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Product Details of [ 22223-49-0 ]

CAS No. :22223-49-0 MDL No. :MFCD06200918
Formula : C9H11NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :VSFYTPXXMLJNAU-UHFFFAOYSA-N
M.W : 165.19 Pubchem ID :2763406
Synonyms :

Calculated chemistry of [ 22223-49-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 47.09
TPSA : 52.32 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) : -5.88 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.97
Log Po/w (XLOGP3) : 2.01
Log Po/w (WLOGP) : 1.37
Log Po/w (MLOGP) : 1.64
Log Po/w (SILICOS-IT) : 1.44
Consensus Log Po/w : 1.69

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.37
Solubility : 0.707 mg/ml ; 0.00428 mol/l
Class : Soluble
Log S (Ali) : -2.74
Solubility : 0.304 mg/ml ; 0.00184 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.49
Solubility : 0.531 mg/ml ; 0.00321 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.31

Safety of [ 22223-49-0 ]

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

Application In Synthesis of [ 22223-49-0 ]

* 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 [ 22223-49-0 ]
  • Downstream synthetic route of [ 22223-49-0 ]

[ 22223-49-0 ] Synthesis Path-Upstream   1~26

  • 1
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  • [ 77287-34-4 ]
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Reference: [1] Bioorganic Chemistry, 2018, vol. 80, p. 433 - 443
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  • [ 58421-80-0 ]
Reference: [1] Bioorganic Chemistry, 2018, vol. 80, p. 433 - 443
  • 3
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  • [ 57772-50-6 ]
Reference: [1] Organic Letters, 2016, vol. 18, # 21, p. 5572 - 5575
  • 4
  • [ 5471-82-9 ]
  • [ 22223-49-0 ]
YieldReaction ConditionsOperation in experiment
99% With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 10 h; Methyl 3-methyl-2-nitro benzoate (1g, 5.2mmol) was dissolved in ethanol (40mL) and then 10percent palladium on charcoal (0.1g) was added to the reaction mixture and stirred at rt for 10h. Then the mixture was filtrated, and evaporation of solvent under reduced pressure afforded the light yellow oil product. (0.85g, 99percent); δH (300MHz, CDCl3) 2.18 (3H, s, Me), 3.88 (3H, s, CO2Me), 5.84 (2H, br s, NH2), 6.61 (1H, t, J 7.7Hz, Ph), 7.22 (1H, d, J 7.3Hz, Ph), 7.79 (1H, d, J 7.7Hz, Ph); δC (75MHz, CDCl3) 17.4, 51.5, 110.1, 115.6, 123.0, 129.1, 134.9, 149.0, 169.0.
97.5% With hydrogen In acetonitrile at 70℃; for 16.5 h; EXAMPLE 4Preparation of 2-amino-5-chloro-N,3-dimethylbenzamideStep A: Preparation of methyl 2-amino-3-methylbenzoateMethyl 3-methyl-2-nitrobenzoate (98.5 g, 505 mmol), 5percent Pd/C (Degussa CE 105 XRCAV, 1.0 g), and acetonitrile (300 mL) were combined in a 600-mL pressure vessel. The mixture was heated to 70 °C and hydrogenated at 65 psi (450 kPa) for 8 h. More 5percent Pd/C (1.0 g) was added and hydrogenation was continued at 100 psi (690 kPa) for 8.5 h. Then the reaction mixture was cooled, purged with nitrogen, and filtered through Celite.(R). diatomaceous filter aid, rinsing with acetonitrile (3 x 25 mL). The combined filtrates were partly evaporated to a weight of ~ 160 g, and then diluted with acetonitrile to a total weight of 200 g. Quantitative HPLC of this solution showed 40.3 wtpercent of the title compound (80.6 g, 97.5percent yield).
Reference: [1] Tetrahedron, 2013, vol. 69, # 32, p. 6679 - 6686
[2] Patent: WO2006/62978, 2006, A1, . Location in patent: Page/Page column 23
[3] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
[4] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5629 - 5633
[5] Chemische Berichte, 1907, vol. 40, p. 4413
[6] Patent: US4456471, 1984, A,
[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
[8] Patent: US2015/111870, 2015, A1, . Location in patent: Paragraph 0685; 0686
  • 5
  • [ 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
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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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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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  • [ 18107-18-1 ]
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YieldReaction ConditionsOperation in experiment
93% for 0.5 h; To a solution of 2-amino-3-methylbenzoic acid (3.41 g, 27.1 mmol) in MeOH (70 mL) was added a 2.0M solution of TMSHCN2 in hexanes (15 mL, 30.0 mmol). The reaction was stirred for 30 minutes and then evaporated under reduced pressure to give the title compound (4.17 g, 93percent) as a brown oil. 1H NMR (300 MHz, DMSO) δ 7.61 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.45 (t, J = 7.4 Hz, 1H), 3.78 (s, 3H), 2.10 (s, 3H). 13C NMR (75 MHz, DMSO) δ 169.9, 149.6, 134.3, 129.0, 122.9, 114.2, 109.3, 51.5, 17.6.
Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 14, p. 3933 - 3937
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 16, p. 3753 - 3757
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  • [ 1122-58-3 ]
  • [ 4389-45-1 ]
  • [ 503-38-8 ]
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Reference: [1] Patent: US5962436, 1999, A,
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Reference: [1] Bulletin de la Societe Chimique de France, 1907, vol. &lt;4&gt; 1, p. 216[2] Bulletin de la Societe Chimique de France, 1911, vol. &lt;4&gt; 9, p. 602,657
[3] Chemische Berichte, 1907, vol. 40, p. 4413
[4] Tetrahedron, 2013, vol. 69, # 32, p. 6679 - 6686
[5] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
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Reference: [1] Chemische Berichte, 1907, vol. 40, p. 4413
[2] Tetrahedron, 2013, vol. 69, # 32, p. 6679 - 6686
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Reference: [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 22, p. 3386 - 3396
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Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 14, p. 3933 - 3937
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Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 14, p. 3933 - 3937
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Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 14, p. 3933 - 3937
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  • [ 67-56-1 ]
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Reference: [1] Angewandte Chemie, 1981, vol. 93, # 10, p. 914 - 915
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  • [ 1885-32-1 ]
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 152, p. 235 - 252
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  • [ 500024-27-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
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  • [ 500024-27-1 ]
Reference: [1] Chemische Berichte, 1907, vol. 40, p. 4413
[2] Chemische Berichte, 1909, vol. 42, p. 433
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  • [ 131001-86-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
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  • [ 22223-49-0 ]
  • [ 206548-14-3 ]
YieldReaction ConditionsOperation in experiment
97.7% With hydrogen bromide; dihydrogen peroxide In water at 30 - 70℃; for 3 h; A solution of methyl 2-amino-3-methylbenzoate (142.1 g, 0.843 mol, purity: 98percent quantitative NMR) in 240 mL of H2O is gradually admixed at 30° C. with hydrogen bromide (48percent of H2O, 149.2 g, 0.885 mol) added dropwise.
The suspension obtained is admixed with hydrogen peroxide (30percent in H2O, 105.1 g, 0.927 mol) added dropwise over 2 h, and the temperature is kept below 70° C. After 1 hour of subsequent stirring, NaHSO3 (39percent in H2O, 33.7 g, 0.126 mol) is added a little at a time (peroxide test was negative).
The suspension obtained is adjusted to pH7-8 with Na2CO3 (0.1 eq., 9.0 g, 0.084 mol), which is added a little at a time.
Following filtration and drying in a vacuum drying cabinet, methyl 2-amino-5-bromo-3-methylbenzoate is isolated as a pale brown solid. Yield: 204.2 g, 97.7percent of theory, purity: 98.5percent quantitative NMR).
1H NMR (600 MHz, (d6-DMSO): δ=7.70 (d, 1H), 7.36 (pt, 1H), 6.63 (br s, 2H), 3.80 (s, 3H), 2.12 (s, 3H)).
62% With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 6 h; To a solution of methyl 2-amino-3-methylbenzoate (4) (1.00 g, 6.10 mmol) in DMF (10 ml) was added NBS (1.10 g, 6.10 mmol), and the reaction mixture was stirred at rt for 6 h. The reaction mixture was diluted with EtOAc (10 ml) and washed with saturated aqueous Na2CO3 solution (10 ml * 3). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes/EtOAc = 100:1) to give compound 5 as pale gray solid (0.93 g, 62percent yield): 1H NMR (400 MHz, CDCl3) δ (ppm) 7.88 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 5.82 (s, 2H), 3.86 (s, 3H), 2.15 (s, 3H).
21 g With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 15℃; for 14 h; Step 1. To a solution of 17 (15.0 g, 90.8 mmol) in DMF (200 mL) was added NBS (16.2 g, 90.8 mmol) at 0°C. After addition, the mixture was warmed to 15°C and stirred for 14 hours. The reaction mixture was quenched by addition of water (200 mL) and then extracted with ethyl acetate (3 x 250 mL). The combined organic phase was washed with water (3 x 250 mL) and brine (2 x 200 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to give 18 (21.0 g) as a gray solid which was used directly in the next transformation. 1H NMR (CDC13, 400MHz) δ 7.90-7.89 (d, 1H), 7.29-7.28 (d, 1H), 5.84 (s, 2H), 3.87 (s, 3H), 2.15 (s, 3H); LCMS (ESI): m/z 246.0 (M+H).
Reference: [1] Patent: US2014/148611, 2014, A1, . Location in patent: Paragraph 0066; 0067; 0068
[2] Helvetica Chimica Acta, 2004, vol. 87, # 6, p. 1333 - 1356
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 3, p. 1156 - 1162
[4] Patent: US2015/111870, 2015, A1, . Location in patent: Paragraph 0687; 0688
[5] Patent: WO2018/49328, 2018, A1, . Location in patent: Page/Page column 26; 27; 28
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YieldReaction ConditionsOperation in experiment
68%
Stage #1: With acetic anhydride; isopentyl nitrite In chloroform at -40 - 20℃; for 1 h;
Stage #2: for 24 h; Heating / reflux
To a solution of the ester (17.5 g, 106 mmol) in chloroform (300 mL) was added acetic anhydride (22.6 mL, 239 mmol, 2.3 eq) while maintaining the temperature below 40 C. The reaction mixture was maintained at room temperature for 1 h when potassium acetate (3.00 g, 30.6 mmol, 0.3 eq) and isoamyl nitrite (30.6 mL, 228 mmol, 2.2 eqiv) 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 filteration, washed with ethyl acetate (20 mL), and dried to provide 15.3 g (68percent) of methyl 1H-indazole-7-carboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) delta; 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)
47%
Stage #1: With tetrafluoroboric acid; sodium nitrite In water at 0 - 20℃; for 1 h;
Stage #2: With 18-crown-6 ether; potassium acetate In chloroform for 1 h;
A cooled (5 °C) solution of sodium nitrite (1.670 g, 24.21 mmol) in water (3.3 mL) was added to a cooled (0 °C) solution of methyl 2-amino-3-methylbenzoate (4.00 g, 24.21 mmol) in 50percent HBF4 (10 ml). After complete addition the mixture was stirred for 1 hour at room temperature. The resultant precipitate was isolated by filtration and washed with Et2O. The diazonium salt was then added in one portion to a stirred mixture of dried and powdered potassium acetate (4.752 g, 48.42 mmol) and 18-crown-6 (0.32 g, 0.4 mmol) in dry chloroform (40 mL). After 1 hour the precipitate was removed and the filtrate was washed with water (20 mL), dried (MgSO4) and evaporated under reduced pressure. Recrystallization of the residue from heptanes gave the title compound (2.017 g, 47percent) as a pale orange powder. mp. 110 – 112 °C. 1H NMR (300 MHz, CDCl3) δ 11.54 (s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 8.05 (dd, J = 7.3, 1.0 Hz, 1H), 7.96 (ddd, J = 8.0, 1.5, 1.0 Hz, 1H), 7.21 (dd, J = 8.0, 7.3 Hz, 1H), 4.03 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 166.7, 138.8, 135.0, 129.2, 126.8, 124.5, 120.5, 112.6, 52.5
Reference: [1] Patent: WO2004/29050, 2004, A1, . Location in patent: Page 64
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 14, p. 3933 - 3937
[3] Journal of Organic Chemistry, 2016, vol. 81, # 15, p. 6855 - 6861
[4] Patent: WO2007/121578, 2007, A1, . Location in patent: Page/Page column 29
[5] Patent: WO2008/65508, 2008, A1,
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  • [ 677304-69-7 ]
Reference: [1] Patent: US2005/20611, 2005, A1, . Location in patent: Page/Page column 44
[2] Patent: WO2008/65508, 2008, A1,
  • 25
  • [ 22223-49-0 ]
  • [ 898747-24-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 3, p. 1156 - 1162
  • 26
  • [ 22223-49-0 ]
  • [ 586374-04-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
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