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Product Details of [ 66607-27-0 ]

CAS No. :66607-27-0 MDL No. :MFCD04972469
Formula : C7H5IN2 Boiling Point : -
Linear Structure Formula :- InChI Key :UDKYMMQGPNFWDA-UHFFFAOYSA-N
M.W : 244.03 Pubchem ID :10911744
Synonyms :

Calculated chemistry of [ 66607-27-0 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 48.81
TPSA : 28.68 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.2 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.24
Log Po/w (XLOGP3) : 2.24
Log Po/w (WLOGP) : 2.17
Log Po/w (MLOGP) : 2.31
Log Po/w (SILICOS-IT) : 3.04
Consensus Log Po/w : 2.2

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.43
Solubility : 0.0906 mg/ml ; 0.000371 mol/l
Class : Soluble
Log S (Ali) : -2.48
Solubility : 0.812 mg/ml ; 0.00333 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.87
Solubility : 0.0331 mg/ml ; 0.000136 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.07

Safety of [ 66607-27-0 ]

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 [ 66607-27-0 ]

* 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 [ 66607-27-0 ]
  • Downstream synthetic route of [ 66607-27-0 ]

[ 66607-27-0 ] Synthesis Path-Upstream   1~11

  • 1
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  • [ 66607-27-0 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium hydroxide; iodine In methanol; water at 20℃; for 73 h;
Stage #2: With hydrogenchloride; sodium thiosulfate In methanol; water at 0℃;
58.1 g of iodine (229 mmol) are introduced in portions into a suspension of 25.6 g of indazole (217 mmol) in 625 ml of methanol and 625 ml of 2N sodium hydroxide solution in the course of 1 hour. The mixture is stirred at room temperature for 3 days and 75 ml of concentrated hydrochloric acid is then added, while cooling with ice, the mixture is rendered acid with 2N hydrochloric acid and 20percent strength sodium thiosulphate pentahydrate solution is added until the iodine colour disappears. The precipitate which separates out is filtered off with suction, washed neutral with water and dried in a vacuum drying cabinet at 50° C. For purification, the solid is taken up in methanol. After undissolved constituents are filtered off, the filtrate is concentrated to dryness on a rotary evaporator, the product being obtained as an almost white solid.Yield: 52.6 g (quantitative)Rf value: 0.63 (silica gel; cyclohexane/ethyl acetate 1:1)Melting point: 137° C.
100% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 3 h; 3-Iodoindazoles were obtained by direct iodination of commercial indazoles by the method previously described by Bocchi [28] with slight modifications. A solution of 1H-indazole (3 g, 25.4 mmol), iodine (12.7 g, 50.03 mmol) and potassium hydroxide (5.34 g, 95.25 mmol)in DMF (7 mL) was stirred for 3 h at room temperature. The reaction was quenched by dilution with saturated solution of sodium bisulfite (150 mL) and a precipitated was formed. The precipitated was filtered over vacuum and washed with water (3 × 30 mL). The solid was left to dry at 30 °C in a vacuum oven overnight obtaining 6.17 g of a pale yellow solid. Yield: 100percent; m.p.: 136–138 °C (lit.:[36] 134–136 °C); IR (KBr) ν (cm−1): 3086 (NH); 424 (C-I). 1H-NMR δ (ppm): 13.50 (1H, s, H-1); 7.55(1H, d, J = 8.6 Hz, H-7); 7.45–7.40 (2H, m, H-6 and H-4); 7.19 (1H, dd, J = 7.5 Hz, H-5). 13C-NMR δ(ppm): 140.41; 127.22; 126.79; 121.23; 120.39; 110.51; 93.49; HRMS calculated for C7H5IN2: 243.9497,Found: 243.9499.3-Iodo-1H-indazole (1a). 3-Iodoindazoles were obtained by direct iodination of commercial indazoles by the method previously described by Bocchi [28] with slight modifications. A solution of 1H-indazole(3 g, 25.4 mmol), iodine (12.7 g, 50.03 mmol) and potassium hydroxide (5.34 g, 95.25 mmol) in DMF(7 mL) was stirred for 3 h at room temperature. The reaction was quenched by dilution with saturated solution of sodium bisulfite (150 mL) and a precipitated was formed. The precipitated was filtered over vacuum and washed with water (3 30 mL). The solid was left to dry at 30 °C in a vacuum oven overnight obtaining 6.17 g of a pale yellow solid. Yield: 100percent; m.p.: 136–138 °C (lit.: [36] 134–136 °C);IR (KBr) (cm1): 3086 (NH); 424 (C-I). 1H-NMR (ppm): 13.50 (1H, s, H-1); 7.55 (1H, d, J = 8.6 Hz,H-7); 7.45–7.40 (2H, m, H-6 and H-4); 7.19 (1H, dd, J = 7.5 Hz, H-5). 13C-NMR (ppm): 140.41; 127.22;126.79; 121.23; 120.39; 110.51; 93.49; HRMS calculated for C7H5IN2: 243.9497, Found: 243.9499.
97% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 2 h; A mixture of 1H-indazole (1.00 g, 8.46 mmol, 1.00 equiv), iodine(4.30 g, 16.94 mmol, 2.00 equiv), and potassium hydroxide (1.19 g, 21.21 mmol, 2.50 equiv) in DMF (49.98 mL) was stirred for 2 hours at room temperature. The resulting solution was diluted with ethyl acetate, washed withwater and sodium thiosulfate pentahydrate, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (2 g, 97percent) as an off-white solid. LC-MS (ES, mlz): 245 [M+H].
96% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; Intermediate 14: 3-Iodoindazole; Powdered potassium hydroxide (3.75 eq, 1.78 g, 31.7 mmol) was added to a solution of indazole (1.0 g, 8.46 mmol) and iodine (4.29 g, 16.9 mmol) in DMF (17 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into aqueous sodium thiosulfate solution (10percent, 200 ml) and extracted with toluene (2 x 75 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried (magnesium sulfate) and concentrated in vacuo to give the title compound as an off-white solid (2.0 g, 96percent). 1H NMR (250 MHz, CDC13) δ 6.98 - 7.27 (m, 2 H) and 7.32 - 7.59 (m, 2 H).
95% With iodine; sodium hydroxide In methanol at 20℃; for 48 h; 3-lodo-1H-indazole   Iodine (5.8 g, 22.9 mmol) was added in portions over approximately 20 min to a solution of   indazole (2.5 g, 21.7 mmol) in   methanol (63 ml) and 2N   sodium hydroxide solution (65 ml). The mixture remained colourless and a white precipitate slowly formed. The mixture was stirred at room temperature 48 h. The mixture was cooled in an ice-bath and 7.5 ml of   concentrated hydrochloric acid was slowly added. The mixture was further acidified with 2N hydrochloric acid. 20percent w/v   Sodium thiosulfate pentahydrate solution was added until the iodine colour disappeared. The precipitate was filtered, washed with water and dried in the oven at 50 ºC to constant weight. The solid was taken up in methanol, filtered and the filtrated was evaporated under reduced pressure to give 5.0 g (20.6 mmol, 95percent) of the   title compound as a white solid. Purity 100percent.1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.43-7.59 (m, 3H), 7.21-7.26 (m, 1H).UPLC/MS (3 min) retention time 1.56 min.LRMS: m/z 245 (M+1).
95% With iodine; sodium hydroxide In methanol at 20℃; for 48 h; Iodine (5.8 g, 22.9 mmol) was added in portions over approximately 20 min to a solution of indazole (2.5 g, 21 .7 mmol) in methanol (63 ml) and 2N sodium hydroxide solution (65 ml). The mixture remained colourless and a white precipitate slowly formed. The mixture was stirred at room temperature 48 h. The mixture was cooled in an ice-bath and 7.5 ml of concentrated hydrochloric acid was slowly added. The mixture was further acidified with 2N hydrochloric acid. 20percent w/v Sodium thiosulfate pentahydrate solution was added until the iodine colour disappeared. The precipitate was filtered, washed with water and dried in the oven at 50 °C to constant weight. The solid was taken up in methanol, filtered and the filtrated was evaporated under reduced pressure to give 5.0 g (20.6 mmol, 95percent) of the title compound as a white solid. Purity 100percent. 1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.43-7.59 (m, 3H), 7.21 -7.26 (m, 1 H). UPLC/MS (3 min) retention time 1 .56 min. LRMS: m/z 245 (M+1 ).
95% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 1.25 h; Step 13 -Io do - 1 H-indazo leIn a 50 mL round-bottomed flask, indazole (0.80 g, 6.8 mmol) was dissolved in DMF (14 mL). Iodine (3.4 g, 13.5 mmol) was added followed by potassium hydroxide (1.47 g, 26.2 mmol). The dark reaction mixture was stirred at room temperature for 1.25 h then was quenched with 10percent aq NaHS03 and extracted with diethyl ether (2x). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 1.65 g (95percent>) of 3-iodo-lH-indazole as a light yellow solid. 1H NMR (CDC13, 300 MHz): ? (ppm) 10.56 (br. s, 1H), 7.47 - 7.57 (m, 3H), 7.23 - 7.30 (m, 1H).
91% With iodine; potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 19 h; 3-iodo-lH-indazole (VII): Indazole (l .Og, 8.47 mmol) and K2C03 (1.71 g, 12.4 mmol) were combined in DMF (5 mL) and chilled to 0 °C. I2 (2.70 g, 1.3 mmol) dissolved in DMF (2 mL) was added dropwise over a one hour time period, then stirred 18 hours at room temperature. The reaction was then poured into a solution of sodiumthiosulfate (2.0 g) and K2C03 (10 mg) in 10 mL water. A white precipitate formed and was stirred at room temperature for 1.5 hours. Product was isolated by filtration and indentified by LCMS yielding (1.87g, 7.68 mmol, 91percent).
77.5% With iodine; sodium hydroxide In N,N-dimethyl-formamide at 25℃; for 6 h; 3-iodo-1 H-indazole
[00446] To a mixture of 1H-indazole (5 g, 42.32 mmol) and NaOH (3.4 g, 84.6 mmol) in DMF (50 mL) was added 12 (16.1 g, 63.4 mmol) in one portion at 25 °C and the mixture wasstirred for 6 h. The mixture was concentrated, diluted with water (150 mL,) extracted with EA (100 mLx3), and the combined organic phase was washed with saturated brine (200 mLx2),dried with anhydrous Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography to afford the title compound (8 g, 77.5percent) as a white solid.
77.5% With iodine; sodium hydroxide In N,N-dimethyl-formamide at 25℃; for 6 h; [3881 To a mixture of 11-1-indazole (5 g, 42.32 mrnoi) and NaOFI (3.4 g, 84.6 minol) in DMF(50 mL) was added 12 (16.1 g, 63.4 mnioi) in one portion at 25 °C and the mixture was stirred for6 h. The mixture was concentrated, diluted with water (150 mL,) extracted with EA (100 mL*3),and the combined organic phase was washed with saturated brine (200 mL*2), dried withanhydrous Na2SO4 and concentrated in vacuum. The residue was purified by silica gelchromatography to afford the title compound (8 g, 77.5percent) as white solid.
68% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere Example 10 N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-lH-indazol-3- yl)pyrimidin-2-yl)amino)phenyl)acrylamide (10) N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indazol-3-yl)pyrimidin- 2- amine (Scheme 8, Intermediate R). Into a 1000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1H- indazole (10 g, 84.65 mmol, 1.00 equiv) in N,N-dimethylformamide (500 mL), I2 (21.5 g, 84.65 mmol, 1.00 equiv). This was followed by the addition of KOH (19 g, 338.62 mmol, 4.00 equiv) in several batches at 0°C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 200 mL of aqueous Na2S203. The resulting solution was extracted with 3x500 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was washed with 1x100 mL of hexane. This resulted in 14 g (68percent) of 3- iodo- lH-indazole as a white solid.
64.7% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 0 - 20℃; for 5 h; 5.5 g (45 mmol) of indazole and 12.69 g (100 mmol) of iodine granules were added to the reaction flask.Dissolved with 100 mL of N,N-dimethylformamide,Stir at 0°C,11.2 g (200 mmol) of potassium hydroxide solids are added in portions.After the addition is completed, it is returned to room temperature and stirred for 5 hours;After the reaction is complete, quench the solution by adding 50 mL of saturated sodium thiosulfate solution to the reaction flask.Then pour the reaction solution into 200mL water,Extract with ethyl acetate (200 mL x 3)Combine organic layers,Wash with saturated brine (200 mL × 3)Drying with anhydrous sodium sulfate,Concentrate under reduced pressure,It was isolated by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give 7.3 g of a white solid (3-iodoindazole).Yield 64.7percent,
64% With potassium hydroxide; iodine In N,N-dimethyl-formamide at 20℃; for 0.5 h; 3. Synthesis of indazole derivatives; A iodine was introduced at 3-positon of an indazole ring (the following scheme). An objective compound, XO-KT30, was prepared by converting the iodine into a cyano group using zinc cyanide, followed by coupling in the usual way, and finally by hydrolysis.; 15) Synthesis of XO-KT30; XO-KT13; Indazole (1.18 g, 10 mmol) was dissolved in dimethylformamide (6 mL), and to the solution were added iodine (2.8 g, 11 mmol) and potassium hydroxide (2.8 g, 50 mmol), and the mixture was allowed to react for 0.5 hour at room temperature. After the reaction, the reaction mixture was extracted with ethyl acetate and water added. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give XO-KT13 (1.55 g, 64percent yield).
52% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 4 h; KOH (31.10g, 0.555mol) was added in portions at 0°C to a solution of 4a (15.80g, 0.134mol) and I2 (85.40g, 0.336mol) in DMF (263.40mL). The mixture was stirred for 4h at room temperature, quenched with saturated Na2S2O3 solution (50mL), diluted with H2O (150mL), and extracted with EtOAc (70mL×3). The organic phase was washed with brine (50mL×3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15:1, v/v) to give an orange solid (16.78g).
8 g With iodine; potassium hydroxide In N,N-dimethyl-formamide at 0 - 20℃; for 2 h; Synthesis of 3-iodo-1 H-indazole (Intermediate-71):Starting Material-28 (42mmol) in DMF (50m1) was cooJed to 0°C. Then potassium hydroxide(84.6mmol) was added which was followed by the addition of Iodine (42mmol). The reactionmixture was maintained at room temperature for 2 hours. Then the reacUon mixture was diluted with ice cooled water and extracted with ethyl acetate. The organic layer was dried over arihydrous MgSO4, and evaporated to give lntermediate-71 (8g, pale yellow solid).
8 g With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 2 h; Synthesis of 3-iodo-1H-indazole (Intermediate-71)
Starting Material-28 (42 mmol) in DMF (50 ml) was cooled to 0° C. Then potassium hydroxide (84.6 mmol) was added which was followed by the addition of Iodine (42 mmol).
The reaction mixture was maintained at room temperature for 2 hours.
Then the reaction mixture was diluted with ice cooled water and extracted with ethyl acetate.
The organic layer was dried over anhydrous MgSO4, and evaporated to give Intermediate-71 (8 g, pale yellow solid).
15.3 g With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; Inert atmosphere Example 1 1. Synthesis of Intermediate 001-2 The intermediate 001-1 (10 g, 84.7 mmol) as the raw material was dissolved in N,N-dimethylformamide (DMF) (500 mL) in a 1000 mL three-necked flask under nitrogen (N2) at room temperature, and then iodine (I2) (21.5 g, 84.8 mmol) and potassium hydroxide (KOH) (19 g, 338.6 mmol) were added sequentially, followed by stirring the reaction overnight at room temperature. After completion of the reaction, 200 mL of 10percent sodium thiosulfate (Na2S2O3) was added to the reaction mixture, and ice water was used to quench the reaction. The mixture was extracted three times with 500 mL of ethyl acetate (EA). The organic phases were combined and washed once with 500 mL of saturated brine (NaCl), and the organic phases were dried over anhydrous sodium sulfate (Na2SO4) and concentrated to give 15.3 g of the intermediate 001-2 (74percent) as an off-white solid. Liquid Chromatography Mass Spectrometry (LCMS): 245.0.

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YieldReaction ConditionsOperation in experiment
100% Sonication A mixture of 3-iodo-1H-indazole (0.2 g, 0.82 mmol), ditert-butyldicarbonate (0.2 g, 0.92 mmol) and triethylamine (1 mL) were put under ultrasonic irradiation for 10 min. The resulted solution was neutralized using HCl 1M and then extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried with anhydrous sodium sulfate and removal of the solvent under vacuum afforded a pure product as a pale yellow crystals.Yield: 100percent; m.p.: 93–95 °C; IR (KBr) ν (cm−1): 1728 (C=O); 1150 (C-O); 424 (C-I). 1H-NMR (CDCl3) δ(ppm): 8.09 (1H, d, J = 8.5 Hz, H-7); 7.55 (1H, t, J = 7.8 Hz, H-4); 7.46 (1H, d, J = 7.9 Hz, H-6); 7.33 (1H,t, J = 7.6 Hz, H-5); 1.71 (9H, s, CH3). 13C-NMR δ (ppm): 148.35; 139.59; 130.17; 129.98; 124.21; 121.96;114.56; 102.95; 85.48; 28.18; HRMS calculated for C12H13IN2O2: 344.0022, Found: 344.0016.tert-Butyl 3-iodo-5-nitro-1H-indazole-1-carboxylate (2b). Prepared from 3-iodo-5-nitro-1H-indazole (0.2g, 0.69 mmol), di-tert-butyldicarbonate (0.17 g, 0.78 mmol) and triethylamine (1 mL) to give 0.27 g ofa pale yellow solid. Yield: 100percent; m.p.: 144–145 °C; IR (KBr) ν (cm−1): 1744 (C=O); 1528 (NO2tert-Butyl 3-iodo-1H-indazole-1-carboxylate (2a). A mixture of 3-iodo-1H-indazole (0.2 g, 0.82 mmol),di-tert-butyldicarbonate (0.2 g, 0.92 mmol) and triethylamine (1 mL) were put under ultrasonicirradiation for 10 min. The resulted solution was neutralized using HCl 1M and then extractedwith dichloromethane (3 30 mL). The combined organic layers were dried with anhydrous sodiumsulfate and removal of the solvent under vacuum afforded a pure product as a pale yellow crystals.Yield: 100percent; m.p.: 93–95 °C; IR (KBr) (cm1): 1728 (C=O); 1150 (C-O); 424 (C-I). 1H-NMR (CDCl3) (ppm): 8.09 (1H, d, J = 8.5 Hz, H-7); 7.55 (1H, t, J = 7.8 Hz, H-4); 7.46 (1H, d, J = 7.9 Hz, H-6); 7.33 (1H,t, J = 7.6 Hz, H-5); 1.71 (9H, s, CH3). 13C-NMR (ppm): 148.35; 139.59; 130.17; 129.98; 124.21; 121.96;114.56; 102.95; 85.48; 28.18; HRMS calculated for C12H13IN2O2: 344.0022, Found: 344.0016.
97.5% With sodium hydroxide In acetonitrile at 25℃; for 12 h; tert-butyl 3-iodo-1 H-indazole-1-carboxylate
[00447] To a mixture of 3-iodo-1H-indazole (8 g, 32.7 mmol) and Boc2O (8.6 g, 39.2mmol) in MeCN (100 mL) was added NaOH (2.0 g, 49.1 mmol) at 25 °C and the mixture was stirred for 12 h. The mixture was poured into water (150 mL), extracted with EA (50 mLx2), andthe combined organic phase was washed with saturated brine (200 mLx2), dried with anhydrousNa2S04 and concentrated under vacuum. The residue was purified by silica gel chromatographyto afford the title compound (11.2 g, 97.5percent) as a white solid. MS (m/z): 477.2 [M+1]+.
97.5% With sodium hydroxide In acetonitrile at 25℃; [390j To a mixture of 3-iodo-1H-indazole (8 g, 32.7 mmol) and Boc2O (8.6 g, 39.2 mmoi) inMeCN (100 mL) was added NaOH (2.0 g, 49,1 mmoi) at 25 °C and the mixture was stirred for12 h. The mixture was poured into water (1 50 mL), extracted with EA (50 mL*2), and the combined organic phase was washed with saturated brine (200 mL*2), dried with anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by silica gel chromatography to afford the title compound (11.2 g, 97.5percent) as white solid.
93% at 20℃; 3-Iodo-1H-indazole (S1, 5.00 g, 19.5 mmol) was placed in a round-bottom flask and dissolved in tetrahydrofuran (100 mL). 4-Dimethylaminopyridine (0.24 g, 1.9 mmol, 0.1 equiv) was then added, followed by di-tert-butyl dicarbonate (5.4 mL, 24 mmol, 1.2 equiv). Triethylamine (5.4 mL, 39 mmol, 2.0 equiv) was slowly added to the clear, brown solution by syringe. The resulting solution was stirred at room temperature until it was complete as determined by TLC. The reaction was then diluted with water (75 mL) and ethyl acetate (50 mL). After separating the layers, the aqueous phase was extracted with additional ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), then shaken over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. This material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 90/10) to give the title compound as an orange solid (6.20 g, 93percent).
93% With dmap; triethylamine In tetrahydrofuran at 20℃; for 2 h; Example 2.1. Pre ration of tert-butyl 3-iodo-lH-indazole-l-carboxylate [00283] 3-Iodo-lH-indazole (5.00 g, 19.5 mmol) was placed in a round-bottom flask and dissolved in tetrahydrofuran (100 ml). 4-Dimethylaminopyridine (0.24 g, 1.9 mmol, 0.1 equiv) was then added, followed by di-iert-butyl dicarbonate (5.4 ml, 24 mmol, 1.2 equiv). Triethylamine (5.4 ml, 39 mmol, 2.0 equiv) was slowly added to the clear brown solution by syringe. The resulting solution was stirred at room temperature and monitored by TLC until complete. The reaction required approximately 2 hours. Once complete, the reaction was diluted with water (75 ml) and ethyl acetate (50 ml). After separating the layers, the aqueous phase was extracted with additional ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine (100 ml), shaken over magnesium sulfate, filtered, and concentrated under reduced pressure to give a dark red oil (8.40 g). The crude material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 90/10) to give the title compound as an orange solid (6.20 g, 93percent). 1H NMR (300 MHz, CDC13): δ 8.12 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 1.73 (s, 9H); 13C NMR (75 MHz, CDC13): δ 148.3, 139.6, 130.2, 129.9, 124.1, 121.9, 114.5, 102.8, 85.4, 28.1; ESI-MS (M-C4H9): m/z 288.
7 g With dmap In acetonitrile at 0 - 20℃; for 16 h; DMAP (16.37mmoI) was added to Intermediate-71(39 mmcl) in acetonitrile (50m1). The reaction mixture was then cooled to 0°C. BOC anhydride (39.9mmol) was added to the cooled reaction mixture. The reaction was carried out at room temperature for 16 hours. Then the reaction mixture was diluted with water (lOOmI) and extracted with ethyl acetate. Theorganic layer was dried over anhydrous Na2SO4 and evaporated to obtain ntermediate-72 (7g, pale yellow sofld).
7 g With dmap In acetonitrile at 20℃; for 16 h; Synthesis of tert-butyl 3-iodo-1H-indazole-1-carboxylate (Intermediate-72)
DMAP (16.37 mmol) was added to Intermediate-71(39 mmol) in acetonitrile (50 ml).
The reaction mixture was then cooled to 0° C. BOC anhydride (39.9 mmol) was added to the cooled reaction mixture.
The reaction was carried out at room temperature for 16 hours.
Then the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate.
The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain Intermediate-72 (7 g, pale yellow solid).

Reference: [1] Molecules, 2018, vol. 23, # 8,
[2] Patent: WO2015/58140, 2015, A1, . Location in patent: Paragraph 00447
[3] Patent: WO2016/58544, 2016, A1, . Location in patent: Paragraph 389; 390
[4] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1501 - 1507
[5] Patent: WO2014/47662, 2014, A2, . Location in patent: Paragraph 00283
[6] Journal of Medicinal Chemistry, 2008, vol. 51, # 12, p. 3460 - 3465
[7] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6206 - 6214
[8] Tetrahedron Letters, 2000, vol. 41, # 22, p. 4363 - 4366
[9] Organic and Biomolecular Chemistry, 2011, vol. 9, # 14, p. 5129 - 5136
[10] Tetrahedron Letters, 2002, vol. 43, # 15, p. 2695 - 2697
[11] Patent: US2010/29733, 2010, A1, . Location in patent: Page/Page column 38
[12] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 23, p. 6998 - 7003
[13] Journal of Medicinal Chemistry, 2010, vol. 53, # 23, p. 8368 - 8375
[14] Patent: WO2013/128465, 2013, A1, . Location in patent: Page/Page column 146
[15] Patent: US2015/158860, 2015, A1, . Location in patent: Paragraph 0520
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1852 - 1856
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