Structure of 279262-11-2
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| CAS No. : | 279262-11-2 |
| Formula : | C8H11BO3 |
| M.W : | 165.98 |
| SMILES Code : | COCC1=CC=C(C=C1)B(O)O |
| English Name : | (4-(Methoxymethyl)phenyl)boronic acid |
| MDL No. : | MFCD03788426 |
| InChI Key : | VTNVZXAYRMTKON-UHFFFAOYSA-N |
| Pubchem ID : | 3723812 |
| Num. heavy atoms | 12 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.25 |
| Num. rotatable bonds | 3 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 2.0 |
| Molar Refractivity | 47.13 |
| TPSA ? Topological Polar Surface Area: Calculated from |
49.69 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.48 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.64 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.06 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.43 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.11 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-1.34 |
| Solubility | 7.53 mg/ml ; 0.0453 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.09 |
| Solubility | 13.4 mg/ml ; 0.0808 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.81 |
| Solubility | 2.56 mg/ml ; 0.0154 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 |
No |
| 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 |
-6.97 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 |
1.0 |
| 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 |
1.0 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) |
1.66 |
* 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 |
|---|---|---|
| 65% | Stage #1: (4-(methoxymethyl)phenyl)boronic acid; resin-bound 3-methoxycarbonyl 4-tosyl 1H-quinolin-2-one With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 14h; Stage #2: With trifluoroacetic acid In dichloromethane |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: C12H13F3N2O4S; (4-(methoxymethyl)phenyl)boronic acid With triethylamine In 1,4-dioxane at 20℃; for 0.0833333h; Stage #2: In 1,4-dioxane at 90℃; for 2h; | B.5 Intermediate compound 4 (150 mg, 0.44 mmol), 4-(methoxymethyl)phenylboronic acid (110 mg, 0.67mmol) were mixed in 1,4-dioxane (5 ml) and Et3N (0.12 ml, 0.89 mmol) at room temperature and N2 was flushed through the mixture for 5 min. Pd(PPh3)4 (77 mg, 0.067 mmol) was added and the resulting mixture was heated at 90 0C for 2 hours. The mixture was cooled to room temperature, diluted with AcOEt and brine. The aqueous phase was extracted with AcOEt (3 x 20 ml). The combined organics layers were dried over Na2SO4, evaporated in vacuum and the residue thus obtained was purified by column chromatography (SiO2, DCM/ AcOEt) to yield 52 mg of final compound 1-103 as a white solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With caesium carbonate In 1,4-dioxane at 80℃; for 6.5h; | 85 To a suspension of 3.00 g (7.71 mmol) of 4-bromo-1-trityl-1H-imidazoie in 30 ml of dioxane1.58 g (9.23 mmol) of 4-methoxymethyi boronic acid, 3.47 g (10.5 mmol) of cesiumcarbonate and 0.121 g (0.131 mmol) of tris-(dibenzylideneaceton)dipalladium are added, followed by 0.315 ml (0.308 ml) of a solution of 5 g of tri-t-buylphosphine in 25 ml of dioxane. The mixture is heated at 80°C and stirred for 6.5 hours. After cooling to room temperature the suspension is diluted with dichloromethane and filtered, the filter cake washed with ethyl acetate and the filtrate concentrated to dryness. The residue is purified by flash chromatography on silica (40 - 63 urn particle size) with hexane / ethyl acetate 7:3, yielding 2.805 g of 4-(4-methoxymethyl-phenyl)-1-trityl-1H-imidazole, Rt = 4.659 min by HPLC on a nucleosil C18HD column with acetonitril + 0.05% TFA / water + 0.05% TFA, 20/80 to 100/0 over 6 min, 1.0 ml/min solvent flow. MS (API-ES, pos. scan): e/m = 431 (M+1). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 59% | With potassium phosphate In tetrahydrofuran at 90℃; for 12h; | 71 Example 71 Preparation of 7-(4-chlorophenyl)-8-(4-(methoxymethyl)phenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one To a stirring solution of 8-bromo-7-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (60 mg, 0.12 mmol) in THF (2 mL) at room temperature under argon was added 4-methoxymethylphenylboronic acid (60.0 mg, 0.36 mmol), Pd(dppf)Cl2.CH2Cl2 (11.0 mg, 0.012 mmol), and K3PO4 (77 mg, 0.36 mmol). The resulting suspension was purged of oxygen by bubbling with argon for 15 min, sealed in a vial under argon, heated at 90° C. for 12 h, and then cooled to room temperature. Analysis by HPLC/MS indicated that starting material was absent and one major new product had formed. The reaction mixture was diluted with EtOAc and washed once with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes). Pooling of the desired fractions, washing with saturated aq. NaHCO3 solution to eliminate any possible boronic acid contaminant, drying the organic phase (MgSO4), filtering and evaporation provided the title compound as a yellow solid, 38 mg, 59%. HPLC/MS: retention time=3.94 min, [M+H]+=539. 1H NMR (CDCl3): δ 7.82 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.25 (m, 5H), 7.05 (d, J=7.7 Hz, 2H), 6.64 (d, J=7.2 Hz, 1H), 5.23 (s, 2H), 4.44 (s, 2H), 3.41 (s, 3H), 2.74 (s, 3H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | Stage #1: 2-[4-(3'-chloro-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-ylmethyl)-pyrazol-1-yl]-ethanol; (4-(methoxymethyl)phenyl)boronic acid With potassium carbonate In tetrahydrofuran; water at 150℃; for 0.25h; Microwave irradiation; Stage #2: With ammonium chloride In methanol for 0.166667h; | 17m Example 17m: 2-{4-[3'-(4-Methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[l,2']bipyrazinyl- 4-ylmethyl]-pyrazol-l-yl}-ethanol hydrochlorideDissolve 2-[4-(3'-chloro-2,3, 5, 6-tetrahydro-[l,2']bipyrazinyl-4-ylmethyl)-pyrazol- l-yl]-ethanol (0.201 g, 0.623 mmol) in tetrahydrofuran (1.7 mL) and water (0.9 mL). --171-Add potassium carbonate (189 mg, 1.37 mmol) then 4-methoxymethylbenzeneboronic acid (145 mg, 0.872 mmol) and degas with nitrogen for 15 min. Add tri-n- butylphosphine tetrafluoroborate (7.2 mg, 0.0249 mmol) and tris(dibenzylideneacetone)dipalladium(0) (11.4 mg, 0.0124 mmol) and microwave at 1500C for 15 min. Cool to room temperature then dilute with saturated aq. sodium bicarbonate and extract 6 times with ethyl acetate. Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 6:94 methanol (with 2 M ammonia):DCM), to give a yellow oil. Dissolve the oil in methanol and add ammonium chloride (1 equivalent) then sonicate the mixture for 10 min. Evaporate the solution to give the title compound as a yellow solid (0.191 g, 75%). MS (ES): m/z = 409 [M+H]+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 86% | With copper(l) iodide; caesium carbonate In 1,4-dioxane under Ar atm. Fe complex, arylboronic acid, catalyst, CuI and Cs2CO3 in 1,4-dioxane were heated at 60°C for 4 h; aq. NH4Cl was added, product was chromd. on silica (CS2); | |
| 73% | With caesium carbonate In 1,4-dioxane under Ar atm. Fe complex, arylboronic acid, catalyst and Cs2CO3 in 1,4-dioxane were heated at 60°C for 4 h; aq. NH4Cl was added, product was chromd. on silica (CS2); |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 96% | With potassium carbonate In 1,2-dimethoxyethane at 100℃; for 17h; | 5 Dissolve 3'-chloro-2,3,5,6-tetrahydro-[l,2']bipyrazinyl-4-carboxylic acid tert- butyl ester (3.0 g, 10.1 mmol, 1 eq.) in 1,2 dimethoxyethane (6 mL). Add A- methoxymethyl-benzene boronic acid (2.01 g, 12.12 mmol, 1.2 eq.). Add tetrakis(triphenylphosphine)-palladium (1.17 g, 1.01 mmol, 0.1 eq.) followed by potassium carbonate (3.77 g, 27.3 mmol, 2.7 eq.). Heat the reaction mixture at 100 0C for 17 hr. Partition the reaction mixture between EtOAc and water. Separate layers. Extract the aqueous layer with dichloromethane. Combine organic layers, dry over anhydrous Na2SO4, filter and concentrate. Purify by normal phase chromatography with 10-30% EtOAc/hexane to afford the title preparation (3.7 g, 96% yield). LC MS(ES): m/z = 385.3[M+H]. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 56% | With potassium carbonate In Isobutyramide; water at 110℃; for 18h; | 30 Dissolve l,3-dimethyl-lH-pyrazole-4-sulfonic acid [2-(3'-chloro-2,3,5,6- tetrahydro-[l,2']bipyrazinyl-4-yl)-ethyl] -methyl-amide (270 mg, 0.652 mmol) in DMA- H2O (10 ml; 3: 1 v/v, previously degassed with nitrogen). Add 4-methoxymethylphenyl boronic acid (130 mg, 0.783 mmol), potassium carbonate (216 mg, 1.56 mmol) and tetrakis(triphenylphosphine)palladium (38 mg, 0.0326 mmol). Heat the reaction mixture at 1100C for 18 hr. Cool and dilute with ethyl acetate and water. Extract the aqueous layer with ethyl acetate and combine the organic layers. Wash the organic layers with brine and concentrate. Purify by chromatography, eluting with 1:2 hexanes: acetone to afford the free base of the title compound (182 mg, 56 % yield) as a white foam.Prepare the hydrochloride salt by dissolving the free base (182 mg) in acetonitrile and adding IN aqueous HCl (0.401 ml, 0.401 mmol). Stir for 1 hr. at ambient temperature. Remove the organics and lyophilize the remaining aqueous portions to afford the title compound (100% yield). MS ES: m/z = 500 [M+H]+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate In 1,2-dimethoxyethane; water at 80 - 95℃; for 44h; | 42 Dissolve N- {2-[4-(2-chloro-pyridin-3-yl)-piperazin-l-yl]-ethyl}-4-fluoro-N- methyl-benzenesulfonamide (0.160 g, 0.387 mmol) in DME (5 mL, previously degassed with nitrogen). Add 4-(methoxymethyl)boronic acid (0.096 g, 0.581 mmol), 2N aqueous potassium carbonate (0.464 mL, 0.129 g, 0.930 mmol), and tetrakis(triphenylphosphine)- palladium (0.022 g, 0.022 mmol). Stir the reaction mixture at 80 0C for 18 hr. Increase the temperature to 95 0C and stir an additional 8 hr. Add fresh catalyst (0.015 g) and boronic acid (0.050 g). Stir 18 hr. at 95 0C. Cool to room temperature and concentrate to remove DME. Dilute with ethyl acetate and brine. Extract the aqueous layer with ethyl acetate. Combine the organic phases, dry over sodium sulfate, filter, and concentrate. Purify by silica gel chromatography eluting with dichloromethane: methanol 98:2 to 90: 10 to afford the free base of the title compound (0.075 g). Prepare the hydrochloride salt by dissolving the free base (0.075 g) in acetone (2 mL) and adding IN HCl in diethyl ether (0.165 mL, 0.165 mmol). Stir for 20 min. at room temperature and then add diethyl ether to precipitate the salt. Wash the salt with diethyl ether and dry to afford the title compound (0.079 g, 38% yield). MS ES: m/z = 499 [M+H]+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate In Isobutyramide; water at 80℃; for 8h; | 37 Dissolve 1 -methyl- lH-pyrazole-4-sulfonic acid (2-[4-(2-chloro-pyridin-3-yl)- piperazin-l-yl]-ethyl} -methyl-amide (0.200 g, 0.501 mmol) in DME-H2O (6 mL; 3: 1 v/v, previously degassed with nitrogen). Add 4-(methoxymethyl)boronic acid (0.125 g, 0.752 mmol), potassium carbonate (0.166 g, 1.203 mmol) and tetrakis(triphenylphosphine)- palladium (0.029 g, 0.025 mmol). Heat the reaction mixture at 800C for 8 hr. Cool to room temperature and concentrate to remove DME. Dilute with ethyl acetate and brine. Extract the aqueous layer with ethyl acetate. Combine the organic phases, dry over sodium sulfate, filter, and concentrate. Purify by silica gel chromatography eluting with dichloromethane: methanol 94:6 to 90: 10 to afford the freebase of the title compound with minor impurities. Purify by SCX eluting sequentially with dichloromethane, dichloromethane:methanol 1 : 1, methanol, and IN ammonia in methanol. Pass the pure free base through a silica gel plug eluting with dichloromethane: methanol 4: 1 to afford the free base of the title compound. Prepare the hydrochloride salt by dissolving the free base (0.193 g) in acetone and adding IN HCl in diethyl ether (0.438 mL, 0.438 mmol). Stir for 20 min. at room temperature and then add diethyl ether to precipitate the salt. Wash the salt with diethyl ether to afford the title compound (0.181 g, 69% yield). MS ES: m/z = 485 [M+H]+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate In water; acetonitrile at 140℃; for 0.333333h; Microwave irradiation; | 16.A Part A: ((IS, 2S)-l-[[Trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-(4'- methoxymethyl-biphenyl-4-yl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert- butyl esterA mixture of [(IS, 2S)-l-({(4-bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2- yl)-cyclopropanecarbonyl]-amino} -methyl)-2-methyl-butyl]-carbamic acid t-butyl ester (78 mg, 0.146 mmol), arylboronic acid (0.18 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and K2C03 (38 mg, 0.27 mmol) in CH3CN/H20 (3.5/0.5 mL) was heated in a microwave at 140°C for 20 min. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to ISCO (12 g column, 0-50% EtOAc in hexane over 25 min) to give the desired products. MS (MH+ 576). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | With potassium carbonate In water; acetonitrile at 140℃; for 0.5h; Microwave irradiation; | 4.B Part B. ((lS,2S)-l-[[(trans)-2-(5-Fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-(4'- methoxymethyl-biphenyl-4-yl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert- butyl esterTo 80 mg (0.15 mmol) of the aryl bromide, [(7S,2S)-l-({(4-bromo-phenyl)-[(trans)-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarbonyl] -amino} -methyl)-2-methyl- butyl] -carbamic acid tert-butyl ester, in a microwave vial was added boronic acid (26 mg, 0.158 mmol), K2C03 (41.5 mg, 0.301 mmol), PdCl2(PPh3)2 (5.3 mg, 0.008 mmol), 6 mL of MeCN, and 1 mL of water. The resulting mixture was microwaved at 140 °C for 30 min. It was then diluted with EtOAc, washed with water, brine and concentrated, and then purified in the neutral PREP HPLC to give 62 mg (72%) of the desired product. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate In water; acetonitrile at 140℃; for 0.333333h; Microwave irradiation; | 8.A Part A. (l-[[Trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-(4'- methoxymethyl-biphenyl-4-yl)-amino] -methyl }-cyclopentyl)-carbamic acid tert-butyl esterA mixture of [l-({(4-bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)- cyclopropanecarbonyl]-amino}-methyl)-cyclopentyl]-carbamic acid t-butyl ester (95 mg, 0.18 mmol), arylboronic acid (0.22 mmol), Pd(PPli3)2Ci2 (14 mg, 0.02 mmol) and K2C03 (47 mg, 0.34 mmol) in CH3CN/H2O (3.5/0.5 mL) was macrowaved at 140°C for 20 min. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to ISCO (12 g column, 0-50% EtOAc in hexane over 25 min) to give the desired products. MS (MH+ 574). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | Stage #1: tert-butyl [(2S,3S)-1-{4-bromophenyl-[(1R,2R)-2-(pyridin-2-yl)cyclopropanecarbonyl]amino}-3-methylpentan-2-yl]carbamate; (4-(methoxymethyl)phenyl)boronic acid With potassium phosphate In 1,2-dimethoxyethane; water at 160℃; for 0.0833333h; Microwave irradiation; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane; water | 1.C Part C. ((15,,25)-l-[(4'-Methoxymethyl-biphenyl-4-yl)-(2-pyridin-2-yl- cyclopropanecarbonyl)-amino] -methyl} -2-methyl-butyl)-carbamic acid tert-butyl esterA mixture of [(R)-3-(4-bromophenyl)-l-((5)-sec-butyl)-4-oxo-4-((lR,2R)-2- pyridin-2-yl-cyclopropyl)-butyl]-carbamic acid tert-butyl ester (32 mg, 0.062 mmol), 4-methoxymethyl phenylboronic acid (15 mg, 0.093 mmol), dichloro[l, l '- bis(diphenylphophino)ferrocene]palladium (II) dichloromethane adduct (5 mg, 0.0062 mmol), potassium phosphate (40 mg, 0.19 mmol), dimethoxyethane (1.5 mL) and water (0.5 mL) was heated in a sealed vessel by microwave irradiation at 160 °C for 5 min. The resulting mixture was poured into 1 N aqueous sodium hydroxide solution (10 mL) and extracted with dichloromethane (3 x 10 mL). Combined organics were dried (MgSC^), filtered and concentrated under reduced pressure to afford a residue that was purified by preparative HPLC (neutral mobile pahse) to afford ((15,25)- 1 - { [(4'-methoxymethyl-biphenyl-4-yl)-(2-pyridin-2-yl- cyclopropanecarbonyl)-amino] -methyl} -2-methyl-butyl)-carbamic acid tert-butyl ester (25 mg, 72% yield) as a colorless oil: XH NMR (400 MHz, CDC13) δ 8.27 - 8.32 (m, 1 H), 7.50 - 7.60 (m, 5 H), 7.43 (d, J=8.1 Hz, 2 H), 7.31 (d, J=7.8 Hz, 2 H), 7.22 (d, J=7.1 Hz, 1 H), 6.97 - 7.08 (m, 1 H), 5.04 - 5.13 (m, 1 H), 4.53 (s, 2 H), 4.37 - 4.49 (m, 1 H), 3.75 - 3.86 (m, 1 H), 3.45 (s, 3 H), 3.15 - 3.26 (m, 1 H), 2.67 - 2.78 (m, 1 H), 1.98 - 2.06 (m, 1 H), 1.61 (br. s., 2 H), 1.51 - 1.56 (m, 1 H), 1.49 (s, 7 H), 1.45 (br. s., 1 H), 1.06 - 1.18 (m, 1 H), 0.84 - 0.94 (m, 7 H); LRMS (ESI) m/e 558.3 [(M + H)+, calcd for C34H44N3O4 558.3]. |