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Chemical Structure| 4389-45-1
Chemical Structure| 4389-45-1
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Product Details of [ 4389-45-1 ]

CAS No. :4389-45-1 MDL No. :MFCD00007745
Formula : C8H9NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :WNAJXPYVTFYEST-UHFFFAOYSA-N
M.W :151.16 Pubchem ID :78101
Synonyms :

Calculated chemistry of [ 4389-45-1 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 42.77
TPSA : 63.32 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.43 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.86
Log Po/w (XLOGP3) : 2.53
Log Po/w (WLOGP) : 1.28
Log Po/w (MLOGP) : 0.21
Log Po/w (SILICOS-IT) : 0.95
Consensus Log Po/w : 1.17

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.71
Solubility : 0.296 mg/ml ; 0.00196 mol/l
Class : Soluble
Log S (Ali) : -3.51
Solubility : 0.0471 mg/ml ; 0.000312 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.78
Solubility : 2.5 mg/ml ; 0.0166 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 4389-45-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4389-45-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 4389-45-1 ]
  • Downstream synthetic route of [ 4389-45-1 ]

[ 4389-45-1 ] Synthesis Path-Upstream   1~33

  • 1
  • [ 4389-45-1 ]
  • [ 77287-34-4 ]
  • [ 19181-54-5 ]
YieldReaction ConditionsOperation in experiment
86% at 160℃; for 16 h; 2-Amino-3-methylbenzoic acid (100 g, 0.66 mol), formamidine acetate (206 g, 1 .98 mol) and formamide (26 mL, 0.6600 mol) were mixed in a 2L R.B fitted with Mechanical stirrer. The reaction mixture was heated at 160 °C for 16h. The reaction completion was monitored by LCMS. After completion, the reaction mixture was cooled to was RT and diluted with 2N NaOH solution (300 mL). After stirring at the same temperature for 15min, the reaction mixture neutralised with 1.5N HCI solution. The solid precipitated was filtered off, washed with ice cold water and dried under vacuum to yield (90 g, 86percent yield) of the titled compound as an off white solid. H NMR (DMSO-d6, 400MHz) δ 12.21 ( bs, 1 H), 8.10 (s, 1 H), 7.95-7.93 (dd, J = 8.8, 7.9 Hz, 1 H), 7.65-7.63 (d, J = 7.9 Hz, 1 H), 7.39-7.35 (t, J = 15.2 Hz, 1 H), 2.51 (s, 3H).
78% at 140℃; General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 °C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2*2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 .x. 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 .x. 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
Reference: [1] Patent: WO2013/96194, 2013, A1, . Location in patent: Page/Page column 28-29
[2] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2794 - 2809
[4] Chemische Berichte, 1905, vol. 38, p. 3555
[5] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153
[6] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 8, p. 1203 - 1207
[7] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 662 - 669
[8] Medicinal Chemistry Research, 2014, vol. 23, # 5, p. 2584 - 2595
[9] Journal of Agricultural and Food Chemistry, 2014, vol. 62, # 36, p. 8928 - 8934
[10] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
  • 2
  • [ 4389-45-1 ]
  • [ 3473-63-0 ]
  • [ 77287-34-4 ]
  • [ 19181-54-5 ]
YieldReaction ConditionsOperation in experiment
94% at 180℃; for 3 h; 2-Amino-3-methylbenzoic acid (125 g, 0.820 mol), formamidine acetate (257 g, 2.46 mol) and formamide (32.5 mL, 0.8200 mol) wereminxed in a 2L R.B fitted with Mechanical stirrer. The reactionminxture was heated at 180 °C for 3h. The reaction completion was monitored by LCMS. After completion, the reactionminxture was cooled to RT and diluted with 2N NaOH solution (300 mL). After stirring at the same temperature for 15 min, the reactionminxture neutralized with 1 .5N HC1 solution. The solid precipitated was filtered off, washed with ice cold water and dried under vacuum to yield 8-methyl-3H-quinazolin-4-one (125 g, 94percent) as an off white solid. 1H NMR (400 MHz, DMSO-d6, ppm) 12.2 (bs, 1H), 8.1 (s, 1H), 8.0 (d, J = 7.8 Hz, 1H), 7.7 (d, J = 7.2 Hz, 1H), 7.4 (t, J = 7.6 Hz, 1H), 2.5 (s, 3H); LC/MS(ESI)161 (M+H).
Reference: [1] Patent: WO2017/106607, 2017, A1, . Location in patent: Paragraph 00223
  • 3
  • [ 4389-45-1 ]
  • [ 19181-54-5 ]
Reference: [1] Patent: US5401745, 1995, A,
  • 4
  • [ 4389-45-1 ]
  • [ 19181-54-5 ]
  • [ 1332493-28-3 ]
  • [ 1332493-36-3 ]
  • [ 1332493-35-2 ]
Reference: [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 17, p. 6089 - 6099
  • 5
  • [ 4389-45-1 ]
  • [ 58421-80-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 8, p. 1203 - 1207
[2] Patent: WO2013/96194, 2013, A1,
[3] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 662 - 669
[4] Medicinal Chemistry Research, 2014, vol. 23, # 5, p. 2584 - 2595
[5] Patent: WO2017/106607, 2017, A1,
  • 6
  • [ 4389-45-1 ]
  • [ 39576-83-5 ]
Reference: [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 14, p. 2763 - 2773
[2] Chemische Berichte, 1907, vol. 40, p. 4413
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 461 - 467
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
[5] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 3, p. 254 - 259
[6] Patent: US2016/90374, 2016, A1,
[7] Patent: US2016/168140, 2016, A1,
[8] Synthesis (Germany), 2016, vol. 48, # 8, p. 1226 - 1234
[9] Patent: EP322133, 1989, A1,
  • 7
  • [ 4389-45-1 ]
  • [ 57-13-6 ]
  • [ 67449-23-4 ]
YieldReaction ConditionsOperation in experiment
77%
Stage #1: at 160℃; for 6 h;
Stage #2: at 100℃; for 0.0833333 h;
General procedure: 2-Amino-3-methylbenzoic acid (5.0 g, 33.1 mmol) and urea (20 g) were stirred at 160oC. After 6 hours the mixture was cooled to 100oC and an equivalent volume of water was added while stirring was continued for 5 minutes. The formed precipitate was filtered off and washed with water to yield a solid cake that was suspended in a solution of 0.5 N NaOH in water. The suspension was heated to boil for 5 minutes and then cooled to r.t. The pH was adjusted to 2 with concentrated HCl and the quinazoline-dione was filtered off. After washing with water:methanol (1:1) the product was dried in vacuo to yield 4.50 g (25.5 mmol, 77percent) of a solid; 1H-NMR (CDCl3) δ (ppm) 7.78-7.74 (m, 1H), 7.49-7.46 (m, 1H), 7.11-7.05 (m, 1H), 2.31 (s, 3H).
74% at 150℃; A suspension of 2-amino-3-methylbenzoic acid (5.20 g, 34.40 mmol) and urea (4.87 mL, 107.33 mmol) in NMP (50 mL) was heated to 150 °C overnight. The resulting solution was cooled to ambient temperature and poured into ice-water (50 mL) and stirred until the ice melted. The white solid was collected by filtration, washed with water (3 x 30 mL) and dried over night to afford 8-methylquinazoline-2,4(1H,3H)-dione (4.50 g, 74percent) as a beige solid.
4.88 g at 190℃; for 4 h; <Step 1> 8-methylquinazoline-2,4(1H,3H)-dione
A mixture of 2-amino-3-methylbenzoic acid (5 g, 33.1 mmol) and urea (5.96 g, 99.2 mmol) was stirred at 190° C. for 4 hours.
After cooling the reaction solution to room temperature, water (70 ml) was added thereto and the reaction solution was stirred for 1 hour.
The resulting solid was filtered and dried in vacuo to give the titled compound (4.88 g) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 11.29 (brs, NH), 10.42 (brs, NH), 7.77 (d, 1H), 7.48 (d, 1H), 7.10 (t, 1H), 2.35 (s, 3H).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 461 - 467
[2] Synthesis (Germany), 2016, vol. 48, # 8, p. 1226 - 1234
[3] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 3, p. 254 - 259
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
[5] Patent: US2016/90374, 2016, A1, . Location in patent: Paragraph 0170; 0171
[6] Patent: US2016/168140, 2016, A1, . Location in patent: Paragraph 0984
  • 8
  • [ 4389-45-1 ]
  • [ 108-95-2 ]
  • [ 67449-23-4 ]
YieldReaction ConditionsOperation in experiment
75% With urea In ethanol EXAMPLE 2
8-Methyl-2,4-(1H,3H)quinazolinedione
3-Methylanthranilic acid (15 g., 0.1 mole), urea (36 g., 0.6 mole) and phenol (86 g.) were mixed together and heated to reflux for three hours.
The reaction was then allowed to cool to 100° C. and ethanol (75 ml.) added dropwise.
The resulting solid was filtered and washed twice with cold ethanol to afford 13.2 g. (75percent yield); m.p. 170° C.
Reference: [1] Patent: US4085213, 1978, A,
  • 9
  • [ 590-28-3 ]
  • [ 4389-45-1 ]
  • [ 67449-23-4 ]
Reference: [1] Chinese Chemical Letters, 2012, vol. 23, # 4, p. 431 - 433
[2] Chemische Berichte, 1907, vol. 40, p. 4413
[3] Journal of Medicinal Chemistry, 1995, vol. 38, # 14, p. 2763 - 2773
  • 10
  • [ 4389-45-1 ]
  • [ 67449-23-4 ]
Reference: [1] Patent: US5064833, 1991, A,
[2] Patent: EP322133, 1991, B1,
[3] Patent: EP322133, 1989, A1,
  • 11
  • [ 4389-45-1 ]
  • [ 57-13-6 ]
  • [ 67449-23-4 ]
Reference: [1] Journal of Natural Products, 2004, vol. 67, # 7, p. 1131 - 1134
  • 12
  • [ 4389-45-1 ]
  • [ 15068-35-6 ]
YieldReaction ConditionsOperation in experiment
80.3% With hydrogenchloride; sodium hydroxide; sodium nitrite In water (i)
2-Chloro-3-methylbenzoic Acid
Sodium nitrite (14.0 g; 0.2 mol) was added to a solution of 2-amino-3-methylbenzoic acid (30.2 g; 0.2 mol) in a mixture of water (200 mL) and NaOH/aq (30percent; 24 mL).
The solution was cooled to 0° C. and was added dropwise, with stirring, to a mixture of HCl (conc.; 87.6 mL) and ice (100 g).
After stirring for a few minutes, the resultant solution was added to an ice cold mixture of HCl/aq (23percent; 100 g), CuCl (20 g; 0.2 mol) and water (40 mL).
The solution was stirred at room temperature for 30 minutes and at 100° C. for 30 minutes, cooled, and the resultant precipitate was isolated by filtration, was washed with water, and was dried overnight, yielding 27.4 g (80.3percent) of a white crystalline material.
LC-MS m/z 169, 171 (M-1)-; 1H-NMR (500 MHz; CDCl3): δ 7.79 (d, 1H); 7.43 (d, 1H); 7.25 (t, 1H); 2.46 (s, 3H).
Reference: [1] Patent: US6255301, 2001, B1,
  • 13
  • [ 4389-45-1 ]
  • [ 57772-50-6 ]
YieldReaction ConditionsOperation in experiment
97% With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 3.5 h; General procedure: To a suspension of lithium aluminum hydride (20.4 mmol) in THF (10 mL) was added benzoic acid (8.5 mmol) dissolved in THF (24 mL) dropwise over 20 minutes at room temperature. The reaction continued to stir at room temperature for 3.5 h, and then was quenched at 0 °C with H2O (10 mL). The suspension was filtered through a Celite plug with EtOAc (100 mL), washed with brine (30 mL), dried with MgSO4 and concentrated in vacuo.
Reference: [1] Chemical Communications, 2017, vol. 53, # 1, p. 216 - 219
[2] Organic Letters, 2017, vol. 19, # 12, p. 3219 - 3222
[3] Tetrahedron Letters, 2017, vol. 58, # 40, p. 3795 - 3799
[4] Journal of the American Chemical Society, 2014, vol. 136, # 24, p. 8729 - 8737
[5] Journal of the American Chemical Society, 2017, vol. 139, # 2, p. 655 - 662
[6] Australian Journal of Chemistry, 1982, vol. 35, # 12, p. 2435 - 2443
[7] Archiv der Pharmazie (Weinheim, Germany), 1929, p. 583
[8] Journal of Pharmaceutical Sciences, 1977, vol. 66, # 8, p. 1180 - 1190
[9] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 42 - 46
[10] Tetrahedron, 2014, vol. 70, # 34, p. 5114 - 5121
[11] Tetrahedron, 2014, vol. 70, # 34, p. 5114 - 5121
[12] Synthesis (Germany), 2014, vol. 46, # 24, p. 3365 - 3373
[13] Organic Letters, 2015, vol. 17, # 19, p. 4750 - 4753
[14] Organic Letters, 2018,
[15] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 9046 - 9074
[16] Chemical Communications, 2016, vol. 52, # 53, p. 8305 - 8308
[17] Organic and Biomolecular Chemistry, 2016, vol. 14, # 38, p. 8966 - 8970
[18] Organic Letters, 2017, vol. 19, # 19, p. 5236 - 5239
[19] Organic and Biomolecular Chemistry, 2018, vol. 16, # 12, p. 2039 - 2042
[20] Organic Letters, 2018, vol. 20, # 10, p. 2939 - 2943
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Reference: [1] Archiv der Pharmazie (Weinheim, Germany), 1929, p. 583
  • 15
  • [ 50424-93-6 ]
  • [ 4389-45-1 ]
  • [ 5437-38-7 ]
  • [ 78876-98-9 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 8, p. 1701 - 1714
  • 16
  • [ 4389-45-1 ]
  • [ 74-88-4 ]
  • [ 22223-49-0 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.666667 h;
Stage #2: at 20℃;
A mixture of 2-amino-3-methylbenzoic acid (15.2 g, 0.10 mol), dimethylformamide (333 mL) and CsCO3 (49 g, 0.15 mol) was stirred at room temperature for about 40 minutes before drop wise addition of iodomethane (14.2 g, 6.2 mL, 0.10 mol) in dimethylformamide ("DMF") (115 mL). The mixture was stirred . at room temperature overnight. The mixture was diluted with water (1 L), and extracted with diethyl ether. The aqueous phase was back extracted with diethyl ether. The combined organic extracts were washed with saturated aqueous NaCI, dried over MgSO4, filtered and concentrated. The resultant material was dried at room temperature/0.5 mmHg to afford methyl 2-amino-3-methylbenzoate (17 g, 100percent).To a solution methyl 2-amino-3-methylbenzoate (16.5 g, 0.10 mol) in CHCI3 (286 mL) was added acetic anhydride (23.5 g, 21.7 mL, 0.23 mol) so as to maintain the internal temperature <40 0C. The mixture was stirred at room temperature for 1 hour before addition of potassium acetate (2.94 g, 30 mmol) and isoamyl nitrite (25.8 g, 30 mL, 0.22 mol). The resultant mixture was heated at reflux overnight. To this was then added methanol (94 mL) and 6 N HCI (94 mL) and the mixture was stirred overnight. The reaction mixture was concentrated to provide an orange solid which was subsequently triturated with ethyl <n="29"/>acetate and the solids were isolated by vacuum filtration. The solids were dried at room temperature/0.5 mmHg to afford methyl 1 H-indazole-7-carboxylate (15.4 g, 88percent). -A solution of methyl 1 H-indazole-7-carboxylate (14.96 g, 84.9 mmol) in methanol (180 ml_) was cooled to 0 0C before addition of 29percent aqueous potassium hydroxide (36 ml_). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The pH was adjusted to 5.5 using concentrated HCI. The volatiles were removed by vacuum filtration and the resultant material was suspended in water (100 mL) and ethyl acetate (200 mL). The resultant precipitate was isolated by vacuum filtration and rinsed with ethyl acetate. The solids were dried at room temperature/0.5 mmHg to afford the title compound (7.54 g, 55percent).
92% With caesium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 18.5 h; To a solution of 2-amino-3-methylbenzoic acid (66.9 mmol) in N, N-dimethylformamide (200 mL) was added cesium carbonate (102 mmol). The mixture was stirred for 30 min. A solution of methyl iodide (67.0 mmol) in NN-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at rt. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated, thus providing methyl 2-amino-3-methylbenzoate in 92percent yield.'H NMR (400 MHz, CDC13) 6 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H). To a solution of the ester (106 mmol) in chloroform (300 mL) was added acetic anhydride (239 mmol) while maintaining the temperature below 40 °C. The reaction mixture was maintained at room temperature for 1 h when potassium acetate (30.6 mmol) and isoamyl nitrite (228 mmol) was added. The reaction mixture was heated at reflux for 24 h and was allowed to cool to room temperature. The reaction mixture was washed with a saturated, aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated. Methanol (100 mL) and 6 N hydrochloric acid (100 mL) were added to the residue and the mixture was maintained for 18 h at rt. The volatiles were removed under reduced pressure and the residue was triturated with ethyl acetate (100 mL). The product was isolated by filtration, washed with ethyl acetate (20 mL), and dried, thus providing methyl 1H-indazole-7-carboxylate hydrochloride in 68percent yield.'H NMR (500 MHz, Me2SO-d6) 8 13.3 (bs, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.25 (dd, 1H), 7.27 (t, 1H), 3.97 (s, 3H); MS (APCI) m/z 177 (M++1). A solution of the indazole (33.0 mmol) in methanol (100 mL) at 0 °C was treated with an 29percent aqueous solution of potassium hydroxide (20 mL). The reaction mixture was allowed to warm to rt and was maintained for 18 h. The pH of the solution was adjusted to 5.5 by the addition of concentrated hydrochloric acid and the volatiles were removed under reduced pressure. The residue was partitioned between brine (100 mL) and ethyl acetate (200 mL) and the aqueous layer was extracted with additional warm ethyl acetate (200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was triturated with ethyl acetate (30 mL) and the solids were isolated by filtration, thus providing the acid in 94percent yield.
77%
Stage #1: With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 1 h;
Stage #2: for 24 h;
The synthesis was conducted in a round bottom flask where the 2-amino-3-methylbenzoic acid (0.3041 g; 2.0116 mmol) was suspended in 15 mL dry DMF and mixed with the catalyst Cs2CO3 (0.9887 g; 3.0345 mmol) in room temperature. After 1 h the appropriate amount of CH3I (0,3098 g; 2.1826 mmol) was added. After 24 h of stirring the suspension was dissolved in distilled water. Then the extraction with the use of diethyl ether was performed. The brown oil ester product (Ea: yield ca. 77percent; 0.2544 g; 1.5402 mmol) was obtained after the solvent evaporation. Anal. Calc. C9H11N1O2: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.14; H, 6.99; N, 8.36. FT-IR (KBr): 3491, 3373 cm-1 ν(N-H), 3075, 2950, 2857 cm-1 ν(C-H), 1692 cm-1 ν(C=O), 1614-1437 cm-1 ν(ringC=C), δ(N-H) and δ(C-H) overlapped, 1303-1087 cm-1 ν(C-O) and ν(C-N) overlapped, 845 cm-1 δ(N-H), 753 cm-1 δ(ringC = C)oop. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.77 (ddd, J = 8.09, 1.60, 0.53 Hz, 1H), 7.26 (CDCl3 signal), 7.19 (ddd, J = 7.12, 1.60, 0.80 Hz, 1H), 6.59 (m, 1H), 5.82 (s, 2H amine), 3.86 (s, 3H), 2.17 (s, 3H).
13C NMR (400 MHz, CDCl3, ppm) δ: 169.00, 148.77, 134.72, 128.93, 122.86, 115.47, 110.18, 51.37, 17.49.
Reference: [1] Patent: WO2008/65508, 2008, A1, . Location in patent: Page/Page column 27-28
[2] Patent: WO2005/92890, 2005, A2, . Location in patent: Page/Page column 77-79
[3] Journal of Molecular Structure, 2017, vol. 1145, p. 86 - 93
[4] Journal of Organic Chemistry, 2016, vol. 81, # 15, p. 6855 - 6861
  • 17
  • [ 4389-45-1 ]
  • [ 22223-49-0 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With caesium carbonate In DMF (N,N-dimethyl-formamide) for 0.5 h;
Stage #2: With methyl iodide In DMF (N,N-dimethyl-formamide) at 20℃; for 18 h;
To a solution of 2-amino-3-methylbenzoic acid (10.1 g, 66.9 mmol) in N, N dimethylformamide (200 mL) was added cesium carbonate (33.2 g, 102 mmol, 1.5 eq). The mixture was stirred for 30 min. A solution of methyl iodide (4.17 mL, 67.0 mmol, 1.0 eq) in N,N-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at rt. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated to provide 10.2 g (92percent) of methyl 2-amino-3-methylbenzoate. 1H NMR (400 MHz, CDCl3) delta; 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H)
Reference: [1] Patent: WO2004/29050, 2004, A1, . Location in patent: Page 64
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 16, p. 3753 - 3757
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  • [ 67-56-1 ]
  • [ 4389-45-1 ]
  • [ 22223-49-0 ]
YieldReaction ConditionsOperation in experiment
24%
Stage #1: for 24 h; Heating / reflux
Stage #2: With sodium hydrogencarbonate In methanol; water
A solution of 2-amino-3-methylbenzoic acid (5.10 g) and concentrated sulfuric acid (5 mL) in methanol (200 mL) was heated under reflux for 24 hours. The reaction mixture was concentrated and was neutralized with a saturated sodium hydrogen carbonate aqueous solution. Insolubles were mixed with ethyl acetate and filtered. The filtrate was partitioned in a separatory funnel and the separated organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate 4:1) and 1.31 g (24percent) of the title compound was obtained as a light brown oil.
Reference: [1] Tetrahedron, 2009, vol. 65, # 2, p. 563 - 578
[2] Patent: EP1764360, 2007, A1, . Location in patent: Page/Page column 142
[3] Bulletin de la Societe Chimique de France, 1907, vol. &lt;4&gt; 1, p. 216[4] Bulletin de la Societe Chimique de France, 1911, vol. &lt;4&gt; 9, p. 602,657
[5] Journal of Organic Chemistry, 2013, vol. 78, # 23, p. 12144 - 12153
[6] Journal of Organic Chemistry, 2015, vol. 80, # 21, p. 11175 - 11183
[7] Patent: WO2007/121578, 2007, A1, . Location in patent: Page/Page column 29
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  • [ 503-38-8 ]
  • [ 22223-49-0 ]
Reference: [1] Patent: US5962436, 1999, A,
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  • [ 4389-45-1 ]
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[2] Journal of Organic Chemistry, 2003, vol. 68, # 7, p. 2972 - 2974
[3] Journal of Organic Chemistry, 2003, vol. 68, # 23, p. 8918 - 8931
[4] Journal of the American Chemical Society, 2002, vol. 124, # 2, p. 184 - 185
[5] Chemistry--A European Journal, 2014, vol. 20, # 36, p. 11336 - 11339,4
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1973, p. 2940 - 2948
[7] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 10, p. 3659 - 3662
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[10] Organic Letters, 2017, vol. 19, # 7, p. 1578 - 1581
  • 23
  • [ 4389-45-1 ]
  • [ 53663-39-1 ]
YieldReaction ConditionsOperation in experiment
1 g
Stage #1: With hydrogen bromide; acetic acid; sodium nitrite In water for 0.166667 h; Cooling with ice
Stage #2: With copper(I) bromide In water at 50℃; for 3 h;
Reference Example 1 (0142) To a mixture of 1.00 g of 2-amino-3-methylbenzoic acid, 8 mL of acetic acid, 4 mL of 50percent hydrobromic acid and 16 mL of water were added 0.46 g of sodium nitrite and 3 mL of water under ice cooling. After stirring the mixture for 10 minutes under ice cooling, disappearance of 2-amino-3-methylbenzoic acid was confirmed by silica gel thin-layer chromatography (developing solvent: hexane/ethyl acetate=1/1, Rf value of 2-amino-3-methylbenzoic acid: 0.67), then 1.42 g of copper bromide and 5 mL of water were added, and the mixture was heated at 50° C. for 3 hours. Water was added to the mixture, and the resulting mixture was filtered to obtain 1.0 g of 2-bromo-3-methylbenzoic acid. (0143) 1H-NMR (CDCl3) δ (ppm): 2.49 (3H, s), 7.29 (1H, t, J=7.6 Hz), 7.42 (1H, d, J=7.2 Hz), 7.70 (1H, t, J=3.9 Hz)
Reference: [1] Patent: US2017/57935, 2017, A1, . Location in patent: Paragraph 0142; 0143
  • 24
  • [ 4389-45-1 ]
  • [ 1885-32-1 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 70℃; for 1 h; Inert atmosphere
Stage #2: With ammonium hydroxide In N,N-dimethyl-formamide for 16 h; Inert atmosphere
2-Amino-3-methylbenzoic acid (2.93 g, 19.8 mmol) in dry DMF (78 mL) was treated with 1,1-carbonyl-diimidazole (3.14 g, 19.4 mmol) at 70°C under Ar for lh, after which aq. NH3 (35percent, 49 mL) was added dropwise and the mixture was stirred for 16 h. The mixture was allowed to cool to 20°C and was diluted with EtOAc (100 mL). The mixture was washed with water (2 x 40 mL) and brine (2 x 40 mL). The organic solution was dried and the solvent was evaporated to give (8) (2.14 g, 98percent) as a white solid: mp 150-152°C (lit.24 mp 150-152°C); NMR ((CD3)2SO) δ 2.05 (3 H, s,), 6.35 (2 H, br), 6.41 (1 H, brt, / = 7.6 Hz,), 7.00 (1 H, brs), 7.04 (1 H, d, / = 6.8 Hz), 7.34 (1 H, dd, / = 8.0, 0.8 Hz), 7.67 (1 H, brs); 13CNMR ((CD3)2SO) δ 17.56, 113.59, 114.17, 122.99, 126.61, 132.67, 148.21, 171.73.
87% With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 60 h; Inert atmosphere Step A: To 2-amino-3-methylbenzoic acid (1.5 g, 10 mmol) in DMF (5 mL) at rt were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and diisopropylethylamine (7.5 ml, 42 mmol). The mixture was purged with N2 and stirred for 60 h. The mixture was poured into water and extracte with EtOAc (50 mL.x.3), and the combined extracts were washed with brine (20 mL.x.2), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM and purified by silica gel chromatography eluting with 1:1 EtOAc/hexanes to afford 2-amino-3-methyl-benzamide as a white solid (1.3 g, 87percent).
64%
Stage #1: With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1.08 h; Inert atmosphere
Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere
1161) A 500 mL round bottom flask was charged with 2-amino-3-methylbenzoic acid (Combi-Blocks, 4.0 g, 26.5 mmol, 1 eq), NH4Cl (4.25 g, 79.4 mmol, 3 eq) and a stir bar. The flask was evacuated and back-filled with Ar (×3). Anhydrous DCM (100 mL) and anhydrous DMF (20 mL) were added. The resulting stirred mixture was cooled to 0° C. 1-hydroxybenzotriazole hydrate (3.93 g, 29.1 mmol, 1.1 eq) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.56 g, 29.1 mmol, 1.1 eq) 5 min later. After 1 h DIPEA (32 mL, 23.9 g, 185 mmol, 7 eq) was added dropwise. The reaction was stirred at 0° C. to room temperature overnight. The volatiles were removed via rotary evaporation. The residue was diluted with water and adjusted to pH≈8-9 with conc. NH3(aq). The resulting mixture was extracted with EtOAc (×3). The combined organics were dried over Na2SO4. The solids were filtered off, and the volatiles were removed via rotary evaporation. The residue was diluted with DCM and the resulting mixture was diluted with hexanes. The solids were collected via vacuum filtration. The filter cake was triturated with 10percent DCM in hexanes and dried. 2.56 g (17.0 mmol, 64percent yield) of 135 was collected as an off-white solid. Mass spectrum (ESI+): m/z=151 [M+1]observed.
63% With ammonia; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In methanol; N,N-dimethyl-formamide at 20℃; for 16 h; 00373] Step A: To solution of 2-amino-3-methylbenzoic acid (4.0 g, 26.5 mmol) in degassed DMF (40 mL) were added HOBt (4.28 g, 31.7 mmol), DIEA (5.52 mL, 31.7 mmol), and 2N NH3/MeOH (19 mL, 37.1 mmol). The solution was stirred at rt for 16 h, then. the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 10-60percent EtOAc/hexanes to afford 2-amino-3-methylbenzamide as a solid (2.52 g, 63percent). 1H NMR (300 MHz, DMSO-J6) δ 2.07 (s, 3H), 6.40 - 6.47 (m, 3H), 7.06 (m, 2H), 7.42 (d, IH), 7.72 (br d, IH).
60% With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; N,N-dimethyl-formamide at 20℃; for 24 h; Inert atmosphere Accordingtoaliteratureprocedure,3toasolutionof2-amino-3-methylbenzoicacid(151mg,1.00mmol,1.0eq)indegassedDMF(2.00mL)wereaddedHOBt(162mg,1.20mmol,1.2eq.),EDCI.HCl(230mg,1.20mmol,1.2eq.),N,N-diisopropylethylamine(350μL,2.00mmol,2.0eq),and7MNH3/MeOH(429μL,1.50mmol,1.5eq.).Thesolutionwasstirredatroomtemperaturefor24hoursthenpouredoverwaterandtheaqueouslayerextractedwithEtOAc(320mL),thecombinedorganiclayerswashedwithbrine(25mL),driedwithNa2SO4andconcentratedinvacuo.TheresiduewaspurifiedbyFCC(gradient50percentEtOAc/hexanes to 80percent EtOAc/hexanes) to give 2-amino-3-methylbenzamide (90.0 mg,0.599mmol,60percent)asawhiteamorphoussolid;mp:144–146°C,lit.144–145°C.
60% With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6 h; To a stirred solution of 2-amino-3-methyl-benzoic acid (0.5 g, 3.31 mmol) in THF (15 mL),EDC.HCl (0.948 g, 4.97 mmol), HOBt·NH3 (0.745 g, 4.97 mmol) and DIPEA (1.76 mL, 9.93mmol) were added at RT and stirred for 6 h (TLC indicates complete conversion of startingmaterial). The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x 100 mL). The combined organic extracts were washed with water (2 x 50 mL), brine (40mL), dried over Na2S04 and concentrated under reduced pressure to give the crude residue The crude material was purified by column chromatography (100-200 silica gel, 20 g, 50percentEtOAc-Hexane) to afford 2-amino-3-methyl-benzamide (0.3 g, 60percent) as a white solid.LCMS: m/z: 151.09 [M+H] +.

Reference: [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 17, p. 6089 - 6099
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 814 - 820
[3] Patent: WO2018/46933, 2018, A1, . Location in patent: Page/Page column 32-33
[4] Patent: US2012/53174, 2012, A1, . Location in patent: Page/Page column 48
[5] Patent: US2016/168140, 2016, A1, . Location in patent: Paragraph 1161
[6] Patent: WO2010/99379, 2010, A1, . Location in patent: Page/Page column 132
[7] Synthesis (Germany), 2017, vol. 49, # 1, p. 135 - 144
[8] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 55; 56
[9] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 12, p. 1173 - 1177
[10] Journal of Agricultural and Food Chemistry, 2015, vol. 63, # 31, p. 6883 - 6889
[11] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 316 - 327
[12] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
  • 25
  • [ 4389-45-1 ]
  • [ 1885-32-1 ]
YieldReaction ConditionsOperation in experiment
63% With DIEA; benzotriazol-1-ol In N,N-dimethyl-formamide Step A:
To solution of 2-amino-3-methylbenzoic acid (4.0 g, 26.5 mmol) in degassed DMF (40 mL) were added HOBt (4.28 g, 31.7 mmol), DIEA (5.52 mL, 31.7 mmol), and 2N NH3/MeOH (19 mL, 37.1 mmol).
The solution was stirred at room temperature for 16 hrs, then.
the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 10-60percent EtOAc/hexanes to afford 2-amino-3-methylbenzamide as a solid (2.52 g, 63percent).
1H NMR (300 MHz, DMSO-d6) δ2.07 (s, 3H), 6.40-6.47 (m, 3H), 7.06 (m, 2H), 7.42 (d, 1H), 7.72 (br d, 1H).
Reference: [1] Patent: US2012/53176, 2012, A1,
  • 26
  • [ 4389-45-1 ]
  • [ 20776-67-4 ]
YieldReaction ConditionsOperation in experiment
83% With N-chloro-succinimide In N,N-dimethyl-formamide for 3 h; Reflux In 100ml of round flask , add 20ml of 3-methyl-2-amino-benzoic acid, 50ml of DMF,30ml mmol of N- chlorosuccinimide(or N- bromosuccinimide ) and after stirred atreflux for 3h, the reaction solution was poured into ice water and dilutehydrochloric acid acidifying to pH = 6. Filtered andthe resulting solid was washed small amount of ethanol to give a gray solidchlorinated or brominated anthranilate III.yield 83percent. Y selected from :cholrine and bromine.
83% With N-chloro-succinimide In N,N-dimethyl-formamide for 3 h; To a 100 ml round bottom flask was added 3.0 g of 20 mmol 3-methyl-2-aminobenzoic acid X,30 ml of DMF,6.7 grams of 30 millimoles of NCS (or 30 millimoles of NBS),After stirring for 3 hours,The reaction solution was poured into ice water,Dilute hydrochloric acid to pH = 6,filter,The resulting solid was washed with a small amount of ethanol to give 2-amino-3-methyl-5-halo-benzoic acid III,Gray solid,4.6 grams or more,Yield is greater than 83percent.Y selected from:chlorine,bromine,The 2-amino-3-methyl-5-halo-benzoic acid III is selected from the group consisting of -2-amino-3-methyl-5-chlorobenzoic acid,2-amino-3-methyl-5-bromo-benzoic acid
75.4% With N-chloro-succinimide In N,N-dimethyl-formamide at 20 - 100℃; EXAMPLE 2 Preparation of methyl 2-amino-5-chloro-3-methylbenzoateStep A: Preparation of 2-amino-5-chloro-3-methylbenzoic acidTo a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in Ny/V-dimethylformamide (5O mL) was added TV-chlorosuccinimide (13.3 g, 99.2 mmol) and the reaction mixture was heated to 100 °C for 30 minutes. The heat was removed and the reaction mixture was cooled to room temperature and allowed to stand overnight. The reaction mixture was then slowly poured into ice water (250 mL) to precipitate a white solid.The solid was filtered and washed four times with water and then taken up in ethyl acetate (900 mL). The ethyl acetate solution was dried (MgSO4) and evaporated under reduced pressure, and the residual solid was washed with ether to afford the desired intermediate as a white solid, 13.9 g (75.4percent yield).1H NMR (DMSO-J6) δ 2.11 (s, 3H), 7.22 (s, IH), 7.55 (s, IH).
13.9 g With N-chloro-succinimide In N,N-dimethyl-formamide at 100℃; for 0.5 h; Step A: Preparation of 2-Amino-3-methyl-5-chlorobenzoic acid
To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g, 99.2 mmol) in N,N-dimethylformamide (50 mL) was added N-chlorosuccinimide (13.3 g, 99.2 mmol) and the reaction mixture was heated to 100° C. for 30 minutes. The heat was removed, the reaction was cooled to room temperature and let stand overnight. The reaction mixture was then slowly poured into ice-water (250 mL) to precipitate a white solid. The solid was filtered and washed four times with water and then taken up in ethyl acetate (900 mL). The ethyl acetate solution was dried over magnesium sulfate, evaporated under reduced pressure and the residual solid was washed with ether to afford the desired intermediate as a white solid (13.9 g). 1H NMR (DMSO-d6) δ 2.11 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H).
13.9 g With N-chloro-succinimide In N,N-dimethyl-formamide at 100℃; for 0.5 h; Step A: Preparation of2-Amino-3-methyl-5-chlorobenzoic acid To a solution of 2-amino-3-methylbenzoic acid (Aldrich,15.0 g, 99.2 mmol) in N,N-dimethylformamide (50 mE) wasadded N-chlorosuccimide (13.3 g, 99.2 mmol) and the reac35 tion mixture was heated to 100° C. for 30 minutes. The heatwas removed, the reaction was cooled to room temperatureand let stand overnight. The reaction mixture was then slowlypoured into ice-water (250 mE) to precipitate a white solid.The solid was filtered and washed four times with water andthen taken up in ethyl acetate (900 mE). The ethyl acetatesolution was dried over magnesium sulfate, evaporated underreduced pressure and the residual solid was washed with etherto afford the desired intermediate as a white solid (13.9 g).‘H NMR (DMSO-d5) ö 2.1 (s, 3H), 7.22 (s, 1H), 7.55 (s,1H).

Reference: [1] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 44, p. 10942 - 10951
[2] Australian Journal of Chemistry, 2014, vol. 67, # 10, p. 1491 - 1503
[3] Patent: CN103450154, 2016, B, . Location in patent: Paragraph 0063-0065
[4] Patent: CN104031026, 2017, B, . Location in patent: Paragraph 0051; 0052; 0053; 0054
[5] Journal of Chemical Research, 2008, # 9, p. 530 - 533
[6] Chinese Journal of Chemistry, 2012, vol. 30, # 8, p. 1748 - 1758
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[9] Patent: WO2006/62978, 2006, A1, . Location in patent: Page/Page column 22
[10] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 22, p. 4898 - 4906
[11] Patent: US2004/110777, 2004, A1,
[12] Patent: WO2004/11447, 2004, A2, . Location in patent: Page 42
[13] Patent: US9113630, 2015, B2, . Location in patent: Page/Page column 37
[14] Patent: US9173400, 2015, B2, . Location in patent: Page/Page column 36
[15] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 3, p. 865 - 875
  • 27
  • [ 4389-45-1 ]
  • [ 206548-13-2 ]
YieldReaction ConditionsOperation in experiment
97% at 20 - 25℃; General procedure: Bromine (3.43 mL, 130 mmol) was added to a solution of 2-amino-5-trifluoromethylbenzoic acid ethyl ester (5.34 g, 23 mmol) in DCM (26.5 mL) at room temperature.
A saturated aqueous sodium thiosulfate solution (30 mL) was added thereto under ice-cooling, and extraction was performed with ethyl acetate.
The extract was washed with brine and then dried over anhydrous sodium sulfate.
The drying agent was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.97 g, 97percent) as a pale yellow oily substance. The title compound was synthesized from 2-amino-3-methyl-benzoic acid under the same conditions as for Compound a9. However, acetic acid was used in place of DCM as a solvent.
85% With hydrogen bromide In water; dimethyl sulfoxide at 20℃; Step A: To a solution of 2-amino-3-methylbenzoic acid (10.0 g, 66 mmol) in DMSO was added 48percent aqueous hydrogen bromide (18.0 ml). The reaction solution was stirred at room temperature overnight and then quenched with saturated sodium bicarbonate. The resultant mixture was stirred overnight. Precipitation was collected by filtration and dried in vacuo to give 2-amino-5-bromo-3-methylbenzoic acid (13.0 g,85percent) as a pink solid: 1H NMR (500 MHz, DMSO) δ 7.69 (d, J = 1.0 Hz, 1 H), 7.33 (d, J = 1.0 Hz, I H), 2.10 (s, 3 H); MS (ESI+) m/z 231 (M+H).
85%
Stage #1: With bromine In acetic acid at 0 - 20℃; for 0.583333 h;
Stage #2: With sodium carbonate In dichloromethane; water; acetic acid
Stage #3: With hydrogenchloride In water
To a solution of 2-amino-3-methylbenzoic acid (5.00 g, 33.1 mmol) in acetic acid (110 mL) at 0 0C was added drop wise a mixture of bromine (1.7 mL, 33 mmol) in acetic acid (50 mL) over about 5 minutes. Following addition, the cooling bath was removed and the mixture was stirred at room temperature for 30 minutes before removal of acetic acid under reduced pressure. The mixture was diluted with CH2CI2 and washed with saturated aqueous Na2CO3. The aqueous phase was back extracted with CH2CI2. The ~aqueoOs phrase'was acidified-using concentrated HCI to pH 7:2rwith intense foaming observed. Copious amounts of precipitate formed and were isolated by vacuum filtration . The filtrate was further acidified with concentrated HCI to pH 6.3 and a second crop of precipitate was collected. The combined solids were dried at 65 0C /0.5 mmHg to provide 2-amino-5-bromo-3-methylbenzoic acid (6.43 g, 85percent).A solution of 2-amino-5-bromo-3-methylbenzoic acid (6.43 g, 27.9 mmol) in DMF (93 mL) containing cesium carbonate (13.7 g, 41.9 mmol) was stirred at room temperature for 40 minutes before drop wise addition of a solution of iodomethane (1.7 mL, 28 mmol) in DMF (21 mL). The mixture was stirred at room temperature for 2 days. The mixture was diluted with water (300 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to afford a brown oil that solidified into a beige solid after drying at room temperature/0.5 mmHg to provide methyl 2-amino- 5-bromo-3-methylbenzoate (5.45 g, 80percent).To a solution of methyl 2-amino-5-bromo-3-methylbenzoate (5.45 g, 22.3 mmol) in CHCI3 (64 mL) was added acetic anhydride (4.9 mL) at such rate as to maintain the internal temperature below 40 0C. The <n="31"/>resulting mixture was stirred at room temperature for 1 hour and then potassium acetate (0.66 g, 6.7 mmol) and isoamyl nitrite (6.6 ml_, 49 mmol) were added. The reaction mixture was heated at reflux overnight and then cooled to room temperature and concentrated. The residue was dissolved in methanol (22 mL) and 6 N HCI (22 mL) and stirred at room temperature for about 4 hours. A yellow solid was isolated by vacuum filtration and rinsed with water. The solids were dried at 65 C/0.5 mmHg to provide methyl δ-bromo-IH-indazole^-carboxylate (4.90 g, 86percent).To a solution of δ-bromo-IH-indazole^-carboxylate (250 mg, 0.98 mmol) in methanol (2 mL) at 0 0C was added 30percent aqueous KOH (0.15 g KOH in 0.5 mL water). The mixture was stirred at room temperature for 2 days. The resultant solids were isolated by vacuum filtration and rinsed with MeOH. The solid material was dried at 65 0C /0.5 mmHg to provide the title compound as a light yellow solid (182 mg, 67 percent).
83% With N-Bromosuccinimide In N,N-dimethyl-formamide for 3 h; Reflux General procedure: In a 100ml of round flask , add 20ml of 3-methyl-2-amino-benzoic acid, 50ml of DMF,30ml mmol of N- chlorosuccinimide(or N- bromosuccinimide ) and after stirred atreflux for 3h, the reaction solution was poured into ice water and dilutehydrochloric acid acidifying to pH = 6. Filtered andthe resulting solid was washed small amount of ethanol to give a gray solidchlorinated or brominated anthranilate III.yield 83percent. Y selected from :cholrine and bromine.
83% With N-Bromosuccinimide In N,N-dimethyl-formamide for 3 h; To a 100 ml round bottom flask was added 3.0 g of 20 mmol 3-methyl-2-aminobenzoic acid X,30 ml of DMF,6.7 grams of 30 millimoles of NCS (or 30 millimoles of NBS),After stirring for 3 hours,The reaction solution was poured into ice water,Dilute hydrochloric acid to pH = 6,filter,The resulting solid was washed with a small amount of ethanol to give 2-amino-3-methyl-5-halo-benzoic acid III,Gray solid,4.6 grams or more,Yield is greater than 83percent.Y selected from:chlorine,bromine,The 2-amino-3-methyl-5-halo-benzoic acid III is selected from the group consisting of -2-amino-3-methyl-5-chlorobenzoic acid,2-amino-3-methyl-5-bromo-benzoic acid
52.2% at 0 - 20℃; for 4 h; To a solution of 19-51 (15 g, 0.1 mol) in AcOH (80 mL) was added Br2 (5.1 mL, 0.1 mol) dropwise at 0 °C. The reaction mixturewas stirred at room temperature for 4 h. The mixture was diluted with EtOAc and basified with aqueous NaOH solution (4 N) to pH 7. The mixture was extracted with EtOAc, dried, and concentrated to afford the crude product, which was purified by column chromatography on silica gel (eluted with DCMIMeOH = 100:0 to 50:1) to afford 19-S2 (12.0 g, 52.2percent yield) as a white solid. LC/MS (ESI) m/z: 230 (M+H).
51% With hydrogen bromide In dimethyl sulfoxide at 20℃; Method AZ: 2-Amino-5-bromo-3-methylbenzoic acid (lvi-a)
To a solution of 2-amino-3-methylbenzoic acid (1.23 g, 8.14 mmol, 1.0 eq) in 15 mL of DMSO was added 40percent HBr (6.00 mL, 44.7 mmol, 5 eq).
The resulting mixture was stirred at room temperature overnight.
A white precipitate formed during the course of the reaction.
The reaction mixture was quenched with saturated aqueous NaHCO3 resulting in a white solid that was filtered and dried in vacuo to yield 950 mg in 51percent yield of lvi-a as white solid. LCMS m/z=229.9 (M+1) (Method B) (retention time=1.20 min).
51% With hydrogen bromide In dimethyl sulfoxide at 20℃; 40percent HBr (6.00 mL, 44.7 mmol, 5 eq) was added to a solution of 2-amino-3-methylbenzoic acid (1.23 g, 8.14 mmol, 1.0 eq) in DMSO (15 mL).The resulting mixture was stirred at room temperature overnight. A white precipitate formed during the course of the reaction.The reaction mixture was quenched with saturated aqueous NaHCO 3 to give a white solid,This was filtered and dried under vacuum to obtain 950 mg (51percent yield) of lvi-a as a white solid. LCMS m / z = 229.9 (M + 1) (Method B) (retention time = 1.20 min).
95% With bromine In acetic acid Example 132
2-Amino-5-bromo-3-methyl-benzoic acid
To a mixture of 1.5g (10mmol) of 3-methyl-2-amino benzoic acid in 50mL of glacial acetic acid was added 1.6 g (10 mmol) of bromine and the resulting mixture was stirred at room temperature for 5 h.
The reaction mixture was then poured into water and the precipitated solid was filtered, washed with water and air dried to provide 2.2g (95percent) of the desired product as a brown solid. m.p.245°C. Electrospray Mass Spec 232 (M+H).

Reference: [1] Patent: EP2842946, 2015, A1, . Location in patent: Paragraph 0309; 0728; 0729
[2] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 44, p. 10942 - 10951
[3] Journal of Organic Chemistry, 2006, vol. 71, # 16, p. 5921 - 5929
[4] Patent: WO2011/8572, 2011, A2, . Location in patent: Page/Page column 70
[5] Patent: WO2008/65508, 2008, A1, . Location in patent: Page/Page column 29-30
[6] Patent: CN103450154, 2016, B, . Location in patent: Paragraph 0063-0065
[7] Patent: CN104031026, 2017, B, . Location in patent: Paragraph 0051; 0052; 0053; 0054
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[9] Patent: US2015/307477, 2015, A1, . Location in patent: Paragraph 1616
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