65651-80-1|(E)-Ethyl 3-(pyrrolidin-1-yl)acrylate| Ambeed

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Quality Control of [ 65651-80-1 ] Purity: 95% SDS Specification

COA

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NMR

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Product Details of [ 65651-80-1 ]

CAS No. :	65651-80-1
Formula :	C₉H₁₅NO₂
M.W :	169.22
SMILES Code :	O=C(OCC)/C=C/N1CCCC1
MDL No. :	MFCD01075735
InChI Key :	VFFHLZJSZHWXAJ-VMPITWQZSA-N
Pubchem ID :	639785

Safety of [ 65651-80-1 ]

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

Computational Chemistry of [ 65651-80-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	0
Fraction Csp3	0.67
Num. rotatable bonds	4
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	50.88
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.54 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.57
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	1.33
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.78
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.	0.9
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	1.29
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.37

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.46
Solubility	5.83 mg/ml ; 0.0344 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.	-1.55
Solubility	4.75 mg/ml ; 0.0281 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	-0.89
Solubility	21.8 mg/ml ; 0.129 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.	-6.39 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)	2.32

Application In Synthesis of [ 65651-80-1 ]

* 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 [ 65651-80-1 ]

[ 65651-80-1 ] Synthesis Path-Downstream 1~42

1
[ 123-75-1 ]
[ 623-47-2 ]
[ 65651-80-1 ]

Yield	Reaction Conditions	Operation in experiment
> 99%	With water; In neat (no solvent); at 20℃; for 0.166667h;Sealed tube; Green chemistry;	General procedure: Ethyl propiolate (0.5 mmol) was slowly added with stirring to amixture of N-methylaniline (0.6 mmol) and distilled H2O (0.1mL) in a 2 mL vial, and the vial then sealed. The mixture washeated at 80 C with stirring for 1 h. The reaction was thenquenched with sat. brine (0.5 mL), and the mixture was cooledto r.t. and extracted with EtOAc (3 × 1 mL) by pipette in thesame vial. The combined organic layers were dried (Na2SO4), filtered,and concentrated under reduced pressure. The residuewas purified by column chromatography [silica gel, PE-EtOAc(8:1)] to give a pale yellow oil
86%	In toluene; at 23℃; for 12h;	To a solution of ethyl propiolate (2.96 mL, 29.6 mmol) in toluene (20 mL) was addeddropwise a solution of pyrrolidine (2.4 mL, 29.0 mmol) in toluene (5 mL). The mixture was stirred at 23 C for 12 h and concentrated. The residue was purified by flash chromatography (eluting gradient: 0-10% ethyl acetate in petroleum ether) to give (E)-ethyl 3-(pyrrolidin- 1- yl)acrylate as a yellow oil (4.2 g, 86%). ‘H NMR (400 MHz, CDC13) 0 7.63 (d, J = 12.8 Hz, 1H), 4.44 (d, J = 12.8 Hz, 1H), 4.10 (q, J =7.2 Hz, 2H), 3.37 - 3.10 (m, 4H), 2.02 - 1.97 (m,4H), 1.23 (t, J =7.2 Hz, 3H).
	In benzene;	EXAMPLE 73 Preparation of Ethyl β-Pyrrolidinylacrylate. A solution of 29.43 g of ethyl propiolate (0.30 mol) in 200 ml of benzene was held at 25 in a water bath with magnetic stirring. A solution of 21.34 g of pyrrolidine in 50 ml of benzene was added dropwise over a period of 45 minutes, during which time the temperature rose to 35. The clear brown solution was stirred overnight and the solvent under reduced pressure at 55. The residue was distilled under reduced pressure to give 35.05 g of yellow oil, boiling point 110 (0.4 torr), which crystallized upon standing. The yellow solid was recrystallized from petroleum ether to give 31.36 (62%) of yellowish platelets, m.p. 37.5-39.5.

In benzene;

EXAMPLE 72 Preparation of Ethyl β-Pyrrolidinylacrylate. A solution of 29.43 g of ethyl propiolate (0.30 mol) in 200 ml of benzene was held at 25 in a water bath with magnetic stirring. A solution of 21.34 g of pyrrolidine in 50 ml of benzene was added dropwise over a period of 45 minutes, during which time the temperature rose to 35. The clear brown solution was stirred overnight and the solvent removed under reduced pressure at 55. The residue was distilled under reduced pressure to give 35.05 g of yellow oil, boiling point 110 (0.4 torr), which crystallized upon standing. The yellow solid was recrystallized from petroleum ether to give 31.36 (62%) of yellowish platelets, m.p. 37.5-39.5.

References: [1]Chemical Biology and Drug Design,2017,vol. 90,p. 820 - 839.
[2]Synlett,2020,vol. 31,p. 878 - 882.
[3]Monatshefte fur Chemie,2010,vol. 141,p. 1329 - 1332.
[4]Patent: WO2018/234345,2018,A1 .Location in patent: Page/Page column 131.
[5]Tetrahedron,1982,vol. 38,p. 3597.
[6]Patent: US4144047,1979,A .
[7]Patent: US4187099,1980,A .
[8]Organic and Biomolecular Chemistry,2021,vol. 19,p. 7914 - 7919.

2
[ 110-78-1 ]
[ 65651-80-1 ]
[ 82957-60-6 ]

References: [1]Chemische Berichte,1982,vol. 115,p. 2674 - 2678.

3
[ 65651-80-1 ]
[ 4392-24-9 ]
[ 4105-92-4 ]
[ 86576-75-2 ]
[ 86576-76-3 ]

References: [1]Tetrahedron,1982,vol. 38,p. 3597.
[2]Tetrahedron,1982,vol. 38,p. 3597.

4
[ 124-38-9 ]
[ 65651-80-1 ]
[ 2401-96-9 ]

References: [1]Chemische Berichte,1982,vol. 115,p. 2674 - 2678.

5
[ 369-57-3 ]
[ 65651-80-1 ]
ethyl 2-benzenehydrazonyl-3-pyrrolidiniumpropanoate tetrafluoroborate [ No CAS ]

References: [1]Tetrahedron,1981,vol. 37,p. 3513 - 3518.

6
[ 369-57-3 ]
[ 65651-80-1 ]
[ 67286-70-8 ]

References: [1]Tetrahedron,1981,vol. 37,p. 3519 - 3523.

7
[ 456-27-9 ]
[ 65651-80-1 ]
C₁₅H₁₉N₄O₄⁽¹⁺⁾*BF₄^(1-) [ No CAS ]

References: [1]Tetrahedron,1981,vol. 37,p. 3513 - 3518.

8
3-methoxybenzenediazonium tetrafluoroborate [ No CAS ]
[ 65651-80-1 ]
ethyl 2-(m-methoxybenzenehydrazonyl)-3-pyrrolidiniumpropanoate tetrafluoroborate [ No CAS ]

References: [1]Tetrahedron,1981,vol. 37,p. 3513 - 3518.

9
[ 100-39-0 ]
[ 65651-80-1 ]
ethyl 2-formyl-3-phenylpropionate [ No CAS ]
[ 86576-74-1 ]

References: [1]Tetrahedron,1982,vol. 38,p. 3597.
[2]Tetrahedron,1982,vol. 38,p. 3597.

10
[ 65651-80-1 ]
C₉H₁₄⁽²⁾HNO₂ [ No CAS ]

References: [1]Tetrahedron Letters,1981,vol. 22,p. 4259 - 4262.

11
[ 65651-80-1 ]
[ 103-71-9 ]
[ 82957-64-0 ]

References: [1]Chemische Berichte,1982,vol. 115,p. 2674 - 2678.

12
[ 65651-80-1 ]
[ 103-72-0 ]
[ 82957-65-1 ]

References: [1]Chemische Berichte,1982,vol. 115,p. 2674 - 2678.

13
[ 65651-80-1 ]
[ 592-82-5 ]
[ 82957-61-7 ]

References: [1]Chemische Berichte,1982,vol. 115,p. 2674 - 2678.

14
[ 65651-80-1 ]
[ 152975-99-0 ]
Triethyl 1,2-dihydro-2,3,5-pyridinetricarboxylate [ No CAS ]

References: [1]Journal of Organic Chemistry,1995,vol. 60,p. 2384 - 2390.

15
[ 65651-80-1 ]
[ 163592-53-8 ]
Triethyl 6-methyl-5-(methoxycarbonyl)-1,2-dihydro-2,2,3-pyridinetricarboxylate [ No CAS ]

References: [1]Journal of Organic Chemistry,1995,vol. 60,p. 2384 - 2390.

16
[ 637-81-0 ]
[ 65651-80-1 ]
1-(ethoxycarbonylmethyl)-4-ethoxycarbonyl-1,2,3-triazole [ No CAS ]

References: [1]Organic Preparations and Procedures International,1995,vol. 27,p. 603 - 612.

17
[ 71754-74-0 ]
[ 65651-80-1 ]
1-(1-ethoxycarbonylethyl)-4-ethoxycarbonyl-1,2,3-triazole [ No CAS ]

References: [1]Organic Preparations and Procedures International,1995,vol. 27,p. 603 - 612.

18
[ 65651-80-1 ]
[ 244238-87-7 ]
2-(4-Methoxy-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester [ No CAS ]

References: [1]Journal of Organic Chemistry,1999,vol. 64,p. 6239 - 6246.
[2]Tetrahedron Letters,1996,vol. 37,p. 6379 - 6382.

19
[ 129570-69-0 ]
[ 65651-80-1 ]
[3-(bis(diisopropylamino)thioxophosphoranyl)-4-(ethoxycarbonyl)-5-pyrrolidinyl]-2-pyrazolinyl}bis(diisopropylamino)methylphosphonium triflate [ No CAS ]

References: [1]Journal of Organic Chemistry,1997,vol. 62,p. 292 - 296.

20
[ 65651-80-1 ]
[ 17982-55-7 ]
1-(Diethoxy-phosphorylmethyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester [ No CAS ]

References: [1]Heterocycles,1998,vol. 48,p. 161 - 170.

21
[ 65651-80-1 ]
[ 17982-55-7 ]
1-(Diethoxy-phosphorylmethyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester [ No CAS ]
3-(Diethoxy-phosphorylmethyl)-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester [ No CAS ]

References: [1]Heterocycles,1998,vol. 48,p. 161 - 170.

22
[ 65651-80-1 ]
(E)-3-[1-Phenyl-meth-(E)-ylidene]-amino}-but-2-enoic acid methyl ester [ No CAS ]
6-methyl-2-phenyl-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester [ No CAS ]

References: [1]Journal of Organic Chemistry,1999,vol. 64,p. 6239 - 6246.

23
[ 65651-80-1 ]
[ 244238-88-8 ]
6-methyl-2-(4-nitro-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester [ No CAS ]

References: [1]Journal of Organic Chemistry,1999,vol. 64,p. 6239 - 6246.

24
[ 65651-80-1 ]
[ 185623-69-2 ]
ethyl 6-(2-furyl)-1,2-dihydro-2,5-diphenylpyridine-3-carboxylate [ No CAS ]

References: [1]European Journal of Organic Chemistry,2001,p. 2115 - 2122.
[2]Heterocycles,2004,vol. 64,p. 229 - 240.

25
[ 65651-80-1 ]
(3Z)-4-phenyl-1,3-bis(3-pyridyl)-2-azabuta-1,3-diene [ No CAS ]
ethyl 5-phenyl-2,6-bis(3-pyridyl)nicotinate [ No CAS ]

References: [1]European Journal of Organic Chemistry,2001,p. 2115 - 2122.

26
[ 65651-80-1 ]
(3Z)-4-phenyl-1,3-bis(2-thienyl)-2-azabuta-1,3-diene [ No CAS ]
ethyl 5-phenyl-2,6-bis(2-thienyl)nicotinate [ No CAS ]

References: [1]European Journal of Organic Chemistry,2001,p. 2115 - 2122.

27
[ 65651-80-1 ]
(1E/1Z,3Z)-1,3,4-triphenyl-2-azabuta-1,3-diene [ No CAS ]
ethyl 1,2-dihydro-2,5,6-triphenylpyridine-3-carboxylate [ No CAS ]

References: [1]European Journal of Organic Chemistry,2001,p. 2115 - 2122.

28
[ 65651-80-1 ]
[ 185623-69-2 ]
5-ethoxycarbonyl-6-furan-2-yl-2,3-diphenyl-1,2-dihydropyridine [ No CAS ]

References: [1]Heterocycles,2004,vol. 64,p. 229 - 240.

29
[ 951397-10-7 ]
[ 65651-80-1 ]
[ 5562-05-0 ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 6747 - 6750.

30
[ 65651-80-1 ]
5-ethoxycarbonyl-2-furan-2-yl-3,6-diphenylpyridine [ No CAS ]

References: [1]Heterocycles,2004,vol. 64,p. 229 - 240.
[2]European Journal of Organic Chemistry,2001,p. 2115 - 2122.

31
[ 65651-80-1 ]
ethyl 2,5,6-triphenylnicotinate [ No CAS ]

References: [1]European Journal of Organic Chemistry,2001,p. 2115 - 2122.

32
[ 65651-80-1 ]
[3-(bis(diisopropylamino)thioxophosphoranyl)-4-(ethoxycarbonyl)pyrazolyl]bis(diisopropylamino)methylphosphonium triflate [ No CAS ]

References: [1]Journal of Organic Chemistry,1997,vol. 62,p. 292 - 296.

33
[ 65651-80-1 ]
5-[(E)-Butylimino]-4-pyrrolidin-1-yl-5H-thiophen-2-one [ No CAS ]

References: [1]Chemische Berichte,1982,vol. 115,p. 2674 - 2678.

34
[ 123-75-1 ]
[ 79-24-3 ]
[ 65651-80-1 ]
[ 103-72-0 ]
[ 623-47-2 ]
[ 20328-15-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In toluene; acetonitrile;	a. 3-Methyl-4-[4-(trifluoromethyl)phenyl-aminocarbonyl]isoxazole. Ethyl propiolate (2.8 g) and pyrrolidine (1.4 g) in 5 mL of acetonitrile are mixed at room temperature for 1 hour, the solvent evaporated and the ethyl 3-pyrrolidin-1-acrylate used as isolated or distilled under vacuum. Triethylamine (0.25 mL) is added to a mixture of 1.8 g of ethyl 3-pyrrolidin-1-acrylate, 0.9 g of nitroethane and 2.5 g of phenyl isothiocyanate in 10 mL of toluene at room temperature and stirred overnight. The mixture is then refluxed for 0.5 hour, cooled, and the diphenylurea removed by filtration. The mixture is washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to dryness under vacuum to give 1.4 g of ethyl 3-methyl-4-isoxazolecarboxylate. (Stork, G., McMurry, J. C., J. Am. Chem. Soc. 89, 5461,1967).

References: [1]Patent: US6316479,2001,B1 .

35
tert-butyl 2-chloro-2-hydroximino-acetate [ No CAS ]
[ 65651-80-1 ]
3-tert-Butyl 4-ethyl isoxazole-3,4-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	3-tert-Butyl 4-ethyl isoxazole-3,4-dicarboxylate STR12 87.7 g (0.52 mol) of ethyl 3-(1pyrrolidinyl) acrylate are dissolved in 500 ml of tetrahydrofuran, and 93.2 g (0.52 mol) of tert-butyl 2-chloro-2-hydroximino-acetate in 500 ml of tetrahydrofuran are added. Refluxing is carried out for about 3 hours. Thereafter, the mixture is diluted with water, rendered neutral with sodium hydroxide solution, stirred for 5 minutes and then acidified again with hydrochloric acid. The solution is extracted with ethyl acetate and the organic phase is washed with 2N hydrochloric acid and with water. Purification is carried out by chromatography over silica gel. 50.6 g of an oil are obtained.

References: [1]Patent: US5576270,1996,A .

36
[ 65651-80-1 ]
[ 121-44-8 ]
[ 29363-98-2 ]

Yield	Reaction Conditions	Operation in experiment
1.27 g (20%)		EXAMPLE 76 Preparation of Ethyl 3-(4-Chlorophenyl)-4-Isoxazolecarboxylate. The crude product from the reaction of 4.23 g of ethyl β-pyrrolidinylacrylate (0.025 mol) and the nitrile oxide from 4.75 g p-chlorobenzohydroxamoyl chloride (0.025 mol) and 3.5 ml Et3 N run as above, gave, after chromatography, 1.27 g (20%) of white solid, m.p. 43-45; infrared (melt); 1725 cm-1 (s), 1290 (s) and 1170 (s); nmr (CCl4) δ 1.35 (t, 3H), 4.30 (q, 2H), 7.4 and 7.8 (ABq, 4H) and 8.95 (s, 1H). Anal. Calc'd. for C12 H10 ClNO3: C, 57.27; H, 4.01; Cl, 14.09; N, 5.57. Found: C, 57.29; H, 3.88; Cl, 14.04; N, 5.35.
1.27 g (20%)		EXAMPLE 75 Preparation of Ethyl 3-(4-Chlorophenyl)-4-Isoxazolecarboxylate. The crude product from the reaction of 4.23 g of ethyl β-pyrrolidinylacrylate (0.025 mol) and the nitrile oxide from 4.75 g p-chlorobenzohydroxamoyl chloride (0.025 mol) and 3.5 ml Et3 N run as above, gave, after chromatography, 1.27 g (20%) of white solid, m.p. 43-45; infrared (melt); 1725 cm-1 (s), 1290 (s) and 1170 (s); nmr (CCl4) δ 1.35 (t, 3H), 4.30 (q, 2H), 7.4 and 7.8 (ABq, 4H) and 8.95 (s, 1H). Anal. Calc'd. for C12 H10 ClNO3: C, 57.27; H, 4.01; Cl, 14.09; N, 5.57. Found: C, 57.29; H, 3.88; Cl, 14.04; N, 5.35.

References: [1]Patent: US4144047,1979,A .
[2]Patent: US4187099,1980,A .

37
[ 65651-80-1 ]
[ 121-44-8 ]
3-(3-chlorophenyl)-isoxazole-4-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.78 g (44%)		EXAMPLE 77 Preparation of Ethyl 3-(3-Chlorophenyl)-4-Isoxazolecarboxylate. The crude oil from the reaction of 4.23 g of ethyl β-pyrrolidinylacrylate (0.025 mol) and the nitrile oxide from 4.75 g of 3-chlorobenzohydroxamoyl chloride and 3.5 ml of Et3 N, run as in Example 75, was twice crystallized from petroleum ether to give 2.78 g (44%) of tan powder, m.p. 43-45; infrared (melt); 1720 cm-1 (s), 1550 (s), 1290 (s), 1125 (s); nmr (CCl4) δ 1.35 (t, 3H), 4.25 (q, 2H), 7.2-7.4 and 7.5-7.9 (complex, 4H), 8.95 (s, 1H). Anal. Calc'd. for C12 H10 ClNO3: C, 57.27; H, 4.01; Cl, 14.09; N, 5.57. Found: C, 57.07; H, 4.02; Cl, 13.99; N, 5.67.
2.78 g (44%)		EXAMPLE 76 Preparation of Ethyl 3-(3-Chlorophenyl)-4-Isoxazolecarboxylate. The crude oil from the reaction of 4.23 g of ethyl β-pyrrolidinylacrylate (0.025 mol) and the nitrile oxide from 4.75 g of 3-chlorobenzohydroxamoyl chloride and 3.5 ml of Et3 N, run as in Example 74, was twice crystallized from petroleum ether to give 2.78 g (44%) of tan powder, m.p. 43-45; infrared (melt); 1720 cm-1 (s), 1550 (s), 1290 (s), 1125 (s); nmr (CCl4) δ 1.35 (t, 3H), 4.25 (q, 2H), 7.2-7.4 and 7.5-7.9 (complex, 4H), 8.95 (s, 1H). Anal. Calc'd. for C12 H10 ClNO3: C, 57.27; H, 4.01; Cl, 14.09; N, 5.57. Found: C, 57.07; H, 4.02; Cl, 13.99; N, 5.67.

References: [1]Patent: US4144047,1979,A .
[2]Patent: US4187099,1980,A .

38
[ 65651-80-1 ]
ethyl 3-(α,α,α-Trifluoro-m-Tolyl)-4-Isoxazolecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In diethyl ether;	EXAMPLE 75 Preparation of Ethyl 3-(α,α,α-Trifluoro-m-Tolyl)-4-Isoxazolecarboxylate. A solution of 4.87 g of ethyl β-pyrrolidinylacrylate (0.0288 mol) and 5.0 ml of triethylamine in 60 ml of ethyl ether was cooled to 0. A solution of 6.43 g of m-trifluoromethylbenzohydroxamoyl chloride in 25 ml of ether was added over a period of 40 minutes with magnetic stirring, during which time a white precipitate of Et3 N.HCl formed. The mixture was stirred at 0 for 2.5 hours and filtered and the solid washed thoroughly with ether. The combined solutions were washed with 5% HCl and water, dried over MgSO4, filtered and concentrated to 7.66 g of orange oil; only one peak was observed on GLC. Double distillation through a 4 inch * 1/2 inch Vigreux column gave 5.95 g (72% crude), boiling point 98-100 (0.08 torr), slightly yellow oil, tlc (Silica Gel G, benzene) showed 3 spots, Rf 0.21, 0.46 and 0.61. Chromatography of 5.80 g of the oil on 110 g of dry column silica gel (~80 cm long) gave 1.79 g of oil (mixture Rf 0.46 and 0.61, faint), first 120 ml benzene eluent and 3.78 g clear colorless oil in the second 120 ml benzene (pure by tlc, Rf 0.46). The second fraction was distilled giving 2.85 g (34%) of pure product, boiling point 94 (0.045 torr), infrared (neat); 1720 cm-1 (s), 1340 (s), 1120 (s); nmr (CCl4) δ 1.25 (t, 3H), 4.26 (q, 2 H), 7.4-8.2 (m, 4H) and 9.0 (s, 1H). Anal. Calc'd. for C13 H10 F3 NO2: C, 54.74; H, 3.53; F, 19.98; N, 4.91. Found: C, 54.68; H, 3.39; F, 19.87; N, 5.00.
	With triethylamine; In diethyl ether;	EXAMPLE 74 Preparation of Ethyl 3-(α,α,α-Trifluoro-m-Tolyl)-4-Isoxazolecarboxylate. A solution of 4.87 g of ethyl β-pyrrolidinylacrylate (0.0288 mol) and 5.0 ml of triethylamine in 60 ml of ethyl ether was cooled to 0. A solution of 6.43 g of m-trifluoromethylbenzohydroxamoyl chloride in 25 ml of ether was added over a period of 40 minutes with magnetic stirring, during which time a white precipitate of Et3 N.HCl formed. The mixture was stirred at 0 for 2.5 hours and filtered and the solid washed thoroughly with ether. The combined solutions were washed with 5% HCl and water, dried over MgSO4, filtered and concentrated to 7.66 g of orange oil; only one peak was observed on GLC. Double distillation through a 4"*1/2" Vigreux column gave 5.95 g (72% crude), boiling point 98-100 (0.08torr), slightly yellow oil, tlc (Silica Gel G, benzene) showed 3 spots, Rf 0.21, 0.46, and 0.61. Chromatography of 5.80 g of the oil on 110 g of dry column silica gel (~80 cm long) gave 1.79 g of oil (mixture Rf 0.46 and 0.61, faint), first 120 ml benzene eluent and 3.78 g clear colorless oil in the second 120 ml benzene (pure by tlc, Rf 0.46). The second fraction was distilled giving 2.85 g (34%) of pure product, boiling point 94 (0.045 torr), infrared (neat); 1720 cm-1 (s), 1340 (s), 1120 (s); nmr (CCl4) δ 1.25 (t, 3H), 4.26 (q, 2H), 7.4-8.2 (m, 4H) and 9.0 (s, 1H). Anal. Calc'd. for C13 H10 F3 NO2: C, 54.74; H, 3.53; F, 19.98; N, 4.91. Found: C, 54.68; H, 3.39; F, 19.87; N, 5.00.

References: [1]Patent: US4144047,1979,A .
[2]Patent: US4187099,1980,A .

39
[ 65651-80-1 ]
ethyl 3-(3-Nitrophenyl)-4-Isoxazolecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.72 g (58%)	With triethylamine;	EXAMPLE 78 Preparation of Ethyl 3-(3-Nitrophenyl)-4-Isoxazolecarboxylate. A mixture of 4.23 g (0.025 mol) of ethyl β-pyrrolidinylacrylate and 3.5 ml of triethylamine in 60 ml of anhydrous ether was cooled to -10. A solution of 5.01 g (0.025 mol) of 3-nitrobenzohydroxamoyl chloride in 20 ml of ether was added dropwise in 30 minutes with rapid magnetic stirring. The mixture was stirred at -10-0 for 4 hours and allowed to warm to room temperature overnight. The solid was removed by filtration and washed four times with 50 ml of boiling ether. The residues from the evaporation of the ether solutions were recrystallized from hexane and combined to give 3.72 g (58%) of white needles, m.p. 90-92; nmr (CCl4) δ 1.30 (t, 3H), 4.27 (q, 2H), 7.47-8.80 (m, 4H) and 9.06 (s, 1H). Anal. Calc'd. for C12 H10 N2 O5: C, 54.97; H, 3.84; N, 10.68. Found: C, 55.07; H, 3.91; N, 10.59.
3.72 g (58%)	With triethylamine;	EXAMPLE 77 Preparation of Ethyl 3-(3-Nitrophenyl)-4-Isoxazolecarboxylate. A mixture of 4.23 g (0.025 mol) of ethyl β-pyrrolidinylacrylate and 3.5 ml of triethylamine in 60 ml of anhydrous ether was cooled to -10. A solution of 5.01 g (0.025 mol) of 3-nitrobenzohydroxamoyl chloride in 20 ml of ether was added dropwise in 30 minutes with rapid magnetic stirring. The mixture was stirred at -10-0 for 4 hours and allowed to warm to room temperature overnight. The solid was removed by filtration and washed four times with 50 ml of boiling ether. The residues from the evaporation of the ether solutions were recrystallized from hexane and combined to give 3.72 g (58%) of white needles, m.p. 90-92; nmr (CCl4) δ 1.30 (t, 3H), 4.27 (q, 2H), 7.47-8.80 (m, 4H) and 9.06 (s, 1H). Anal. Calc'd. for C12 H10 N2 O5: C, 54.97; H, 3.84; N, 10.68. Found: C, 55.07; H, 3.91; N, 10.59.

References: [1]Patent: US4144047,1979,A .
[2]Patent: US4187099,1980,A .

40
[ 123-75-1 ]
[ 105-37-3 ]
[ 65651-80-1 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10090 - 10107.

41
[ 29203-59-6 ]
[ 65651-80-1 ]
3-(3-chlorophenyl)-isoxazole-4-carboxylic acid ethyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10090 - 10107.

42
[ 65651-80-1 ]
[ 100-52-7 ]
[ 65651-78-7 ]

References: [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 7933 - 7937.
Angew. Chem.,2014,vol. 126,p. 8067 - 8071,5.

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• Acyl Group Substitution • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Complex Metal Hydride Reductions • Ester Cleavage • Reactions with Organometallic Reagents • Specialized Acylation Reagents-Carbodiimides and Related Reagents

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CAS No.: 65651-80-1

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