3095-48-5|Methyl 4-amino-3,5-dimethylbenzoate| Ambeed

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Quality Control of [ 3095-48-5 ] Purity: 97% SDS Specification

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Product Details of [ 3095-48-5 ]

CAS No. :	3095-48-5
Formula :	C₁₀H₁₃NO₂
M.W :	179.22
SMILES Code :	COC(=O)C1=CC(C)=C(N)C(C)=C1
MDL No. :	MFCD09833906
Boiling Point :	No data available
InChI Key :	ARSRTLJLMXSRPV-UHFFFAOYSA-N
Pubchem ID :	11030398

Safety of [ 3095-48-5 ]

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

Computational Chemistry of [ 3095-48-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.3
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	52.06
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	52.32 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.19
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	1.82
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.68
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.	1.94
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	1.93
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.91

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.31
Solubility	0.883 mg/ml ; 0.00493 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.	-2.54
Solubility	0.519 mg/ml ; 0.00289 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	-2.89
Solubility	0.232 mg/ml ; 0.00129 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	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	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.	-6.1 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)	1.4

Application In Synthesis of [ 3095-48-5 ]

* 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.

Downstream synthetic route of [ 3095-48-5 ]

[ 3095-48-5 ] Synthesis Path-Downstream 1~35

1
[ 67-71-0 ]
[ 3095-48-5 ]
[ 56066-81-0 ]

Yield	Reaction Conditions	Operation in experiment
	In water; dimethyl sulfoxide;	A suspension of 33 g. of dimethylsulfone and 11 g. of sodium hydride (50percent dispersion in oil) in 160 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for 3 hours. Then, 18 g. of <strong>[3095-48-5]4-amino-3,5-dimethyl-benzoic acid methyl ester</strong> were added. The mixture was stirred at 80° C. for 30 minutes and at room temperature for 1 hour and then dissolved in 400 ml. of water. The solution was neutralized with glacial acetic acid. The precipitate which formed was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 4'-amino-3',5'-dimethyl-2-(methylsulfonyl)-acetophenone having a melting point of 179°-180° C.

References: [1]Patent: US4515948,1985,A .
[2]Patent: FR2242984,1975, .
Patent: DE2443682,1975, .
Chem.Abstr.,1975,vol. 83.

2
[ 67-71-0 ]
[ 3095-48-5 ]
[ 77-78-1 ]
[ 56066-87-6 ]

References: [1]Patent: FR2242984,1975, .
Patent: DE2443682,1975, .
Chem.Abstr.,1975,vol. 83.

3
[ 3095-48-5 ]
3,5-dimethyl-4-(6-nitro-2-oxo-3,4-dihydro-2<i>H</i>-quinazolin-1-yl)-benzoic acid methyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 357 - 360.

4
[ 3095-48-5 ]
[ 167626-74-6 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 3033 - 3044.

5
[ 3095-48-5 ]
1-(3,5-dimethyl-4-propionylamino)benzoyl-4-(N-methyl-2-phenylethyl)aminopiperidine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 3033 - 3044.

6
[ 18595-14-7 ]
[ 3095-48-5 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 3033 - 3044.
[2]Patent: CN109761817,2019,A .

7
[ 3095-48-5 ]
[ 56066-82-1 ]

References: [1]Patent: FR2242984,1975, .
Patent: DE2443682,1975, .
Chem.Abstr.,1975,vol. 83.

8
[ 3095-48-5 ]
[ 56066-88-7 ]

References: [1]Patent: FR2242984,1975, .
Patent: DE2443682,1975, .
Chem.Abstr.,1975,vol. 83.

9
[ 3095-48-5 ]
3-(4-Dimethylamino-3,5-dimethyl-phenyl)-2-phenylaminomethyl-propionitrile [ No CAS ]

References: [1]Patent: FR2242984,1975, .
Patent: DE2443682,1975, .
Chem.Abstr.,1975,vol. 83.

10
[ 3277-04-1 ]
[ 3095-48-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogenchloride; iron; In methanol; at 0 - 80℃; for 16h;	Scheme 5, step B. To a solution ofmethyl3,5-dimethyl-4-nitrobenzoate (10.0 g,0.0478 mol) in methanol (100 mL), iron powder (15.7 g, 0.2869 mol) and 37percent HCl (1.72g, 0.0478 mol) is added at 0 °C. The reaction is heated at 80 oc for 16 hours. The mixture is cooled to room temperature and filtered through Celite? bed and washed withmethanol followed by evaporation of filtrate to dryness to afford the title compound as abrown solid (7.8 g, 99percent). Mass spectrum (m/z): 180.2 (M+ 1).
99%	With hydrogenchloride; iron; In methanol; water; at 0 - 80℃; for 16h;	To a solution of methyl 3,5-dimethyl-4-nitrobenzoate (10.0 g, 0.0478 mol) in MeOH (100 mL), iron powder (15.7 g, 0.2869 mol) and 37percent HC1 (1.72 g, 0.0478 mol) are added at 0 °C. The reaction mixture is heated at 80 °C for 16 hours. The mixture is cooled to room temperature, filtered through diatomaceous earth, and washed with MeOH. The filtrate is concentrated to afford the title compound as brown solid (7.8 g, 99percent). Mass spectrum (m/z): 180.2 (M+H)+.

References: [1]Patent: US6342610,2002,B2 .Location in patent: Page column 125.
[2]Patent: WO2014/4230,2014,A1 .Location in patent: Sheet 18; 19.
[3]Patent: WO2015/94912,2015,A1 .Location in patent: Page/Page column 10.
[4]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 105 - 109.

11
[ 499-06-9 ]
[ 79-37-8 ]
[ 3277-04-1 ]
[ 3095-48-5 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid; sodium hydrogencarbonate;palladium; N,N-dimethyl-formamide; In methanol; acetic acid; ethyl acetate;	B. 4-Carbomethoxy-2,6-dimethylaniline To a warm solution of 3,5-dimethyl benzoic acid (5 g, 33.33 mmol) in acetic acid (30 ml) was added fuming nitric acid (30 ml), dropwise. After completion of the addition the reaction mixture was warmed with a heat gun. This was stirred for an additional 2 hours during which period a solid was precipitated. The reaction mixture was diluted with water (200 ml) and filtered. The solid was dried under reduced pressure. To the above solid was added 20 ml of oxalyl chloride and a catalytic amount of DMF (2 drops). This was stirred at room temperature for 3 hours during which period a clear solution was formed. Excess oxalyl chloride was removed under reduced pressure to give yellow solid. To the yellow solid was added dry methanol (100 ml) and the mixture stirred at room temperature for 1 hour. Excess methanol was removed under reduced pressure and the residue dissolved in ether (200 ml). This was washed with water (100 ml) followed by saturated NaHCO3 solution (100 ml). The organic layer was dried over magnesium sulfate and the solvent removed giving 4-carbomethoxy-2,6-dimethylnitrobenzene as a yellow solid (5.8 g, 83percent yield). 4-Carbomethoxy-2,6-dimethylnitrobenzene (2 g, 9.5 mmol) was dissolved in in ethyl acetate (20 ml) and subjected to catalytic hydrogenation using 10percent palladium on carbon (300 mg) at 55 psi for 30 min. The catalyst was filtered and solvent removed to give 4-carbomethoxy-2,6-dimethylaniline as a solid (1.7 g, 100percent yield).
	With nitric acid; sodium hydrogencarbonate;palladium; N,N-dimethyl-formamide; In methanol; acetic acid; ethyl acetate;	B. 4-Carbomethoxy-2,6-dimethylaniline To a warm solution of 3,5-dimethyl benzoic acid (5 g, 33.33 mmol) in acetic acid (30 ml) was added fuming nitric acid (30 ml), dropwise. After completion of the addition the reaction mixture was warmed with a heat gun. This was stirred for an additional 2 hours during which period a solid was precipitated. The reaction mixture was diluted with water (200 ml) and filtered. The solid was dried under reduced pressure. To the above solid was added 20 ml of oxalyl chloride and a catalytic amount of DMF (2 drops). This was stirred at room temperature for 3 hours during which period a clear solution was formed. Excess oxalyl chloride was removed under reduced pressure to give yellow solid. To the yellow solid was added dry methanol (100 ml) and the mixture stirred at room temperature for 1 hour. Excess methanol was removed under reduced pressure and the residue dissolved in ether (200 ml). This was washed with water (100 ml) followed by saturated NaHCO3 solution (100 ml). The oganic layer was dried over magnesium sulfate and the solvent removed giving 4-carbomethoxy-2,6-dimethylnitrobenzene as a yellow solid (5.8 g, 83percent yield). 4-Carbomethoxy-2,6-dimethylnitrobenzene (2 g, 9.5 mmol) was dissolved in in ethyl acetate (20 ml) and subjected catalytic hydrogenation using 10percent palladium on carbon (300 mg) at 55 psi for 30 min. The catalyst was filtered and solvent removed to give 4-carbomethoxy-2,6-dimethylaniline as a solid (1.7 g, 100percent yield).

References: [1]Patent: US2002/95041,2002,A1 .
[2]Patent: US5962490,1999,A .

12
[ 184041-97-2 ]
N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-carboxylthiophene-3-sulfonamide [ No CAS ]
[ 3095-48-5 ]
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triethylamine; In hydrogenchloride; methanol; oxalyl dichloride; dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-carboxylthiophene-3-sulfonamide (3.5 g, 8.5 mmol) (from step A) was dissolved in oxalyl chloride (5 ml) and a drop of DMF was added. This was stirred at room temperature for 6 hours. Excess oxalyl chloride was removed under reduced pressure and the mixture dried under high vacuum. To a solution of <strong>[3095-48-5]4-carbomethoxy-2,6-dimethylaniline</strong> (0.9 g) (from step B) and triethyl amine (2 ml) in methylene chloride (20 ml) at 0° C. was added the acid chloride in 10 ml of methylene chloride (2.4 g, 4.98 mmol) prepared in the above step. The reaction mixture was permitted to warm to room temperature, was diluted with methylene chloride (50 ml) and was washed with 1 N HCl followed by saturated NaHCO3 solution. The organic layer was dried over magnesium sulfate and the solvent removed giving the crude product. This was purified by column chromatography using 4:6 ethyl acetate and hexane as a eluent to give N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide an oil (0.6 g, 20percent yield). N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide (0.6 g) was dissolved in a mixture of methanol (8 ml) and concentrated HCl (1.5 ml) and the resultant reaction mixture was refluxed under stirring for 8 hours. Excess methanol was removed under reduced pressure and the residue dissolved in ethyl acetate (50 ml). This was washed with saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent removed giving N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide which was crystallized using methylene chloride and hexane (0.23 g, 47percent yield, m.p. 152-154° C.).

References: [1]Patent: US2002/95041,2002,A1 .

Yield	Reaction Conditions	Operation in experiment
		Step A: Preparation of 4-methoxycarbonyl-3,5-dimethylaniline Employing the procedure substantially as described in Example 4, Steps A and B but substituting for the 3-methyl-4-nitrobenzoic acid used as starting material in Step A, an equimolar amount of 3,5-dimethyl-4-nitrobenzoic acid, there is produced 4-methoxycarbonyl-2,6-dimethylaniline, m.p. 104°-106° C.

14
[ 3095-48-5 ]
[ 77-78-1 ]
4-(dimethylamino)-3,5-dimethyl-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In tetrahydrofuran; dichloromethane; water;	50.4 G. of dimethylsulfate were added dropwise over a period of 20 minutes to a suspension of 18 g. of <strong>[3095-48-5]4-amino-3,5-dimethyl-benzoic acid methyl ester</strong> and 69 g. of potassium carbonate in 1 liter of absolute tetrahydrofuran with stirring at room temperature. The mixture was refluxed for 18 hours with stirring and then filtered. The filtrate was evaporated to dryness under vacuum. The residue was treated with 500 ml. of water and then extracted with two 300 ml. portions of ethyl acetate. The ethyl acetate extract was washed with two 150 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on 500 g. of silica gel using methylene chloride, and there was obtained 4-(dimethylamino)-3,5-dimethyl-benzoic acid methyl ester as a colorless oil.

References: [1]Patent: US4515948,1985,A .

15
C₁₈H₁₉NO₄ [ No CAS ]
[ 3095-48-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6707 - 6713.

16
[ 3095-48-5 ]
[ 432022-88-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6707 - 6713.

17
[ 184041-92-7 ]
[ 3095-48-5 ]
[ 184041-97-2 ]

References: [1]Patent: US6342610,2002,B2 .Location in patent: Page column 125.

18
[ 75-18-3 ]
[ 18595-14-7 ]
[ 3095-48-5 ]

References: [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2010,vol. 75,p. 320 - 324.

19
[ 3095-38-3 ]
[ 3095-48-5 ]

References: [1]Patent: WO2014/4230,2014,A1 .
[2]Patent: WO2015/94912,2015,A1 .
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 105 - 109.

20
[ 3095-48-5 ]
[ 146328-85-0 ]
[ 1529760-76-6 ]

Yield	Reaction Conditions	Operation in experiment
69%		Scheme 6, step A. To a solution of 5-bromo-2-fluorobenzoic acid (3.50 g, 15.9mmol) in CH2Ch (50 mL) at 0 oc are added methyl4-amino-3,5-dimethylbenzoate (2.86g, 15.9 mmol, see preparation 12) and N,N-diisopropylethylamine (8.35 ml, 47.9 mmol).After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50percent solution in ethyl acetate, 20.5 ml, 31.9 mmol) is added via syringe andstirred at ambient temperature. After 36 hours, the solvent is removed under reducedpressure and the residue is diluted with water and extracted with ethyl acetate. Theorganic layers are combined and dried over anhydrous Na2S04, filtered, and concentratedunder reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 10percent ethyl acetate in hexane to give the title compound as a white solid (4.20g, 69 percent). Mass spectrum (m/z): 380.2 (M+1).

References: [1]Patent: WO2014/4230,2014,A1 .Location in patent: Page/Page column 19; 20.

21
[ 3095-48-5 ]
[ 79669-49-1 ]
[ 1529760-86-8 ]

Yield	Reaction Conditions	Operation in experiment
80%		Scheme 11, step A. To a solution of 5-bromo-2-methyl-benzoic acid (2.0 g,0.0093 mol) in CH2Ch (20 ml) at room temperature are added methyl3-amino-3,5-dimethylbenzoate (1.49 g, 0. 0083 mol, see preparation 12) and N,N-diisopropylethylamine (4.79 g, 0.037 mol). After stirring the reaction mixture for 10minutes, 1-propanephosphonic acid cyclic anhydride (50percent solution in ethyl acetate, 8.87g, 0.027 mol) is added via syringe and heated at 50°C. After 16 hours, the reactionmixture is diluted with CH2Ch, washed with water and brine. The organic layers arecombined and dried over anhydrous Na2S04, filtered, and concentrated under reduced5 pressure. The residue is purified by flash chromatography (silica gel) using 10percent EtOAcin hexanes to give the title compound as a white powder (2.8 g, 80 percent).

References: [1]Patent: WO2014/4230,2014,A1 .Location in patent: Page/Page column 34; 35.

22
[ 3095-48-5 ]
[ 79669-49-1 ]
[ 1529760-92-6 ]

Yield	Reaction Conditions	Operation in experiment
97%		Scheme 9, step A. To a solution of 5-bromo-2-methylbenzoic acid (2.0 g, 0.008mol) in CH2Ch (20 mL) at 0 °C are added methyl4-amino-3,5-dimethylbenzoate (1.28 g,0.0072, see preparation 12) and N,N-diisopropylethylamine ( 4.12 g, 0.032 mol). Afterstirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50percent solution in ethyl acetate, 7.63 g, 0.024 mol) is added via syringe and stirred at 50°C.After 16 hours, the solvent is removed under reduced pressure and the residue is dilutedwith water and extracted twice with ethyl acetate. The organic layers are combined anddried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Theresulting residue is purified by flash chromatography (silica gel) using 12percent ethyl acetate in hexane to give the title compound as a white solid (2.9 g, 97 percent). Mass spectrum (m/z):376.0 (M+ 1).

References: [1]Patent: WO2014/4230,2014,A1 .Location in patent: Page/Page column 29.

23
[ 5467-57-2 ]
[ 3095-48-5 ]
[ 1529761-33-8 ]

Yield	Reaction Conditions	Operation in experiment
96%		Scheme 22, step A. To a solution of 2-chloroquinoline-4-carboxylic acid (5.00 g,0.0024 mol) in CH2Ch (50 mL) at 0°C are added methyl4-amino-3,5-dimethylbenzoate(3.88 g, 0. 02167 mol, see preparation 12) and N,N-diisopropylethylamine (12.5 ml,0.07225 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50percent solution in ethyl acetate, 31.0 ml, 0.048 mol) is added viasyringe and heated at 40°C. After 5 hours, the reaction mixture is diluted with water andextracted with dichloromethane. The organic layers are combined and dried overmagnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of0-40percent ethylacetate in hexanes. After purification the solid is triturated with 20 percent diethyl ether inpentane and dried to give the title compound as a white solid (8.50 g, 96 percent). Massspectrum (m/z): 369.1 (M+1).

References: [1]Patent: WO2014/4230,2014,A1 .Location in patent: Page/Page column 65; 66.

24
[ 3095-48-5 ]
[ 654-97-7 ]
[ 1529761-45-2 ]

Yield	Reaction Conditions	Operation in experiment
39%		Scheme 25, step A. To a solution of 5-bromo-2-(trifluoromethyl)benzoic acid (1.0g, 3.53 mmol) in CH2Ch (6 ml) at room temperature are added methyl3-amino-3,5-dimethylbenzoate (0.44 g, 2.47 mmol, see preparation 12) and trimethylamine (1.0 ml,7.06 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonicacid cyclic anhydride (50percent solution in ethyl acetate, 5.6 ml, 8.83 mmol) is added viasyringe. After 14 hours at ambient temperature, the reaction mixture is diluted with CH2Cl2, washed with water and brine. The organic layers are combined and dried overanhydrous Na2S04, filtered, and concentrated under reduced pressure. The resultingresidue is purified by flash chromatography (silica gel) using 20percent ethyl acetate inhexanes to give the title compound as a white solid (0.6 g, 39 percent).

References: [1]Patent: WO2014/4230,2014,A1 .Location in patent: Page/Page column 75; 76.

25
[ 3095-48-5 ]
4-[[6-(4-hydroxy-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoic acid hydrate [ No CAS ]

References: [1]Patent: WO2014/4230,2014,A1 .
[2]Patent: WO2014/4230,2014,A1 .

26
[ 3095-48-5 ]
[ 1529760-77-7 ]