287193-07-1|Ethyl 4-oxotetrahydro-2H-pyran-2-carboxylate| Ambeed

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Quality Control of [ 287193-07-1 ] Purity: 95% SDS Specification

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Product Details of [ 287193-07-1 ]

CAS No. :	287193-07-1
Formula :	C₈H₁₂O₄
M.W :	172.18
SMILES Code :	CCOC(=O)C1CC(=O)CCO1
MDL No. :	MFCD20922879
InChI Key :	MECFFZNWFZDTRY-UHFFFAOYSA-N
Pubchem ID :	54067561

Safety of [ 287193-07-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H227-H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 287193-07-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	0
Fraction Csp3	0.75
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	41.03
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	52.6 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.68
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	-0.15
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.3
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	1.24
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.56

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.62
Solubility	41.8 mg/ml ; 0.243 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.	-0.5
Solubility	54.4 mg/ml ; 0.316 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	-1.14
Solubility	12.4 mg/ml ; 0.0719 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.	-7.46 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)	2.76

Application In Synthesis of [ 287193-07-1 ]

* 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 [ 287193-07-1 ]

[ 287193-07-1 ] Synthesis Path-Downstream 1~13

1
[ 1551-45-7 ]
[ 287193-07-1 ]
ethyl 4-hydroxytetrahydro-2H-pyran-2-carboxylate [ No CAS ]

References: [1]Journal of the Chemical Society,1945,p. 571,574.

2
[ 64-17-5 ]
(+-)-tetrahydrocomanic acid [ No CAS ]
[ 287193-07-1 ]

References: [1]Journal of the Chemical Society,1945,p. 571,574.

3
[ 287193-07-1 ]
[ 1116-98-9 ]
[ 330192-64-8 ]
[ 330192-65-9 ]

Yield	Reaction Conditions	Operation in experiment
	With morpholine; sulfur; In ethanol; at 50℃; for 18h;	To a solution of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl (0.6 g, 3.5 mmol) in absolute ethanol (6 ml) was added sulfur (0.12 g, 3.85 mmol) and tert-butyl cyanoacetate (0.64 g, 4.55 mmol). The solution was stirred under nitrogen in a 50 C oil bath and morpholin (0.61 ml, 7.0 mmol) was added. The reaction was stirred for 18 hours and then cooled to ambient temperature and excess sulfur removed by filtration. The filtrate was concentrated in vacuo and reconstituted in ethyl acetate (50 ml). The organic phase was washed with brine (2 x 10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo . The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (20 to 25 % gradient) as eluent. Pure fraction of the two isomers were collected and the solvent evaporatedin vacuo which afforded 0.47 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (A) and 0.3 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester 7-ethyl ester (B) in 62 % combined yield. (A)1H-NMR (300 MHz, CDCl3) delta 5.96 (bs, 2H), 4.77-4.61 (m, 2H), 4.32-4.18 (m, 3H), 3.19-3.12 (m, 1H), 2.90-2.80 (m, 1H), 1.52 (s, 9H), 1.29 (t, 3H, J = 7 Hz).(B)1H-NMR (300 MHz, CDCl3) delta 5.10 (s, 1H), 4.28-4.13 (m, 3H), 3.98-3.91 (m, 1H), 2.82-2.76 (m, 2H), 1.51 (s, 9H), 1.31 (t, 3H, J = 7 Hz).
	With morpholine; sulphur; In ethanol; at 50℃; for 18h;	To a solution of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl (0.6 g, 3.5 mmol) in absolute ethanol (6 ml) was added sulfur (0.12 g, 3.85 mmol) and tert-butyl cyanoacetate (0.64 g, 4.55 mmol). The solution was stirred under nitrogen in a 50 C. oil bath and morpholin (0.61 ml, 7.0 mmol) was added. The reaction was stirred for 18 hours and then cooled to ambient temperature and excess sulfur removed by filtration. The filtrate was concentrated in vacuo and reconstituted in ethyl acetate (50 ml). The organic phase was washed with brine (2*10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (20 to 25% gradient) as eluent. Pure fraction of the two isomers were collected and the solvent evaporated in vacuo which afforded 0.47 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (A) and 0.3 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester 7-ethyl ester (B) in 62% combined yield. (A)1H-NMR (300 MHz, CDCl3) delta 5.96 (bs, 2H), 4.77-4.61 (m, 2H), 4.32-4.18 (m, 3H), 3.19-3.12 (m, 1H), 2.90-2.80 (m, 1H), 1.52 (s, 9H), 1.29 (t, 3H, J=7 Hz).(B)1H-NMR (300 MHz, CDCl3) delta 5.10 (s, 1H), 4.28-4.13 (m, 3H), 3.98-3.91 (m, 1H), 2.82-2.76 (m, 2H), 1.51 (s, 9H), 1.31 (t, 3H, J=7 Hz).
	With morpholine; sulfur; In ethanol; at 50℃; for 18h;	Example 30 2-(Oxalyl-amino)-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3 carboxylic acid; A solution of glyoxylic acid ethyl ester, polymer form (2.02 g, 8.9 mmol) and (3-methoxy-1-methylene-allyloxy)-trimethyl-silane (1.9 ml, 8.9 mmol, Danishefsky's diene) in benzene (12 ml) was placed under nitrogen. Zinc chloride (0.5N in tetrahydrofuran, 8.9 ml, 4.45 mmol) was added and the reaction stirred at ambient temperature for 72 h. The mixture was concentrated in vacuo, diluted with ethyl acetate (100 ml) and washed with 1 N hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml), and brine (20 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexane (1:2) as eluant. Pure fractions were collected and the solvent evaporated in vacuo which afforded 1.2 g (75%) of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester as an oil.1H NMR (400 MHz, CDCl3) delta 7.40 (d, J=6, 1H), 5.48 (d, J=6, 1H), 5.01 (t, J=8, 1H), 4.28 (q, J=7, 2H), 2.85 (d, J=8, 2H), 1.29 (t, J=7, 3H).To a solution of the above of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (1.0 g, 5.9 mmol) in ethyl acetate (12 ml) was added 10% palladium on activated carbon (0.15 g). The reaction was shaken on a Parr hydrogenator under a hydrogen atmosphere (30 psi) for 1.5 h. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography sing diethyl ether as eluant. Pure fractions were collected and the solvent evaporated in vacuo which affording 0.6 g (60%) of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl as an oil.1H NMR (300 MHz, CDCl3) delta 4.41-4.35 (m, 1H), 4.26 (q, J=7, 2H), 3.81-3.70 (m, 1H), 2.73-2.58 (m, 3H), 2.44-2.36 (m, 1H), 1.29 (t, J=7, 3H).To a solution of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl (0.6 g, 3.5 mmol) in absolute ethanol (6 ml) was added sulfur (0.12 g, 3.85 mmol) and tert-butyl cyanoacetate (0.64 g, 4.55 mmol). The solution was stirred under nitrogen in a 50 C. oil bath and morpholin (0.61 ml, 7.0 mmol) was added. The reaction was stirred for 18 h. and then cooled to ambient temperature and excess sulfur removed by filtration. The filtrate was concentrated in vacuo and reconstituted in ethyl acetate (50 ml). The organic phase was washed with brine (2×10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (20 to 25% gradient) as eluant. Pure fraction of the two isomers were collected and the solvent evaporated in vacuo which afforded 0.47 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (A) and 0.3 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester 7-ethyl ester (B) in 62% combined yield.(A)1H NMR (300 MHz, CDCl3) delta 5.96 (bs, 2H), 4.77-4.61 (m, 2H), 4.32-4.18 (m, 3H), 3.19-3.12 (m, 1H), 2.90-2.80 (m, 1H), 1.52 (s, 9H), 1.29 (t, J=7, 3H).APCI-MS: [M+H]+=272.4 (loss of t-butyl)(B)1H NMR (300 MHz, CDCl3) delta5.10 (s, 1H), 4.28-4.13 (m, 3H), 3.98-3.91 (m, 1H), 2.82-2.76 (m, 2H), 1.51 (s, 9H), 1.31 (t, J=7, 3H).APCI-MS: [M+H]+=272.4 (loss of t-butyl)The above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (275 mg, 0.84 mmol) was dissolved in a mixture of ethanol (4 ml) and tetrahydrofuran (1 ml). Sodium hydroxide (1N, 1.6 ml, 1.68 mmol) was added and the reaction stirred at ambient temperature for 5 h. after which TLC analysis indicated that the reaction was complete. The reaction was monitored with a pH meter and neutralized with 1N hydrochloric acid until pH=6.9. The solution was concentrated in vacuo to give 2-amino-4+/-7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester as a solid. Sodium chloride remained as an impurity.1H NMR (300 MHz, CD3OD) delta 4.67-4.54 (m, 2H), 4.00-3.95 (m, 1H), 3.20-3.12 (m, 1H), 2.74-2.63 (m, 1H), 1.54 (s, 9H).APCI-MS: [M+H]+=300.0To a solution of the above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester (94 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.37 mmol) in distilled dichloromethane (4 ml) under nitrogen was added aniline (32 mul, 0.34 mmol) followed by 2,6-lutidine (0.11 ml, 0.93 mmol). The reaction was stirred for 72 h., concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 51 mg (45%) of 2-amino-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.1H NMR (400 MHz, CDCl3) delta 8.40 (s, 1H), 7.60 (d, 1H, J=7), 7.49 (d, 1H, =8), 7.34 (t, 1H, J=8), 7.32 (t, 1H, J=8), 7.13 (t, 1H, J=7)...

References: [1]Patent: EP1214325,2005,B1 .Location in patent: Page/Page column 50.
[2]Patent: US7019026,2006,B1 .Location in patent: Page/Page column 72-73.
[3]Patent: US7115624,2006,B1 .Location in patent: Page/Page column 85-87.

4
[ 287193-06-0 ]
[ 287193-07-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃; for 12h;Inert atmosphere;	Into a 100-mL round-bottom flask containing a solution of 258.2 (2.0 g, 11.75 mmol, 1.00 equiv) in ethyl acetate (50 mL) was added palladium on activated carbon (10%, 200 mg) under nitrogen at room temperature. Then (g) was introduced in and degassed three times. The resulting solution was stirred for 12 h at ambient temperature. The solids were filtered out by filtration and washed with EtOAc (3 x). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column with EtOAc/PE (1:20) to give the desired 258.3 (1.62 g, 80%) as a light yellow oil.
60%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 1551.49 Torr; for 1.5h;	To a solution of the above of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (1.0 g, 5.9 mmol) in ethyl acetate (12 ml) was added 10 % palladium on activated carbon (0.15 g). The reaction was shaken on a Parr hydrogenator under a hydrogen atmosphere (30 psi) for 1.5 hour. The mixture was filtered through celite and concentrated invacuo. The residue was purified by silica gel chromatography using diethyl ether as eluent. Pure fractions were collected and the solvent evaporated invacuo which affording 0.6 g (60 %) of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl as an oil.1H-NMR (300 MHz, CDCl3) delta 4.41-4.35 (m, 1H), 4.26 (q, 2H, J = 7 Hz), 3.81-3.70 (m, 1H), 2.73-2.58 (m, 3H), 2.44-2.36 (m, 1H), 1.29 (t, 3H, J = 7 Hz).
60%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 1551.49 Torr; for 1.5h;	To a solution of the above of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (1.0 g, 5.9 mmol) in ethyl acetate (12 ml) was added 10% palladium on activated carbon (0.15 g). The reaction was shaken on a Parr hydrogenator under a hydrogen atmosphere (30 psi) for 1.5 hour. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography using diethyl ether as eluent. Pure fractions were collected and the solvent evaporated in vacuo which affording 0.6 g (60%) of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl as an oil.1H-NMR (300 MHz, CDCl3) delta 4.41-4.35 (m, 1H), 4.26 (q, 2H, J=7 Hz), 3.81-3.70 (m, 1H), 2.73-2.58 (m, 3H), 2.44-2.36 (m, 1H), 1.29 (t, 3H, J=7 Hz).

60%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 1551.49 Torr; for 1.5h;	Example 30 2-(Oxalyl-amino)-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3 carboxylic acid; A solution of glyoxylic acid ethyl ester, polymer form (2.02 g, 8.9 mmol) and (3-methoxy-1-methylene-allyloxy)-trimethyl-silane (1.9 ml, 8.9 mmol, Danishefsky's diene) in benzene (12 ml) was placed under nitrogen. Zinc chloride (0.5N in tetrahydrofuran, 8.9 ml, 4.45 mmol) was added and the reaction stirred at ambient temperature for 72 h. The mixture was concentrated in vacuo, diluted with ethyl acetate (100 ml) and washed with 1 N hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml), and brine (20 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexane (1:2) as eluant. Pure fractions were collected and the solvent evaporated in vacuo which afforded 1.2 g (75%) of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester as an oil.1H NMR (400 MHz, CDCl3) delta 7.40 (d, J=6, 1H), 5.48 (d, J=6, 1H), 5.01 (t, J=8, 1H), 4.28 (q, J=7, 2H), 2.85 (d, J=8, 2H), 1.29 (t, J=7, 3H).To a solution of the above of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (1.0 g, 5.9 mmol) in ethyl acetate (12 ml) was added 10% palladium on activated carbon (0.15 g). The reaction was shaken on a Parr hydrogenator under a hydrogen atmosphere (30 psi) for 1.5 h. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography sing diethyl ether as eluant. Pure fractions were collected and the solvent evaporated in vacuo which affording 0.6 g (60%) of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl as an oil.1H NMR (300 MHz, CDCl3) delta 4.41-4.35 (m, 1H), 4.26 (q, J=7, 2H), 3.81-3.70 (m, 1H), 2.73-2.58 (m, 3H), 2.44-2.36 (m, 1H), 1.29 (t, J=7, 3H).To a solution of 4-oxo-tetrahydro-2H-pyran-2-carboxylic acid ethyl (0.6 g, 3.5 mmol) in absolute ethanol (6 ml) was added sulfur (0.12 g, 3.85 mmol) and tert-butyl cyanoacetate (0.64 g, 4.55 mmol). The solution was stirred under nitrogen in a 50 C. oil bath and morpholin (0.61 ml, 7.0 mmol) was added. The reaction was stirred for 18 h. and then cooled to ambient temperature and excess sulfur removed by filtration. The filtrate was concentrated in vacuo and reconstituted in ethyl acetate (50 ml). The organic phase was washed with brine (2×10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (20 to 25% gradient) as eluant. Pure fraction of the two isomers were collected and the solvent evaporated in vacuo which afforded 0.47 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (A) and 0.3 g of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,7-dicarboxylic acid 3-tert-butyl ester 7-ethyl ester (B) in 62% combined yield.(A)1H NMR (300 MHz, CDCl3) delta 5.96 (bs, 2H), 4.77-4.61 (m, 2H), 4.32-4.18 (m, 3H), 3.19-3.12 (m, 1H), 2.90-2.80 (m, 1H), 1.52 (s, 9H), 1.29 (t, J=7, 3H).APCI-MS: [M+H]+=272.4 (loss of t-butyl)(B)1H NMR (300 MHz, CDCl3) delta5.10 (s, 1H), 4.28-4.13 (m, 3H), 3.98-3.91 (m, 1H), 2.82-2.76 (m, 2H), 1.51 (s, 9H), 1.31 (t, J=7, 3H).APCI-MS: [M+H]+=272.4 (loss of t-butyl)The above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester 5-ethyl ester (275 mg, 0.84 mmol) was dissolved in a mixture of ethanol (4 ml) and tetrahydrofuran (1 ml). Sodium hydroxide (1N, 1.6 ml, 1.68 mmol) was added and the reaction stirred at ambient temperature for 5 h. after which TLC analysis indicated that the reaction was complete. The reaction was monitored with a pH meter and neutralized with 1N hydrochloric acid until pH=6.9. The solution was concentrated in vacuo to give 2-amino-4+/-7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester as a solid. Sodium chloride remained as an impurity.1H NMR (300 MHz, CD3OD) delta 4.67-4.54 (m, 2H), 4.00-3.95 (m, 1H), 3.20-3.12 (m, 1H), 2.74-2.63 (m, 1H), 1.54 (s, 9H).APCI-MS: [M+H]+=300.0To a solution of the above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester (94 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.37 mmol) in distilled dichloromethane (4 ml) under nitrogen was added aniline (32 mul, 0.34 mmol) followed by 2,6-lutidine (0.11 ml, 0.93 mmol). The reaction was stirred for 72 h., concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 51 mg (45%) of 2-amino-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.1H NMR (400 MHz, CDCl3) delta 8.40 (s, 1H), 7.60 (d, 1H, J=7), 7.49 (d, 1H, =8), 7.34 (t, 1H, J=8), 7.32 (t, 1H, J=8), 7.13 (t, 1H, J=7)...
33%	With palladium on activated charcoal; hydrogen; In ethyl acetate; under 760.051 Torr; for 4h;	1002881 Step B: A mixture of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 46 mmol) and Pd/C (10%, 0.20 g) in ethyl acetate (70 mL) was stirred under hydrogen (1 atm) for 4 hours. The mixture was filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by silica gel column using 30% EtOAc in petroleum ether to give 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.62 g, 33% yield) as an oil. ?H NMR (500 MHz, CDC13) 6 4.40 (m, 1H), 4.23-4.3 1 (m, 3H), 3.79 (m, 1H), 2.6 1-2.74 (m, 3H), 2.40 (d, J = 15.0 Hz, 1H), 1.31 (t, J = 7.5 Hz, 3H).
2.62 g (33%)	palladium-carbon; In hydrogen; ethyl acetate;	4-Oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester: A mixture of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 46.0 mmol) and Pd/C (10%, 0.20 g) in EtOAc (70 mL) was shaken in a Parr bottle with hydrogen at 50 psi overnight and filtered through a pad of Celite. The filtrate was concentrated and the residue was distilled to give 2.62 g (33%) of yellowish oil: 1H NMR (CDCl3) delta 1.29 (t, 3H), 2.40 (d, 1H), 2.58-2.75 (m 3H), 3.79 (tt, 1H), 4.23 (q, 2H), 4.28 (m 1H), 4.40 (m, 1H).

References: [1]Patent: WO2013/106535,2013,A1 .Location in patent: Paragraph 001250.
[2]Patent: EP1214325,2005,B1 .Location in patent: Page/Page column 49-50.
[3]Patent: US7019026,2006,B1 .Location in patent: Page/Page column 72.
[4]Patent: US7115624,2006,B1 .Location in patent: Page/Page column 85-87.
[5]Patent: WO2013/130976,2013,A1 .Location in patent: Paragraph 00288.
[6]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 1284 - 1289.
[7]Patent: US6284764,2001,B1 .

5
[ 287193-07-1 ]
C₈H₁₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; hydroxylamine hydrochloride; In ethanol; at 65℃; for 1h;	A solution of <strong>[287193-07-1]ethyl 4-oxotetrahydro-2H-pyran-2-carboxylate</strong> [CAS 287193-07-1] (4. 0g) in ethanol (40ml) was treated with pyridine (4ml) and hyrroxylamine hydrochloride (4. 0g). The mixture was heated at 65C for 1 hr then concentrated in vacuo. The residue was taken up in water (20ml) and saturated with potassium carbonate then extracted with dichloromethane, dried (MgS04) and concentrated in vacuo. Chromatographic purification on silica (90g Biotage), using 1: 1 ethyl acetate/cyclohexane gave the title compound (3. 0g) as a colourless oil. LC-MS (System A): Rt = 1.74min. Mass Spectrum m/z 188[MH+]

References: [1]Patent: WO2003/97618,2003,A1 .Location in patent: Page/Page column 42.

6
[ 287193-07-1 ]
[ 2999-46-4 ]
[ 1447957-50-7 ]
[ 1447957-49-4 ]

Yield	Reaction Conditions	Operation in experiment
46%	With morpholine; sulfur; In ethanol; at 50℃; for 4h;Inert atmosphere;	To a solution of 258.3 (1.62 g, 9.4 mmol, 1.00 equiv) in ethanol (60 mL) was added S (361 mg, 11.28 mmol, 1.20 equiv), ethyl 2- isocyanoacetate (1.28 g, 11.28 mmol, 1.20 equiv), morpholine (1.23 g, 14.1 mmol, 1.50 equiv) sequentially under nitrogen. The resulting mixture was stirred for 4 h at 50 C in an oil bath. The resulting mixture was evaporated in vacuo, diluted with water and extracted with 3 x 80 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30 to 1:15) to give 258.5 (1.3 g, 46%) as a light yellow solid. The regioisomer 258.4 is a by-product of the reaction

References: [1]Patent: WO2013/106535,2013,A1 .Location in patent: Paragraph 001251.

7
[ 287193-07-1 ]
(4-methylenetetrahydro-2H-pyran-2-yl)methanol [ No CAS ]