15012-36-9|Methyl 2,3-dimethylbenzoate| Ambeed

CAS No. :	15012-36-9
Formula :	C₁₀H₁₂O₂
M.W :	164.20
SMILES Code :	O=C(OC)C1=CC=CC(C)=C1C
MDL No. :	MFCD06203773
InChI Key :	RQTXEJYGOHZSIW-UHFFFAOYSA-N
Pubchem ID :	27000

Safety of [ 15012-36-9 ]

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

Computational Chemistry of [ 15012-36-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.3
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	47.65
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.34
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	3.11
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.09
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.	2.55
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	2.64
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.55

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.06
Solubility	0.145 mg/ml ; 0.00088 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.	-3.33
Solubility	0.0767 mg/ml ; 0.000467 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	-3.24
Solubility	0.0947 mg/ml ; 0.000577 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.	-5.09 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.46

Application In Synthesis of [ 15012-36-9 ]

* 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 [ 15012-36-9 ]

[ 15012-36-9 ] Synthesis Path-Downstream 1~55

1
[ 15012-36-9 ]
[ 603-79-2 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1974,p. 2339 - 2342.

2
[ 55262-06-1 ]
[ 15012-36-9 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1974,p. 2339 - 2342.

3
C₁₀H₁₃O₂⁽¹⁺⁾ [ No CAS ]
[ 15012-36-9 ]

References: [1]Journal of the American Chemical Society,1993,vol. 115,p. 12071 - 12078.

4
[ 15012-36-9 ]
[ 13651-14-4 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

5
[ 15012-36-9 ]
[ 127168-91-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 16h;	Step a. To a solution of <strong>[15012-36-9]methyl 2,3-dimethylbenzoate</strong> (CAS Number 15012-36-9, available from Accela Chembio) (5 g, 30.48 mmol) in CC14 (40 ml) were added NBS (10.8 g, 61 mmol) and AIBN (0.2 g, 0.91 mmol) at rt. The reaction mixture was heated at 80C for 16 h. The reaction mixture was filtered and evaporate to yield methyl 2,3-bis(bromomethyl)benzoate (10.1 g, quantitative). This material was used directly for the next step without further purification.
96%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 2h;Heating / reflux;	Compound 5 (53.3 g; 0.32 mol) was dissolved in carbon tetrachloride (850 mL), under nitrogen. To the solution was added N-bromosuccinimide (115.5 g; 0.65 mol) and 2,2'-azobis(2-methyl-propionitrile (1.6 g; 0.010 mol). The reaction mixture was stirred at reflux for approximately 2 hours and the colour of this mixture changed from yellow to colorless. It was allowed to cool to room temperature and filtered off. The filtrate was evaporated in vacuo to give compound 6 (98.7 g; 96%) as a yellow liquid.1H-NMR (300 MHz, CDCI3): delta 3.95 (s, 3H), 4.68 (s, 2H), 5.14 (s, 2H), 7.36 (t, 1H), 7.55 (dd, 1 H), 7.90 (dd, 1 H). GC-MS m/z = 322.
94%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Reflux;	[0506] Preparation of compound 3 (Scheme 13): To a solution of 2 (2.1 g, 13.3 mmol, 1.0 eq) in Cd4 (30 mL) was added NBS (4.7 g, 26.6 mmol, 2.0 eq) and BPO (0.2 g). The mixture was heated to reflux for 4h. The reaction was diluted with DCM (30 mL), washed by water (2 x 30 mL), dried over Na2SO4, concentrated to give a crude product, which was purified by column chromatography to give compound 3; methyl 2,3-bis(bromomethyl)benzoate (4.0 g, 94%).

With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane;Heating / reflux;

To a stirred solution of <strong>[15012-36-9]methyl 2,3-dimethylbenzoate</strong> (1.75 g, 10.7 mmol) in carbon tetrachloride (35 mL) under argon was added freshly recrystallized N-bromosuccinimide (3.90 g, 21.9 mmol) and AIBN (50 mg). The reaction mixture was heated to reflux under argon for 4 h and then cooled and filtered. Evaporation gave a yellow oil, 3.53 g, predominantly methyl 2,3-bis(bromomethyl)benzoate.

References: [1]Patent: WO2017/158388,2017,A1 .Location in patent: Page/Page column 60.
[2]Patent: WO2008/53319,2008,A1 .Location in patent: Page/Page column 55.
[3]Patent: WO2015/116923,2015,A1 .Location in patent: Paragraph 0503; 0506.
[4]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.
[5]Patent: US2003/225091,2003,A1 .Location in patent: Page 28.

6
[ 576-23-8 ]
[ 616-38-6 ]
[ 15012-36-9 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

7
[ 576-23-8 ]
[ 616-38-6 ]
[ 15012-36-9 ]
[ 1217-63-6 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

8
[ 15012-36-9 ]
[ 202719-50-4 ]

References: [1]Tetrahedron,1998,vol. 54,p. 1207 - 1220.

9
[ 67-56-1 ]
[ 603-79-2 ]
[ 15012-36-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With thionyl chloride;Heating / reflux;	Step 1. To a solution of 2,3-dimethylbenzoic acid (50.2 g; 0.33 mol) in MeOH (1L) was added dropwise thionyl chloride (62 mL; 0.83 mol, exothermic). The reaction mixture was stirred at reflux overnight and allowed to cool to room temperature. Evaporation of the solvent in vacuo yielded compound 5 (53.3 g; 98%) as a yellow liquid.1H-NMR (300 MHz, CDCI3): delta 2.34 (s, 3H), 3.45 (s, 3H), 3.90 (s, 3H), 7.15 (t, 1H), 7.28 (d, 1H), 7.62 (d, 1H).
98%	With thionyl chloride; for 3h;Reflux;	[0505] Preparation of compound 2 (Scheme 13): To a solution of 1; 2,3- dimethylbenzoic acid (2.0 g, 13.3 mmol, 1.0 eq) in MeOH (30 mL) was added thionyl chloride (1.5 mL) and stirred at reflux for 3h. The mixture was concentrated, extracted with EA (30 mL). The organic layers were washed with water (2 x 30 mL),dried over Na2504, concentrated to give the desired product 2 without further purification (2.1 g, 98%).

References: [1]Patent: WO2008/53319,2008,A1 .Location in patent: Page/Page column 55.
[2]Patent: WO2015/116923,2015,A1 .Location in patent: Paragraph 0503; 0505.
[3]Tetrahedron,1998,vol. 54,p. 1207 - 1220.
[4]Patent: WO2018/205948,2018,A1 .Location in patent: Page/Page column 46.
[5]Tetrahedron Letters,2009,vol. 50,p. 6803 - 6806.

10
[ 62708-44-5 ]
[ 124-41-4 ]
[ 15012-36-9 ]
[ 40851-62-5 ]

References: [1]Helvetica Chimica Acta,1998,vol. 81,p. 251 - 267.

13
methyl 1-methyl-6-methylidenecyclohexa-2,4-diene-1-carboxylate [ No CAS ]
[ 15018-12-9 ]
[ 15012-36-9 ]
[ 14920-81-1 ]

References: [1]Australian Journal of Chemistry,2000,vol. 53,p. 435 - 437.

14
[ 186581-53-3 ]
[ 603-79-2 ]
[ 15012-36-9 ]

References: [1]Magnetic Resonance in Chemistry,2004,vol. 42,p. 844 - 851.

15
[ 15012-36-9 ]
[ 107-30-2 ]
[ 745074-47-9 ]

Yield	Reaction Conditions	Operation in experiment
1.1 g	With iron(III) chloride; thionyl chloride; In 1,2-dichloro-ethane; at 0 - 55℃; for 2h;	To a stirred solution of <strong>[15012-36-9]methyl 2,3-dimethylbenzoate</strong> (2.0 g, 12.2 mmol) in 1,2-dichloroethane (10 mL) were added chloromethyl methyl ether (5 mL, 36.0 mmol), thionylchloride (0.36 mL, 5.0 mmol) and ferric chloride (0.4 g, 2.4 mmol) at 0 C. The resulting mixture was heated to 55 C for 2 h. After cooling to room temperature, the mixture was extracted with EtOAc (3 x 100 mL) and washed with water (20 mL) and brine (20 mL). The combined organic extracts were dried over anhydrous Mg504, filtered and concentrated.Silica gel chromatography (hexane:EtOAc) afforded the title compound (1.1 g). MS (ES) m/z 213 (M+H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2411 - 2415.
[2]Patent: WO2018/89261,2018,A2 .Location in patent: Paragraph 0940; 0941; 0942.

16
[ 15012-36-9 ]
potassium; 2,3-dimethyl-benzoate [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 565 - 567.

17
[ 15012-36-9 ]
2,3-dimethyl-benzoic acid allyl ester [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 565 - 567.

18
[ 15012-36-9 ]
2,3-dimethyl-benzoic acid benzyl ester [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 565 - 567.

19
[ 15012-36-9 ]
[ 745074-48-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2411 - 2415.

20
[ 15012-36-9 ]
[ 745074-49-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2411 - 2415.

21
[ 15012-36-9 ]
[ 745074-50-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2411 - 2415.

22
[ 15012-36-9 ]
[ 745074-51-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2411 - 2415.

23
[ 15012-36-9 ]
BMS-488516 [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2411 - 2415.

24
[ 15012-36-9 ]
<i>N</i>-{5-[3-(4-acetyl-piperazine-1-carbonyl)-4,5-dimethyl-benzylsulfanyl]-thiazol-2-yl}-4-[(1-hydroxymethyl-2-methyl-propylamino)-methyl]-benzamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2411 - 2415.

25
[ 70588-24-8 ]
[ 15012-36-9 ]

References: [1]Australian Journal of Chemistry,2000,vol. 53,p. 435 - 437.

26
[ 15012-36-9 ]
(7S,8S)-8-Bromo-7-methoxy-bicyclo[4.2.0]octa-1⁽⁶⁾,2,4-triene-2-carboxylic acid methyl ester [ No CAS ]

References: [1]Tetrahedron,1998,vol. 54,p. 1207 - 1220.

27
[ 15012-36-9 ]
(5S,8R)-8-Bromo-6,6,7,7-tetracyano-5-methoxy-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid methyl ester [ No CAS ]

References: [1]Tetrahedron,1998,vol. 54,p. 1207 - 1220.

28
[ 15012-36-9 ]
(7R,8S)-7,8-Dibromo-bicyclo[4.2.0]octa-1⁽⁶⁾,2,4-triene-2-carboxylic acid methyl ester [ No CAS ]

References: [1]Tetrahedron,1998,vol. 54,p. 1207 - 1220.

29
[ 15012-36-9 ]
[ 90484-24-5 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.

30
[ 15012-36-9 ]
[ 72288-77-8 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.
[2]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.

31
[ 15012-36-9 ]
[ 72288-74-5 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.

32
[ 15012-36-9 ]
[ 2211-83-8 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.

33
[ 15012-36-9 ]
[ 37678-61-8 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

34
[ 15012-36-9 ]
[ 13651-55-3 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

35
[ 15012-36-9 ]
[ 72288-75-6 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.

36
[ 15012-36-9 ]
[ 5779-93-1 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

37
[ 15012-36-9 ]
[ 1963-30-0 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

38
[ 15012-36-9 ]
[ 25173-73-3 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

39
[ 15012-36-9 ]
4,5-Dimethyl-2-(4,5-dimethylindanyliden-1)-indan-1-on [ No CAS ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

40
[ 15012-36-9 ]
2-Formyl-3-methyl-benzoic acid methyl ester [ No CAS ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.

41
[ 15012-36-9 ]
(E)-3-(2,3-Dimethyl-phenyl)-acrylic acid methyl ester [ No CAS ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

42
[ 15012-36-9 ]
3-Ethoxy-4-methylphthalid [ No CAS ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.

43
[ 15012-36-9 ]
2-Carboxymethyl-4,5-dimethylindan [ No CAS ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

44
[ 15012-36-9 ]
[ 177166-03-9 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

45
[ 15012-36-9 ]
[ 177166-14-2 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 201 - 217.

46
[ 87-59-2 ]
[ 15012-36-9 ]

References: [1]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.
[2]Monatshefte fur Chemie,1996,vol. 127,p. 185 - 200.

47
[ 56-23-5 ]
[ 15012-36-9 ]
[ 127168-91-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; dibenzoyl peroxide;	(2) 24.6 g of <strong>[15012-36-9]methyl 2,3-dimethylbenzoate</strong>, 53.4 g of N-bromosuccinimide, 300 mg of benzoyl peroxide, and 300 ml of carbontetrachloride were processed in a similar manner as in Reference Example 6-(1) to give a mixture containing methyl 2,3-bis-(bromomethyl)benzoate as a major component.

References: [1]Patent: US5026856,1991,A .

48
[ 603-79-2 ]
[ 15012-36-9 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In N,N-dimethyl-formamide;	(1) To 160 ml of methanol cooled to -10 C. was dropwise added 46.4 ml of thionyl chloride while stirring. To the solution was added a mixture of 24 g of 2,3-dimethyl benzoic acid and 1 ml of DMF, and the mixture was stirred at room temperature for 4 days. After concentration, the residue was dissolved in ether. The solution was washed with water, 5% sodium carbonate, and water in this order. The solvent was evaporated and the residue was purified by vacuum distillation to obtain 25.1 g of methyl 2,3-dimethylbenzoate.

References: [1]Patent: US5026856,1991,A .

49
[ 15012-36-9 ]
[ 199620-14-9 ]
[ 33479-86-6 ]

References: [1]Monatshefte fur Chemie,1968,vol. 99,p. 578.
[2]Gmelin Handbuch der Anorganischen Chemie,Gmelin Handbook: Cr: Org.Verb., 1.6.1.2.3, page 249 - 253.

50
[ 74-88-4 ]
[ 603-79-2 ]
[ 15012-36-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	3-Aminomethyl-2-methyl-benzoic acid methyl ester: 2,3-Dimethylbenzoic acid (1.0 g, 6.66 mmol) was dissolved in DMF (15 mL) and then Cs2CO3 (1.5 equiv.) and MeI (1.2 equiv.) were added. The mixture was stirred for 2 h at room temperature then diluted with EtOAc and H2O. The organic layer was washed with H2O and a saturated LiCl solution, and then dried over MgSO4 and concentrated under reduced pressure to give sticky oil. The oil was dissolved in CCl4 (20 mL) and NBS (1.1 equiv.) and AIBN (0.1 equiv.) were added. The mixture was heated at reflux for 4 h then cooled to room temperature to give a white precipitate which was filtered off. The yellow solution was concentrated, the oil was dissolved in DMF (15 mL) and then NaN3 (1.2 equiv.) was added. The mixture was stirred for 2 h at room temperature then diluted with ethyl acetate and H2O. The organic layer was washed with H2O and a saturated lithium chloride solution, dried over MgSO4, and concentrated under reduced pressure to give sticky oil. The crude oil was dissolved in of CHCl3 (20 mL) and MeOH (20 mL), and then 10% Pd/C (0.20 g) and conc. HCl (1.5 mL) were added. The mixture was shaken under H2 gas (50 psi) for 16 h. The Pd/C was filtered through a pad of Celite and the pad was washed with a solution of 20% MeOH in CH2Cl2. The pale yellow solution was concentrated under reduced pressure, and the residual was dissolved in MeOH (10 mL) and diluted with Et2O (100 mL) to give a white precipitate. The precipitate was collected by filteration and dried to give the title compound (0.79 g, 55%).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	I-144: N2-(3,4-dimethyl-5-methoxycarbonyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine 2,3-Dimethylbenzoic acid (1 g) and K2CO3 (1.1 g, 1.2 eq.) were suspended in DMF (10 mL). To the reaction mixture, was added iodomethane (0.5 mL, 1.2 eq.). The reaction was stirred at rt overnight, then diluted with water (80 mL). The solution was extracted with ethyl acetate (80 mL) and evaporated to give the methyl ester. 1H NMR (300 MHz, DMSO) delta 7.49 (d, J=7.8 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 3.79 (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H).

References: [1]Patent: US2009/275583,2009,A1 .Location in patent: Page/Page column 31.
[2]Patent: US2012/28923,2012,A1 .Location in patent: Page/Page column 59.
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365.

51
[ 15012-36-9 ]
[ 1379358-75-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 4h;Reflux;	3-Aminomethyl-2-methyl-benzoic acid methyl ester: 2,3-Dimethylbenzoic acid (1.0 g, 6.66 mmol) was dissolved in DMF (15 mL) and then Cs2CO3 (1.5 equiv.) and MeI (1.2 equiv.) were added. The mixture was stirred for 2 h at room temperature then diluted with EtOAc and H2O. The organic layer was washed with H2O and a saturated LiCl solution, and then dried over MgSO4 and concentrated under reduced pressure to give sticky oil. The oil was dissolved in CCl4 (20 mL) and NBS (1.1 equiv.) and AIBN (0.1 equiv.) were added. The mixture was heated at reflux for 4 h then cooled to room temperature to give a white precipitate which was filtered off. The yellow solution was concentrated, the oil was dissolved in DMF (15 mL) and then NaN3 (1.2 equiv.) was added. The mixture was stirred for 2 h at room temperature then diluted with ethyl acetate and H2O. The organic layer was washed with H2O and a saturated lithium chloride solution, dried over MgSO4, and concentrated under reduced pressure to give sticky oil. The crude oil was dissolved in of CHCl3 (20 mL) and MeOH (20 mL), and then 10% Pd/C (0.20 g) and conc. HCl (1.5 mL) were added. The mixture was shaken under H2 gas (50 psi) for 16 h. The Pd/C was filtered through a pad of Celite and the pad was washed with a solution of 20% MeOH in CH2Cl2. The pale yellow solution was concentrated under reduced pressure, and the residual was dissolved in MeOH (10 mL) and diluted with Et2O (100 mL) to give a white precipitate. The precipitate was collected by filteration and dried to give the title compound (0.79 g, 55%).

References: [1]Patent: US2009/275583,2009,A1 .Location in patent: Page/Page column 31.

52
[ 15012-36-9 ]
[ 1245919-85-0 ]

References: [1]Tetrahedron Letters,2009,vol. 50,p. 6803 - 6806.

53
[ 15012-36-9 ]
[ 74-88-4 ]
[ 90922-71-7 ]

Yield	Reaction Conditions	Operation in experiment
		Methyl 2,3-dimethylbenzoate was dissolved in concentrated sulfonic acid (10 mL). KNO3 (808 mg, 1.2 eq.) was added to the solution at 0 C., then slowly warmed to rt overnight. The reaction was quenched with water (80 mL), extracted with ethyl acetate (2×80 mL). The organic layers were evaporated to give mixture of nitrated ester and acid (1:1). The mixture was redissolved in DMF (10 mL). K2CO3 (1.1 g) and iodomethane (0.5 mL) were added to the solution. The reaction was stirred at rt for three days, then diluted with water (80 mL). It was extracted with ethyl acetate (3×80 mL) and evaporated. The residue was purified by column chromatography (EtOAc in hexanes=0-30% in 45 min) to give the desired nitrobenzoate ester. 1H NMR (300 MHz, DMSO) delta 8.31 (s, 1H), 8.24 (s, 1H), 3.86 (s, 3H), 2.46 (s, 3H), 2.40 (s, 3H).

References: [1]Patent: US2012/28923,2012,A1 .Location in patent: Page/Page column 60.

54
[ 15012-36-9 ]
[ 90922-71-7 ]
[ 110969-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; potassium nitrate; at 0 - 20℃;	Methyl 2,3-dimethylbenzoate was dissolved in concentrated sulfonic acid (10 mL). KNO3 (808 mg, 1.2 eq.) was added to the solution at 0 C., then slowly warmed to rt overnight. The reaction was quenched with water (80 mL), extracted with ethyl acetate (2×80 mL). The organic layers were evaporated to give mixture of nitrated ester and acid (1:1). The mixture was redissolved in DMF (10 mL). K2CO3 (1.1 g) and iodomethane (0.5 mL) were added to the solution. The reaction was stirred at rt for three days, then diluted with water (80 mL). It was extracted with ethyl acetate (3×80 mL) and evaporated. The residue was purified by column chromatography (EtOAc in hexanes=0-30% in 45 min) to give the desired nitrobenzoate ester. 1H NMR (300 MHz, DMSO) delta 8.31 (s, 1H), 8.24 (s, 1H), 3.86 (s, 3H), 2.46 (s, 3H), 2.40 (s, 3H).

References: [1]Patent: US2012/28923,2012,A1 .Location in patent: Page/Page column 60.

55
[ 15012-36-9 ]
[ 1357101-77-9 ]

References: [1]Patent: US2012/28923,2012,A1 .
[2]Patent: US2012/28923,2012,A1 .

Historical Records

Technical Information

• Acyl Group Substitution • Benzylic Oxidation • Birch Reduction • Blanc Chloromethylation • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Complex Metal Hydride Reductions • Ester Cleavage • Friedel-Crafts Reaction • Hydrogenolysis of Benzyl Ether • Preparation of Alkylbenzene • Reactions of Benzene and Substituted Benzenes • Reactions with Organometallic Reagents • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Vilsmeier-Haack Reaction

Related Functional Groups of
[ 15012-36-9 ]

Aryls

A102579 [89-71-4]

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A105884 [4122-56-9]

Methyl 2-formylbenzoate

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A136167 [23617-71-2]

Methyl 2,4-dimethylbenzoate

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A201986 [28269-31-0]

Dimethyl 2-methylisophthalate

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A281507 [4376-18-5]

2-(Methoxycarbonyl)benzoic acid

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Esters

A102579 [89-71-4]

Methyl 2-methylbenzoate

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A105884 [4122-56-9]

Methyl 2-formylbenzoate

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A136167 [23617-71-2]

Methyl 2,4-dimethylbenzoate

Similarity: 1.00

A201986 [28269-31-0]

Dimethyl 2-methylisophthalate

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CAS No.: 15012-36-9

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CAS No.: 15012-36-9

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[ 15012-36-9 ] Synthesis Path-Downstream 1~55

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