401564-36-1|(S)-tert-Butyl 4-oxo-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate| Ambeed

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Quality Control of [ 401564-36-1 ] Purity: 95% SDS Specification

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Product Details of [ 401564-36-1 ]

CAS No. :	401564-36-1
Formula :	C₁₃H₂₀N₂O₄S
M.W :	300.37
SMILES Code :	O=C(N1[C@H](C(N2CSCC2)=O)CC(C1)=O)OC(C)(C)C
MDL No. :	MFCD22665915
InChI Key :	ULXKZRPRLJGLDM-JTQLQIEISA-N
Pubchem ID :	58516805

Safety of [ 401564-36-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 401564-36-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	20
Num. arom. heavy atoms	0
Fraction Csp3	0.77
Num. rotatable bonds	5
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	83.7
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	92.22 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.47
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	0.75
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.34
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.	0.27
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	0.84
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.93

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.84
Solubility	4.29 mg/ml ; 0.0143 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.	-2.27
Solubility	1.63 mg/ml ; 0.00542 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	-1.1
Solubility	23.9 mg/ml ; 0.0796 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	No
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.	-7.6 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<0.0
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)	3.49

Application In Synthesis of [ 401564-36-1 ]

* 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 [ 401564-36-1 ]

[ 401564-36-1 ] Synthesis Path-Downstream 1~35

1
[ 401564-30-5 ]
[ 401564-36-1 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sulfur trioxide pyridine complex; triethylamine; In dichloromethane; dimethyl sulfoxide; for 2h;Cooling with ice;	A mixture of N-tert-butoxycarbonyl-l-trans-hydroxyproline (6a) (69.4 g, 0.3 mol), thiazolidine (29.4 g, 0.33 mmol), HOBT (50.5 g, 0.33 mol) and EDC (63.3 g, 0.33 mol) in DMF (300 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure to give 3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidin-2-ylcarbonyl]thiazolidine (56.3 g, 62%) as a colorless oil. To a solution of the above compound (55.4 g, 183 mmol) and triethylamine (46 mL, 330 mmol) in dichloromethane (350 mL) was added sulfur trioxide-pyridine complex (52.4 g, 329 mmol) in DMSO (150 mL) under ice cooling and the mixture was stirred for 2 h. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried and concentrated under reduced pressure. The residue purified by silica gel chromatography with n-hexane/ethyl acetate (1:1, v/v) to give the title compound (30.3 g, 55%) as a white powder. 1H NMR (500 MHz, DMSO-d6): delta 1.36, 1.40 (9H, s), 2.36-2.45 (1H, m), 2.97-3.12 (3H, m), 3.62-3.71 (2H, m), 3.74-3.94 (2H, m), 4.33-4.80 (2H, m), 4.91-5.04 (1H, m).
	With sulfur trioxide pyridine complex; triethylamine; In dichloromethane; dimethyl sulfoxide; at 0℃; for 2h;	(1) N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline (69.4 g) and thiazolidine (29.4 g) were dissolved in DMF (300 mL), and HOBT (50.5 g) and EDC hydrochloride (63.3 g) were added successively. The mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated and saturated brine and a saturated aqueous sodium hydrogen carbonate solution were added to the concentrate. The mixture was extracted with ethyl acetate. The extract solution was dried and the solvent was evaporated under reduced pressure to give 3-((2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolizinylcarbonyl)-1,3-thiazolidine (56.3 g) as a colorless transparent oil.(2) The above-mentioned compound (55.4 g) and triethylamine (46 mL) were dissolved in dichloromethane (350 mL), and a solution of pyridine sulfur trioxide complex (52.4 g) in dimethyl sulfoxide (150 mL) was added under ice-cooling and the mixture was stirred for 2 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (30.3 g) as a white solid.1H-NMR(CDCl3)delta 1.47(9H,s), 2.45-2.57(1H,m), 2.70-2.93(1H,m), 2.97-3.22(2H,m), 3.66-3.78(0.6H,m), 3.80-4.10(3H,m), 4.28-4.38(0.4H,m), 4.45-5.08(3H,m).
	With sulfur trioxide pyridine complex; triethylamine; In dimethyl sulfoxide; at 0 - 20℃; for 2h;	(2S, 4R)-4-Hydroxy-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.34 g, 0.0111 mol, Example 17A) was dissolved in DMSO and cooled to 0 C. To the cold solution, triethylamine (7.37 g, 0.0729 mol) and sulfur trioxide pyridine complex (8.44 g, 0.0530 mol) were added. The mixture was stirred at 0 C. for 2 hours, brought to room temperature and quenched with water. The mixture was extracted with ethyl acetate and washed with 1 M HCl (60 mL), saturated NaHCO3 (240 mL) and brine (130 mL). The organic layer was dried with Na2SO4, filtered, concentrated, and purified by column chromatography (ethyl acetate/hexane, 1/1) to give the titled compound 2.05 g. MS (ESI APCI) m/e 299 (M-H)+; 1H NMR (300 MHz, methanol-d4): delta ppm 5.07 (d, 1H), 4.80 (m, 1H), 4.57-4.68 (m, 2 H), 4.45 (m, 1H), 3.85 (d, 2H), 3.78 (m, 2H), 3.17 (t, 1H), 3.05 (m, 2 H), 2.44-2.49 (d, 1H), 1.47 (s, 9H).

With sulfur trioxide pyridine complex; triethylamine; In dimethyl sulfoxide; at 0℃; for 2h;

Example 1A (2S)-4-Oxo-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2S, 4R)-4-Hydroxy-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.34 g, 0.0111 mol, Example 17A) was dissolved in DMSO and cooled to 0 C. To the cold solution, triethylamine (7.37 g, 0.0729 mol) and sulfur trioxide pyridine complex (8.44 g, 0.0530 mol) were added. The mixture was stirred at 0 C. for 2 hours, brought to room temperature and quenched with water. The mixture was extracted with ethyl acetate and washed with 1 M HCl (60 mL), saturated NaHCO3 (2*40 mL) and brine (1*30 mL). The organic layer was dried with Na2SO4, filtered, concentrated, and purified by column chromatography (ethyl acetate/hexane, 1/1) to give the titled compound 2.05g. MS (ESI APCI) m/e 299 (M-H)+; 1H NMR (300 MHz, methanol-d4): delta ppm 5.07 (d, 1H), 4.80 (m, 1H), 4.57-4.68 (m, 2H), 4.45 (m, 1H), 3.85 (d, 2H), 3.78 (m, 2H), 3.17 (t, 1H), 3.05 (m, 2H), 2.44-2.49 (d, 1H), 1.47 (s, 9H).

References: [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5033 - 5041.
[2]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 3662 - 3671.
[3]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2618 - 2621.
[4]Patent: EP1426366,2004,A1 .Location in patent: Page 23.
[5]Patent: US2005/209249,2005,A1 .Location in patent: Page/Page column 25-26.
[6]Patent: US2005/215603,2005,A1 .Location in patent: Page/Page column 26.

2
[ 401564-36-1 ]
[ 106-47-8 ]
[ 401565-11-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 3662 - 3671.

3
[ 401564-36-1 ]
[ 104-94-9 ]
[ 401565-10-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 3662 - 3671.

4
[ 401564-36-1 ]
[ 14268-66-7 ]
[ 401565-14-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 3662 - 3671.

5
[ 401564-36-1 ]
[ 62-53-3 ]
[ 401565-09-1 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 3662 - 3671.

6
[ 401564-36-1 ]
[ 5345-54-0 ]
[ 401565-13-7 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 3662 - 3671.

7
[ 401564-36-1 ]
[ 496-15-1 ]
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 641 - 655.

8
[ 401564-36-1 ]
[ 635-46-1 ]
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1,2,3,4-tetrahydro-1-quinolyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 641 - 655.

9
[ 401564-36-1 ]
[ 22190-33-6 ]
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-bromo-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 641 - 655.

10
[ 401564-36-1 ]
[ 21857-45-4 ]
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-methoxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 641 - 655.

11
[ 401564-36-1 ]
[ 2343-22-8 ]
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-fluoro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 641 - 655.

12
[ 401564-36-1 ]
[ 25658-80-4 ]
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-chloro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 641 - 655.

13
[ 401564-36-1 ]
[ 32692-19-6 ]
3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-nitro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 641 - 655.

14
[ 401564-36-1 ]
[ 906093-30-9 ]
Teneligliptin hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%		(1) To a suspension of sodium triacetoxyborohydride (13.68 kg) in toluene (300 L) were added 1-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine acetate (15.00 kg) and 3-[(2S)-1-(1,1-dimethylethyloxycarbonyl)-4-oxopyrrolidin-2-ylcarbonyl] thiazolidine (14.90 kg), and the mixture was stirred at room temperature for 2.5 hrs. Water (90 L) was added dropwise to the reaction mixture and the mixture was stirred for 0.5 hr. The toluene layer was separated, washed successively with 5% aqueous sodium hydrogencarbonate solution (90 L) and water (90 L) and concentrated to dryness under reduced pressure. IPA (224 L) was added to the residue and 48% hydrobromic acid (25.08 kg) was added dropwise at about 80C, and the mixture was refluxed for 2.5 hrs. The reaction mixture was allowed to cool, and stirred at about 60C for 1.5 hrs, at about 40C for 2 hrs, and then at room temperature for 2 hrs. The precipitate was collected by filtration, washed with IPA (30 L) and dried with warm air to give the title compound as a solid (29.76 kg, yield 91%). (2) To the solid (28.00 kg) obtained in (1) was added ethanol (168 L), and the solid was dissolved by heating. The solution was filtered hot. The reaction vessel was washed with ethanol (28 L), and the filtrate and washing were combined. Water (3 L) was added at 67C, and the mixture was allowed to cool and stirred at 49C for 1 hr and then at 20-15C for 1 hr. The precipitate was collected by filtration, washed with ethanol (28 L) and dried with warm air to give the title compound as crystals (25.84 kg, yield 92%). XRD: 5.4, 13.4, 14.4, 22.6, 26.5.

References: [1]Patent: EP1854795,2007,A1 .Location in patent: Page/Page column 9.

15
[ 109-01-3 ]
[ 401564-36-1 ]
[ 401566-05-0 ]