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Structure of 76513-69-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 76513-69-4 |
Formula : | C6H15ClOSi |
M.W : | 166.72 |
SMILES Code : | C[Si](C)(CCOCCl)C |
MDL No. : | MFCD00009919 |
InChI Key : | BPXKZEMBEZGUAH-UHFFFAOYSA-N |
Pubchem ID : | 2724271 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H226-H314 |
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 |
Class: | 8(3) |
UN#: | 2920 |
Packing Group: | Ⅱ |
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 ? Topological Polar Surface Area: Calculated from |
9.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.63 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.96 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.54 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.89 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.69 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.14 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.47 |
Solubility | 0.559 mg/ml ; 0.00335 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.82 |
Solubility | 0.254 mg/ml ; 0.00153 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.71 |
Solubility | 0.326 mg/ml ; 0.00195 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.22 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.96 |
* 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.
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; | General Method D Intermediate 4 i) 2- (2-ff2- (Trimethylsilvl) ethoxvlmethoxy} phenvl) ethanol A solution of 2-(2-hydroxyphenyl) ethanol (69 mg) in dry DMF (10mL) was treated with potassium carbonate (86mg) under nitrogen. 2- (trimethylsilyl) ethoxymethy chloride (110 , uL) was added and the reaction mixtures stirred at room temperature for 16 h prior to partitioning between EtOAc and water. The organic phase was washed with sat. NH4CI (aq), water and dried (MgS04) and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient from cyclohexane to EtOAc) to give the title compound. (49mg) LCMS RT= 3.59 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In acetone; at 20℃; for 10h; | A flask charged with <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (0.5 g, 5.2 mmol) {Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 EPO <DP n="43"/>(1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 1O h at RT. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30 percent EtOAc/hexane to give 0.80 g (70 percent) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m/z) Calcd. for Ci0Hi7N3OSi, 224.1 (M+H), found 224.1. |
70% | With potassium carbonate; In acetone; at 20℃; for 10h;Product distribution / selectivity; | Example 34-Cyano-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carboxyIate potassium salt; EPO <DP n="38"/> a) 1 -(2-Trimethylsilanyl-ethoxymethyl)- 1 H-<strong>[57090-88-7]imidazole-4-carbonitrile</strong> A flask charged with <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (0.50 g, 5.2 mmol) (Synthesis, 677(2003)) 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30 percent EtOAc/hexane to give 0.80 g (70 percent) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m/z) Calcd. for C10Hi7N3OSi, 224.1 (M+H), found 224.1. |
70% | With potassium carbonate; In acetone; at 20℃; for 10h; | A flask charged with <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (0.5 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30percent EtOAc/hexane to give 0.80 g (70percent) of the title compound as a colorless oil. Mass spectrum (CI(CH4), m/z) Calcd. for C10H17N3OSi, 224.1 (M+H), found 224.1. |
70% | With potassium carbonate; In acetone; at 20℃; for 10h; | A flask charged with <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (0.50 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with ethyl acetate (EtOAc) (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer was dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30percent EtOAc/hexane to give 0.80 g (70percent) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m/z) Calcd. for C10H17N3OSi, 224.1 (M+H), found 224.1. |
70% | With potassium carbonate; In acetone; at 20℃; for 10h; | a) 1-(2-Trimethylsilanyl-ethoxymethyl)-<strong>[57090-88-7]1H-<strong>[57090-88-7]imidazole-4-carbonitrile</strong></strong> A flask charged with <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (0.50 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with ethyl acetate (EtOAc) (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30percent EtOAc/hexane to give 0.80 g (70percent) of the title compound as a colorless oil: Mass spectrum (CI (CH4), m/z) Calcd. for C10H17N3OSi, 224.1 (M+H), found 224.1. |
70% | With potassium carbonate; In acetone; at 20℃; for 10h; | A flask charged with <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (0.50 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL), washed with water (20 mL), brine (20 mL) and the organic layer was dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30percent EtOAc/hexane to give 0.80 g (70percent) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m/z): Calcd. for C10H17N3OSi, 224.1 (M+H), found 224.1. |
70% | With potassium carbonate; In acetone; at 20℃; for 10h; | a) 1-(2-Trimethylsilanyl-ethoxymethyl)-<strong>[57090-88-7]1H-<strong>[57090-88-7]imidazole-4-carbonitrile</strong></strong> A flask charged with <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (0.5 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30percent EtOAc/hexane to give 0.80 g (70percent) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m/z) Calcd. for C10H17N3OSi, 224.1 (M+H). found 224.1. |
70% | With potassium carbonate; In acetone; at 20℃; for 10h;Product distribution / selectivity; | A flask charged with <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (0.5 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimcthylsilyl)cthoxymcthyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30 percent EtOAc/hexane to give 0.80 g (70 percent) of the title compound as a colorless oil. Mass spectrum (CT (CH4), m/z) Calcd. for C1OHi7NsOSi, 224.1 (M+H), found 224.1. |
70% | With potassium carbonate; In acetone; at 20℃; for 10h; | Example 11; 4-Cyano- lH-imidazole-2-carboxylic acid (4-bromo-2-cyclohex- 1 -enyl-phenyl)-amide; a) l-(2-Trimethylsilanyl-ethoxymethyl)-lH-<strong>[57090-88-7]imidazole-4-carbonitrile</strong>; A flask charged with <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (0.50 g, 5.2 mmol) (Synthesis, 677, 2003), <n="43"/>2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. ,The crude product was eluted from a 20-g SPE cartridge (silica) with 30 percent EtOAc/hexane to 'give 0.80 g (70 percent) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m/z) Calcd. for Cj0HnN3OSi, 224.1 (M+H), found 224.1. |
With sodium hydride; In tetrahydrofuran; at 20℃; for 18h; | To a round bottom flask was added NaH (60percent in mineral oil) (200 mg, 5.22 mmol) in dry THF (12 ml), followed by the addtion of <strong>[57090-88-7]1H-<strong>[57090-88-7]imidazole-4-carbonitrile</strong></strong> (400 mg, 4.3 mmol), SEMCl (1433 mg, 8.6 mmol). The reactiom mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtO Ac/sat. NaHCO3. The organic phase was separated, washed with water, <n="131"/>brine, dried over anhy. Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (0-3percent MeOH/CH2Cl2). The product fractions were collected and concentrated to afford 355 mg of 1-(2-trimethylsilanyl- ethoxymethyl)-<strong>[57090-88-7]1H-<strong>[57090-88-7]imidazole-4-carbonitrile</strong></strong>, m/z 224.6 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20℃; for 20h; | A 22-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and an addition funnel with a nitrogen inlet was charged with IH- <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (830 g, 8.91 mol, as prepared in the previous step), potassium carbonate (2.47 kg, 17.8 mol), and acetone (6.0 L). Agitation was initiated and the mixture was cooled to 10 0C with an ice bath. SEMCl (1.50 kg, 9.00 mol) was added through the addition funnel over 210 min to maintain the internal temperature below 15 0C. The reaction was then allowed to warm to ambient temperature and stirred at ambient temperature overnight (20 h). The reaction mixture was then cooled in an ice bath to 10 0C and quenched by the slow addition of water (8.0 L) over 30 min to maintain the internal temperature below 30 °C. The resulting mixture was transferred to a 22-L separatory funnel and extracted with ethyl acetate (2 x 7.0 L). The combined organics were concentrated under reduced pressure at 35 0C to give the crude product as a dark brown oil, EPO <DP n="133"/>which was purified through a plug of silica gel (16.5 x 20 cm, 2.4 kg silica gel) using 2:1 heptane/ethyl acetate (15 L) as eluent. The fractions containing the product were combined and concentrated under reduced pressure at 35 0C to afford a mixture of the title compounds as a light brown oil [1785 g, 90percent). The 1H NMR spectrum was consistent with the assigned structure and indicated the presence of a 64:36 ratio of regioisomers. | |
With potassium carbonate; In acetone; at 10 - 20℃; for 23.5h;Product distribution / selectivity; | b) l-(2-Trimethylsilanyl-ethoxymethyl)-lH-<strong>[57090-88-7]imidazole-4-carbonitrile</strong> and 3-(2- trimethylsilanyl-ethoxymethyl)-3H-<strong>[57090-88-7]imidazole-4-carbonitrile</strong>; A 22-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and an addition funnel with a nitrogen inlet was charged with IH- <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (830 g, 8.91 mol, as prepared in the previous step), potassium carbonate (2.47 kg, 17.8 mol), and acetone (6.0 L). Agitation was initiated and the mixture was cooled to 10 0C with an ice bath. SEMCl (1.50 kg, 9.00 mol) was added through the addition funnel over 210 min to maintain the internal temperature below 15 °C. The reaction was then allowed to warm to ambient temperature and stirred at ambient temperature overnight (20 h). The reaction mixture was then cooled in an ice bath to 10 °C and quenched by the slow addition of water (8.0 L) over 30 min to maintain the internal temperature below 30 °C. The resulting mixture was transferred to a 22-L separatory funnel and extracted with ethyl acetate (2 x 7.0 L). The combined organics were EPO <DP n="149"/>concentrated under reduced pressure at 35 °C to give the crude product as a dark brown oil, which was purified through a plug of silica gel (16.5 x 20 cm, 2.4 kg silica gel) using 2:1 heptane/ethyl acetate (15 L) as eluent. The fractions containing the product were combined and concentrated under reduced pressure at 35 °C to afford a mixture of the title compounds as a light brown oil [1785 g, 90percent). The 1H NMR spectrum was consistent with the assigned structure and indicated the presence of a 64:36 ratio of regioisomers. | |
With potassium carbonate; In acetone; at 0 - 10℃; for 23.5h; | A 22-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and an addition funnel with a nitrogen inlet was charged with <strong>[57090-88-7]1H-<strong>[57090-88-7]imidazole-4-carbonitrile</strong></strong> (830 g, 8.91 mol, as prepared in the previous step), potassium carbonate (2.47 kg, 17.8 mol), and acetone (6.0 L). Agitation was initiated and the mixture was cooled to 10° C. with an ice bath. SEMCl (1.50 kg, 9.00 mol) was added through the addition funnel over 210 min to maintain the internal temperature below 15° C. The reaction was then allowed to warm to ambient temperature and stirred at ambient temperature overnight (20 h). The reaction mixture was then cooled in an ice bath to 10° C. and quenched by the slow addition of water (8.0 L) over 30 min to maintain the internal temperature below 30° C. The resulting mixture was transferred to a 22-L separatory funnel and extracted with ethyl acetate (2.x.7.0 L). The combined organics were concentrated under reduced pressure at 35° C. to give the crude product as a dark brown oil, which was purified through a plug of silica gel (16.5.x.20 cm, 2.4 kg silica gel) using 2:1 heptane/ethyl acetate (15 L) as eluent. The fractions containing the product were combined and concentrated under reduced pressure at 35° C. to afford a mixture of the title compounds as a light brown oil [1785 g, 90percent). The 1H NMR spectrum was consistent with the assigned structure and indicated the presence of a 64:36 ratio of regioisomers. |
With potassium carbonate; In acetone; at 10 - 20℃; for 20h; | A 22-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and an addition funnel with a nitrogen inlet was charged with <strong>[57090-88-7]1H-<strong>[57090-88-7]imidazole-4-carbonitrile</strong></strong> (830 g, 8.91 mol, as prepared in the previous step), potassium carbonate (2.47 kg, 17.8 mol), and acetone (6.0 L). Agitation was initiated and the mixture was cooled to 10° C. with an ice bath. SEMCl (1.50 kg, 9.00 mol) was added through the addition funnel over 210 min to maintain the internal temperature below 15° C. The reaction was then allowed to warm to ambient temperature and stirred at ambient temperature overnight (20 h). The reaction mixture was then cooled in an ice bath to 10° C. and quenched by the slow addition of water (8.0 L) over 30 min to maintain the internal temperature below 30° C. The resulting mixture was transferred to a 22-L separatory funnel and extracted with ethyl acetate (2.x.7.0 L). The combined organics were concentrated under reduced pressure at 35° C. to give the crude product as a dark brown oil, which was purified through a plug of silica gel (16.5.x.20 cm, 2.4 kg silica gel) using 2:1 heptane/ethyl acetate (15 L) as eluent. The fractions containing the product were combined and concentrated under reduced pressure at 35° C. to afford a mixture of the title compounds as a light brown oil [1785 g, 90percent). The 1H NMR spectrum was consistent with the assigned structure and indicated the presence of a 64:36 ratio of regioisomers. | |
With potassium carbonate; In acetone; at 10 - 30℃; for 23.5h;Product distribution / selectivity; | A 22-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and an addition funnel with a nitrogen inlet was charged with IH- <strong>[57090-88-7]imidazole-4-carbonitrile</strong> (830 g, 8.91 mol, as prepared in the previous step), potassium carbonate (2.47 kg, 17.8 mol), and acetone (6.0 L). Agitation was initiated and the mixture was cooled to 10 0C with an ice bath. SEMCl (1.50 kg, 9.00 mol) was added through the addition funnel over 210 min to maintain the internal temperature below 15 0C. The reaction was then allowed to warm to ambient temperature and stirred at ambient temperature overnight (20 h). The reaction mixture was then cooled in an ice bath to 10 0C and quenched by the slow addition of water (8.0 L) over 30 min to maintain the internal temperature below 30 0C. The resulting mixture was transferred to a 22-L separatory funnel and extracted with ethyl acetate (2 x 7.0 L). The combined organics were concentrated under reduced pressure at 35 0C to give the crude product as a dark brown oil, which was purified through a plug of silica gel (16.5 x 20 cm, 2.4 kg silica gel) using 2:1 heptane/ethyl acetate (15 L) as eluent. The fractions containing the product were combined and concentrated <n="150"/>under reduced pressure at 35 °C to afford a mixture of the title compounds as a light brown oil [1785 g, 90percent). The 1H NMR spectrum was consistent with the assigned structure and indicated the presence of a 64:36 ratio of regioisomers. | |
With potassium carbonate; In acetone; at 20℃; for 48h;Inert atmosphere; | lH-<strong>[57090-88-7]imidazole-4-carbonitrile</strong> (1 g, 10.74 mmol) and potassium carbonate (2.97 g, 21.49 mmol) were added to a round bottomed flask and placed under an atmosphere of nitrogen by evacuation-refill. Acetone (10 mL) was added, evacuation-refill of the vessel repeated, and the mixture stirred prior to addition of (2- (chloromethoxy)ethyl)trimethylsilane (2.091 mL, 11.82 mmol). The reaction vessel was placed under an atmosphere of nitrogen and stirred at RT for 48 h. The solvent was removed under reduced pressure, and the residue redissolved in 30 mL EtOAc and washed sequentially with 20 mL water and 20 mL brine. The combined aqueous layers were extracted with further EtOAc (2 x 30 mL). The organic layers were combined and passed through a hydrophobic frit, and the solvent was removed under reduced pressure. The sample was dissolved in DCM and purified by column chromatography using a silica cartridge (120 g) with an ethyl acetate-cyclohexane solvent system [3CV, 10-20percent; 3CV, 20percent; 5CV, 20-50percent; 9CV, 50percent]. The appropriate fractions were combined and the solvent removed in vacuo to afford the title compound in a 2: 1 ratio of the l-((2-(trimethylsilyl)ethoxy)methyl)-lH-<strong>[57090-88-7]imidazole-4-carbonitrile</strong> and l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazole-5-carbonitrile regioisomers, as a pale yellow oil (1.71 g, 7.66 mmol, 71percent). LCMS (System B): tRET = 1.08 min; MH+ 224 (both regioisomers). |
Yield | Reaction Conditions | Operation in experiment |
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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). |
Yield | Reaction Conditions | Operation 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), ¾0 (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. |
Yield | Reaction Conditions | Operation in experiment |
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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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Intermediate J(i): tert-butyl 3-amino-6,6-dimethyl-1 -[2-(trimethylsilyl)ethoxy]methyl}-4,6- dihydropyrrolo[3,4-c]pyrazole-5(1 H)-carboxylate.; To a suspension of tert-butyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1 /-/)-carboxylate (8.5 g, 33.9 mmol) and diisopropyl ethylamine (18mL, 3.0 equiv) in <n="66"/>dichloromethene (200 ml_) was added 2-(trimethylsilyl)ethoxymethyl chloride (6.0 ml_, 1.0 equiv) dropwise at 0 0C under nitrogen. The mixture was been stirred at 0 0C under nitrogen for two hours then warmed to room temperature and stirred over night. The reaction mixture was concentrated and purified by column chromatography to give the title compound J[i] as a white solid (2.27 g, 18%). 1 H NMR (400 MHz, METHANOL-^): delta ppm 0.81- 0.97 (m, 2 H) 1.45- 1.59 (m, 9 H) 1.72 (d, J=5.29 Hz, 13 H) 3.53- 3.67 (m, 2 H) 4.26 (d, J=7.55 Hz, 2 H) 5.17 (s, 2 H). 2D-NOESY NMR showed proton at 5.17 ppm is correlated with proton at 1.72ppm. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Intermediate EKIII-2): tert-Butyl 3-amino-6,6-dimethyl-1-[2- (trimethylsilyl)ethoxy]methyl}-4.6-dihydropyrrolo[3,4-c]pyrazole-5(1 H)-carboxylateMe3SiTo the mixture of the intermediate EKII) (87g), methylene chloride (1.74L) and diisopropylethylamine (87g) at O0C were added 2-(trimethylsilyl)ethoxymethyl chloride (63g) drop wise at O0C (1 hour addition). The reaction mixtures were stirred at room temperature over night. The reaction was a light brown solution. Then the mixture was concentrated to give a light yellow/brown oil and the residue was mixed with ethyl acetate and the salts were filter off. The mixture was purified with silica gel (2:1 to 1:1 EtOAc/Hexane with 0.5% of TEA) to afford the regioisomers EKIII-2) (24g, >90% purity by HPLC) and E(III-D (1Og, >98% purity by HPLC). 1H NMR (400 MHz, CD3OD) ppm - 0.03 (s, 9H) 0.88 (t, J=8.2 Hz, 2H) 1.48 and 1.53 (s, 4.5H each, a total of 9H), 1.70 (s, 3H), 1.72 (s, 3H), 3.56-3.62 (m, 2H), 4.24-4.26 (m, 2H), 5.16 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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To a solution of ethyl 3-methyl-1 H-pyrazole-4-carboxylate (Preparation 21 , 1 g, 6.48 mmol) in tetrahydrofuran (THF, 10 ml) was added sodium hydride (0.285 g, 7.14 mmol) and the reaction stirred for 10 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride was added (1.190 g, 7.14 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was quenched with water (20 ml) and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated in vacuo to afford the title compounds as a mixture of N1 and N2 regioisomers (1.57 g, 85% yield). Regioisomers were not separated.1HNMR (d^DMSO): 0.01 (s, 9H), 0.89 (t, 2H), 1.23 (m, 3H), 2.40 (s, 2H), 2.56 (s, 1 H), 3.58 (m, 2H), 4.24 (m, 2H), 5.40 (s, 1H), 5.51 (s, 1H), 7.87 (s, 0.5H), 8.43 (s, 0.5H) |
Yield | Reaction Conditions | Operation in experiment |
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1.24 g | lH-<strong>[57090-88-7]imidazole-4-carbonitrile</strong> (1 g, 10.74 mmol) and potassium carbonate (2.97 g, 21.49 mmol) were added to a round bottomed flask and placed under an atmosphere of nitrogen by evacuation-refill. Acetone (10 mL) was added, evacuation-refill of the vessel repeated, and the mixture stirred prior to addition of (2- (chloromethoxy)ethyl)trimethylsilane (2.091 mL, 11.82 mmol). The reaction vessel was placed under an atmosphere of nitrogen and stirred at RT for 48 h. The solvent was removed under reduced pressure, and the residue redissolved in 30 mL EtOAc and washed sequentially with 20 mL water and 20 mL brine. The combined aqueous layers were extracted with further EtOAc (2 x 30 mL). The organic layers were combined and passed through a hydrophobic frit, and the solvent was removed under reduced pressure. The sample was dissolved in DCM and purified by column chromatography using a silica cartridge (120 g) with an ethyl acetate-cyclohexane solvent system [3CV, 10-20percent; 3CV, 20percent; 5CV, 20-50percent; 9CV, 50percent]. The appropriate fractions were combined and the solvent removed in vacuo to afford the title compound in a 2: 1 ratio of the l-((2-(trimethylsilyl)ethoxy)methyl)-lH-<strong>[57090-88-7]imidazole-4-carbonitrile</strong> and l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazole-5-carbonitrile regioisomers, as a pale yellow oil (1.71 g, 7.66 mmol, 71percent). LCMS (System B): tRET = 1.08 min; MH+ 224 (both regioisomers). l-((2-(Trimethylsilyl)ethoxy)methyl)-lH-<strong>[57090-88-7]imidazole-4-carbonitrile</strong> (for an example preparation, see Intermediate 15, 1.68 g, 7.52 mmol (2: 1 ratio of l-((2- (trimethylsilyl)ethoxy)methyl)-lH-<strong>[57090-88-7]imidazole-4-carbonitrile</strong> and H(2- (trimethylsilyl)ethoxy)methyl)-lH-imidazole-5-carbonitrile)) was added to a round bottomed flask containing THF (40 mL). Once dissolved, /V-bromosuccinimide (1.473 g, 8.27 mmol) was added, and the flask placed under an atmosphere of nitrogen. The reaction mixture was stirred at 60 °C overnight. Further 0.2 equivalents of /V-bromosuccinimide (0.268 g, 1.504 mmol) was added to the reaction mixture and the reaction left stirring at 60 °C for a further 8h. The reaction mixture was quenched with saturated sodium hydrogencarbonate solution (40 mL) and brine (40 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were passed through a hydrophobic frit and the solvent removed under reduced pressure. The sample was loaded as a neat liquid and purified by column chromatography using a silica cartridge (80 g) with an ethyl acetate-cyclohexane solvent system [3CV, 0percent; 7CV, 0-10percent; 3CV, 10percent]. The appropriate fractions were combined and the solvent removed in vacuo to give the crude product. The crude product was dissolved in diethyl ether and filtered through Celite®, the solvent was removed from the filtrate under reduced pressure to afford the title compound as a pale yellow oil, (1.24 g, 4.10 mmol, 55percent). LCMS (System A): tRET = 1.23 min; MH+ 302, 304. |
Yield | Reaction Conditions | Operation in experiment |
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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. |
Yield | Reaction Conditions | Operation in experiment |
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Example 102 (method 2) (Synthetic Intermediate)(2-Bromo-pyridin-4-yl)-[5-(4-dimethylamino-piperidin-1-yl)-1-(2-trimethylsilanyl- ethoxymethyl)-1 H-benzoimidazol-2-yl]-methanone (as a mixture with the 6- regioisomer). Starting with Example 25, Step 1 was performed by following procedures describe for Example 42. Step 2 and Step 3 were performed by following procedures describe for Example 48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 102 (method 2) (Synthetic Intermediate)(2-Bromo-pyridin-4-yl)-[5-(4-dimethylamino-piperidin-1-yl)-1-(2-trimethylsilanyl- ethoxymethyl)-1 H-benzoimidazol-2-yl]-methanone (as a mixture with the 6- regioisomer). Starting with Example 25, Step 1 was performed by following procedures describe for Example 42. Step 2 and Step 3 were performed by following procedures describe for Example 48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Sodium hydride (1.2eq) was added to a solution of 3-bromo-lH-[l,2,4]triazole (leq) in dry DMF (2.3ml/mmol) at 00C and under an atmosphere of nitrogen The solution was stirred at 00C for 20min, then, SEM-Cl (1.2eq) was added. The mixture was stirred at room temperature overnight and diluted with H2O and ethyl acetate. The organic layers was washed with H2O then brine, dried on anhydrous Na2SO4, filtered and concentrated in vacuum to give the titled compound. Crude compound 3- bromo-l-(2-trimethylsilanyl-ethoxymethyl)-lH-[l,2,4]triazole was engaged in step 2 without purification. IH-NMR (CDCl3): delta (ppm) 0.00 (t, 9H); 0.92 (t, 2H); 3.64 (t, 2H); 5.44 (s, 2H); 8.13 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
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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) |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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) |
Yield | Reaction Conditions | Operation 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) |
Yield | Reaction Conditions | Operation 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) |
Yield | Reaction Conditions | Operation 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) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a stirred solution of 6-bromo-1H-i,2,3-triazolo[4,5-b]pyridine (250 mg, 1.26 mmol) in DMF (5 mL) at rt was added 60% sodium hydride in mineral oil (55 mg, 1.38 mmol) and the mixture was stirred at rt for 30 mins. (2-(Chloromethoxy)ethyl)trimethylsilane (419 mg, 2.51 mmol) was added and the mixture was stirred for 15 h. The reaction mixture was partitioned between water and EtOAc and the aqueous layer was separated and further extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0 - 20% EtOAc in hexanes to afford a 1:1 mixture of 6-bromo- 1 -((2- (trimethylsilyl)ethoxy)methyl)- 1H- [1,2,3 ]triazolo [4,5-b]pyridine and 6-bromo-3 -((2- (trimethylsilyl)ethoxy)methyl)-3H- [1,2,3 ]triazolo[4,5 -b]pyridine (240 mg) as an oil, which was not purified further. LC-MS (ESI) mlz 329 and 331 (M+H).v [000223] Step 2: A 1:1 mixture of N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-3 - yl)-2-(4-(l -((2-(trimethylsilyl)ethoxy)methyl)- 1H- [1,2,3 ]triazolo [4,5 -b]pyridin-6- yl)phenyl)acetamide and N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-3 -yl)-2-(4-(3 -((2- (trimethylsilyl)ethoxy)methyl)-3H- [1,2,3 ]triazolo [4,5 -b]pyridin-6-yl)phenyl)acetamide (71 mg, 40%) was obtained as a solid using a procedure analogous to that described in Step 3 of Example4, substituting the product obtained from Step 1 of this example for the 2-chloro-6,7- dimethoxyquinoxaline used in Example 4 and substituting 2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-3 -yl)acetamide (Ref: S. Abraham et al, WO 2011022473 Al) for the 2-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-N-(5 -(1 -(trifluoromethyl)cyclopropyl)isoxazol-3 -yl)acetamide used in Example 4. LC-MS (ESI) mlz 561 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | General procedure: To a stirred solution of 6-bromo-1H-i,2,3-triazolo[4,5-b]pyridine (250 mg, 1.26 mmol) in DMF (5 mL) at rt was added 60% sodium hydride in mineral oil (55 mg, 1.38 mmol) and the mixture was stirred at rt for 30 mins. (2-(Chloromethoxy)ethyl)trimethylsilane (419 mg, 2.51 mmol) was added and the mixture was stirred for 15 h. The reaction mixture was partitioned between water and EtOAc and the aqueous layer was separated and further extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0 - 20% EtOAc in hexanes to afford a 1:1 mixture of 6-bromo- 1 -((2- (trimethylsilyl)ethoxy)methyl)- 1H- [1,2,3 ]triazolo [4,5-b]pyridine and 6-bromo-3 -((2- (trimethylsilyl)ethoxy)methyl)-3H- [1,2,3 ]triazolo[4,5 -b]pyridine (240 mg) as an oil, which was not purified further. LC-MS (ESI) mlz 329 and 331 (M+H).v [000223] Step 2: A 1:1 mixture of N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-3 - yl)-2-(4-(l -((2-(trimethylsilyl)ethoxy)methyl)- 1H- [1,2,3 ]triazolo [4,5 -b]pyridin-6- yl)phenyl)acetamide and N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-3 -yl)-2-(4-(3 -((2- (trimethylsilyl)ethoxy)methyl)-3H- [1,2,3 ]triazolo [4,5 -b]pyridin-6-yl)phenyl)acetamide (71 mg, 40%) was obtained as a solid using a procedure analogous to that described in Step 3 of Example4, substituting the product obtained from Step 1 of this example for the 2-chloro-6,7- dimethoxyquinoxaline used in Example 4 and substituting 2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-3 -yl)acetamide (Ref: S. Abraham et al, WO 2011022473 Al) for the 2-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-N-(5 -(1 -(trifluoromethyl)cyclopropyl)isoxazol-3 -yl)acetamide used in Example 4. LC-MS (ESI) mlz 561 (M+H).[000224] Step 3: To a 1:1 mixture of N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-3 - yl)-2-(4-(l -((2-(trimethylsilyl)ethoxy)methyl)- 1H- [1,2,3 ]triazolo [4,5 -b]pyridin-6- yl)phenyl)acetamide and N-(5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-3 -yl)-2-(4-(3 -((2- (trimethylsilyl)ethoxy)methyl)-3H- [1,2,3 ]triazolo [4,5 -b]pyridin-6-yl)phenyl)acetamide (71 mg, 0.127 mmol) was added trifluoroacetic acid (5 mL), and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse-phase preparative HPLC using a mixture of water (containing 5% CH3CN and 0.05% HCOOH) and CH3CN (containing 0.05% HCOOH) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 2-(4-(3H-[l,2,3]triazolo[4,5-b]pyridin-6-yl)phenyl)-N- (5 -(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-3 -yl)acetamide (12 mg, 22%) as a solid. ?H NMR (500 MHz, DMSO-d6) oe 11.41 (br s, 1H), 9.00 (d, J= 2.0 Hz, 1H), 8.60 (br s, 1H), 7.80 (d, J 8.5 Hz, 2H), 7.48 (d,J 8.5 Hz, 2H), 6.95 (s, 1H), 3.77 (s, 2H), 1.53 (s, 6H); LC-MS (ESI) m/z 431 (M+H). |
Yield | Reaction Conditions | Operation 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)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.26 g | To a solution of <strong>[5654-97-7]1H-pyrrolo[2,3-b]pyridin-2(3H)-one</strong> (2.00 g, 14.9 mmol) in DMF (30 mL) and THF (30 mL) under nitrogen at 0 C was added sodium hydride, 60% in mineral oil (0.600 g, 15.0 mmol). The reaction mixture was stirred at 0 C for 1 h. Then (2- (chloromethoxy)ethyl)trimethylsilane (3.17 mL, 17.9 mmol) was added dropwise over 3 min and the reaction was allowed to warm up to rt without removing the cold bath over 21 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL), the aqueous was extracted with EtOAc (2 x 50 mL), the combined organic component was washed with water (2 x 50 mL), brine (50 mL), dried over MgS04, filtered, concentrated and purified with a Biotage Horizon (25% EtOAc/hexanes) to afford the title compound (2.26 g ) as viscous orange oil. LC-MS retention time = 3.49 min; m/z = 265.20 [M+H]+. (Column: Phenomenex C18 50 x 2.0 mm 3 muiotaeta. Solvent A = 90% Water : 10% MeOH : 0.1% TFA. Solvent B = 10% Water : 90% MeOH : 0.1% TFA. Flow Rate = 0.8 mL/min. Start % B = 0. Final % B = 100. Gradient Time = 4 minutes, then a l-minute hold at l00% B. Oven temperature = 40 C. Wavelength = 220 nm). 1H NMR (400 MHZ, DMSO-d6) delta 8.15 (d, J=5.0 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.05 (dd, J=7.2, 5.4 Hz, 1H), 5.07 (s, 2H), 3.69 (s, 2H), 3.59 (t, J=8.0 Hz, 2H), 0.85 (t, J=8.0 Hz, 2H), -0.06 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | To a solution of 4-bromo-5-methyl-lH-indazole (0.7 g, 3.3 mmol) in dimethyl acetamide (30 mL) cooled to 0 C was added NaH (0.19 g, 4.6 mmol) in portions and the reaction mixture was purged with nitrogen. The reaction was stirred for 20 minutes, and then (2- (chloromethoxy)ethyl)trimethylsilane (0.83 g, 5.0 mmol) was added and the reaction was stirred for 2 hours while warming to room temperature. The reaction was quenched by pouring into water and the aqueous layer was extracted into ethyl acetate. The combined organic layers were washed with water and brine, dried over MgS04 and concentrated under vacuum. The crude material was purified by chromatography using 10-50% ethyl acetate/hexanes as the eluent to give 4-bromo-5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole (0.87 g, 79%). | |
79% | To a solution of <strong>[926922-40-9]4-bromo-5-methyl-1H-indazole</strong> (0.7 g, 3.3 mmol) in dimethyl acetamide (30 mL) cooled to 0° C. was added NaH (0.19 g, 4.6 mmol) in portions and the reaction mixture was purged with nitrogen. The reaction was stirred for 20 minutes, and then (2-(chloromethoxy)ethyl)trimethylsilane (0.83 g, 5.0 mmol) was added and the reaction was stirred for 2 hours while warming to room temperature. The reaction was quenched by pouring into water and the aqueous layer was extracted into ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO 4 and concentrated under vacuum. The crude material was purified by chromatography using 10-50% ethyl acetate/hexanes as the eluent to give 4-bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.87 g, 79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | To a solution of 4-chloro-lH-pyrazolo[4,3-c]pyridine (1.0 g, 6.5 mmol, 1.0 eq) in THF (20.0 mL) at 0 °C was added NaH (60percent in mineral oil, 0.52 g, 13 mmol, 2.0 eq). The mixture was stirred at 0 °C for 30 mins. then SEMC1 (1.3 g, 7.8 mmol, 1.2 eq) was added. The mixture was stirred at rt overnight. After the reaction was complete, water was added to quench the reaction, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and filtered. The filtrate was concentrated in vacuo and The resulting residue was purified by column chromatography (PE:EA = 3 : 1) to provide 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[4,3-c]-pyridine (1.2 g, 65percent) as yellow oil. | |
46% | [00849] To a solution of 4-chloro-lH-pyrazolo[4,3-c]pyridine (2 g, 13.02 mmol) in anhydrous THF (25 mL) was added NaH (625 mg, 15.6 mmol, 60percent) at 0°C. After stirring at 25 °C for 20 min SEM-C1 (2.82 g, 16.93 mmol, 3 mL) was added dropwise at 0 °C. The reaction was stirred at 25 °C for 2 hrs and then quenched by slowly adding H2O. After extraction with EtOAc the combined organic phases were washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrazolo[4,3-c]pyridine (1.7 g, 5.99 mmol, 46percent yield). LCMS (ESI): m/z [M +H] calculated for C12H19CIN3OS1: 284.1; found 284.1. |
Yield | Reaction Conditions | Operation 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. |