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

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

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

CAS No.: 100858-32-0

Category Products

Cat.NO.:A145605 Purity:97%

Product Details of [ 100858-32-0 ]

CAS No. :	100858-32-0
Formula :	C₁₂H₁₅NO₃
M.W :	221.25
SMILES Code :	O[C@@H]1CN(C(OCC2=CC=CC=C2)=O)CC1
MDL No. :	MFCD07784363
InChI Key :	MBLJFGOKYTZKMH-NSHDSACASA-N
Pubchem ID :	13438604

Safety of [ 100858-32-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H317-H319
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 100858-32-0 ] 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.	2.33
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 [ 100858-32-0 ]

* 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.

Downstream synthetic route of [ 100858-32-0 ]

[ 100858-32-0 ] Synthesis Path-Downstream 1~35

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

References: [1]Heterocycles,1989,vol. 28,p. 283 – 294.

2
[ 31970-04-4 ]
[ 100858-32-0 ]
[ 100858-33-1 ]

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

3
[ 100858-32-0 ]
[ 124-63-0 ]
[ 122536-69-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h;	Example M48: (R)-l-methylcyclopropyl 4-((5-(4-(pyrrolidin-3- ylsulfonyl)piperazin-l-yl)pyrazin-2-yloxy)methyl)piperidine-l-carboxylateCl M48a M48b M48c M48dStep E r M48e: R=Cbz^ Example M48: R=H <n=”129″/>Step A: A solution of M48a (10 g, 45.2 mmol) in dichloromethane (200 mL) is cooled in an ice/water bath and treated with diisopropylethylamine (9.4 mL, 54.3 mmol) followed by dropwise addition of methanesulfonyl chloride (3.8 mL, 50 mmol). The resulting solution is stirred at 0 0C for 1 hour, concentrated and purified on silica gel using a linear gradient of 0-100% ethyl acetate in hexane to afford M48b; ESIMS m/z for (M+H)+ C13H18NO5S calcd: 300.1, found: 300.0.

References: [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 1764 – 1773.
[2]Patent: WO2009/38974,2009,A1 .Location in patent: Page/Page column 127-128.

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

References: [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 1764 – 1773.
[2]Organic and Biomolecular Chemistry,2003,vol. 1,p. 1498 – 1502.

5
[ 501-53-1 ]
[ 100243-39-8 ]
[ 100858-32-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In dichloromethane; at 5 – 20℃; for 48h;	Step 1: preparation of benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate. A solution of (3S)-pyrrolidin-3-ol (10.0 g, 0.12 mol) in dichloromethane (130 mL) was cooled to 5C. Triethylamine (16.9 mL, 0.12 mol) was added, followed by drop wise addition ofbenzyl chloroformate (13.9 mL, 0.10 mol), ensuring that the temperature did not exceed5C. The reaction mixture was then allowed to stir at ambient temperature for 48h, after which it was poured into aqueous saturated sodium bicarbonate and extracted into dichloromethane. The combined organic layers were washed with aqueous saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude oil was purified by silica gel column chromatography (50% ether hexanes followed by ether) to afford the title compound as a clear oil (14 g, 92%).

References: [1]Patent: WO2014/68527,2014,A1 .Location in patent: Page/Page column 81; 82.
[2]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1773 – 1778.

6
[ 100858-32-0 ]
[ 98-59-9 ]
[ 158654-83-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1773 – 1778.
[2]Organic and Biomolecular Chemistry,2003,vol. 1,p. 1498 – 1502.

7
[ 14661-69-9 ]
[ 100858-32-0 ]
[ 328404-62-2 ]

References: [1]Journal of Organic Chemistry,2001,vol. 66,p. 8513 – 8517.

8
(R)-3-(2-Chloro-acetoxy)-pyrrolidine-1-carboxylic acid benzyl ester [ No CAS ]
[ 100858-32-0 ]

References: [1]Journal of Organic Chemistry,2001,vol. 66,p. 8513 – 8517.

9
[ 369-34-6 ]
[ 100858-32-0 ]
(S)-3-(2-Fluoro-4-nitro-phenoxy)-pyrrolidine-1-carboxylic acid benzyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 4229 – 4233.

10
[ 100858-32-0 ]
[ 163457-21-4 ]

References: [1]Chemistry – A European Journal,2019,vol. 25,p. 7259 – 7264.
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 1265 – 1268.

11
[ 130403-93-9 ]
[ 100858-32-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; water; In ethanol; for 0.25h;	To a 20-L, three neck round bottom flask containing 427 g (1.62 mol) of benzyl (3S)-3-ACETOXYPYRROLIDINE-1-CARBOXYLATE was added 4 L of absolute ethanol followed by 101 g (1.57 mol) of potassium hydroxide in about 400 ML of water. After about 15 min, the reaction mixture was poured into 8 L of water and extracted with 8 L of ethyl acetate. The aqueous layer was then extracted with an additional 4 L of ethyl acetate. The combined organics were washed with saturated aqueous brine, dried over magnesium sulfate and concentrated to a thick oil and solids.
	With potassium hydroxide; ethanol; water; for 0.25h;	Step B: Benzyl (3S)-3-hydroxypyrrolidine-l-carboxylate; To a 20-L, three neck round bottom flask containing 427 g (1.62 mol) of benzyl (3S)-3- acetoxypyrrolidine-1-carboxylate was added 4 L of absolute ethanol followed by 101 g (1.57 mol) of potassium hydroxide in about 400 mL of water. After about 15 min, the reaction mixture was poured into 8 L of water and extracted with 8 L of ethyl acetate. The aqueous layer was then extracted with an additional 4 L of ethyl acetate. The combined organics were washed with saturated aqueous brine, dried over magnesium sulfate and concentrated to a thick oil and solids.
	With potassium hydroxide; ethanol; water; for 0.25h;	To a 20-L, three neck round bottom flask containing 427 g (1.62 mol) of benzyl (3S)-3- acetoxypyrrolidine-1-carboxylate was added 4 L of absolute ethanol followed by 101 g (1.57 mol) of potassium hydroxide in about 400 mL of water. After about 15 min, the reaction mixture was poured into 8 L of water and extracted with 8 L of ethyl acetate. The aqueous layer was then extracted with an additional 4 L of ethyl acetate. The combined organics were washed with saturated aqueous brine, dried over magnesium sulfate and concentrated to a thick oil and solids.

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 1265 – 1268.
[2]Patent: WO2004/43940,2004,A1 .Location in patent: Page 47.
[3]Patent: WO2005/116029,2005,A1 .Location in patent: Page/Page column 50-51.
[4]Patent: WO2005/108382,2005,A1 .Location in patent: Page/Page column 38.

12
[ 108-05-4 ]
[ 95656-88-5 ]
(R)-benzyl 3-acetoxypyrrolidine-1-carboxylate [ No CAS ]
[ 100858-32-0 ]

References: [1]Tetrahedron Asymmetry,2007,vol. 18,p. 435 – 442.

13
[ 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
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