34113-69-4|4-Chloro-3-hydroxybenzoic acid| Ambeed

Structure of 34113-69-4

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Quality Control of [ 34113-69-4 ] Purity: 98% SDS Specification

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Product Details of [ 34113-69-4 ]

CAS No. :	34113-69-4
Formula :	C₇H₅ClO₃
M.W :	172.57
SMILES Code :	C1=C(C(=CC=C1C(O)=O)Cl)O
MDL No. :	MFCD00153892
InChI Key :	SCPUNJAMWFAYED-UHFFFAOYSA-N
Pubchem ID :	141872

Safety of [ 34113-69-4 ]

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

Computational Chemistry of [ 34113-69-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	40.43
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	57.53 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.26
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	2.41
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.74
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.	1.59
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	1.38
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.68

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.77
Solubility	0.296 mg/ml ; 0.00171 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.	-3.26
Solubility	0.0948 mg/ml ; 0.000549 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	-1.81
Solubility	2.69 mg/ml ; 0.0156 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.	-5.64 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.	0.56

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)	1.16

Application In Synthesis of [ 34113-69-4 ]

* 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 [ 34113-69-4 ]

[ 34113-69-4 ] Synthesis Path-Downstream 1~54

1
[ 67-56-1 ]
[ 34113-69-4 ]
[ 166272-81-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With thionyl chloride; at 70℃; for 2h;	Thionyl chloride (6 g) was added to a solution of <strong>[34113-69-4]4-chloro-3-hydroxybenzoic acid</strong> (4.4 g, 25.50 mmol) in methanol (100 mL) and the reaction was stirred for 2 h at 70C. Then the reaction was concentrated in vacuo. The resulting solution was diluted with n-hexane (50 mL). The solids were collected by filtration, dried in an oven under reduced pressure to afford methyl 4-chloro-3-hydroxybenzoate as a light yellow solid (4 g, 84%). LC/MS (ES, m/z): [M+H]+ 187.0 *H NMR (300 MHz, DMSO) δ 10.69 (s, 1H), 7.55 (d, / = 2.10 Hz, 1H), 7.49 (d, / = 8.40 Hz, 1H), 7.36 - 7.40 (m, 1H), 3.83 - 3.85 (d, / = 8.40 Hz, 3H)
83%	With thionyl chloride; at 0℃; for 3h;Reflux;	General procedure: To a solution of 2-fluoro-5-hydroxybenzoic acid(1.56 g, 10 mmol) in anhydrous methanol (10 mL), thionly chloride (1.42 mL, 20mmol) was added dropwise at 0 C. The reaction was allowed to warm to rt andreflux for 3 h. The solvent was removed under reduced pressure, water wasadded, and the mixture was extracted with DCM (80 mL). The organic layer was washedwith water, saturated brine, dried over anhydrous sodium sulfate, evaporated togive title compound as a white solid (1.5 g, 88% yield), which was used in thefollowing step without any further purification
	sulfuric acid; for 30h;Heating / reflux;	Example VII This example illustrate the preparation of [4-Methoxy-4-(3-phosphoryloxy-4-chlorophenyl)] spiro [1, 2-dioxetane-3,2'-(5-methoxy(D3)admantane)], disodium salt (56).; The sequence of the reactions in accordance herewith: (a). Synthesis of Methyl 3-hydroxy-4-chlorobenzoate (50), (a starting ester). In a 250mL round bottom flask, 15 parts of 3-hydroxy-4-chlorobenzoicacid (11, commercially available) was dissolved in methanol (150mL) and concentrated sulfuric acid (2mL). The reaction mixture was heated at reflux for 30 hours. TLC on silica gel plates showed formation of the product The solvent was evaporated under reduced pressure and the residue was dissoved in ethyl acetate (150 ml). The organic layer was washed with 5% aqueous sodium bicarbonate solution (100mL) and deionized water (150mL). The organic sovent was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and residue purified by chromatography on silica gel column eluting with 25% ethyl acetate-hexanes. Product containing fractions were checked by TLC on silica gel plates & combined. The solvent was evaporated under reduced pressure gave 14.5 parts of the titile compound (50) as off-white solid. The structure was confirmed by 1H NMR. The reaction proceeded as follows :

	With sulfuric acid; for 2h;Reflux;	A 500 mL round bottomed flask was charged with 4-chloro-3-hydroxy-benzoic acid (30 g, 0.175 mmol), 200 mL of MeOH and 10 mL of H2SO4. The resultant mixture was refluxed for 2 hours and then concentrated. Then ethyl acetate and water was added. The organic phase was dried over anhydrous Na2SO4 and then concentrated to give methyl 4-chloro-3-hydroxy-benzoate which used directly in the next step.
	With sulfuric acid; for 2h;Reflux;	Step 1: Preparation of methyl 4-ehIoro-3-h droxy-ben/oate A 500 ml, round bottomed flask was charged with 4-chloro-3-hydroxy-benzoic acid (30 g, 0. 1 75 mmol), 200 mL of MeOt 1 and 10 mL of H2SO4. The resultant mixture was refluxed for 2 hours and then concentrated. Then ethyl acetate and water was added. The organic phase was dried over anhydrous NajSOa and then concentrated to give methyl 4-chloro-3-hydroxy-benzoate which used directly in the next step.
902 mg	With sulfuric acid; at 75℃; for 14h;	To a stirred solution of <strong>[34113-69-4]4-chloro-3-hydroxybenzoic acid</strong> (690 mg, 4.00 mmol) in methanol(8.0 mL) was added sulfuric acid (10 jiL, 0.20 mmol) and the mixture was heated at 75 C for14 h. The mixture was concentrated, residue was cooled to 0 C and neutralized using aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated to yield 902 mg of thedesired product. ‘H NMR (400 MHz, DMSO-d6) ö 3.91 (s, 3H), 5.66 (d, J = 4.4 Hz, 1H),7.39 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.3, 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H); ESI-MS (m/z) 187 (M+H).

References: [1]Chemical and Pharmaceutical Bulletin,1994,vol. 42,p. 2365 - 2369.
[2]Patent: WO2014/66795,2014,A1 .Location in patent: Paragraph 0175.
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3141 - 3147.
[4]Journal of Medicinal Chemistry,2005,vol. 48,p. 3290 - 3312.
[5]Patent: EP2048140,2009,A1 .Location in patent: Page/Page column 25.
[6]Patent: US2015/210682,2015,A1 .Location in patent: Paragraph 1502; 1503.
[7]Patent: WO2015/113990,2015,A1 .Location in patent: Page/Page column 211; 212.
[8]Journal of Medicinal Chemistry,2017,vol. 60,p. 10188 - 10204.
[9]Patent: WO2018/215668,2018,A1 .Location in patent: Page/Page column 63.

2
[ 34113-69-4 ]
[ 75-03-6 ]
4-chloro-3-ethoxy-benzoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In N,N-dimethyl-formamide; for 6h;	Example 1 N-[1-(4-Chloro-3-ethoxy-benzyl)piperidin-4-yl]-6-imidazol-1-yl-nicotinamide 4-Chloro-3-ethoxy-benzaldehyde The title compound was prepared from commercially available 4-chloro-3-hydroxy-benzoic acid as follows: 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17 mmol) was dissolved in DMF (15 ml) and K2CO3 (4.7 g, 34.0 mmol) and EtI (6.0 g, 38 mmol) were added and the reaction stirred for 6 h. The reaction was then diluted with water and extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated to afford 3.6 g (91% yield) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to -78 C. under Ar. Di-isobutylaluminium hydride (95 mL, 1M in THF, 95 mmol) was then slowly added (15 min), the cooling bath removed on completion of addition and the reaction allowed to reach 0 C. (1 h). The reaction was then cooled to -78 C., the excess hydride was quenched by cautious addition of 1N HCl. The mixture was brought to room temperature, the organic separated and the aqueous extracted with EtOAc. The combined organic were dried (Na2SO4) and concentrated to afford 2.9 g (100% yield) of 4-chloro-3-ethoxy-benzyl alcohol. 2.94 g (16 mmol) of the crude alcohol was dissolved in DCM (15 mL) and MnO2 (5.5 g, 63 mmol) was added. The reaction was stirred for 16 h, after which time the reaction was filtered through Hyflo and concentrated. The residue was purified by flash column chromatography (EtOAc:Heptane 1:4) to yield 1.5 g (52% yield) of the title aldehyde. 1H NMR (300 MHz, CDCl3): δ1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	B] 4-Chloro-3-ethoxy-benzaldehvde; To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mMol, 1.0 eq.) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mMol, 2.0 eq.) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mMol, 2.2 eq.). The reaction mixture was stirred for 6 h at RT, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic EPO <DP n="71"/>acid ethyl ester. The crude ester was then dissolved in THF (20 rnL) and cooled to -78 0C under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mMol, 6.0 eq.; 1 M solution in THF) was slowly added over a time periode of 15 min, the cooling bath removed after completion of addition and the reaction allowed to reach 0 0C. After 1 h, the reaction was cooled to -78 0C and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to RT, the organic phase separated and the aqueous layer extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure to afford 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mMol, 1.0 eq.) was dissolved in dichloromethane (15 mL) and MnO2 (5.48 g, 63.0 mMol, 4.0 eq.) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52% yield) of the title compound. 1U NMR (300 MHz, CDCl3): δ 1.51 ( t, / = 7.1 Hz, 3H ), 4.19 (q, J= 7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J= 9.0 Hz, IH), 9.94 (s, IH).
91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv; commercially available) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3*50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester.

91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	Intermediate D2; 4-Chloro-3-ethoxy-benzaldehvde [CAS RN 85259-46-7]; To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy- benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to -78 0C under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solution in THF) was slowly added over a time period of 15 min, the <n="79"/>cooling bath removed on completion of addition and the reaction allowed to warm up to 0 0C. After stirring for 1 h, the reaction was cooled to -78 0C and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure providing 2.94 g (100%) of 4- chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super CeI and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 ( t, / = 7.1 Hz, 3H), 4.19 (q, / = 7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, / = 9.0 Hz, IH), 9.94 (s, IH).
91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	4-Chloro-3-ethoxy-benzaldehyde [CAS RN 85259-46-7] To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3*50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester.
91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to -78 C. under Ar. A solution of diisobutylaluminum hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed after completion of addition and the reaction allowed to reach 0 C. After stirring for 1 h, the reaction was cooled to -78 C. and the excess of hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was warmed up to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure providing 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to -78 C. under Ar. A solution of diisobutylaluminum hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed after completion of addition and the reaction allowed reaching 0 C. After stirring for 1 h, the reaction was cooled to -78 C. and the excess of hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was warmned up to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure providing 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. 1 H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to -78 C. under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to reach 0 C. After 1 h, the reaction was cooled to -78 C. and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure to afford 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52% yield) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to -78 C. under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to reach 0 C. After stirring for 1 h, the reaction was cooled to -78 C. and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure providing 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	Intermediate Bl 4-Chloro-3-ethoxy-benzaldehvde [CAS RN 85259-46-7]. To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phase was dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to -78 0C under Ar. A solution of diisobutylaluminum hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed after completion of addition and the reaction allowed to reach 0 0C. After stirring for 1 h, the reaction was cooled to -78 0C and the excess of hydride quenched by cautious addition of a solution of 1 M HCl ( 10 mL). The mixture was warmed up to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure providing 2.94 g ( 100%) of 4-chloro-3-ethoxy- benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane ( 15 mL) and activated Mnθ2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super CeI and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane / ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 ( t, / = 7.1 Hz, 3H), 4.19 (q, / = 7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, / = 9.0 Hz, IH), 9.94 (s, IH).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a solution of <strong>[34113-69-4]4-chloro-3-hydroxybenzoic acid</strong> (10 g, 57.9 mmol) in DMF (200 mL) was added iodoethane (20 g, 128.2 mmol) and potassium carbonate (16 g, 115.8 mmol) at room temperature. After 3 hours, the volume was reduced in vacuo to afford a residue, which was dissolved in ethyl acetate (100 mL), washed with brine (4 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to afford crude ethyl 4-chloro-3-ethoxybenzoate as a white solid (12 g), which was carried on crude to the next step.

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3
[ 34113-69-4 ]
3-[2-(4-acetylamino-phenyl)-ethoxy]-4-chloro-benzoic acid [ No CAS ]