[ CAS No. 88709-17-5 ] {[proInfo.proName]}

Name: 88709-17-5|Ethyl 2-ethoxy-4-methylbenzoate|97%
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Quality Control of [ 88709-17-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 88709-17-5 ]

SDS Specification

Alternatived Products of [ 88709-17-5 ]

Product Details of [ 88709-17-5 ]

CAS No. :	88709-17-5	MDL No. :	MFCD09701458
Formula :	C₁₂H₁₆O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PQLJVFJXXWBUPR-UHFFFAOYSA-N
M.W :	208.25	Pubchem ID :	11816602
Synonyms :

Calculated chemistry of [ 88709-17-5 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.42
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	58.79
TPSA :	35.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.55 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.93
Log Po/w (XLOGP3) :	2.84
Log Po/w (WLOGP) :	2.57
Log Po/w (MLOGP) :	2.51
Log Po/w (SILICOS-IT) :	2.94
Consensus Log Po/w :	2.76

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.89
Solubility :	0.271 mg/ml ; 0.0013 mol/l
Class :	Soluble
Log S (Ali) :	-3.24
Solubility :	0.119 mg/ml ; 0.00057 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.8
Solubility :	0.0327 mg/ml ; 0.000157 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.99

Safety of [ 88709-17-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 88709-17-5 ]

* 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.

Upstream synthesis route of [ 88709-17-5 ]
Downstream synthetic route of [ 88709-17-5 ]

[ 88709-17-5 ] Synthesis Path-Upstream 1~3

1
[ 74-96-4 ]
[ 50-85-1 ]
[ 88709-17-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In dimethyl sulfoxide at 35 - 40℃; for 11 h;	Potassium carbonate (68.0 g, 0.492 mole) was added to a well-stirred solution of 4-methylsalicylic acid (25 g, 0.164 mole) in dimethylsulfoxide (75 ml ). The mixture was stirred at 35-40° C. and 1st lot of ethyl bromide (27.0 g, 0.247 mole) was added slowly over a period of 30 minutes then stirred for two hours and a second lot of ethyl bromide (27.0 g, 0.247 mole) was added over a period of 30 minutes at 35-40° C. The reaction mixture was further stirred at 35-40° C. for eight hours, cooled to 20-25° C., and diluted with dichloromethane (50 ml). The inorganics were removed by filtration and washed with dichloromethane. The combined filtrate and washings were diluted with water (50 ml), stirred for 30 minutes, and the organic layer was separated. The aqueous layer was further extracted with dichloromethane and the combined dichloromethane layer was washed with water (2.x.50 ml). The solvent was removed under vacuum to afford ethyl 2-ethoxy-4-methylbenzoate 34.2 g (quantitative yield).
88%	With potassium carbonate In dimethyl sulfoxide at 40℃; for 10.5 h;	To a mixture of 2-hydroxy-4-methylbenzoic acid (20.0 g, 131.5 mmol) and K2CO3 (54.5 g, 394.5 mmol) in DMSO (50 mL) at 40 °C was added bromoethane (21 .5 g, 197.2 mmol) over 30 minutes. The reaction was then stirred at 40 C for 2 hours. Further bromoethane (21.5 g, 197.2 mmol) was then added dropwise and the reaction stirred at 40 °C for 8 hours. DCM (200 mL) was added and the mixture was filtered. The organic layer was washed with water (4 x 150 mL), dried (Na2SO.i) and concentrated to give the title compound (24.1 g, 88percent) as a clear oil. LCMS-C: RT 2.77 min; m/z 209.1 [M+H] ⁺

Reference： [1] Patent: US6686497, 2004, B1, . Location in patent: Page column 3-4
[2] Organic Process Research and Development, 2002, vol. 6, # 2, p. 184 - 186
[3] Patent: WO2016/34673, 2016, A1, . Location in patent: Page/Page column 103
[4] Journal of Medicinal Chemistry, 1998, vol. 41, # 26, p. 5219 - 5246

2
[ 50-85-1 ]
[ 75-03-6 ]
[ 88709-17-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In dimethyl sulfoxide at 40℃; for 11 h;	To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 54 mmol) and K2CO3 (22.4 g, 162 mmol) in DMSO (70 mL) at 40 C was added ethyl iodide (12.6 g, 80.8 mmol) drop-wise over a period of 30 minutes. The reaction was stirred for 2 hours then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 minutes. The resulting mixture was stirred for another 8 hours at 40 C, then diluted with DCM (150 mL) and filtered. The filtrate was washed with water (200 mL ^χ 10) and brine (200 mL 2), dried ( a2S0₄) and concentrated to give the desired compound (10.1 g, 90percent yield) as a yellow liquid. LCMS-C: RT 2.70 min; m/z 209.1 [M+H]^*
90%	With potassium carbonate In dimethyl sulfoxide at 40℃; for 11 h;	To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 53.9 mmol) and K2CO3 (22.4 g, 161.7 mmol) in dimethylsulfoxide (70 mL) at 40 ^C was added and ethyl iodide (12.6 g, 80.8 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 h then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 min. The resulting mixture was stirred a further 8 h at 40 ^C, then diluted with CH2Cl2 (150 mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried (Na₂SO₄) and concentrated to give the desired compound as a yellow liquid (10.1 g, 90percent): LCMS: RT 2.70min; m/z 209.1 [M+H]⁺.
90%	With potassium carbonate In dimethyl sulfoxide at 40℃; for 11 h;	To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 53.9 mmol) and K2CO3 (22.4 g, 161 .7 mmol) in dimethylsulfoxide (70 mL) at 40 °C was added ethyl iodide (12.6 g, 80.8 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 hours then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 min. The resulting mixture was stirred a further 8 hours at 40 °C, diluted with CH2CI2 CI 5O mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried (Na2SC>4), filtered and concentrated to give the desired compound as a yellow liquid (10.1 g, 90percent): LCMS: RT 2.70min; m/z 209.1 [M+H]⁺.

85%

With potassium carbonate In acetone at 20℃; for 72 h;

[00463] Intermediate 48: Synthesis of ethyl 2-ethoxy-4-formylbenzoate[00464] Step 1: Synthesis of ethyl 2-ethoxy-4-methylbenzoate: To a mixture of 2- hydroxy-4-methylbenzoic acid (5.0 g, 32.9 mmol), K₂C0₃ (18.9 g, 136.6 mmol) and acetone (50 mL) was added ethyl iodide (41.0 g, 263.2 mmol). The mixture was stirred at room temperature for 3 days. After filtration, the organic layer was concentrated to afford ethyl 2- ethoxy-4-methylbenzoate as colorless oil (5.7 g, 85percent), which was used directly for next step.

Reference： [1] Patent: WO2016/34673, 2016, A1, . Location in patent: Page/Page column 88; 89
[2] Patent: WO2017/153513, 2017, A1, . Location in patent: Page/Page column 72
[3] Patent: WO2017/153519, 2017, A1, . Location in patent: Page/Page column 63; 64
[4] Patent: WO2011/38204, 2011, A1, . Location in patent: Page/Page column 150

3
[ 64-67-5 ]
[ 50-85-1 ]
[ 88709-17-5 ]

Yield	Reaction Conditions	Operation in experiment
94.11%	With potassium carbonate In toluene at 25 - 45℃; for 21 - 31.5 h; Heating / reflux	Added 260 ml (3.0 mol) of diethyl sulfate to the mixture of 1000 ml of toluene, 272.5 g (3.0 mol) of potassium carbonate and 100 g (1.0 mol) of 2-Hydroxy-4-methyl-benzoic acid at 25-45° C. for 1 hr to 1 hr 30 min. Heated the reaction mass to azeotropic reflux for 20-30 hr. Cooled the reaction mixture to 25-35° C. and collected the unwanted material by filtration, washed the unwanted material with 500 ml of toluene. Combined filtrate was washed with water (1.x.1000 ml and 1.x.500 ml) at 80-85° C. Total organic layer was concentrated to residue under vacuum at below 70° C. The yield of the title compound is 128 g (94.11percent). [0036] The obtained product was characterised by analytical techniques like IR, Mass and 1H-NMR
87%	With potassium carbonate In acetonitrile for 12 h; Heating / reflux	4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry acetonitrile and mixture was refluxed for 12 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=6 g (87percent).
84%	With potassium carbonate In 1,4-dioxane for 16 h; Heating / reflux	4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry dioxane and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=5.8 g (84percent).

75%

With potassium carbonate In acetone for 16 h; Heating / reflux

4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry acetone and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=5.2 g (75percent)

Reference： [1] Patent: US2004/249188, 2004, A1, . Location in patent: Page 2; 3; 5
[2] Patent: US2004/192955, 2004, A1, . Location in patent: Page 3
[3] Patent: US2004/192955, 2004, A1, . Location in patent: Page 3
[4] Patent: US2004/192955, 2004, A1, . Location in patent: Page 3

[ 88709-17-5 ] Synthesis Path-Downstream 1~88

1
[ 74-96-4 ]
[ 50-85-1 ]
[ 88709-17-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In dimethyl sulfoxide; at 35 - 40℃; for 11h;	Potassium carbonate (68.0 g, 0.492 mole) was added to a well-stirred solution of 4-methylsalicylic acid (25 g, 0.164 mole) in dimethylsulfoxide (75 ml ). The mixture was stirred at 35-40 C. and 1st lot of ethyl bromide (27.0 g, 0.247 mole) was added slowly over a period of 30 minutes then stirred for two hours and a second lot of ethyl bromide (27.0 g, 0.247 mole) was added over a period of 30 minutes at 35-40 C. The reaction mixture was further stirred at 35-40 C. for eight hours, cooled to 20-25 C., and diluted with dichloromethane (50 ml). The inorganics were removed by filtration and washed with dichloromethane. The combined filtrate and washings were diluted with water (50 ml), stirred for 30 minutes, and the organic layer was separated. The aqueous layer was further extracted with dichloromethane and the combined dichloromethane layer was washed with water (2×50 ml). The solvent was removed under vacuum to afford ethyl 2-ethoxy-4-methylbenzoate 34.2 g (quantitative yield).
88%	With potassium carbonate; In dimethyl sulfoxide; at 40℃; for 10.5h;	To a mixture of 2-hydroxy-4-methylbenzoic acid (20.0 g, 131.5 mmol) and K2CO3 (54.5 g, 394.5 mmol) in DMSO (50 mL) at 40 C was added bromoethane (21 .5 g, 197.2 mmol) over 30 minutes. The reaction was then stirred at 40 C for 2 hours. Further bromoethane (21.5 g, 197.2 mmol) was then added dropwise and the reaction stirred at 40 C for 8 hours. DCM (200 mL) was added and the mixture was filtered. The organic layer was washed with water (4 x 150 mL), dried (Na2SO.i) and concentrated to give the title compound (24.1 g, 88%) as a clear oil. LCMS-C: RT 2.77 min; m/z 209.1 [M+H] +

Reference： [1]Patent: US6686497,2004,B1 .Location in patent: Page column 3-4
[2]Organic Process Research and Development,2002,vol. 6,p. 184 - 186
[3]Patent: WO2016/34673,2016,A1 .Location in patent: Page/Page column 103
[4]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

2
[ 88709-17-5 ]
[ 110017-07-7 ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In cyclohexane; for 3 - 5h;Heating / reflux;	To the suspension of 700 ml of cyclo hexane, 86 g (1.0 mol) of N-bromo succinimide and 3 g (0.03 mol) of AIBN was added 100 g (1.0 ml) of Ethyl-2-ethoxy-4-methyl benzoate. Heated the resulted mass to reflux and stirred for 3-5 hr. Cooled to 50-60 C. and charged 200 ml of water, then stirred for 10-15 min. Separated the aqueous phase and organic phase. The organic phase was washed with 200 ml of 5% hydrose followed by water (200 ml) at 50-60 C. Total organic phase was distilled completely under vacuum at below 60 C. Cooled to 25-35 C. and the title compound was isolated from residue with 100 ml n-Heptane at 0-5 C. The obtained compound was recrystallised from 400 ml of n-Heptane. Dried the compound under reduced pressure at 45-50 C. The yield of the recrystallised compound is 59.2 g (43%). [0038] The obtained product was characterised by analytical techniques like IR, Mass and 1H-NMR
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 2-methylbenzotrifluoride; for 24h;Reflux;	00465] Step 2: Synthesis of ethyl 4-(bromomethyl)-2-ethoxybenzoate: To a solution of <strong>[88709-17-5]ethyl 2-ethoxy-4-methylbenzoate</strong> (100 mg, 0.481 mmol) in 2 mL oftrifluoromethyl toluene was added NBS (94 mg, 0.529 mmol) and AIBN (10 mg) in portions. The mixture was heated to reflux and stirred for 24 h. The reaction mixture was concentrated, diluted with 10 mL of EA, washed with 5 mL of 4 N NaOH, 5 mL of brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford ethyl 4-(bromomethyl)- 2-ethoxybenzoate as brown oil (42 mg, 30%), which was used for the next step directly.

Reference： [1]Patent: US2004/249188,2004,A1 .Location in patent: Page 2; 4; 5
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[3]Patent: WO2011/38204,2011,A1 .Location in patent: Page/Page column 150-151

3
[ 88709-17-5 ]
[ 99470-01-6 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

4
[ 88709-17-5 ]
[ 220438-80-2 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

5
[ 88709-17-5 ]
ethyl 4-(2-amino-2-oxoethyl)-2-ethoxybenzoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

6
[ 88709-17-5 ]
[ 99469-99-5 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246
[3]Patent: CN110483292,2019,A
[4]Patent: CN110483292,2019,A

7
[ 88709-17-5 ]
[ 332347-69-0 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 5219 - 5246

8
[ 88709-17-5 ]
4-[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid [ No CAS ]