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[ CAS No. 76513-69-4 ] {[proInfo.proName]}

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Chemical Structure| 76513-69-4
Chemical Structure| 76513-69-4
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Quality Control of [ 76513-69-4 ]

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Product Details of [ 76513-69-4 ]

CAS No. :76513-69-4 MDL No. :MFCD00009919
Formula : C6H15ClOSi Boiling Point : No data available
Linear Structure Formula :ClCH2OCH2CH2Si(CH3)3 InChI Key :BPXKZEMBEZGUAH-UHFFFAOYSA-N
M.W : 166.72 Pubchem ID :2724271
Synonyms :

Calculated chemistry of [ 76513-69-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 4
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 44.71
TPSA : 9.23 ?2

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) : -5.22 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.63
Log Po/w (XLOGP3) : 2.96
Log Po/w (WLOGP) : 2.54
Log Po/w (MLOGP) : 1.89
Log Po/w (SILICOS-IT) : 0.69
Consensus Log Po/w : 2.14

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.47
Solubility : 0.559 mg/ml ; 0.00335 mol/l
Class : Soluble
Log S (Ali) : -2.82
Solubility : 0.254 mg/ml ; 0.00153 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.71
Solubility : 0.326 mg/ml ; 0.00195 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.96

Safety of [ 76513-69-4 ]

Signal Word:Danger Class:8,3
Precautionary Statements:P210-P233-P240-P241-P242-P243-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P370+P378-P403+P235-P405-P501 UN#:2920
Hazard Statements:H226-H314 Packing Group:Ⅱ
GHS Pictogram:

Application In Synthesis of [ 76513-69-4 ]

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

  • Downstream synthetic route of [ 76513-69-4 ]

[ 76513-69-4 ] Synthesis Path-Downstream   1~16

  • 1
  • [ 33543-78-1 ]
  • [ 76513-69-4 ]
  • [ 329984-05-6 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydride; In N,N-dimethyl-formamide; at 0 - 25℃; for 12h;Inert atmosphere; SEM-Cl (18.98 mL, 107.04 mmol) was added to ethyl lH-imidazole-2-carboxylate (10 g, 71.36 mmol) and NaH (4.28 g, 107 mmol) in DMF (50 mL) at 0°C under nitrogen. The resulting mixture was then stirred at 25 °C for 12 hours. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (2 x 100 mL), the organic layer was dried over Na2S04, filtered and evaporated to afford a yellow residue. The crude product was purified by flash silica chromatography, elution gradient 30 to 70percent EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford ethyl 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazole-2-carboxylate (Intermediate 16; 20 g, 100percent) as a yellow oil. H NMR (400 MHz, DMSO, 30 °C) delta 0.00 (9H, s), 0.03 - 0.08 (2H, m), 1.37 (3H, t), 3.53 - 3.62 (2H, m), 4.37 (2H, q), 5.76 (2H, s), 7.18 (1H, d), 7.68 (1H, d). m/z: ES+ [M+H]+ 271
76% With potassium carbonate; In acetone; at 20℃; for 10h; a) 1-(2-Trimethylsilanyl-ethoxymethyl)-<strong>[33543-78-1]1H-<strong>[33543-78-1]imidazole-2-carboxylic acid ethyl ester</strong></strong> A flask charged with <strong>[33543-78-1]1H-<strong>[33543-78-1]imidazole-2-carboxylic acid ethyl ester</strong></strong> (1.03 g, 7.36 mmol), K2CO3 (2.00 g, 14.5 mmol), SEM-Cl (1.56 mL, 8.89 mmol), and 20 mL of acetone was stirred for 10 h at RT. The reaction was diluted with EtOAc (100 mL), washed with NaHCO3 (2*100 mL), brine (100 mL), and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 50percent EtOAc/hexanes to give 1.50 g (76percent) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H22N3O3Si, 271.1 (M+H), found 271.1.
70% With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; Synthesis of Ethyl 1~((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2- carboxylate (lnt~1a) ciInMa2-(Trimethylsilyl)ethoxymethyi chloride (12.8 g, 0.077 mol) was added to a stirred solution of <strong>[33543-78-1]ethyl imidazole-2-carboxylate</strong> (9.0 g, 0.064 mol) and potassium carbonate (17.7 g, 0.128 mol) in NtN-dimethylformamide (50 mL) at 0 °C. The mixture was allowed to stir from 0 °C to r.t. overnight. Water and ethyl acetate were added and the layers were separated. The separated aqueous layer was extracted with ethyl acetate (X2). The combined organic layers were washed with water (X2). The separated organic layer was dried (MgS04) and filtered. The solvents were removed in vacuo andchromatographic purification (ethyl acetate - hexane) of the residue gave imidazole InMa (12 g, 70percent) as a colorless oil. LCMS m/e (M + H+) - 271.1.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; SEMCI (1.519 ml_, 8.56 mmol) was added to a DMF (10 mL) suspension of K2C03 (1.972 g, 14.27 mmol) and <strong>[33543-78-1]ethyl imidazole-2-carboxylate</strong> (CAS 33543-78-1 ) (1 g, 7.14 mmol). After the mildly exothermic reaction subsided, the mixture was allowed to stir one hour at room temperature and was quenched with the addition of water and ethyl acetate. The organic phase was washed with water, brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by FCC (100percent Heptane to 50percent ethyl acetate/Heptane) afforded the title compound. MS (ESI+) m/z 271.4 (M+H).

  • 2
  • [ 76513-69-4 ]
  • [ 894807-98-8 ]
YieldReaction ConditionsOperation in experiment
61% 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (348 mg, 1.8 mmol) was dissolved in DMF (5 mL) and sodium hydride (60percent dispersion, 86 mg, 2.15 mmol) added. The mixture heated to 60° C. for 5 min. Upon cooling and stirring for an additional 15 min, trimethylsilylethoxymethyl chloride (358 mg, 2.15 mmol, 381 muL) was added dropwise over 5 min and mixture stirred for 16 h. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5percent lithium chloride (5.x.), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with hexanes and ethyl acetate; gradient 100percent hexanes to 50percent hexanes over 30 min at 30 mL/min) to provide the SEM-protected pyrazole (360 mg, 61percent) as a colorless oil; 1H NMR (500 MHz, CDCl3) delta 7.84 (s, 1H), 7.80 (s, 1H), 5.42 (s, 2H), 3.56-3.53 (t, J=8.3 Hz, 2H), 1.31 (s, 12H), 0.91-0.87 (t, J=8.3 Hz, 2H), -0.03 (s, 9H).
  • 3
  • [ 269410-08-4 ]
  • [ 76513-69-4 ]
  • [ 894807-98-8 ]
YieldReaction ConditionsOperation in experiment
86% With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 16h;Inert atmosphere; Synthesis of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2~yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 t-15a)lnt-15aTo a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- H- pyrazole (8.2 g, 41 mmol) in NMP (60 mL) was added K2C03 (12 g, 82 mmoi) and 2-(trimethylsilyi)ethoxymethy. chloride (7.8 mL, 43 mmol) in sequence. The reaction mixture was stirred at r.t. under N2 for 16 h. Then, the reaction mixture was diluted and filtered, and then the filtrate was diluted with EtOAc (300 mL). The resulting solution was washed with sat. NaHC03 (aq) (3 x 200 mL), H20 (4 x 200 mL), brine (1 x 200 mL), dried over Na2S04, filtered, concentrated and dried in vacuo to yield intermediate .nt-15a (11.4 g, 86 %) as a clear yellowish oil.
86% [96] SEM-pyrazolo-4-boronic acid pinacol ester was prepared according the procedure from WO2011/130146, page 84. A solution of pyrazolboronic acid pinacolester (20 g, 103 mmol) in DMF (180 mL) was cooled to 0 C and treated with sodium hydride (60 % dispersion in oil) (6.2 g, 150 mmol) in nitrogen athmosphere. [97] The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then cooled to 0 C and (2-(chloromethoxy)ethyl)trimethylsilane (23.65 ml, 134 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. [98] The reaction mixture was poured into aqueous saturated ammonium chloride (200 mL) containing ice (approximately 200 mL) and stirred until the ice melted. The cold mixture was extracted with ethyl acetate twice. The combined organic extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford SEM-pyrazolo-4-boronic acid pinacol ester (27.6 g, 86 % yield).
72% With sodium hydride; In tetrahydrofuran; at 20℃;Inert atmosphere; Compound 280.1. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazole. Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.82 g, 30.0 mmol) in tetrahydrofuran (80 mL). This was followed by the addition of NaH (70%) (2.05 g, 85.4 mmol) in portions at 0 C. To this was added SEMC1 (6.4 mL, 36.1 mmol) dropwise. The reaction mixture was stirred overnight at room temperature, then quenched with 50 mL of NH4CI (sat). The aqueous phase was extracted with 2 x 100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 7 g (72%) of the title compound as colorless oil.
65.94% With caesium carbonate; In tetrahydrofuran; acetonitrile; at 20℃; for 2h; 13.2 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl- ethoxymethyl)-1 H-p razole To a solution of 1H-pyrazole-4-boronic acid pinacol ester (0.5 g, 2.57 mmol), in tetrahydrofuran/acetonitrile (3:2, 20ml), 2-(chloromethoxylethyl)trimethyl- silane (0.51 g, 3.09 mmol) and cesium carbonate (1.67 g, 5.15 mmol) are added and stirred for 2 hours at room temperature. The reaction mixture is filtered through celite, and concentrated, the crude mass is taken in ethylacetate (30 ml), washed with water, brine solution, dried over anhydrous MgS04 and concentrated to get the product as brown oil (0.55 g, 65.94 %); TLC: Pet ether/ethyl acetate(8/2) R - 0.5; 1H NMR: 400 MHz, DMSO-d6: delta [ppm] 8.08 (s, 1H), 7.64 (s, 1 H), 5.40 (s, 2H), 3.48-3.54 (m, 2H), 1.24 (s, 12H), 0.81-0.85 (m, 2H), -0.049(s, 9H);
61% 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (348 mg, 1.8 mmol) was dissolved in DMF (5 mL) and sodium hydride (60% dispersion, 86 mg, 2.15 mmol) added and the mixture heated to 60 C. for 5 min. Upon cooling and stirring for an additional 15 min, trimethylsilylethoxymethyl chloride (358 mg, 2.15 mmol, 381 muL) was added dropwise over 5 min and mixture stirred for 16 h. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% lithium chloride (5×), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with hexanes and ethyl acetate; gradient 100% hexanes to 50% hexanes over 30 min at 30 mL/min) to provide the SEM-protected pyrazole (360 mg, 61%) as a colorless oil; 1H NMR (500 MHz, CDCl3) delta 7.84 (s, 1H), 7.80 (s, 1H), 5.42 (s, 2H), 3.56-3.53 (t, J=8.3 Hz, 2H), 1.31 (s, 12H), 0.91-0.87 (t, J=8.3 Hz, 2H), -0.03 (s, 9H).
56% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; To a solution of methyl 4-(tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1H-pyrazole (1 .238 g, 6.316 mmol) in DMF (20 mL) was added potassium carbonate (2.62 g, 18.95 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (1 .68 mL, 9.48 mmol) at room temperature. The mixture was stirred for 3 hours and then partitioned between TBME (100 ml.) and water (50 ml_). The organic layer was separated, washed with water (2 x 30 mL) and brine (30 ml_), dried (Na2S04) and concentrated at reduced pressure. The residue was purified by Biotage Isolera chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-50% EtOAc in heptane]. The product containing fractions were combined, concentrated in vacuo to give the title compound (1 .20 g, 56% yield) as colourless oil. 1H NMR (500 MHz, chloroform-d) delta [ppm] 7.88 (s, 1 H), 7.84 (s, 1 H), 5.46 (s, 2H), 3.61- 3.55 (m, 2H), 1 .35 (s, 12H), 0.96 - 0.90 (m, 2H), 0.00 (s, 9H). LCMS (Analytical Method A): Rt = 1 .34 mins; MS (ESIPos) m/z = 324.95 (M+H)
46% 32-(a) 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazole; Under argon atmosphere, to 20 ml of tetrahydrofuran solution containing 1.09 g (5.62 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole was added 443 mg (11.1 mmol) of 60% sodium hydride under ice-cooling, and the mixture was stirred for 5 minutes. Then, 3 ml (17.0 mmol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, and the solutions were washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 832 mg of the title compound as a colorless oil. (46%) Mass Spectrum (CI, m/z): 325 (M++1). 1H-NMR Spectrum (CDCl3, delta ppm): -0.03 (s, 9H), 0.86-0.94 (m, 2H), 1.32 (s, 12H), 3.51-3.59 (m, 2H), 5.43 (s, 2H), 7.81 (d, J=0.5 Hz, 1H), 7.86 (d, J=0.5 Hz, 1H).
44% With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; To a stirred solution of 4-(4 , 4,5 , 5-tetra methyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2 g, 10.3 mmol) in DMF (30 mL), (2-(chloromethoxy)ethyl)trimethylsilane (2 g, 12.3 mmol), and CS2CO3 (10 g, 30.9 mmol) were added. The resulting mixturen was stirred at rt for 3 h. Solvents were evaporated and the crude residue was diluted with ice cold water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4 and filtered. The filtered solution was concentrated under reduced pressure and the resulting crude compound was purified by flash column chromatography using 20-30% EtOAc/Pet ether to get the title compound (1.5 g, 44%) as pale yellow gummy.LC-MS (method 14): R, = 3.08 min; m/z = 325.2 (M+H?).
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 25℃; for 0.75h; Preparative Example 1; To a suspension of potassium carbonate (5.85 g, 1.5 equiv) and 4- (4,4,5,5-tetramethyM ,3,2-dioxaborolan-2-yl)-1 h-pyrazole (5.48 g, 1.0 equiv) in NMP (50 mL) at rt was added SEMCI (5.2 mL, 1.05 equiv) dropwise (mildly exothermic). The resulting mixture was allowed to stir an additional 45 min at rt. The reaction was diluted with ethyl acetate, rinsed with water (2x), brine and dried (sodium sulfate). Filtration and concentration afforded the title compound that was used without purification. MH+ = 325.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; for 1h; A mixture of 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.48 g), SEMCl (5.2 mL), and K2CO3 (5.85 g) in NMP (50 mL) was stirred under N2 for 1 hr. The reaction mixture was diluted with EtOAc, rinsed with H2O, brine, and dried over Na2SO4. The mixture was filtered, the solvents were evaporated and the residue was used directly in the next step.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 0.75h; To a suspension of potassium carbonate (5.85 g, 1.5 equiv) and 1H-pyrazole-4-boronate (5.48 g, 1.0 equiv) in NMP (50 mL) at room temperature was added SEMCI (5.2 mL, 1.05 equiv) dropwise (mildly exothermic). The resulting mixture was allowed to stir for an additional 45 min at room temperature. The reaction was diluted with ethyl acetate, rinsed with water (×2), brine and dried (sodium sulfate). Filtration and concentration afforded the title compound (270) that used directly in the next step.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 0.75h; Example 270; To a suspension of potassium carbonate (5.85 g, 1.5 equiv) and 1H-pyrazole-4-boronate (5.48 g, 1.0 equiv) in NMP (50 mL) at room temperature was added SEMCl (5.2 mL, 1.05 equiv) dropwise (mildly exothermic). The resulting mixture was allowed to stir for an additional 45 min at room temperature. The reaction was diluted with ethyl acetate, rinsed with water (×2), brine and dried (sodium sulfate). Filtration and concentration afforded the title compound (270) that used directly in the next step.
Preparation E4-(4A5 -tetramethyl-l ,3,2-dioxaborolan-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazole [00624] A solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole(10.00 g, 51.54 mmol) in DMF (100 mL) was cooled to 0 C in an ice bath and treated with sodium hydride (60% dispersion in oil) (3.092 g, 77.30 mmol) in one portion. The reaction mixture was stirred at 0 C for 2 minutes, then at ambient temperature for 30 minutes. The reaction mixture was cooled to 0 C and (2-(chloromethoxy)ethyl)trimethylsilane (11.82 mL, 67.00 mmol) was added. The reaction mixture was warmed to ambient temperature and allowed to stir overnight. The reaction mixture was poured into aqueous saturated ammonium chloride (100 mL) containing ice (approximately 100 mL) and stirred until the ice melted. After the ice melted, the cold mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over MgS04, and concentrated under reduced pressure to afford the title compound (14.45 g, 44.56 mmol, 86.46% yield). MS (apci) m/z = 325.0 (M+H).
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 16h;Inert atmosphere; To a solution of 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (8.2 g, 41 mmol) in NMP (60 mL) were added K2C03 (12 g, 82 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.8 mL, 43 mmol) in sequence. The reaction mixture was stirred at RT under N2 for 16 h. Then, the reaction mixture was diluted filtered and the filtrate was diluted with EtOAc (300 mL), The resulting solution was washed with sat NaHC03(aq) (3 x 200 mL), ?0 (4 x 200 mL), brine (1 x 200 mL), dried over Na2S0 , filtered, concentrated and dried in vacuo to yield Int-37 as clear yellowish oil
0.9 g A) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [1064] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (770 mg) in DMF (10 mL) was added sodium hydride (60%, 114 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise (2-(chloromethoxy)ethyl)(trimethyl)silane (990 mg) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 5% aqueous lithium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.90 g). MS(ESI+): [M+H]+ 325.2. MS(ESI+), found: 325.2.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; To a solution of 4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (1.00 g, 5.15 mmol) in DMF (20 mL) was added K2C03 (1.07 g, 7.73 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (1.03 g, 6.18 mmol). The reaction was stirred at ambient temperature for 16 h and then diluted with water (20 mL). The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrazole (1.00 g, 60% yield) as ayellow oil.A mixture of 2-(3-bromophenyl)- 1,1,1 -trifluorobut-3 -yn-2-ol (500 mg, 1.79 mmol), 4-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazole (872 mg, 2.69 mmol), Cs2CO3 (1.17 g, 3.58 mmol) and 1,1?-Bis(diphenylphosphion) ferrocene dichloride palladium(II) (66 mg, 0.09 mmol) in dioxane/H20 (5 mL/1 mL) was heated at 110 Cfor 0.5 h under microwave conditions. The solvent was removed and the crude residue was purified by column chromatography (petroleum ether: EtOAc = 4:1) to give the title compound (300 mg, 42% yield) as a colorless oil.

  • 4
  • [ 76513-69-4 ]
  • [ 271-73-8 ]
  • [ 1021938-94-2 ]
YieldReaction ConditionsOperation in experiment
l-(2-TrimethylsilanylethoxymethylV4,5,6,7-tetrahvdro-lH-pyrazolor3,4-b1pyridine To a solution of lH-<strong>[271-73-8]pyrazolo[3,4-b]pyridine</strong> (380 mg, 3.2 mmol) in DMF (5 mL) was added NaH (60percent dispersion in mineral oil, 153 mg, 3.8 mmol). After stirring for 20 min, the mixture was heated with a heat gun and then allowed to cool to rt. SEM-Cl (647 muL, 3.8 mmol) was added dropwise and stirring continued for 2 h. The resulting mixture was partitioned between water and ethyl acetate. The organic layer was separated and concentrated, and the residue was purified by flash column chromatography (silica gel, eluting with 0-50percent ethyl acetate in hexanes) to provide l-(2-trimethylsilanylethoxymethyl)-lH-<strong>[271-73-8]pyrazolo[3,4-b]pyridine</strong>, which was dissolved in ethanol (30 mL) and flushed with a nitrogen stream. Palladium on charcoal (5percent wet on carbon, -50 mg) was added and the mixture was placed under hydrogen (50 psi) for 2 days. The reaction mixture was filtered, and the filtrate was concentrated to provide the title compound: 1H NMR (500 MHz, CDCl3) delta 7.13 (s, IH), 5.24 (s, 2H), 3.68 (br, IH), 3.54 (t, J = 8.2 Hz, 2H), 3.28 (m, 2H), 2.51 (t, J = 6.1, 2H), 1.81 (m, 2H), 0.89 (t, J = 8.2 Hz, 2H), -0.01 (s, 9H).
  • 5
  • [ 5932-27-4 ]
  • [ 76513-69-4 ]
  • [ 869558-94-1 ]
YieldReaction ConditionsOperation in experiment
63% To a suspension of sodium hydride (60percent in oil,0.45 g, 11.3 mmol, 1.6 equiv) in dry THF (16 mL) was added a solution of <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (1.00 g, 7.14 mmol,1.0 equiv) in dry THF (16 mL). The resulting dark brown solution was stirred at rt for 3 h. A solution of SEM-Cl (1.52 mL, 8.56 mmol,1.2 equiv) in dry THF (6 mL) was then added dropwise at 0°C. The solution was then allowed to warm up to rt and stirred overnight. Water was added to the reaction mixture, the aqueous phase was extracted 4 times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo togive a dark red oil. Purication by ash column chromatography (Et2O/CH2Cl2 0:100 to 5:95) led to the desired product ethyl 1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-pyrazole-3-carboxylate asa light orange oil (1.22 g, 4.50 mmol, 63percent yield).
1 - ( [2-(trimethylsilyl)ethoxy]methyl) - lH-pyrazole-3 -carbaldehyde was prepared as follows: 3-Methyl pyrazole (50 g, 0.61 mol) was placed in a 5 L round-bottom flask equipped with mechanical stirrer. 3 L of water was added and heated to 80 C. KMn04 (211.90 g, 1.34 mol) was added portion wise and refluxed for 4.5 h. After stirring at rt overnight, solid was filtered and washed with water. The water was removed in vacuo and 100 mL of water was kept in the flask which was acidified with 1 N HCl to pH 4. It was extracted with EtOAc (2x 1L), washed with brine (2x150 mL), dried over MgS04, filtered and removed in vacuo to yield 1H-pyrazole-3-carboxylic acid (38 g, 56percent) as a white solid. 38 g (0.34 mol) of IH-pyrazole-3-carboxylic acid was refluxed in anhydrous ethanol (1 L) and conc. sulfuric acid (60 mL) for 20 h under nitrogen. Ethanol was removed and crude was basified to pH 8. Precipitated solid was filtered. The filtrate was extracted with THF/CHC13 (2: 3, 3x 1 L), dried over MgS04, filtered and removed in vacuo to yield ethyl 1H-pyrazole-3- carboxylate (39 g, 82percent) as a white solid. To a suspension of <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (4.42 g, 31.57 mmol) in 1,4-dioxane (140 mL) under N2 atmosphere at 0 C was added NaH (0.91 g, 37.88 mmol) and stirred for 15 min. Neat SEM-Cl (5.79 g, 34.73 mmol) was added drop wise to reaction mixture and stirred overnight at rt. It was quenched with water (30 mL) and excess 1,4-dioxane was removed in vacuo. The residue was extracted with EtOAc (2x250 mL), washed with water (1x50 mL), dried over MgS04, filtered and removed in vacuo to give crude ethyl 1 - [2- (trimethylsilyl)ethoxy]methyl}-1H pyrazole-3-carboxylate (8.84 g) as a yellow oil. The crude material was used in next step without purification. To a suspension of LiAlH4 in THF (100 mL) at 0 C under N2 atmosphere was added a solution of ethyl 1- f [2-(trimethylsilyl)ethoxy]methyl}-1H pyrazole-3-carboxylate (8.88 g, 32.88 mmol) slowly. After addition was completed the cooling bath was removed and reaction mixture was stirred overnight. It was quenched with water (10 mL) carefully at 0 C. THF was removed and residue was diluted with DCM (250 mL) and organic layer was separated, dried over MgS04 and removed in vacuo. The crude material was plugged thru a pad of silica gel with EtOAc/hexanes (from 10percent to 100percent) to yield (1-[2- (trimethylsilyl)ethoxy]methyl) -lH-pyrazol-3-yl)methanol (5.80 g, 77percent) as an yellow oil. 53.75 g (0.24 mol) of (1- f [2-(trirnethylsilyl)ethoxy]methyl}-1H pyrazol-3-yl)methanol was dissolved in THF and 122.97 g (1.41 mol) of Mn02 was added. The resulting mixture was refluxed for 60 h. Solid material was filtered through a pad of celite and washed with hot THF. The filtrate was removed in vacuo to give crude product. The crude was plugged thru a pad of silica gel and eluted with EtOAc/hexanes (from 20percent to 50percent) to yield 1-[2- (trimethylsilyl)ethoxy]methyl}-1H pyrazole-3-carbaldehyde (50.88 g, 86.5percent) as a red oil.
  • 6
  • [ 76513-69-4 ]
  • [ 89830-98-8 ]
  • [ 1434588-82-5 ]
  • [ 1434588-77-8 ]
YieldReaction ConditionsOperation in experiment
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BuLi (1.6M in hexane)(1 1 mL; 17.6 mmol) was added to a solution of J-1 b (3.5 g; 14.7 mmol) in THF (60 mL) at -50°C. The mixture was stirred at the sametemperature for 30 min and DMF (1 .7 mL; 22 mmol) was added. The mixture was warmed slowly to RT in 1 h and NH2OH,HCI (970 mg; 29.4 mmol) was added and the mixture was stirred at RT for 16h. Water was added and the product was extracted with DCM (3 times), washed with brine, dried over MgS04 and the solvent was removed under reduced pressure to give 4.1 g (quantitative yield) of the mixture of isomers K-1 as yellow oil.HPLC Rt (min) = 5.30, 5.41 and 5.90 ; MS M+ (H+): 282 (method V2002V2002) K-1 ( 3.1 g; 1 1 mmol) was dissolved in DCM (18 mL) and pyridine (19 mL) at RT. The mixture was cooled to 0°C and TFAA (4.6 mL; 33 mmol) was added. The mixture was stirred at RT for 24h. The solvent was removed under reduced pressure and the residue was dissolved in AcOEt. The organic layer was washed with water and brine, dried over MgS04, filtered and the solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 15-40??? 90g merck, mobile phase Heptane/DCM 30/70 to DCM 100percent) to give 2.14 g of intermediate J-1 (73percent) as a mixture of two isomers.HPLC Rt (min) = 6.51 ; MS M+ (H+): 264 (method V2002V2002)
  • 7
  • [ 76513-69-4 ]
  • [ 89830-98-8 ]
  • [ 1434588-68-7 ]
  • [ 1434588-73-4 ]
YieldReaction ConditionsOperation in experiment
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H).
  • 8
  • [ 76513-69-4 ]
  • [ 89830-98-8 ]
  • [ 1434588-92-7 ]
  • [ 1434588-87-0 ]
YieldReaction ConditionsOperation in experiment
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BuLi (1.6M in hexane)(1 1 mL; 17.6 mmol) was added to a solution of J-1 b (3.5 g; 14.7 mmol) in THF (60 mL) at -50°C. The mixture was stirred at the sametemperature for 30 min and DMF (1 .7 mL; 22 mmol) was added. The mixture was warmed slowly to RT in 1 h and NH2OH,HCI (970 mg; 29.4 mmol) was added and the mixture was stirred at RT for 16h. Water was added and the product was extracted with DCM (3 times), washed with brine, dried over MgS04 and the solvent was removed under reduced pressure to give 4.1 g (quantitative yield) of the mixture of isomers K-1 as yellow oil.HPLC Rt (min) = 5.30, 5.41 and 5.90 ; MS M+ (H+): 282 (method V2002V2002)
  • 9
  • [ 506-68-3 ]
  • [ 76513-69-4 ]
  • [ 89830-98-8 ]
  • [ 1434588-82-5 ]
  • [ 1434588-77-8 ]
YieldReaction ConditionsOperation in experiment
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BrCN (6.1 1 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7 mmol) in DMF (60 mL) at 10°C. The reaction was exothermic to 35°C and a pale yellow precipitate was formed. The mixture was cooled to 10°C and J-1 b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40°C for 6 h. Water was added and product was extracted with Et20 (2 times). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure.The crude was purified by preparative LC (Irregular SiOH 15-40 ??? 220 g grace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impure J-1 , which was further purified by preparative LC (irregular SiOH 15-40 ??? 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 as a mixture of two region-isomers(15percent yield).HPLC Rt (min) = 6.1 1 ; MS M+ (H+): 264 (method V1004V1012)
  • 10
  • [ 506-68-3 ]
  • [ 76513-69-4 ]
  • [ 89830-98-8 ]
  • [ 565473-06-5 ]
  • [ 1434584-96-9 ]
YieldReaction ConditionsOperation in experiment
120 mg J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BrCN (6.1 1 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7 mmol) in DMF (60 mL) at 10°C. The reaction was exothermic to 35°C and a pale yellow precipitate was formed. The mixture was cooled to 10°C and J-1 b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40°C for 6 h. Water was added and product was extracted with Et20 (2 times). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure.The crude was purified by preparative LC (Irregular SiOH 15-40 ??? 220 g grace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impure J-1 , which was further purified by preparative LC (irregular SiOH 15-40 ??? 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 as a mixture of two region-isomers(15percent yield).HPLC Rt (min) = 6.1 1 ; MS M+ (H+): 264 (method V1004V1012) EtONa (904 mg; 13.3 mmol) was added to a solution of 2-cyano-imidazole 1-1 (0.7 g; 2.66 mmol) and intermediate C-1 (736 mg; 2.66 mmol) in EtOH (30 ml_). The mixture was stirred at 90°C for 16 h. The solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 45g Merck, mobile phase 97/3/0.1 to 95/5/0.5) to give 0.51 g of the SEM-protected ethoxy intermediate as a lightly yellow solid (38percent yield).HPLC Rt (min) = 7.45 ; MS M+ (H+): 506 method (v2003v2002) NaF (170 mg; 4.05 mmol) was added to a solution of SEM-protected ethoxy intermediate (0.41 g; 0.81 1 mmol) in THF (28 ml_), HCI (37percent in H20) (28 mL) and MeOH (10 mL). The mixture was stirred at 40°C for 16h. The mixture was cooled to RT and a 10percent solution of K2C03 was added until the pH of the solution was basic. The aqueous layer was saturated with K2C03 powder and the product was extracted with DCM/MeOH (5percent) (3 times). The combined organic layers were dried over MgS04, filtered and the solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 15-40??"?, mobile phase DCM/MeOH/NH3aq 95/5/0.5 to 90/10/0.5) to give 120 mg of compound 1 as a white powder (43percent yield)
  • 11
  • [ 506-68-3 ]
  • [ 76513-69-4 ]
  • [ 89830-98-8 ]
  • [ 565473-06-5 ]
  • C24H31N7O2Si [ No CAS ]
  • C24H31N7O2Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
J-1 a (4.84 g; 44.8 mmol) in TH F (60 mL) was added dropwise to a suspension of NaH (1 .97 g; 49.2 mmol) in TH F (200 mL) at 0°C under N2. The mixture was stirred at RT for 30 min and SEM-CI (9.9 mL; 55.9 mmol) in THF(20 mL) was added dropwise at 0°C. The mixture was stirred at RT under N2 for 16 h. Water was added and the product was extracted with DCM. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude was purified by preparative LC (Irregular SiOH 20-45 [Jim , 150g Merck, Mobile phase Gradient from 50percent DCM, 50percent heptane to 100percent DCM). The fractions containing pure compound were combined and the solvent was removed under reduced pressure to give 6.6 g of J-1 b as a yellow oil (62percent).Mixture of 2 regioisomers : 70/30Minoritory regioisomer : 1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.64 (s, 1 H), 6.56 (s, 1 H), 5.34 (s, 1 H), 3.45 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.52-0.57 (m, 2H), -0.04 (s, 9H).Majoritory regioisomer :1H NMR (DMSO-de, 400MHz) : 5(ppm) 7.56 (s, 1 H), 6.94 (s, 1 H), 5.20 (s, 1 H), 3.43 (t, J = 8.08 Hz, 2H), 1 .73-1 .78 (m, 1 H), 0.80-0.86 (m, 2H), 0.72-0.74 (m, 2H), 0.56-0.62 (m, 2H), -0.04 (s, 9H). BrCN (6.1 1 g; 57.7 mmol) was added to a solution of DMAP (7.05 g; 57.7 mmol) in DMF (60 mL) at 10°C. The reaction was exothermic to 35°C and a pale yellow precipitate was formed. The mixture was cooled to 10°C and J-1 b (5.5 g; 23.1 mmol) was added. The mixture was stirred at 40°C for 6 h. Water was added and product was extracted with Et20 (2 times). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure.The crude was purified by preparative LC (Irregular SiOH 15-40 ??? 220 g grace, mobile phase Heptane/DCM 50/50 to 10/90) to give 2.2 g impure J-1 , which was further purified by preparative LC (irregular SiOH 15-40 ??? 90 g Merck, mobile phase heptane/DCM 30/70) to give 0.94 g of J-1 as a mixture of two region-isomers(15percent yield).HPLC Rt (min) = 6.1 1 ; MS M+ (H+): 264 (method V1004V1012) EtONa (904 mg; 13.3 mmol) was added to a solution of 2-cyano-imidazole 1-1 (0.7 g; 2.66 mmol) and intermediate C-1 (736 mg; 2.66 mmol) in EtOH (30 ml_). The mixture was stirred at 90°C for 16 h. The solvent was removed under reduced pressure. The crude was purified by preparative LC (irregular SiOH 45g Merck, mobile phase 97/3/0.1 to 95/5/0.5) to give 0.51 g of the SEM-protected ethoxy intermediate as a lightly yellow solid (38percent yield).HPLC Rt (min) = 7.45 ; MS M+ (H+): 506 method (v2003v2002)
  • 12
  • [ 33543-78-1 ]
  • [ 76513-69-4 ]
  • ethyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate [ No CAS ]
  • 13
  • [ 76513-69-4 ]
  • [ 35344-95-7 ]
  • [ 869558-91-8 ]
YieldReaction ConditionsOperation in experiment
57% With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h; To a stirring solution of ?H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> SM1 (500 mg, 5.2mmol) in DMF (lOmL) was added NaH (248mg, 6.2mmol), followed by SEMC1 (1.03g,6.2mmol) at 0 °C and stirred at room temperature for ?H. The reaction mixture was diluted with water and extracted with EA. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude product, which was purified by silica gel column chromatography to afford compound 1 (800mg,57percent). TLC:20percent EtOAc/Hexane (Rf: 0.5). LC-MS: m/z = 227[(M+1)].
  • 14
  • [ 6494-19-5 ]
  • [ 76513-69-4 ]
  • [ 1214900-04-5 ]
  • 15
  • [ 76513-69-4 ]
  • [ 271-73-8 ]
  • 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-b]pyridine [ No CAS ]
  • 16
  • [ 76513-69-4 ]
  • [ 17288-32-3 ]
  • C16H24N2O3Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a mixture of ethyl 1 H-pyrrolo[3 ,2- bjpyridine-2-carboxylate (3.95 g, 20.8mmol, 1 eq) in 40 mL of DMF was added NaH (1.3 g, 31.2 mmol, 60percent purity, 1.5 eq) at 0°C and the mixture was stirred at 15°C for 0.5 hour. SEM20 Cl (5.2 g, 31.2 mmol, 1.5 eq) was added and the mixture was stirred at 15 °C for 0.5 hour underN2 atmosphere. To the reaction mixture was added in 150 mL of icy saturated NH4C1 dropwise to quench NaH, then the mixture was extracted with twice 100 mL portions of ethyl acetate. The combined organic layers were washed with 100 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 85 (12.9 g, cmde) as a brown oil.
12.9 g To a mixture of compound 77 (3.95 g, 20.8 mmol, 1.0 eq) in 40mL of DMF was added NaH (1.25 g, 31.2 mmol, 60percent purity, 1.5 eq) at 0°C and then the mixturewas stirred at 15°C for 0.5 hour. SEM-Cl (5.2 g, 31.2 mmol, 1.5 eq) was added and the mixture was stirred at 15°C for 0.5 hour under N2 atmosphere. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was added dropwise to 150 mL of icy saturated aqueous NH4C1 to quench any remaining NaH, then the mixture was extracted twicewith 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL of brine, dried over Na2504, filtered and concentrated under reduced pressure to give 12.9 g of compound 78as a brown oil.
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