137496-71-0|(S)-tert-Butyl 2-methylpyrrolidine-1-carboxylate| Ambeed

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Quality Control of [ 137496-71-0 ] Purity: 97% SDS Specification

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Product Details of [ 137496-71-0 ]

CAS No. :	137496-71-0
Formula :	C₁₀H₁₉NO₂
M.W :	185.26
SMILES Code :	O=C(N1[C@@H](C)CCC1)OC(C)(C)C
MDL No. :	MFCD06858469
InChI Key :	PPUYUEPZGGATCN-QMMMGPOBSA-N
Pubchem ID :	9794078

Safety of [ 137496-71-0 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H227-H301-H315-H318-H335-H410
Precautionary Statements:	P261-P273-P280-P301+P310-P305+P351+P338
Class:	8(6.1)
UN#:	2922
Packing Group:	Ⅲ

Computational Chemistry of [ 137496-71-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	0.9
Num. rotatable bonds	3
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	56.59
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.54 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.76
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	2.03
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.02
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.	1.71
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	1.23
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.95

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.07
Solubility	1.58 mg/ml ; 0.00852 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.28
Solubility	0.977 mg/ml ; 0.00527 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-1.38
Solubility	7.69 mg/ml ; 0.0415 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.	-5.99 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	1.0
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)	2.38

Application In Synthesis of [ 137496-71-0 ]

* 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 [ 137496-71-0 ]

[ 137496-71-0 ] Synthesis Path-Downstream 1~32

1
[ 24424-99-5 ]
[ 765-38-8 ]
[ 137496-71-0 ]

References: [1]Tetrahedron,1994,vol. 50,p. 6089 - 6096.
[2]Organic and Biomolecular Chemistry,2010,vol. 8,p. 4533 - 4535.

2
[ 39637-99-5 ]
[ 137496-71-0 ]
(R)-3,3,3-Trifluoro-2-methoxy-1-((S)-2-methyl-pyrrolidin-1-yl)-2-phenyl-propan-1-one [ No CAS ]

References: [1]Tetrahedron,1994,vol. 50,p. 6089 - 6096.

3
[ 77-78-1 ]
[ 137496-71-0 ]
[ 92012-42-5 ]
[ 156038-84-5 ]

References: [1]Journal of the American Chemical Society,1994,vol. 116,p. 3231 - 3239.

4
[ 86953-79-9 ]
[ 74-88-4 ]
[ 137496-71-0 ]
[ 157007-54-0 ]

References: [1]Journal of the American Chemical Society,1994,vol. 116,p. 3231 - 3239.

5
(R)-2-Ethylsulfanylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
[ 137496-71-0 ]

References: [1]Tetrahedron Letters,1995,vol. 36,p. 1223 - 1226.

6
[ 86953-79-9 ]
[ 77-78-1 ]
[ 137496-71-0 ]

References: [1]Journal of the American Chemical Society,2001,vol. 123,p. 315 - 321.

7
[ 77-78-1 ]
N-(tert-butoxycarbonyl)-2-trimethylstannylpyrrolidine [ No CAS ]
[ 137496-71-0 ]
[ 157007-54-0 ]

References: [1]Journal of the American Chemical Society,2001,vol. 123,p. 315 - 321.

8
[ 137496-71-0 ]
[ 565-80-0 ]
trans-4,4-diisopropyl-8-methyl-3-oxa-1-azabicyclo[3.3.0]octan-2-one [ No CAS ]

References: [1]Journal of the American Chemical Society,2001,vol. 123,p. 315 - 321.

9
[ 137496-71-0 ]
[ 99-33-2 ]
N-(3,5-dinitrobenzoyl)-2-(R)-methylpyrrolidine [ No CAS ]
N-(3,5-dinitrobenzoyl)-2-(S)-methylpyrrolidine [ No CAS ]

References: [1]Journal of the American Chemical Society,2001,vol. 123,p. 315 - 321.

10
[ 59378-81-3 ]
[ 137496-71-0 ]

References: [1]Tetrahedron Letters,1995,vol. 36,p. 1223 - 1226.
[2]Journal of Peptide Science,2019,vol. 25.

11
[ 37784-17-1 ]
[ 137496-71-0 ]

References: [1]Tetrahedron Letters,1995,vol. 36,p. 1223 - 1226.
[2]Journal of Peptide Science,2019,vol. 25.

12
[ 132482-10-1 ]
[ 137496-71-0 ]

Yield	Reaction Conditions	Operation in experiment
88%		Slowly add lithium triethylborohydride (1M in THF, 17 mL, 17. mmol) to a 0 C solution of 2R-methanesulfonyloxymethyl-pyrrolidine-l-carboxylic acid tert-butyl ester (1.6 g, 5.73 mmol) in 10 mL of tetrahydrofuran. Warm the reaction mixture to ambient temperature and stir for 16 hours. Dilute the reaction mixture with ethyl acetate and water and wash successively with 0.1N HC1 and brine. Dry the crude organic extracts over MgS04, filter and concentrate to afford the title compound as a clear oil (0.930 g, 88%). 400 MHz NMR (CDC13) 8 3.83 (m, 1H), 3.38 (m, 2H), 1.92 (m, 3H), 1.58 (m, 1H), 1.48 (s, 9H), and 1.2 (d, J = 8 Hz, 3H).

References: [1]Patent: WO2006/19833,2006,A1 .Location in patent: Page/Page column 61.
[2]Journal of Peptide Science,2019,vol. 25.
[3]Tetrahedron Letters,1995,vol. 36,p. 1223 - 1226.

13
[ 137496-71-0 ]
[ 117968-50-0 ]

References: [1]Journal of the American Chemical Society,1994,vol. 116,p. 3231 - 3239.

14
[ 137496-71-0 ]
(S,S)-2,5-dimethyl-N-(3,5-dinitrobenzoyl)pyrrolidine [ No CAS ]

References: [1]Journal of the American Chemical Society,1994,vol. 116,p. 3231 - 3239.

15
(S)-2-methyl-N-(N'-tert-butylformimide)pyrrolidine [ No CAS ]
[ 137496-71-0 ]

References: [1]Tetrahedron,1994,vol. 50,p. 6089 - 6096.

16
[ 128510-88-3 ]
[ 137496-71-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With lithium triethylborohydride; In tetrahydrofuran; at 0℃; for 15.0h;	Step 3: Preparation of 2-(S)-methyl-pyrrolidine-1-carboxylic Tert-butyl Ester (5) To a solution of 2-(S)-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (compound (4), 1.77 g, 4.99 mmol) in 5 ML of THF at 0 C. was added dropwise 15 ML (15 mmol) of a 1 M THF solution of lithium triethylborohydride.After 15 hours, the reaction was quenched by addition of 7.39 ML of water.The reaction was diluted with 35 ML of chloroform, and poured into a separatory funnel.The mixture was diluted with dichloromethane and washed with saturated aqueous NaCl solution.The organic phase then was dried over sodium sulfate.The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluding with 1:3 ethyl acetate/hexane to give pure product as a clear oil (0.73 g, 79% yield).
79%	With lithium triethylborohydride; In tetrahydrofuran; at 0℃; for 15.0h;	Step 3: Preparation of 2-(S)-methyl-pyrrolidine-1-carboxylic tert-butyl ester (5) To a solution of 2-(S)-(toluene-4-sulfonyloxymethyl)-pyrrolidine- 1-carboxylic acid tert-butyl ester (compound (4), 1.77 g, 4.99 mmol) in 5 mL of THF at 0 C. was added dropwise 15 mL (15 mmol) of a 1 M THF solution of lithium triethylborohydride. After 15 hours, the reaction was quenched by addition of 7.39 mL of water. The reaction was diluted with 35 mL of chloroform, and poured into a separatory funnel. The mixture was diluted with dichloromethane and washed with saturated aqueous NaCl solution. The organic phase then was dried over sodium sulfate. The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluding with 1:3 ethyl acetate/hexane to give pure product as a clear oil (0.73 g, 79% yield).

References: [1]Patent: US2004/171845,2004,A1 .Location in patent: Page 8.
[2]Patent: US2004/260100,2004,A1 .Location in patent: Page 8.

17
[ 137496-71-0 ]
(S)-2-methylpyrrolidine hydrogen chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With hydrogenchloride; In diethyl ether; at 20℃; for 1.0h;	Add IN HC1 in ether to neat 2S-methyl-pyrrolidine-l-carboxylic acid tert-butyl ester (0.930 g, 5.02 mmol) at ambient temperature. The mixture is stirred for 1 hour and then concentrated to afford an oily solid. The solid is triturated with diethyl ether and dried to give (0.109 g, 18%) of the title compound. 400 MHz NMR (Methanol-d4) 5 3.67 (m, 1H), 3.35 (m, 2H), 2.25 (m, 1H) 2.1 (m, 2H), 1.66 (m, 1H), and 1.43 (d, /= 8Hz, 3H).

References: [1]Patent: WO2006/19833,2006,A1 .Location in patent: Page/Page column 61-62.
[2]Organic and Biomolecular Chemistry,2010,vol. 8,p. 4533 - 4535.

18
(S)-2-lithium-N-(tert-butoxycarbonyl)pyrrolidine [ No CAS ]
[ 74-88-4 ]
[ 137496-71-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tert-butyl methyl ether; cyclohexane;	Into a 25 mL round bottom flask was added 480 muL (2.7 mmol) of tert-butyl pyrrolidine- 1-carboxylate, 650 muL (2.8 mmol) of (-)-sparteine, and 8 mL of methyl-tert-butyl ether. The resulting solution was cooled in an acetone/dry ice bath. The cold solution was then treated dropwise with 2.4 ml (3.4 mmol) of a 1.4M solution of sec-butyllithium in cyclohexane. After stirring for 90 minutes at -78C, a small sample of the reaction solution was treated with methyl iodide and analyzed by GC/MS. The GC/MS analysis showed about 60% conversion to the methylated derivative of the lithiated intermediate. After a total of 130 minutes at -78C, the reaction was treated with 1.8 mL (1.8 mmol) of a IM solution of ZnCl2 in diethyl ether. The cooling bath was then removed and the reaction was allowed to warm to ambient temperature. After 1 hour at ambient temperature 438 mg (0.77 mmol) of 4-iodo-1- (3'-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole was added as a solution in 2 mL of methyl-tert-butyl ether. The mixture was then treated with 35 mg (160 mumol) ofPd(OAc)2, and 50 mg (170 mumol) of 1Bu3PHBF4. The resulting pale brown suspension was heated to 50C. After stirring for 16 hours at 50C, most of the solvent had evaporated. The reaction was treated with 10 mL of methyl-tert-butyl ether and a sample analyzed by LC/MS. LC/MS showed no remaining 4-iodo-1-(3'-(methylsulfonyl)biphenyl-4- yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole, a quantity of de-iodinated material and a smaller peak that appeared to be product. The reaction mixture was diluted with EtOAc and with 1N HCl. The layers were separated and the acidic aqueous was extracted with EtOAc (3x). Combined organics were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a brown semi-solid. The crude product was purified on the reverse phase preparative HPLC eluting with acetonitrile/water. (Phenomenex Axia Gemini C18 30 x 100 mm 5 mum, A = H2O with 0.1% trifluoroacetic acid, B = acetonitrile with 0.1% trifluoroacetic acid, 8 minute gradient from 30% B to 65% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3x), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting (2R)-tert-butyl 2-(1-(3'-(methylsulfonyl)biphenyl-4-yl)- <n="295"/>2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidine-1-carboxylate was isolated as a clear film; ~75 mg (15%). The NMR of the product was very complicated, possibly due to rotamers of the material. Treatment of the CDCI3 NMR sample with 100 muL of trifluoroacetic acid for ~65 hours showed complete conversion to a product by NMR. LC/MS analysis of the reaction solution showed a large peak with the correct mass for the desired deprotected amine product.

References: [1]Patent: WO2008/73825,2008,A1 .Location in patent: Page/Page column 292-294.

19
[ 86953-79-9 ]
[ 137496-71-0 ]

References: [1]Patent: WO2008/73825,2008,A1 .

20
[ 86953-79-9 ]
[ 77-78-1 ]
[ 137496-71-0 ]
[ 157007-54-0 ]

References: [1]Organic Letters,2013,vol. 15,p. 5424 - 5427.

21
[ 24424-99-5 ]
[ 137496-71-0 ]
[ 157007-54-0 ]

References: [1]Organic Letters,2013,vol. 15,p. 5424 - 5427.

22
[ 137496-71-0 ]
tert-butyl (2S)-4,4-difluoro-2-methylpyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine tris(hydrogen fluoride); ethanaminium,N-(difluoro-lambda4-sulfanylidene)-N-ethyl-,tetrafluoroborate; trimethylamine; In cis-1,2-Dichloroethylene; dichloromethane; at 80℃; for 1.5h;	To a solution of triethylamine trihydrofluoride (0.82 mL, 5.0 mmol) and trimethylamine (0.35 mL, 2.5 mmol) in DCM (2 mL) at room temperature in an oven-dried microwave vial were successively added XtalFluor-E (860 mg, 3.8 mmol) and (S)-1-Boc-2-methylpyrrolidin-4-one (500 mg in 1.9 mL DCE). The reaction was stirred at 80 C. for 90 min then was allowed to cool to room temperature and stirred at room temperature overnight. The reaction was next cooled to 0 C. and slowly quenched with saturated aqueous sodium bicarbonate and was stirred at room temperature for 15 minutes. The reaction was extracted with DCM (3×), dried over anhydrous magnesium sulfate, filtered over Celite, and concentrated to dryness. The residue was purified by FCC (0-20% EtOAc/hexanes) to give the title compound as a brown oil.

References: [1]Patent: US2017/313691,2017,A1 .Location in patent: Paragraph 0303-0305.

23
[ 137496-71-0 ]
[ 1212353-38-2 ]