1246616-66-9|Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate| Ambeed

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Quality Control of [ 1246616-66-9 ] Purity: 97% SDS Specification

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Product Details of [ 1246616-66-9 ]

CAS No. :	1246616-66-9
Formula :	C₁₆H₁₄O₇
M.W :	318.28
SMILES Code :	O=C(C1=C(OCC2=CC=CC=C2)C(C(C(OC)=O)=CO1)=O)OC
MDL No. :	MFCD28128927
InChI Key :	REVROVKRCYLCAT-UHFFFAOYSA-N
Pubchem ID :	87339061

Safety of [ 1246616-66-9 ]

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

Computational Chemistry of [ 1246616-66-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	23
Num. arom. heavy atoms	12
Fraction Csp3	0.19
Num. rotatable bonds	7
Num. H-bond acceptors	7.0
Num. H-bond donors	0.0
Molar Refractivity	78.52
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	92.04 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.62
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	1.93
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.64
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.	0.55
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	2.75
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.9

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.95
Solubility	0.354 mg/ml ; 0.00111 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.	-3.49
Solubility	0.104 mg/ml ; 0.000326 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	-4.73
Solubility	0.00591 mg/ml ; 0.0000186 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	Yes
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	Yes
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	Yes
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.	-6.87 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	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<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)	3.62

Application In Synthesis of [ 1246616-66-9 ]

* 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 [ 1246616-66-9 ]

[ 1246616-66-9 ] Synthesis Path-Downstream 1~35

1
[ 32807-28-6 ]
[ 1246616-66-9 ]

References: [1]Patent: US2012/22251,2012,A1 .
[2]Patent: EP2602260,2013,A1 .
[3]Patent: CN108101838,2018,A .
[4]Organic Process Research and Development,2019,vol. 23,p. 565 - 570.

2
[ 100-51-6 ]
[ 1246616-66-9 ]

References: [1]Patent: US2012/22251,2012,A1 .
[2]Patent: EP2602260,2013,A1 .
[3]Patent: CN108101838,2018,A .
[4]Organic Process Research and Development,2019,vol. 23,p. 565 - 570.

3
[ 870-46-2 ]
[ 1246616-66-9 ]
[ 1246616-89-6 ]

Yield	Reaction Conditions	Operation in experiment
72.9%	With acetic acid; In toluene; at 65℃; for 5h;	Example 10 First StepCompound 1D (318.3 mg, 1.0 mmol) and acetic acid (0.023 mL, 0.4 mmol) were dissolved in toluene (2 mL), a solution of tert-butylcarbazate (132.3 mg, 1.0 mmol) in toluene (2 mL) was added dropwise at 65 C., and the mixture was stirred at 65 C. for 5 hours. Saturated sodium bicarbonate water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride water, and dried with anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50?33:67) to obtain 315.3 mg (yield 72.9%) of Compound 10B.1H-NMR (DMSO-d6) delta: 1.36 (9H, s), 3.84 (6H, s), 5.11 (2H, s), 7.34-7.38 (5H, m), 8.33 (1H, s), 11.11 (1H, br s).

References: [1]Patent: US2012/22251,2012,A1 .Location in patent: Page/Page column 31.

4
[ 82961-76-0 ]
[ 1246616-66-9 ]

References: [1]Patent: US2012/22251,2012,A1 .
[2]Patent: EP2602260,2013,A1 .
[3]Patent: CN108101838,2018,A .
[4]Organic Process Research and Development,2019,vol. 23,p. 565 - 570.

5
[ 553-90-2 ]
[ 1246616-65-8 ]
[ 1246616-66-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium t-butanolate; In toluene; at 105℃; for 6h;	30 mol of methyl 4-benzyloxy-2-((dimethylamino)methylene)-3-acetoacetate obtained in Example 2 and 45 mol of dimethyl oxalate,15 mol of sodium t-butoxide and 300 ml of toluene were placed in a reaction flask, and then the reaction flask was placed in an oil bath, heated to 105 C, refluxed for 6 h, after completion of the reaction, cooled to room temperature, and filtered.The toluene solvent was removed by rotary evaporation, followed by separation of the crude product by column chromatography, eluent: n-hexane: ethyl acetate = 9:4.Thus obtaining dimethyl 4-oxo-3-benzyloxy-4H-pyran-2,5-dicarboxylate in a yield of 90%;
85%		Third StepSodium tert-butoxide (2.55 g, 23.2 mmol), dimethyl oxalate (639 mg, 5.41 mmol) and DMI (3 ml) were added to a three-neck flask under a nitrogen atmosphere, and a solution of Compound 1C (0.50 g, 1.80 mmol) in DMI (2 ml) was added dropwise thereto at 25 to 30 C. After stirring at room temperature for 7 hours, 2N hydrochloric acid (10 ml) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was extracted with ethyl acetate two times, and the combined extracts were washed sequentially with water, saturated sodium bicarbonate water, water and saturated sodium chloride water, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 2:1 to 1:1, v/v) to obtain 488 mg (yield 85%) of Compound 1D as a white crystal.1H-NMR (CDCl3) delta: 3.89 (3H, s), 3.93 (3H, s), 5.34 (2H, s), 7.32-7.40 (3H, m), 7.45-7.49 (2H, m), 8.50 (1H, s).
85%		Sodium tert-butoxide (2.55 g, 23.2 mmol), dimethyl oxalate (639 mg, 5.41 mmol), and DMI (3 ml) were added to a three-neck flask in a nitrogen atmosphere, and a DMI (2 ml) solution of compound 1C (0.50 g, 1.80 mmol) was added dropwise thereto at 25-30C. After stirring at room temperature for 7 hours, 2 N hydrochloric acid (10 ml) was added thereto, and the mixture was stirred at room temperature for 15 hours. After extraction two times with ethyl acetate, the combined extracts were washed with water, a saturated aqueous solution of sodium bicarbonate, water, and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate: 2:1 1 ? 1:1, v/v) to obtain 488 mg (yield: 85%) of compound 1D as white crystals. 1H-NMR (CDCl3) delta: 3.89 (3H, s), 3.93 (3H, s), 5.34 (2H, s), 7.32-7.40 (3H, m), 7.45-7.49 (2H, m), 8.50 (1H, s).

References: [1]Patent: CN108101838,2018,A .Location in patent: Paragraph 0038; 0039; 0040; 0041.
[2]Patent: US2012/22251,2012,A1 .Location in patent: Page/Page column 24-25.
[3]Patent: EP2602260,2013,A1 .Location in patent: Paragraph 0124.
[4]Organic Process Research and Development,2019,vol. 23,p. 565 - 570.

6
[ 943323-35-1 ]
[ 1246616-66-9 ]
[ 1246617-09-3 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 100℃; for 2.5h;	Fourth StepDimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (313 mg, 0.983 mmol) and 28D (246 mg, 0.983 mmol) were added to toluene (3 ml), and the mixture was stirred at 100 C. for 2.5 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 98.2, v/v) to obtain 320 mg of Compound 28E as a pale yellow gummy substance.1H-NMR (CDCl3) delta: 1.42 (9H, s), 3.07 (2H, m), 3.56 (2H, m), 3.68 (3H, s), 3.95 (3H, s), 4.26 (1H, s), 4.86 (1H, s), 5.18 (1H, d, J=10.8 Hz), 5.22 (1H, d, J=10.8 Hz), 7.01 (2H, m), 7.24-7.38 (8H, m), 8.22 (1H, s).MS: m/z=551 [M+H]+.

References: [1]Patent: US2012/22251,2012,A1 .Location in patent: Page/Page column 37.

7
[ 1160984-36-0 ]
[ 1246616-66-9 ]
[ 1246617-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 110℃; for 5h;	Sixth StepDimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (974 mg, 3.06 mmol) and 12F (999 mg, 3.06 mmol) were added to toluene (10 ml), and the mixture was stirred at 110 C. for 5 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 98:2, v/v) to obtain 1.51 g of Compound 12G as a pale yellow solid.1H-NMR (CDCl3) delta: 1.36 (9H, s), 3.40 (1H, m), 3.53 (1H, m), 3.82 (3H, s), 3.91 (3H, s), 4.29 (1H, d, J=11.3 Hz), 4.78 (1H, m), 4.82 (1H, m), 5.11 (1.9H, d, J=7.5 Hz), 7.10-7.38 (10H, m), 8.27 (1H, s).

References: [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 8101 - 8114.
[2]Patent: US2012/22251,2012,A1 .Location in patent: Page/Page column 35.

8
[ 1246616-66-9 ]
[ 1246617-15-1 ]
[ 1246617-16-2 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 110℃; for 1h;	Third StepDimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (488 mg, 1.53 mmol) and 43C (500 mg, 1.53 mmol) were added to toluene (8 ml), and the mixture was stirred at 110 C. for 1 hour. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3?96:4?94:6, v/v) to obtain 667 mg of Compound 43D as a pale yellow gummy substance.1H-NMR (CDCl3) delta: 1.28 (9H, s), 3.63 (3H, s), 3.80 (1H, m), 3.87 (3H, s), 4.02 (1H, dd, J=14.5, 10.1 Hz), 4.21 (1H, d, J=10.4 Hz), 4.47 (2H, m), 5.20 (1H, d, J=10.8 Hz), 5.26 (1H, d, J=10.7 Hz), 7.30 (15H, m), 8.05 (1H, s).MS: m/z=627 [M+H]+.
667 mg	In toluene; at 110℃; for 1h;	Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (488 mg, 1.53 mmol) and 43C (500 mg, 1.53 mmol) were added to toluene (8 ml), and the mixture was stirred at 110 C. for 1 hour. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 97:3?96:4?94:6, v/v) to obtain 667 mg of compound 43D as a pale yellow gummy substance. [0910] 1H-NMR (CDCl3) delta: 1.28 (9H, s), 3.63 (3H, s), 3.80 (1H, m), 3.87 (3H, s), 4.02 (1H, dd, J=14.5, 10.1 Hz), 4.21 (1H, d, J=10.4 Hz), 4.47 (2H, m), 5.20 (1H, d, J=10.8 Hz), 5.26 (1H, d, J=10.7 Hz), 7.30 (15H, m), 8.05 (1H, s). [0911] MS: m/z=627 [M+H]+.

References: [1]Patent: US2012/22251,2012,A1 .Location in patent: Page/Page column 38-39.
[2]Patent: US2013/197219,2013,A1 .Location in patent: Paragraph 0904; 0909; 0910; 0911.

9
[ 1246617-22-0 ]
[ 1246616-66-9 ]
[ 1246617-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 100℃; for 4h;	Fourth StepDimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (610 mg, 2.09 mmol) and 49D (664 mg, 2.09 mmol) were added to toluene (6 ml), and the mixture was stirred at 100 C. for 4 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 884 mg of Compound 49E as a pale yellow gummy substance.MS: m/z=593 [M+H]+.

References: [1]Patent: US2012/22251,2012,A1 .Location in patent: Page/Page column 40.

10
[ 825626-98-0 ]
[ 1246616-66-9 ]
[ 1246617-79-7 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 100℃; for 1.5h;	Third StepDimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (660 mg, 1.99 mmol) and 171B (609 mg, 1.99 mmol) were added to toluene (8 ml), and the mixture was stirred at 100 C. for 1.5 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (chloroform-methanol, 99:1, v/v) to obtain 1.02 g of Compound 171C as a pale yellow gummy substance.

References: [1]Patent: US2012/22251,2012,A1 .Location in patent: Page/Page column 53.

11
[ 1246616-66-9 ]
[ 1246617-88-8 ]
[ 1246617-89-9 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 100℃; for 2h;	Fourth StepDimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (390 mg, 1.22 mmol) and 175C (468 mg, 1.22 mmol) were added to toluene (5 ml), and the mixture was stirred at 100 C. for 2 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 391 mg of Compound 175D as a pale yellow gummy substance.
391 mg	In toluene; at 100℃; for 2h;	Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (390 mg, 1.22 mmol) and compound 175C (468 mg, 1.22 mmol) were added to toluene (5 ml), and the mixture was stirred at 100 C. for 2 hours. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 391 mg of compound 175D as a pale yellow gummy substance

References: [1]Patent: US2012/22251,2012,A1 .Location in patent: Page/Page column 55.
[2]Patent: US2013/197219,2013,A1 .Location in patent: Paragraph 1460; 1466.

12
[ 1246616-66-9 ]
[ 1246617-10-6 ]