1-Boc-3-hydroxy-1,2,3,6-tetrahydropyridine | Pyridines

CAS No. :	224779-27-5
Formula :	C₁₀H₁₇NO₃
M.W :	199.25
SMILES Code :	O=C(N1CC(O)C=CC1)OC(C)(C)C
MDL No. :	MFCD04972246
InChI Key :	NICJOYHYEDFTIX-UHFFFAOYSA-N
Pubchem ID :	17750131

Safety of [ 224779-27-5 ]

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

Computational Chemistry of [ 224779-27-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	0
Fraction Csp3	0.7
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	57.28
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.	2.37
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	0.69
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.77
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.	0.76
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	0.15
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.95

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.31
Solubility	9.71 mg/ml ; 0.0487 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.	-1.31
Solubility	9.71 mg/ml ; 0.0487 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	-0.23
Solubility	116.0 mg/ml ; 0.582 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.	-7.03 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	1.0 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)	3.68

Application In Synthesis of [ 224779-27-5 ]

* 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 [ 224779-27-5 ]

[ 224779-27-5 ] Synthesis Path-Downstream 1~54

1
[ 691-64-5 ]
1,2,3,6-Tetrahydro-pyridin-3-ol [ No CAS ]
[ 224779-27-5 ]

References: [1]Tetrahedron Letters,1994,vol. 35,p. 3589 - 3592.

2
[ 224779-27-5 ]
[ 156496-89-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With Dess-Martin periodane; In dichloromethane; for 3h;	To a solution of <strong>[224779-27-5]tert-butyl 3-hydroxy-3,6-dihydropyridine-1(2H)-carboxylate</strong> (CAS: 224779-27-5, 10 g, 50.19 mmol) in DCM (200 mL) was added Dess-Martin periodinane (25.55 g, 60.2 mmol). After stirring for 1.5 h additional amount of Dess-Martin periodinane (2.50 g, 12.54 mmol) was added together with DCM (50 mL). The reaction mixture was stirred for additional 1.5 h; then 750 mL of hexane was added and stirring was continued for 10 min. The solid that precipitated was filtered off. The filtrate was concentrated and treated with a fresh portion of hexane (500 mL), filtered and concentrated in vacuo to give 10.01 g (100%) of tert-butyl 3-oxo-3,6-dihydropyridine-1(2H)-carboxylate as a pale orange solid. ESI+MS: m/z=142.20 (M-56+1)+. 1H NMR (700 MHz, 300 K, DMSO-d6) delta 7.22 (bs, 1H), 6.10 (dt, J=10.3, 2.3 Hz, 1H), 4.18 (bs, 1H), 4.01 (bs, 1H), 1.42 (s, 9H).
98%	With Dess-Martin periodane; In dichloromethane; at 20℃; for 2h;	Step 8) l-(tert-butoxycarbonyl)-L6-dihvdropyridin-3(2H)-one [0248] To a solution of l-(tert-butoxycarboxyl)-l,2,3,6-tetrahydropyridin-3-ol (350mg, 1.76 mmol) in DCM (12mL) was added Dess-Martin Oxidant (1.5 g, 3.52mmol). The reaction was stirred at rt for 2h, then filtered.The filtrate was washed with saturated aqueous a2CO3(50 mL), and concentrated in vacuo. The resulted residue was purified bya silica gel column chromatography (PE/EtOAc (v/v) =2/1) to give the title compound as colorless oil(340mg, 98%). LC-MS (ESI, pos. ion) m/z: 142[(M + H)+ - C4H8],220[M + Naf; 'tlNMR (400 MHz, CDC13) delta (ppm): 1.48(s, 9H), 4.11 (s, 2H), 4.24 (s, 2H), 6.16-6.20(m, 1H), 7.04 (s, 1H).
94%	With Dess-Martin periodane; In dichloromethane; at 20℃; for 12h;	To a solution of l-(tert-butoxycarboxyl)-l,2,3 ,6-tetrahydropyridin-3-ol (300 mg, 1.50 mmol) in DCM (25 mL) was added Dess-Martin Oxidant (1.27 g, 3.00 mmol). The reactionsolution was stirred at RT for 12 hours and then filtered. The filtrate was washed with saturated aqueous Na2CO3 (50 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a colorless oil (280mg, yield 94%). MS (ES+) C10H15N03 requires: 197, found: 142 [M+H-56].

91%	With Dess-Martin periodane; In dichloromethane; at 20℃;	Example 10 Preparation of (E)-N-hydroxy-3-{4-[3-[(Z)-hydroxyimino]-5-(2-methyl-1H-indol-3-yl)-piperidin-1-ylmethyl]-phenyl}-acrylamide (8) To a solution of N-BOC-3-hydroxyl-1,2,3,6-tetrahydropyridine (0.988 g, 4.96 mmol) in dichloromethane (20 mL) is added Dess-Martin reagent (2.49 g, 5.69 mmol) and the resulting mixture is stirred at room temperature. After 2 h, the reaction mixture is treated with 20% aqueous sodium thiosulfate solution (40 mL) and extracted with ethyl acetate (370 mL). The combined organics are washed with a saturated aqueous solution of sodium bicarbonate (250 mL), brine (50 mL), dried over magnesium sulfate, filtered, and concentrated, and the residue is purified via a silica gel column chromatography to give 3-oxo-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.890 g, 91% yield). LCMS (m/z): 198.1 (M+1).
91%	With Dess-Martin periodane; In dichloromethane; at 20℃; for 2h;	To a solution ofN-BOC-3-hydroxyl- l ,2,3,6-tetrahydropyridine (0.988 g, 4.96 mmol) in dichloromethane (20 mL) is added Dess-Martin reagent (2.49 g, 5.69 mmol) and the resulting mixture is stirred at room temperature. After 2 h, the reaction mixture is treated with 20% aqueous sodium thiosulfate solution (40 mL) and extracted with ethyl acetate (3 x 70 mL). The combined organics are washed with a saturated aqueous solution of sodium bicarbonate(2 x 50 mL), brine (50 mL), dried over magnesium sulfate, fi ltered, and concentrated, and the residue is purified via a silica gel column chromatography to give 3-oxo-3,6-dihydro-2H- pyridine- l -carboxylic acid tert-butyl ester (0.890 g, 91 % yield). LCMS (m/z): 1 8. 1 (M+ l ).
61%	With pyridinium chlorochromate; In dichloromethane; for 1h;Inert atmosphere;	3-Hydroxy-3,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (3.1 g, 17.3 mmol) was dissolved in dichloromethane (30 mL) under an argon atmosphere. Pyridinium chlorochromate (5 g, 23 mmol) was added in portions over 1 hour. The dichloromethane solution was filtered through silica gel (100 g), eluting withdichloromethane. The crude brown solid (2.84 g) was purified by MPLC (Companion) on a silica cartridge (40 g), eluting with 100% heptane followed by a gradient of ethyl acetate/heptane (0 to 60%). The product containing fractions were combined, concentrated, and dried under high vacuum for 1 hour at room temperature to provide 3- oxo-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (2.1 g, 61% yield) as a clear oil that solidified on standing at low temperature. 1H NMR (300 MHz,CDCI3/TMS): delta = 6.95 (m, 1H), 6.08 (d, 1H, J= 10.5 Hz), 4.15 (m, 2H), 4.02 (br s, 2H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCI3/TMS): delta = 193.11, 154.02, 147.17, 127.40, 80.89, 51.97, 42.69, 28.41.

References: [1]Patent: US2019/300525,2019,A1 .Location in patent: Paragraph 0294-0297; 0512-0514.
[2]Patent: WO2013/138210,2013,A1 .Location in patent: Paragraph 0248.
[3]Patent: WO2017/181117,2017,A1 .Location in patent: Page/Page column 240.
[4]Patent: US2011/53925,2011,A1 .Location in patent: Page/Page column 23.
[5]Patent: WO2012/25155,2012,A1 .Location in patent: Page/Page column 41.
[6]Synlett,2007,p. 741 - 744.
[7]Patent: WO2012/54535,2012,A2 .Location in patent: Page/Page column 178; 179.
[8]Tetrahedron Letters,1994,vol. 35,p. 3589 - 3592.

3
[ 36178-05-9 ]
[ 224779-27-5 ]
[ 564484-63-5 ]

References: [1]Tetrahedron Letters,2003,vol. 44,p. 2995 - 2999.

4
[ 108-05-4 ]
[ 224779-27-5 ]
[ 780782-28-7 ]
[ 780782-21-0 ]

References: [1]Journal of Organic Chemistry,2005,vol. 70,p. 5207 - 5214.
[2]Tetrahedron Letters,2004,vol. 45,p. 7053 - 7056.
[3]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3558 - 3568.

5
[ 541-41-3 ]
[ 224779-27-5 ]
[ 224779-28-6 ]

References: [1]Journal of the American Chemical Society,2000,vol. 122,p. 7905 - 7920.

6
[ 224779-26-4 ]
[ 224779-27-5 ]

References: [1]Journal of Organic Chemistry,2005,vol. 70,p. 5207 - 5214.
[2]Advanced Synthesis and Catalysis,2007,vol. 349,p. 685 - 693.
[3]Patent: WO2020/53600,2020,A1 .Location in patent: Page/Page column 22.
[4]Journal of the American Chemical Society,2000,vol. 122,p. 7905 - 7920.
[5]Synlett,2007,p. 741 - 744.

7
[ 24424-99-5 ]
[ 224779-27-5 ]
(+/-)-(3S,5S)-tert-butyl-2,4,5-trihydroxypiperidine-1-carboxylate [ No CAS ]
[ 858930-31-1 ]

References: [1]Journal of Organic Chemistry,2005,vol. 70,p. 5207 - 5214.

8
[ 1666-17-7 ]
[ 224779-27-5 ]
C₂₄H₂₉N₃O₄S [ No CAS ]

References: [1]Journal of Organic Chemistry,2006,vol. 71,p. 7113 - 7116.

9
[ 79-22-1 ]
[ 224779-27-5 ]
[ 656223-58-4 ]