Benzyl (R)-3-hydroxypyrrolidine-1-carboxylate

Cat.NO.:A172077 Purity:98%

Product Details of [ 100858-33-1 ]

CAS No. :	100858-33-1
Formula :	C₁₂H₁₅NO₃
M.W :	221.25
SMILES Code :	O=C(N1C[C@H](O)CC1)OCC2=CC=CC=C2
MDL No. :	MFCD07368258
InChI Key :	MBLJFGOKYTZKMH-LLVKDONJSA-N
Pubchem ID :	11183628

Safety of [ 100858-33-1 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H301-H315-H319-H335
Precautionary Statements:	P261-P301+P310-P305+P351+P338
Class:	6.1
UN#:	2811
Packing Group:	Ⅲ

Computational Chemistry of [ 100858-33-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.42
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	62.98
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.77 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.35
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.13
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.86
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.14
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.13
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.32

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.94
Solubility	2.56 mg/ml ; 0.0116 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.77
Solubility	3.77 mg/ml ; 0.017 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.14
Solubility	1.61 mg/ml ; 0.00726 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.85 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12’782’590 molecules and tested on 40 external molecules (r² = 0.94)	2.63

Application In Synthesis of [ 100858-33-1 ]

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

Downstream synthetic route of [ 100858-33-1 ]

[ 100858-33-1 ] Synthesis Path-Downstream 1~7

1
[ 31970-04-4 ]
[ 100858-32-0 ]
[ 100858-33-1 ]

References: [1]Journal of the American Chemical Society,1986,vol. 108,p. 2049 – 2054.

2
[ 100858-33-1 ]
[ 100858-32-0 ]

Yield	Reaction Conditions	Operation in experiment
89%		Sodium trifluoroacetate (32.6 g) was suspended in toluene (213 g), and DFI (32.6 g) was added dropwise thereto at 0C. The mixture was stirred at 0C for 1 hour, and then R-CHP (44.2 g) was added thereto. The reaction solution was stirred at 0C for 1 hour, and then at 50C for 2 hours. The reaction solution was kept at 15C or lower, a 5 wt% aqueous sodium hydrogen carbonate solution (480 g) was added dropwise to the reaction solution, which was stirred at room temperature for 30 min. Subsequently, the toluene layer was separated. The toluene layer was washed three times with water (100 g), and then concentrated under reduced pressure. To the obtained residue were added toluene (40 g) and hexane (80 g), and the mixture was crystallized at 0C. The obtained crystal was collected by filtration, and dried at 40C for 12 hours under reduced pressure to obtain a target compound. Amount 39.3 g Yield 89% Stereoisomer ratio S-CHP:R-CHP=99.9:0.1 1H-NMR (toluene-d8, 400 MHz) delta 7.23-7.20 (m, 2H), 7.13-6.98 (m, 3H), 5.11-4.99 (m, 2H), 3.93 (bs, 1H), 3.46-3.12 (m, 4H), 1.65-1.45 (m, 1H), 1,45-1.30 (m, 1H) The stereoselectivity in the reaction was determined by using the concentrated residue before crystallization and using the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition 6. S-CHP:R-CHP=99.8:0.2
85%		Sodium trifluoroacetate (2.04 g) was suspended in toluene (10 g), and PPDA (3.35 g) was added dropwise thereto at 0C. The mixture was stirred at 0C for 1 hour, and then R-CHP (1.11 g) was added thereto. The reaction solution was stirred at 0C for 1 hour, and then at 50C for 2 hours. To the reaction solution was added toluene (20 g), and the mixture was kept at 15C or lower, and added dropwise to an ice-cooled, 5 wt% aqueous sodium hydrogen carbonate solution (30 g). The reaction solution was stirred at room temperature for 30 min, and then the toluene layer was separated. The toluene layer was washed three times with water (20 g), and then concentrated under reduced pressure to obtain a residue as a pale brown solid containing a target compound. Amount 0.94 g Yield 85% The stereoselectivity in this reaction was determined from the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition-6. Stereoisomer ratio S-CHP:R-CHP=96:4 1H-NMR (toluene-d8, 400 MHz) was consistent with that in Example 29.
78%		Sodium trifluoroacetate (2.04 g) was suspended in toluene (10 g), and BDDF (2.07 g) was added dropwise thereto at 0C. The mixture was stirred at 0C for 1 hour, and then R-CHP (1.11 g) was added thereto. The reaction solution was stirred at 0C for 1 hour, and then at 50C for 2 hours. To the reaction solution was added toluene (20 g), and the mixture was kept at 15C or lower, and added dropwise to an ice-cooled, 5 wt% aqueous sodium hydrogen carbonate solution (30 g). The reaction solution was stirred at room temperature for 30 min, and then the toluene layer was separated. The toluene layer was washed three times with water (20 g), and then concentrated under reduced pressure to obtain a residue as a pale brown solid containing a target compound. Amount 0.87 g Yield 78% The stereoselectivity in this reaction was determined from the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition-6. Stereoisomer ratio S-CHP:R-CHP=94:6 1H-NMR (toluene-d8, 400 MHz) was consistent with that in Example 29.

References: [1]Patent: EP2039680,2009,A1 .Location in patent: Page/Page column 43.
[2]Patent: EP2039680,2009,A1 .Location in patent: Page/Page column 44.
[3]Patent: EP2039680,2009,A1 .Location in patent: Page/Page column 45-46.
[4]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 1265 – 1268.
[5]Journal of Organic Chemistry,2001,vol. 66,p. 8513 – 8517.
[6]Patent: WO2004/43940,2004,A1 .
[7]Patent: WO2005/108382,2005,A1 .

3
[ 95656-88-5 ]
[ 100858-33-1 ]

References: [1]Bulletin of the Chemical Society of Japan,1996,vol. 69,p. 207 – 215.

4
[ 501-53-1 ]
[ 122536-94-1 ]
[ 100858-32-0 ]
[ 100858-33-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water;	a) Preparation of benzyl (S)-3-hydroxy-pyrrolidine-1-carboxylate The pH of a solution of 6.18 g of (S)-3-hydroxy-pyrrolidine hydrochloride in 175 ml of water was adjusted to 10 with 10% sodium hydroxide solution and cooled to 0-5 C. 7.1 ml of benzyl chloroformate were added dropwise within 30 minutes under argon, with the pH of the solution being held between 9.5 and 11.5 by the dropwise addition of 10% sodium hydroxide solution. After completion of the addition the suspension was stirred at room temperature for 16 hours. The suspension was extracted with ethyl acetate, the organic phase was washed with water, dried over Na2 SO4, filtered and the filtrate was concentrated. Purification of the crude product over a silica gel column gave 7.33 g of benzyl (R)-3-hydroxy-pyrrolidine-1-carboxylate as a beige liquid.

References: [1]Patent: US5977381,1999,A .

5
[ 25070-74-0 ]
[ 100858-32-0 ]
[ 100858-33-1 ]

References: [1]Advanced Synthesis and Catalysis,2010,vol. 352,p. 3380 – 3390.

6
[ 108-22-5 ]
[ 95656-88-5 ]
(R)-benzyl 3-acetoxypyrrolidine-1-carboxylate [ No CAS ]
[ 100858-32-0 ]
[ 100858-33-1 ]

References: [1]Advanced Synthesis and Catalysis,2011,vol. 353,p. 2321 – 2327.

7
[ 95656-88-5 ]
[ 100858-32-0 ]
[ 100858-33-1 ]

References: [1]Chemical Communications,2017,vol. 53,p. 509 – 512.

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