1~22

1
[ 330681-18-0 ]
[ 28920-43-6 ]
[ 1009335-28-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydrogencarbonate; In 1,4-dioxane; water; toluene; at 20℃;	(3R,4R)-tert-butyl 3-amino-4-hydroxypyrrolidine-l-carboxylate (0.05 g, 0.25 mmol) was dissolved in 1,4-dioxane (1 mL), water (1 mL), and toluene (0.3 mL). Then 9- fluorenylmethyl chloroformate (0.077 g, 0.30 mmol) was added slowly followed by sodium bicarbonate (0.083 g, 0.99 mmol). The reaction mixture was stirred at room temperature overnight. After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted once more with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by silica flash chromatography (gradient elution, using 1 : 1 hexane-ethyl acetate and ethyl acetate) to provide the title compound (0.090 g, 90%).

Reference： [1]Patent: WO2008/24725,2008,A1 .Location in patent: Page/Page column 124

2
[ 145783-15-9 ]
[ 330681-18-0 ]
(3R,4R)-3-[[5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino]-4-hydroxy-1-pyrrolidinecarboxylate, 1,1-dimethylethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; at 100℃; for 24h;	Triethylamine (18.8ml) was added to a solution of <strong>[330681-18-0](3R,4R)-4-amino-3-hydroxy-1-pyrrolidinecarboxylate, 1,1-dimethylethyl ester</strong> (prepared as described in J. Org. Chem.,1997, 62, 4197 using the (S,S)(salen)Cr(III)complex) (3.63g) and 4,6-dichloro-2-propylthiopyrimidine-5-amine (prepared as described in EP508687) (3.56g) and the resulting mixture was heated at 100C for 24 hours. The excess triethylamine was removedin vacuo and the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated in vacuo. The residue was purified by chromatography (SiO2, dichloromethane:methanol, 97:3 as eluant) followed by trituration with diethylether/iso-hexane to give the subtitle compound (4.16g). MS (APCI) 404 (M+H+, 100%).

Reference： [1]Patent: EP1216248,2004,B1 .Location in patent: Page column 10-11

3
[ 259103-43-0 ]
[ 330681-18-0 ]
[ 333743-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 28h;	(3R,4R)- 3-Amino-4-hydroxy-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (0.73g), diisopropylethylamine (1.0 ml) and the product of example 4 step b), were stirred in NMP (10ml) at 100§C for 28hrs. The cooled mixture was poured onto water and the solid produced collected, washed with water and air dried. The crude material was purified (SiO2, ethyl acetate as eluant) to give the subtitle compound as a colourless solid (0.58g). m.p. 182-5§C MS (APCI) 511 (M+H, 100%).

Reference： [1]Patent: EP1348709,2003,A2 .Location in patent: Page/Page column 15

4
[ 3913-18-6 ]
[ 330681-18-0 ]
[ 952444-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 70℃; for 1h;	(1) To a mixture of 2-chloro-4,6-dimethylquinoline (0.40 g), Pd2(dba)3 (0.095 g), (+-)-BINAP (0.20 g), (S)-t-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (0.51 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.60 g) under nitrogen atmosphere, and the mixture was stirred at 70C for 1 h. The reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the solids were washed with ethyl acetate and diisopropyl ether to obtain (3R,4R)-t-butyl 3-(4,6-dimethylquinolin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylate (0.39 g).

Reference： [1]Patent: EP2003131,2008,A1 .Location in patent: Page/Page column 75

5
[ 330681-18-0 ]
[ 407-25-0 ]
[ 1202067-37-5 ]

Yield	Reaction Conditions	Operation in experiment
> 99%	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 19h;	INTERMEDIATE 21(3i?,4i?)-3-Hydroxy-4-(2,2,2-trifluoroacetylamino)pyrrolidine-l -carboxylic acid fert-butyl esterTo a solution of Intermediate 20 (500 mg, 2.5 mmol) in THF (12 mL) cooled to O0C was added trifluoroacetic anhydride (0.35 mL, 2.5 mmol) followed by triethylamine (0.2 mL, 3.0 mmol), and the mixture was stirred for 1 h at 00C and 18 h at ambient temperature. After this time water (10 mL) was added and the mixture was extracted with 9:1 DCM:2-propanol (3 x 25 mL). The combined organics were dried (Na2SO4), filtered and the volatiles evaporated in vacuo to afford the title compound as a colourless oil (814 mg, >99%). deltaH (CDCl3) 4.34-4.27 (IH, m), 4.27-4.18 (IH, m), 3.85 (IH, dd, J 12.1, 6.4 Hz), 3.68-3.58 (IH, m), 3.55-3.27 (2H, m), 1.48 (9H, s).

Reference： [1]Patent: WO2009/153554,2009,A1 .Location in patent: Page/Page column 43

6
[ 1202067-36-4 ]
[ 330681-18-0 ]

Yield	Reaction Conditions	Operation in experiment
89%		INTERMEDIATE 20r3i?.4i?V3-Amino-4-hydroxypyrrolidine-l-carboxylic acid tert-butyl esterTo a solution of Intermediate 19 (2.5 g, 8.4 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 (1.5 g, 89%). deltaH (CDCl3) 3.99 (IH, m), 3.70 (2H, m), 3.34 (2H, m), 3.12 (IH, m), 1.48 (9H, s).

Reference： [1]Patent: WO2009/153554,2009,A1 .Location in patent: Page/Page column 43

7
[ 330681-18-0 ]
[ 1062243-48-4 ]
[ 1201691-88-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 103 (3R,4R)-3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (I-103) A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.024 g (0.12 mmole) of <strong>[330681-18-0](3R,4R)-3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester</strong> was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluding with water-acetonitrile (gradient, 0:100-80:20) to give 0.053 g of (3R,4R)-3-[4-(9-cyclopentyl-7,7-difluoro-5- methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (I-103) as a white solid.

Reference： [1]Patent: US2009/318408,2009,A1 .Location in patent: Page/Page column 46-47

8
[ 926912-99-4 ]
[ 330681-18-0 ]