51135-73-0|Ethyl 5-methylisoxazole-4-carboxylate| Ambeed

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Quality Control of [ 51135-73-0 ] Purity: 97% SDS Specification

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Product Details of [ 51135-73-0 ]

CAS No. :	51135-73-0
Formula :	C₇H₉NO₃
M.W :	155.15
SMILES Code :	O=C(C1=C(C)ON=C1)OCC
MDL No. :	MFCD01631119
InChI Key :	KOMSQTMQKWSQDW-UHFFFAOYSA-N
Pubchem ID :	7009317

Safety of [ 51135-73-0 ]

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

Computational Chemistry of [ 51135-73-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	5
Fraction Csp3	0.43
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	37.56
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	52.33 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.11
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	0.99
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.16
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.	0.33
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	1.39
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.2

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.56
Solubility	4.23 mg/ml ; 0.0273 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.	-1.68
Solubility	3.26 mg/ml ; 0.021 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	-2.09
Solubility	1.26 mg/ml ; 0.00809 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.	-6.54 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)	2.72

Application In Synthesis of [ 51135-73-0 ]

* 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 [ 51135-73-0 ]

[ 51135-73-0 ] Synthesis Path-Downstream 1~39

1
[ 51135-73-0 ]
[ 141-52-6 ]
[ 634-55-9 ]

References: [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 836.
Chem.Abstr.,1960,p. 1493.

2
[ 51135-73-0 ]
[ 42831-50-5 ]

Yield	Reaction Conditions	Operation in experiment
99.9%	With sulfuric acid; In o-tolyl acetic acid;	EXAMPLE 4 Preparation of 5-Methylisoxazole-4-Carboxylic Acid A two-necked flask fitted with mechanical stirrer and a horizontal condenser for distillation was charged with 40.0 g of crude Ethyl-5-methylisoxazole-4-carboxylate and 44 g of 60% sulfuric acid and the mixture was heated to 85 C. with continuous distillation of ethanol from the reaction product. After four hours of heating at 85 C., TLC showed the complete disappearance of the upper spot of ester. The mixture was allowed to cool in the refrigerator and the solid acid was filtered (16.5 g) Filtrate kept at room temperature for second crop. Acid was crystallized in 60 mL 2% acetic acid-Toluene to obtain about 99.9% pure acid (9.5 g). Mother liquor of the final crystallization was kept for second crop. Crystallization was accomplished by: The crude acid was taken in 2% acetic acid-toluene mixture and heated for 30 minutes. Brown oil was separated at the bottom of the flask. The clear organic phase was neatly transferred and kept for crystallization.
60%	With sulfuric acid; In water; at 20℃; for 20.0h;Reflux;	Ethyl-5-methylisoxazole-4-carboxylate 7 g (0.045 mol) was heated under reflux in aqueous sulphuric acid (20 % v/v, 30 ml) for 16 hr followed by cooling to room temperature with stirring for 4 h. The crystallized solid product was filtered and washed using toluene followed by water and dried. The product then was crystallized from ethanol to produce 3.5 g (60 %) of 5-Methylisoxazole-4-carboxylic acid as a white solid, mp. 147-148 C (reported mp. 144-147 C).
	With sulfuric acid; In water; for 16.0h;Heating / reflux;	S-MethyIisoxazole-4-carboxyiic acid:Ethyl-5-methylisoxazole-4-carboxylate 72.58 g (0.47 mol) was taken in 20% v/v aqueous sulphuric acid (193.5 ml) and refluxed for 16 hours. Toluene (73 ml) was added at 90 0C, cooled to 25 to 35 0C and stirred for 4 hours. The crystallized solid product was filtered and washed with toluene (2x36 ml) followed by water (2x72.5 ml). The product was dried under vacuum to get 27.2 g of 5-Methylisoxazole-4-carboxylic acid as an off white solid with 99.5 % HPLC purity having isomeric impurity 0.27 %

	In hydrogenchloride;	(iii) 5-Methylisoxazol-4-yl carboxylic acid <strong>[51135-73-0]Ethyl 5-methylisoxazol-4-yl carboxylate</strong> (65 g) was heated under reflux in 10 M HCl (500 ml) for 3 hours. On cooling the product crystallized out. This was filtered and dried giving 42 g of a white crystalline solid, m.p. 134-136C.
	In hydrogenchloride;	(iii) 5-Methylisoxazol-4-yl carboxylic acid <strong>[51135-73-0]Ethyl 5-methylisoxazol-4-yl carboxylate</strong> (65 g) was heated under reflux in 10M HCl (500 ml) for 3 hours. On cooling the product crystallized out. This was filtered and dried giving 42 g of a white crystalline solid, m.p. 134-136 C.
	In hydrogenchloride;	(iii) 5-Methylisoxazol-4-yl carboxylic acid <strong>[51135-73-0]Ethyl 5-methylisoxazol-4-yl carboxylate</strong> (65 g) was heated under reflux in 10 M HCl (500 ml) for 3 hours. On cooling the product crystallized out. This was filtered and dried giving 42 g of a white crystalline solid, m.p. 134-136 C.

References: [1]Patent: US2003/139606,2003,A1 .
[2]Letters in drug design and discovery,2016,vol. 13,p. 912 - 920.
[3]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 453 - 457.
[4]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 836.
Chem.Abstr.,1960,p. 1493.
[5]Journal of the Chemical Society. Perkin transactions I,1988,p. 1875 - 1880.
[6]Patent: WO2007/86076,2007,A2 .Location in patent: Page/Page column 5; 7.
[7]Asian Journal of Chemistry,2010,vol. 22,p. 1503 - 1506.
[8]Patent: EP257882,1991,B1 .
[9]Patent: US4892963,1990,A .
[10]Patent: US4983619,1991,A .
[11]Patent: DE634286,1935, .
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 23,p. 502.

3
[ 33142-24-4 ]
[ 51135-73-0 ]

References: [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 836.
Chem.Abstr.,1960,p. 1493.

4
[ 51135-73-0 ]
[ 563-41-7 ]
[ 108161-15-5 ]

References: [1]Journal of Heterocyclic Chemistry,1986,vol. 23,p. 1035 - 1038.

5
[ 51135-73-0 ]
[ 368-39-8 ]
C₉H₁₄NO₃⁽¹⁺⁾*BF₄^(1-) [ No CAS ]

References: [1]Synthesis,1988,vol. 1,p. 203 - 207.

6
[ 51135-73-0 ]
[ 4637-24-5 ]
[ 132934-75-9 ]

References: [1]Chemistry Letters,1991,p. 41 - 42.

7
[ 51135-73-0 ]
[ 62-53-3 ]
[ 39603-90-2 ]

References: [1]Journal of Heterocyclic Chemistry,1986,vol. 23,p. 1035 - 1038.

8
[ 51135-73-0 ]
[ 75-65-0 ]
2-tert-Butyl-4-ethoxycarbonyl-5-methyl-isoxazol-2-ium; perchlorate [ No CAS ]

References: [1]Synthesis,1988,vol. 1,p. 203 - 207.

9
[ 51135-73-0 ]
[ 634-55-9 ]

References: [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 453 - 457.

10
[ 51135-73-0 ]
Sodium; (E)-1-cyano-1-ethoxycarbonyl-propen-2-olate [ No CAS ]

References: [1]Journal of Heterocyclic Chemistry,1986,vol. 23,p. 1035 - 1038.

11
[ 134653-70-6 ]
[ 20328-15-8 ]
[ 51135-73-0 ]

References: [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 453 - 457.

12
[ 3788-94-1 ]
[ 51135-73-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With hydroxylamine; In methanol; water; at -5 - 30℃; for 2.5h;Heating / reflux;	Ethyl-5-methylisoxazole-4-carboxylate:Ethyl ethoxymethyleneacetoacetate, 110.00 g (0.59 mol) was taken in methanol (330 ml) and cooled to -5 0C and 50% aqueous hydroxyl amine 39.03 g (0.59 mol on anhydrous basis) was added drop wise over a period of 1 hour at -5 to O0C. It was stirred for 30 minutes. The reaction mixture was allowed to attain temperature of 20 to 30 0C and then refluxed for 1 S hour. Solvent was removed under reduced pressure and the reaction mass was cooled to room temperature. n-Hexane (500 ml) was added and stirred for 30 minutes. Saturated sodium bicarbonate solution (100 ml) was added followed by water (400 ml) and stirred well. The organic layer was separated. The aqueous layer was re-extracted with n-hexane (2x200 ml). The combined organic layer was washed with water (2x250 ml). After removal of the solvent <n="8"/>72.5 g (79%) of Ethyl-5-methylisoxazole-4-carboxylate was obtained as yellowish thick oil with 98.7 % HPLC purity and having isomeric impurity less than 0.5 %.
78%	With hydroxylamine hydrochloride; sodium acetate; In methanol; water; at 0 - 20℃;	Solution of hydroxylamine hydrochloride (4.1 g, 0.059 mol) and sodium acetate (4.84 g, 0.059 mol) in water (10 ml) was added dropwise to a solution of compound 3 (11 g, 0.059 mol) in methanol (25 ml) at 0 C. The mixture was stirred during overnight at room temperature followed by extraction with EtOAc (3 x 50 ml), the combined EtOAc extract was washed by aqueous sodium bicarbonate solution to minimize the impurities and dried over Na2SO4. After that the solvent was removed to afford 7.16 g (78 %) of Ethyl-5-methylisoxazole-4-carboxylate as yellow oil, which was used directly in the next step.

References: [1]Patent: WO2007/86076,2007,A2 .Location in patent: Page/Page column 5-7.
[2]Letters in drug design and discovery,2016,vol. 13,p. 912 - 920.
[3]Journal of the Chemical Society. Perkin transactions I,1988,p. 1875 - 1880.
[4]Asian Journal of Chemistry,2010,vol. 22,p. 1503 - 1506.

Yield	Reaction Conditions	Operation in experiment
85%		EXAMPLE 3 Preparation of Ethyl-5-Methylisoxazole-4-Carboxylate Into a three-necked RB flask was charged with 185 g (0.99 mole) of ethyl ethoxymethyleneacetoacetic ester and 89.7 g (1.09 mole) of sodium acetate dissolving in minimum amount of water. To this mixture was added 300 mL ethanol. The mixture was cooled to about -5 C. by acetone-salt-ice mixture. To this cooled reddish brown syrupy liquid (which became solidified initially but became liquid on addition of hydroxylamine sulfate solution) was added dropwise a clear cooled (temperature 3 C. to 4 C.) solution of 89.8 g (0.54 mole) hydroxylamine sulfate dissolving in minimum amount of water with vigorous stirring. Addition was made through a dropping funnel for a period of at least one hour with vigorous stirring while the temperature was maintained minimum 0 C. inside the flask. After addition the stirring was continued at this temperature for another 30 minutes. After this the mixture was allowed to cool to room temperature with stirring. The mixture was then again refluxed for 30 minutes (oil bath temperature 85-90 C.). After the reaction the solution was brought to room temperature and the supernatant was decanted to remove the salt. Ethanol was removed from the mixture by rotary evaporator (water bath temp. 60 C.) under reduced pressure. The aqueous part was extracted with dichloromethane (200 mL3). The dichloromethane extract was washed with cold saturated brine water (100 mL2) and dried over anhydrous sodium sulfate. Removal of dichloromethane in rotary evaporator under reduced pressure resulted in orange liquid (130 g, 85% crude yield).
		(ii) Ethyl 5-methylisoxazol-4-yl carboxylate Hydroxylamine hydrochloride (52.6 g) was dissolved in water (150 ml) and stirred while an ice-cold solution of sodium hydroxide (30.28 g) in water (100 ml) was added. This solution was stirred for 15 minutes then absolute ethanol (600 ml) added and the solution stirred for a further 15 minutes. Ethyl ethoxymethyleneacetoacetate (128 g) was dissolved in absolute ethanol (100 ml) and added to the hydroxylamine solution. After stirring for 30 hours the solvents were removed on a rotary evaporator (bath at 45C). The clear oil was distilled at reduced pressure through a 15 cm Vigreaux column. Product collected at a clear oil at 50-54C/0.5 mm Hg.
		(ii) Ethyl 5-methylisoxazol-4-yl carboxylate Hydroxylamine hydrochloride (52.6 g) was dissolved in water (150 ml) and stirred while an ice-cold solution of sodium hydroxide (30.28 g) in water (100 ml) was added. This solution was stirred for 15 minutes then absolute ethanol (600 ml) added and the solution stirred for a further 15 minutes. Ethyl ethoxymethyleneacetoacetate (128 g) was dissolved in absolute ethanol (100 ml) and added to the hydroxylamine solution. After stirring for 30 hours the solvents were removed on a rotary evaporator (bath at 45 C.). The clear oil was distilled at reduced pressure through a 15 cm Vigreaux column. Product collected as a clear oil at 50-54 C./0.5 mm Hg.

(ii) Ethyl 5-methylisoxazol-4-yl carboxylate Hydroxylamine hydrochloride (52.6 g) was dissolved in water (150 ml) and stirred while an ice-cold solution of sodium hydroxide (30.28 g) in water (100 ml) was added. This solution was stirred for 15 minutes then absolute ethanol (600 ml) added and the solution stirred for a further 15 minutes. Ethyl ethoxymethyleneacetoacetate (128 g) was dissolved in absolute ethanol (100 ml) and added to the hydroxylamine solution. After stirring for 30 hours the solvents were removed on a rotary evaporator (bath at 45 C.). The clear oil was distilled at reduced pressure through a 15 cm Vigreux column. Product collected as a clear oil at 50-54 C./0.5 mmHg.

14
2-acetyl-ξ-ethoxy-acrylic acid ethyl ester [ No CAS ]
[ 51135-73-0 ]

References: [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 836.
Chem.Abstr.,1960,p. 1493.
[2]Patent: DE634286,1935, .
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 23,p. 502.

15
[ 64-17-5 ]
[ 3788-94-1 ]
hydroxylamine hydrochloride [ No CAS ]
[ 51135-73-0 ]

16
[ 64-17-5 ]
[ 33142-24-4 ]
hydroxylamine hydrochloride [ No CAS ]
[ 51135-73-0 ]

References: [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 836.
Chem.Abstr.,1960,p. 1493.

17
[ 51135-73-0 ]
[ 116545-16-5 ]

References: [1]Synthesis,1988,vol. 1,p. 203 - 207.

18
[ 51135-73-0 ]
[ 116545-34-7 ]

References: [1]Synthesis,1988,vol. 1,p. 203 - 207.

19
[ 51135-73-0 ]
[ 116545-65-4 ]

References: [1]Synthesis,1988,vol. 1,p. 203 - 207.

20
[ 51135-73-0 ]
[ 116545-45-0 ]

References: [1]Synthesis,1988,vol. 1,p. 203 - 207.

21
[ 51135-73-0 ]
[ 116545-57-4 ]

References: [1]Synthesis,1988,vol. 1,p. 203 - 207.

22
[ 51135-73-0 ]
[ 67305-24-2 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 1875 - 1880.
[2]Asian Journal of Chemistry,2010,vol. 22,p. 1503 - 1506.
[3]Letters in drug design and discovery,2016,vol. 13,p. 912 - 920.
[4]Patent: US4892963,1990,A .

23
[ 51135-73-0 ]
[ 77120-94-6 ]