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Product Details of [ 420-37-1 ]

CAS No. :420-37-1 MDL No. :MFCD00011798
Formula : C3H9BF4O Boiling Point : -
Linear Structure Formula :- InChI Key :CZVZBKHWOFJNCR-UHFFFAOYSA-N
M.W : 147.91 Pubchem ID :2735153
Synonyms :

Safety of [ 420-37-1 ]

Signal Word:Danger Class:8
Precautionary Statements:P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501 UN#:3261
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 420-37-1 ]

* 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 [ 420-37-1 ]
  • Downstream synthetic route of [ 420-37-1 ]

[ 420-37-1 ] Synthesis Path-Upstream   1~26

  • 1
  • [ 1121-76-2 ]
  • [ 420-37-1 ]
  • [ 63071-10-3 ]
YieldReaction ConditionsOperation in experiment
43%
Stage #1: at 20℃; for 2 h;
Stage #2: With ammonium peroxodisulfate In methanol; water for 1 h; Heating / reflux
4-Chloro-2-(hydroxymethyl)pyridine : A solution of 4-CHLOROPYRIDINE ASOXIDE (5 G, 38.6 MMOL) and TRIMETHYLOXONIUM TETRAFLUOROBORATE (5.94 G, 40.1 MMOI) in CH2CL2 (115 mL) was stirred for two hours at ambient temperature. The solvent was evaporated and the residue taken up in MeOH (115 mL) and heated to near boiling. Ammonium persulfate (1.76 G, 7.72 MMOL) dissolved in H2O (7.7 mL) was added and the mixture was heated to reflux for 30 min. A second portion of ammonium persulfate (0.88 G) in H2O (3.9 mL) was added and the mixture was refluxed for another 30 min. The solvent was evaporated and the residue was partitioned between CHZCTZ and aqueous Na2CO3 (10percent w/v). The organic layer was washed with H2O, dried over MgSO4 and evaporated leaving 2.4 G (43percent) of the title compound. 1H NMR (CDC13) 8 8.20 (d, 1H, J=5. 0 Hz, H-6); 7.31 (s, 1H, H-3); 7.04 (d, 1H, J=5. 0 Hz, H-5); 5.46 (s, LH, OH); 4.61 (s, 2H, CH2).
Reference: [1] Patent: WO2005/12323, 2005, A2, . Location in patent: Page/Page column 46
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 11, p. 1777 - 1788
[3] Patent: EP1422228, 2004, A1, . Location in patent: Page 199
  • 2
  • [ 616-45-5 ]
  • [ 420-37-1 ]
  • [ 5264-35-7 ]
Reference: [1] Organic Letters, 2012, vol. 14, # 18, p. 4906 - 4909,4
[2] Organic Letters, 2012, vol. 14, # 18, p. 4906 - 4909
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 19, p. 4359 - 4362
  • 3
  • [ 134469-06-0 ]
  • [ 420-37-1 ]
  • [ 19975-56-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4539 - 4544
  • 4
  • [ 105-60-2 ]
  • [ 420-37-1 ]
  • [ 2525-16-8 ]
Reference: [1] Organic Preparations and Procedures International, 1992, vol. 24, # 2, p. 147 - 158
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 19, p. 2651 - 2653
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 19, p. 4359 - 4362
[4] Patent: US6046211, 2000, A,
[5] Patent: US5854234, 1998, A,
[6] Journal of the American Chemical Society, 2009, vol. 131, p. 8714 - 8718
[7] Patent: WO2010/68520, 2010, A2, . Location in patent: Page/Page column 29
  • 5
  • [ 1003-67-4 ]
  • [ 420-37-1 ]
  • [ 42508-74-7 ]
YieldReaction ConditionsOperation in experiment
78% With hydrogenchloride; ammonium hydroxide; ammonium persulfate In methanol; dichloromethane; water Example 215
4-Amino-6-chloro-2-(1-(4-methyl-2-pyridyl)ethyl)thio-pyrimidine hydrochloride (Cpd #215)
A solution of 4-picoline-N-oxide (3.0 g, 27.52 mmol) in 90 ml of methylene chloride at room temperature is reacted with trimethyloxonium tetrafluoroborate (4.07 g, 27.52 mmol, 1.0 equiv.) for 1.5 h.
The reaction mixture is concentrated directly at reduced pressure, the white solid dissolved in 60 ml of refluxing methanol and treated with ammonium persulfate (1.25 g, 5.50 mmol, 0.20 equiv.) in 5.5 ml of water with another addition of ammonium persulfate (0.625 g, 0.10 equiv.) in 2.5 ml of water 30 min later.
After refluxing for an additional 40 min, the contents are concentrated at reduced pressure, treated with 75 ml of saturated brine plus 75 ml of water and finally 50 ml of 3N HCl.
After stirring at room temperature for 1 h, the mixture is basified with 20 ml of 29percent ammonium hydroxide, extracted 4 times with chloroform, dried the combined organic extracts with anhydrous Na2 SO4 and concentrated in vacuo.
Chromatography with 250 g of silica gel, packed and eluted with acetone-chloroform-methanol (1:2:2percent), yielded 2.65 g (78percent) of 2-hydroxymethyl-4-methylpyridine.
TLC (silica gel GF): Rf =0.32 acetone-chloroform-methanol (1:2:2percent).
1 H NMR (CDCl3,TMS):δ 8.38 (d, 1H, J=5.05 Hz), 7.18 (s, 1H), 7.03 (d, 1H, J=4.86 Hz), 5.02 (s, 1H), 4.75 (s, 2H), 2.37 (s, 3H). UV (λ max, ethanol): 254 sh (2,240), 259 (2,690), 266 (2,180). Analysis:
Calculated for C7 H9 NO: C, 68.29; H, 7.32; N, 11.38. Found: C, 67.35; H, 7.37; N, 11.22.
Mass Spectrum: M/Z (relative intensity percent): 123 (48), 122 (100), 94 (43), 93 (30), 92 (27), 39 (17).
Reference: [1] Patent: US6043248, 2000, A,
[2] Patent: EP1422228, 2004, A1, . Location in patent: Page 200
  • 6
  • [ 3279-76-3 ]
  • [ 420-37-1 ]
  • [ 63071-03-4 ]
YieldReaction ConditionsOperation in experiment
27% With sodium hydroxide In dichloromethane PREPARATION 133
2-Methoxy-6-methylpyridine
Trimethyloxonium tetrafluoroborate (10.0 g, 67.6 mmol) was added portionwise to a suspension of 6-methylpyridin-2-one (7.3 g, 67.0 mmol) in dichloromethane (100 ml), and once addition was complete, the reaction was stirred at room temperature for 24 hours.
Dichloromethane (50 ml) and aqueous sodium hydroxide solution (50 ml, 2N) were added and the layers separated.
The aqueous phase was extracted with dichloromethane (2*50 ml), the combined organic solutions washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure.
The crude product was purified by column chromatography on silica gel, using an elution gradient of pentane: dichloromethane (66:34 to 0:100) to afford the title compound (2.25 g, 27percent) as a colourless oil. δ (CDCl3): 2.49 (3H, s), 3.90 (3H, s), 6.38-6.73 (2H, m), 7.23-7.40 (1 H, br d).
Reference: [1] Patent: US6251904, 2001, B1,
  • 7
  • [ 53857-57-1 ]
  • [ 420-37-1 ]
  • [ 465529-56-0 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: at 20℃; Inert atmosphere
Stage #2: With sodium hydroxide In waterCooling with ice
Preparation 1
Synthesis of 5-bromo-2-methyl-2H-indazole
Add at room temperature under nitrogen, trimethyloxonium tetrafluoroborate (229.34 g, 1.52 mol) portion wise to a mixture of 5-bromo-1H-indazole (199.6 g, 1.01 mol) in ethyl acetate (3.04 L, 31.06 mol), stir 2.5 h and filter to give a white solid.
Wash the recovered solid twice with ethyl acetate (500 mL) and then add it portion wise to a cooled aqueous solution of 2 M sodium hydroxide (3.80 L, 7.60 mol) in an ice bath.
Stir the mixture for 1 h, sonicate for 15 min., filter and wash the recovered solid twice with water (200 mL).
Dry the solid overnight under vacuum, slurry in dichloromethane (1 L) and filter.
Concentrate the filtrate and purify by silica gel chromatography eluding with dichloromethane to give the title compound as a yellow solid (149.77 g, 70percent). MS (m/z): 211, 213 (M+1).
Reference: [1] Patent: US2009/253750, 2009, A1, . Location in patent: Page/Page column 6
  • 8
  • [ 420-37-1 ]
  • [ 65750-01-8 ]
  • [ 5228-48-8 ]
YieldReaction ConditionsOperation in experiment
92.5% at 20℃; for 5 h; Preparation 43A: 2-Methyl-5-nitroindazole
To a solution of 5-nitroindazole (15 g, 91.95 mmol) in ethylacetate (150 mL), was added BF4OMe3 (17.68 g, 119.54 mmol) at r.t. The mixture was stirred for 5 hr at r.t. aq NaHC03 was added to adjust the pH to 7-8, extracted with ethylacetate, dried, concentrated to afford the title compound (15 g, 92.5percent). [M+H] Calc'd for C8H7N302, 178; Found, 178.
Reference: [1] Patent: WO2016/4105, 2016, A1, . Location in patent: Paragraph 00146
  • 9
  • [ 420-37-1 ]
  • [ 5401-94-5 ]
  • [ 5228-48-8 ]
Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 10, p. 4093 - 4095
  • 10
  • [ 420-37-1 ]
  • [ 71759-88-1 ]
Reference: [1] Canadian Journal of Chemistry, 2001, vol. 79, # 7, p. 1110 - 1114
  • 11
  • [ 420-37-1 ]
  • [ 107-07-3 ]
  • [ 627-42-9 ]
Reference: [1] Journal of the American Chemical Society, 1978, vol. 100, p. 4242 - 4248
  • 12
  • [ 420-37-1 ]
  • [ 627-18-9 ]
  • [ 36865-41-5 ]
Reference: [1] Helvetica Chimica Acta, 1980, vol. 63, # 8, p. 2152 - 2158
  • 13
  • [ 420-37-1 ]
  • [ 143673-66-9 ]
  • [ 109838-85-9 ]
YieldReaction ConditionsOperation in experiment
71.5%
Stage #1: at 20℃; for 41 h;
Stage #2: With ammonia; water In dichloromethane at 0℃; for 1 h;
Step A:
Preparation of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1):
To a 2 L round-bottomed flask were added (R)-3-isopropylpiperazine-2,5-dione (20.7 g, 133 mmol), Me3OBF4 (49.0 g, 331 mmol) and CH2Cl2 (500 mL).
The slurry was stirred vigorously at room temperature under nitrogen atmosphere.
After stirring 18 hours, the slurry became a clear solution with very viscous yellow oil settling on the bottom of the flask.
An additional equivalent of Me3OBF4 (19.6 g, 133 mmol) was added and the mixture was stirred at room temperature.
After 23 hours, the mixture was cooled in an ice bath, and 200 g of ice and 100 mL of concentrated ammonium hydroxide solution (28percent) were added to the reaction mixture.
The reaction mixture was stirred in an ice bath for 1 hour.
The layers were separated and aqueous layer was extracted with CH2Cl2 (2*50 mL).
The combined organic layers were washed with saturated NaHCO3 solution (2*100 mL) and brine (100 mL), dried over K2CO3, filtered through a Celite pad, and concentrated under reduced pressure to provide 25.9 g of light brown oil.
The crude material was purified by chromatography with 1:4 ether/pentane to provide 17.464 g of compound 1 as a colorless oil (71.5percent yield).
1H NMR (400 MHz, CDCl3) δ 4.08-3.94 (m, 3H), 2.95 (s, 3H), 2.87 (s, 3H), 2.30-2.18 (m, 1H), 1.04 (d, J=7.03 Hz, 3H), 0.76 (d, J=6.64 Hz, 3H).
Reference: [1] Organic Process Research and Development, 2005, vol. 9, # 2, p. 185 - 187
[2] Patent: US2006/264431, 2006, A1, . Location in patent: Page/Page column 20-21
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 2, p. 157 - 166
  • 14
  • [ 115-10-6 ]
  • [ 109-63-7 ]
  • [ 420-37-1 ]
YieldReaction ConditionsOperation in experiment
98% With epichlorohydrin In dichloromethaneCooling with acetone-dry ice; Inert atmosphere Preparation of trimethyloxonium tetrafluoroborate (adapted from TJ. Curphey, Org. Synth., Coll. Vol. 6, p.1019 (1988) with slight modification as follows): [00143] An oven-dried 500 mL 3 -neck round-bottomed flask (marked with a line marked at about 190 mL), equipped with a N2 inlet, 60 mL pressure- equalized dropping funnel, magnetic stirrer bar and rubber septum was placed under a blanket of dry nitrogen gas. DCM (80 mL) was added, followed by boron trifluoride diethyl etherate (33.3 mL, 270 mmol) and the mixture was cooled in a dry ice-acetone bath. Dimethyl ether was condensed into the DCM solution via a needle (through the rubber septum) that remained just below the surface until the total volume of the liquid reached the 190 mL mark. The mixture was stirred vigorously while epichlorohydrin (24.1 mL, 307 mmol) was added drop wise over approximately 15 minutes (the mixture became very thick and required occasion manual swirling to ensure good stirring). The bath was removed and the mixture was stirred vigorously overnight. The resulting solid was collected by filtration through an oven dried, medium frit glass Buchner funnel under a stream of N2 and the flask and filter were rinsed with DCM (2x100 mL). The trimethyloxonium tetrafluoroborate product was isolated as a free-flowing white solid (29.4 g, 98percent) after drying under nitrogen and was stored under nitrogen in an oven-dried glass bottle in a freezer.
Reference: [1] Patent: WO2010/68520, 2010, A2, . Location in patent: Page/Page column 28-29
  • 15
  • [ 115-10-6 ]
  • [ 420-37-1 ]
Reference: [1] Tetrahedron Asymmetry, 1998, vol. 9, # 2, p. 321 - 327
  • 16
  • [ 115-10-6 ]
  • [ 74-88-4 ]
  • [ 420-37-1 ]
Reference: [1] Journal of Organic Chemistry, 1984, vol. 49, # 12, p. 2112 - 2116
  • 17
  • [ 186581-53-3 ]
  • [ 115-10-6 ]
  • [ 420-37-1 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1955, vol. 592, p. 81,113
  • 18
  • [ 623-73-4 ]
  • [ 115-10-6 ]
  • [ 420-37-1 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1955, vol. 592, p. 81,113
  • 19
  • [ 115-10-6 ]
  • [ 368-39-8 ]
  • [ 420-37-1 ]
Reference: [1] Chemische Berichte, 1956, vol. 89, p. 2060,2072
[2] Organic Syntheses, 1966, vol. 46, p. 120
  • 20
  • [ 115-10-6 ]
  • [ 18346-68-4 ]
  • [ 420-37-1 ]
Reference: [1] Tetrahedron, 2015, vol. 71, # 39, p. 7367 - 7385
  • 21
  • [ 33613-52-4 ]
  • [ 100-68-5 ]
  • [ 420-37-1 ]
Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, # 4, p. 853 - 856
  • 22
  • [ 420-37-1 ]
  • [ 16944-60-8 ]
  • [ 78342-42-4 ]
Reference: [1] Angewandte Chemie, 1981, vol. 93, # 9, p. 793 - 795
[2] Tetrahedron, 1983, vol. 39, # 12, p. 2085 - 2092
[3] Tetrahedron Asymmetry, 1998, vol. 9, # 2, p. 321 - 327
[4] Organic Process Research and Development, 2005, vol. 9, # 2, p. 185 - 187
  • 23
  • [ 420-37-1 ]
  • [ 94444-96-9 ]
  • [ 541539-88-2 ]
YieldReaction ConditionsOperation in experiment
59% at 20℃; for 3 h; To a solution of 5-methoxy-indazole (1.0 g, 6.7 mmol) in ethyl acetate (10 ml) was added BF40(CH3)3(1.3 g, 8.9 mmol). The solution was stirred at rt for 3 h. Sat. NaHC03aq. (10 ml) was added and extracted with ethyl acetate (20 ml). Organics were dried over Na2S04, concentrated, and purified by flash chromatography on silica gel (PE /EA = 2/1) to afford 0.64 g (59percent) of the title compound as a yellow solid. [M+H] Calc'd for C9H10N2O, 163; Found, 163.
Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 10, p. 4093 - 4095
[2] Patent: WO2016/44138, 2016, A1, . Location in patent: Paragraph 00116
[3] Patent: WO2007/3419, 2007, A1, . Location in patent: Page/Page column 69-72
  • 24
  • [ 6494-19-5 ]
  • [ 420-37-1 ]
  • [ 444731-73-1 ]
YieldReaction ConditionsOperation in experiment
82.4% at 25 - 30℃; for 20 h; Example 1
Trimethyloxonium tetrafluoroborate (125.2 g, 0.85 mol) was added to a stirred suspension of 3-methyl-6-nitro-indazole (100 g, 0.56 mol) in ethyl acetate (2000 mL) over a period of 4 hours in four equal lots at 1 hour time intervals.
The reaction mixture was stirred at 25° C. to 30° C. for 16 hours.
The solvent was recovered under reduced pressure.
A saturated sodium bicarbonate solution (3240 mL) was added to the mixture slowly, and the reaction mixture was extracted with 4:1 mixture of dichloromethane isopropyl alcohol (1080 mL*5).
The solvent was recovered under reduced pressure.
Methyl tert-butyl ether (800 mL) was added to the residue, and the reaction mixture was stirred for 30 minutes at 45° C. to 50° C.
The reaction mixture was cooled to 25° C. to 30° C. and was stirred at this temperature for 30 minutes.
The solid was filtered, washed with methyl tert-butyl ether (100 mL*2), and dried in an air oven at 50° C. for 12 hours to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid.
Yield: 82.4percent w/w
73% at 20℃; for 3 h; To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-7H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added <n="26"/>saturated aqueous NaHCO3 (600 mL) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro- 2tf-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
73% at 20℃; for 3 h; To a stirred solution of 18.5 g (0.11 mol) of [3-METHYL-6-NITRO-1H-INDAZOLE] in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of [TRIMETHYLOXONIUM] [TETRAFLOUROBORATE.] After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous [NAHC03] (600 mL) and a 4: 1 mixture of chloroform-isopropanol (200 [ML),] the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried [(NA2S04).] Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2, 3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 [G,] 73 [percent).APOS;H] NMR (300 MHz, [DMSO-D6)] 8 8.51 (s, [1 H),] 7.94 (d, [J= 9.] 1 Hz, [1 H),] 7.73 (d, [J =] 8.9 Hz, [1 H),] 4.14 (s, 3H), 2.67 (s, 3H). MS [(ES+,] [M/Z)] 192 (M+H).
73% at 20℃; for 3 h; To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro- 7H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml_) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H)1 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
73% at 20℃; for 3 h; Inert atmosphere Intermediate Example 11
Preparation of 2,3-dimethyl-2H-indazol-6-amine
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate.
After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure.
To the resulting solid was added saturated aqueous NaHCO3 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated.
The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 ml) and the combined organic phase was dried (Na2SO4).
Filtration and removal of solvent gave a tan solid.
The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73 percent).
1H NMR (300 MHz, d6DMSO) δ 8.51 (s, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).; To a stirred solution of 2,3-dimethyl-6-nitro-2H-indazole (1.13 g) in 2-methoxyethyl ether (12 ml), at 0 °C, was added a solution of 4.48 g of tin(II) chloride in 8.9 ml of concentrated HCl dropwise over 5 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 40 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (1.1 g, 95 percent), the HCl salt 2,3-dimethyl-2H-indazol-6-amine. 1H NMR (300 MHz, d6DMSO) δ 7.77 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 7.88 (m, 1H), 4.04 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 162 (M+H).
73% at 20℃; for 3 h; Inert atmosphere 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H-indazole was dissolved in 350 ml of acetone,20 g (0.14 mol) of trimethyloxonium tetrafluoroborate was added with stirring at room temperature,The reaction solution was filled with argon for 3 h,The solvent was removed under reduced pressure,The solid was added with 600 ml of aqueous NaHCO3 solution,200 ml of a mixture of chloroform and isopropanol (4: 1)The organic phase was dried over anhydrous sodium sulfate,filter,The solvent was distilled off,To give a brown solid,Washed with ether,15.85 g of 2,3-dimethyl-6-nitro-2H-indazole was obtained in a yield of 73percent.
73%
Stage #1: at 20℃; for 3 h;
Stage #2: With sodium hydrogencarbonate In chloroform; water; isopropyl alcohol
Intermediate Example 1
Preparation of 2,3-dimethyl-6-nitro-2H-indazole
Procedure 1:
To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetrafluoroborate.
After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure.
To the resulting solid was added saturated aqueous NaHCO3 (600 mL) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated.
The aqueous phase was washed with additional chloroform: isopropanol (4*200 mL) and the combined organic phase was dried (Na2SO4).
Filtration and removal of solvent gave a tan solid.
The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73percent).
1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
73% at 20℃; for 3 h; Intermediate Example 1 Preparation of 2,3-dimethyl-6-nitro-2H-indazole Procedure 1: To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro-1H- indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHC03 (600 mL) and a 4: 1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2S04). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73 percent).
73% at 20℃; for 3 h; To a stirred solution of 18.5 g (0.1 1 mol) of 3-methyl-6-nitro-7/-/-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of thmethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHCO3 (600 ml_) and a 4:1 mixture of chloroform-isopropanol (200 ml), the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 mL) and the combined organic phase was dried (Na2SO4). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 mL) to afford 2,3-dimethyl-6-nitro-2/-/-indazole as a yellow solid (15.85 g, 73 percent). 1H NMR (300 MHz, DMSOd6) δ 8.51 (s, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).
32%
Stage #1: at 20℃; for 7.5 h; Inert atmosphere
Stage #2: With sodium hydrogencarbonate In water
Example 50: Process for preparation of DMND[000167] To a stirred solution of 3-methyl-6-nitro- l H-indazole (MNID) (5.0 g, 28.2 mmol) in acetone (95 mL, 19V) at ambient temperature was added trimethyloxonium tetrafluoroborate (5.3 g, 35.8 mmol, 1 .27 eq). Stirring was continued under nitrogen and the reaction was monitored by TLC. After 5.5 h another 1 g of trimethyloxonium tetrafluoroborate was added to the reaction in an attempt to push it to completion. After 7.5 h total reaction time the solvent was removed and saturated sodium bicarbonate ( 162 mL) was added to the residue, followed by a 4: 1 mixture of CHC : IPA (54 mL). The resulting mixture was agitated and the layers were separated. The aqueous phase was washed with additional CHCI3: IPA 4: 1 (4x54 mL) and the combined organic phases were dried ( a2SO,)), filtered and evaporated to dryness. The resulting brown solid was washed with diethylether (about 160 mL) and dried on the filter under nitrogen/vacuum to afford crude DMND (3.2 g, 87.5percent purity). The crude material (2.9 g) was then dissolved in EtOH (50 mL) at reflux and the solution was gradually cooled to ambient temperature and then to 5 °C, and was kept at this temperature for 1 h. The resulting precipitate was isolated by filtration and the filter cake was washed with cold EtOH ( 10 mL) and dried in a vacuum oven (35 mbar) at 55°C for 4 h to give 2,3-dimethyl-6-nitro-2H-indazole ( 1 .57g, ca 32percent) as a yellow solid.

Reference: [1] Patent: US2015/329526, 2015, A1, . Location in patent: Paragraph 0033; 0034
[2] Patent: WO2007/64753, 2007, A2, . Location in patent: Page/Page column 24-25
[3] Patent: WO2003/106416, 2003, A2, . Location in patent: Page 40
[4] Patent: WO2006/20564, 2006, A1, . Location in patent: Page/Page column 12
[5] Patent: EP2311825, 2015, B1, . Location in patent: Paragraph 0178 - 0180
[6] Patent: CN103319410, 2016, B, . Location in patent: Paragraph 0018; 0019
[7] Patent: US2008/293691, 2008, A1, . Location in patent: Page/Page column 8
[8] Patent: WO2005/105094, 2005, A2, . Location in patent: Page/Page column 27
[9] Patent: WO2007/143483, 2007, A2, . Location in patent: Page/Page column 28
[10] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4632 - 4640
[11] Patent: WO2011/69053, 2011, A1, . Location in patent: Page/Page column 34
  • 25
  • [ 420-37-1 ]
  • [ 186407-74-9 ]
  • [ 590417-93-9 ]
YieldReaction ConditionsOperation in experiment
95% at 20℃; Reference Example 33
4-bromo-2-methyl-2H-indazole
To a solution of 4-bromo-1H-indazole (2.24 g, 11.4 mmol) in ethyl acetate (110 mL) was added trimethyloxonium tetrafluoroborate (2.19 g, 14.8 mmol) at room temperature, and the mixture was stirred for 3 hr.
The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90-->40/60) to give the title compound (2.29 g, yield 95percent).
1H-NMR (CDCl3) δ: 4.23 (3H, s), 7.13 (1H, dd, J = 8.5, 7.2 Hz), 7.23 (1H, dd, J = 7.2, 0.8 Hz), 7.60 - 7.64 (1H, m), 7.91 (1H, m),
MS (ESI+): 211 (M+H).
Reference: [1] Patent: EP2141150, 2010, A1, . Location in patent: Page/Page column 63-64
  • 26
  • [ 55919-82-9 ]
  • [ 420-37-1 ]
  • [ 1150617-94-9 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: at 20℃; for 2 h;
Stage #2: With sodium hydroxide In water; ethyl acetateCooling with ice
Preparation 6
5-iodo-2-methyl-2H-indazole
To a solution of 5-iodo-1H-indazole (500 g, 2.05 mol) in EtOAc (4 L) is added trimethyloxonium tetrafluoroborate (450 g, 3.04 mol).
After the resulting white suspension is stirred at room temperature for 2 h, it is concentrated under vacuum.
Ice water (1 L) is added to the residue, and it is basified to pH 12 with 10percent aqueous NaOH solution.
The solids are collected by filtration, and redissolved in DCM (5 L).
The insolubles are filtered off and the filtrate is washed with 10percent aqueous NaOH solution (2*100 mL).
The organic layer is dried over anhydrous Na2SO4, filtered through a short silica gel column, and concentrated.
Methyl tert-butyl ether is added to the residue to give a slurry and the product is collected by filtration to give the title compound (360 g, 68.0percent). MS (m/z): 259.0 (M+H).
Reference: [1] Patent: US2012/28984, 2012, A1, . Location in patent: Page/Page column 3
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