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Structure of 156001-68-2
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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.
4.5
*For Research Use Only! Not for Human Use. We Do Not Sell to Patients.
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| CAS No. : | 156001-68-2 |
| Formula : | C9H7NO3 |
| M.W : | 177.16 |
| SMILES Code : | COC(=O)C1=CC(C#N)=C(O)C=C1 |
| English Name : | Methyl 3-cyano-4-hydroxybenzoate |
| MDL No. : | MFCD13248596 |
| InChI Key : | AHPCEMBOTQXADD-UHFFFAOYSA-N |
| Pubchem ID : | 11769089 |
| GHS Pictogram: | |
| Signal Word: | |
| Hazard Statements: | |
| Precautionary Statements: | |
| Class: | |
| UN#: | |
| Packing Group: |
| Num. heavy atoms | 13 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.11 |
| Num. rotatable bonds | 2 |
| Num. H-bond acceptors | 4.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 44.46 |
| TPSA ? Topological Polar Surface Area: Calculated from |
70.32 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.68 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.69 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.05 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.7 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.21 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.27 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.21 |
| Solubility | 1.09 mg/ml ; 0.00613 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.78 |
| Solubility | 0.293 mg/ml ; 0.00165 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.98 |
| Solubility | 1.85 mg/ml ; 0.0104 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 |
-6.18 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 |
0.0 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) |
1.73 |
* 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 |
|---|---|---|
| 52% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2 h; Inert atmosphere | To a stirred solution of methyl 3-cyano-4-hydroxybenzoate (2.0 g, 1 1.20 mmol) in DMF (20 mL) were added CH3I (2.40 g, 16.01 mmol) and K2CO3 (2.30 g, 16.01 mmol) at 0 0C under a N2 atmosphere. The reaction mixture was stirred at 80 0C for 2 h. After completion of starting material (monitored by TLC), reaction mixture was diluted with water and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (2 x 50 mL), brine and dried over anhydrous Na2Sψ4. After filtration and evaporation in vacuo, the crude material was purified by silica gel column chromatography to afford methyl 3-cyano-4-methoxybenzoate (1.1 g, 52percent), as a pale yellow solid. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With potassium carbonate In DMF (N,N-dimethyl-formamide) at 50℃; for 16h; | 66 To a solution of methyl 3-cyano-4-hydroxybenzoate (82 g, 463 mmol; J. Med. Chem, 2002,45, 5769) in dimethylfonnamide (800 mL) was added 2-iodopropane (93 mL, 926 mmol) and potassium carbonate (190 g, 1.4 mol). The resulting mixture was heated at 50 °C for 16 h, at which time it was allowed to cool to room temperature. The reaction was filtered and the mother liquor diluted with 0.5 N sodium hydroxide (1 L). The resulting mixture was extracted with ether (2 x I L) and the organics washed with 1 N HCI (1 L) and brine (700 mL), dried (MgSO4) and concentrated to give 100 g (-100%) of methyl 3-cyano-4- [(1-methylethyl) oxy]benzoate as a yellow solid. 3-Cyano-4-[(1-methylethyl)oxy]benzoic acid: [00392] To a cooled (0 °C) solution of methyl 3-cyano-4-[(1-methylethyl)oxyJbenzoate (100 g, 463 mmol) in tetrahydrofuran (500 mL) was added 10% potassium hydroxide (500 mL). The resulting solution was allowed to warm to room temperature and maintained for 16 h, at which time it was concentrated to remove the tetrahydrofuran. The residue was diluted with water (500 mL) and washed with ether (2 x 500 mL). The aqueous layer was then acidified with 3 N HCI and stood for 2 h. The solids were collected by filtration and washed several times with water, then dissolved in methylene chloride (1 L). The mostly homogeneous mixture was filtered through Celite and concentrated to a minimal volume of methylene chloride. Collection ofthe solids by filtration gave 82 g (87%) of 3-cyano-4-[(1- methylethyl)oxy]benzoic acid as a white solid. Scheme B: Reagents and Conditions: a) 4N HCI/dioxane, rt; b) HBTU, i-Pr2NEt, DMF, rt; c) 1- ethoxyvinyltn-n-butyltin, PdCh(PPh3)2, dioxane, 100 °C; d) NBS, THF/HzO (3:1), rt; e) 2- amino-3-picoline, NaHC03, i-PrOH, 80 °C . (3tS)-3-Amino-4-(4-bromophenyl)-1 -butane. hydrochloride. [00393] 1,1-Dimethylethyl {(I S)-l-[( 4-bromophenyl)methyl]-3- hydroxypropyl}carbamate (4.4 g, 12.8 mmol) was dissolved in 4N HCl/dioxane (20 mL). After 2 h, the reaction mixture was concentrated in vacuo to give 3.69 g (94%) of the title compound as a white solid. LC/MS (ES) m/e 244.0 (M + H)+. N- {( 1 S)- I -[ (4-Bromophenyl)methyl]-3-hydroxypropyl }-3-cyano-4-[(1- methylethyl)oxy]benzamide. [00394] To a suspension of (3S)-3-Amino-4-(4-bromophenyl)-1-butanol hydrochloride (1.80 g, 6.42 mmol) in dry DMF (32 mL) was added N, N-diisopropylethyl amine (2.49 g, 19.3 mmol) and the resultant clear solution was stirred for 3 min. 3-Cyano-4-[(1- methylethyl) oxy]benzoic acid (1.45 g, 7.06 mmol) and HBTU (2.68 g, 7.06 mmol) were added and the reaction was stirred at rt under nitrogen. After 1.5 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 X 30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (75% EtOAc/hexanes) to give 2.18 g (78%) of the title compound as a white solid. LC/MS (ES) m/e 431.2 (M + H)+. N-«(1S)-I- [ 4-(Bromoacetyl)phenyl]methyl }-3-hydroxypropyl)-3-cyano-4-[(1- methylethyl) oxy]benzamide. [00395] A flask, dried with a heat gun under argon purge, was charged with N-{(1S)-1- [(4-bromophenyl)methyl]-3-hydrox5propyl}-3-cyano-4-[(1-methylethyl)oxy]benzamide (1.0 g, 2.32 mol). dichlorobis(triphenylphosphine)-palladium(II) (81 mg, 0.116 mol), tributyl(1- ethoxyvinyl) tin (1.68 g, 4.64 mmol), and 1,4-dioxane (15 mL). The mixture was stirred at 100 °C for 2 hours under argon. Upon completion, as monitored by LCMS, the reaction was concentrated under reduced pressure and the residue was purified immediately on deactivated silica gel (65% EtOAc/hexanes with 5% triethylamine) to give 720 mg (1.70 mmol) of enol ether intennediate as a colorless foam which was immediately dissolved in THF:H20 (3: 1, 18 mL) and treated with N-bromosuccinimide (3 IS mg, 1.79 mmol). After 15 min at rt, the reaction mixture was concentrated under reduced pressure and the crude residue was diluted with EtOAc (30 mL), washed with biine (10 mL) and water (10 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80% EtOAc/hexanes) to give 651 mg (59%) of N-«(lS)-I- [ 4-(bromoacetyJ)phenyl)methyl}-3- hydroxypropyl)-3-cyano-4-[(l -methylethyl)oxy]benzamide as a white tacky solid. LC/MS (ES) m/e 473.2 (M + H)+. 3-Cyano-N ((1S'(at)-3-hydroxy-1-[(at)4-(8-methylimidazo[1,2-a]p(at)a-idin-2- yl)phenyl ] methj/I ) propyl)-4-[ ( 1 -methyl ethyl)oxy]benzamide. [00396] To a solution of N-( (1 S)-l- [ 4-(bromoacetyl)phenyl]methyl }-3- hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide (300 mg, 0.634 mmol) in i-PrOH (6 mL) was added 2-amino-3-picoline (Aldrich, 69 mg, 0.634 mmol) followed by solid NaHCO3 (64 mg, 0.761 mmol). The resultant suspension was heated to 80 °C. After 7 h, a majority of the i-PrOH was removed under reduced pressure and the residue was dissolved in 3% MeOH/EtOAc (30 mL) and washed with water (10 mL) and brine (10 mL). The combined aqueous layers were extracted with 3% MeOH/EtOAc (30 mL) and the combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (MeCN/H20 with 0.1 % TFA) and the clean fractions were adjusted to pH -8 with saturated aqueous NaHC03 and extracted with 3% MeOH/EtOAc (3 X 30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 215 mg (70%) of the title compound as a pale yellow solid. LC/MS (ES) m/e 453.2 (M + H)+. Scheme C: enantiomer A enantiomer B 1-(?-amino-3-pyridinyl)ethanol: [00397] To a dry flask (dried with a heat gun under argon purge) was added dry THF (400 mL) and MeLi-LiBr (137 mL of a 1.5M solution in Et20, 204.9 mmol) via cannula. This solution was cooled to -78 °C when a solution of 2-aminopy(at)(at)idine-3-carboxaldehyde (10.0 g, 82.0 mmol) in THF (150 mL) was added dropwise via a pressure equalizing addition funnel over -45 with vigorous stirring (exotherm observed, orange color persisted). Upon complete addition, the solution was allowed to stir for 1 hour at -78 °C, at which time TLC (KMn04 stain with heat) indicated that most of the starting material had been converted to product. The reaction was quenched very carefully with water (200 mL; dropwise initially), diluted with EtOAc (200 mL) and allowed to warm to rt. The layers were separated and the aqueous layer was extracted with 3% MeOH in EtOAc, The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Analogix; 0 to 5% MeOH in EtOAc) to give 7.78 g (68%) of the desired racemic product as a yellow oil that solidified under high vac over several days. This material was separated into its respective enantiomers (>98% ee) by SFC with a chiralcel OD-H (20x250mm) column (10% EtOH/'0.1% isopropylamine in heptane/O.I % isopropylamine), Scheme D: 1,1-Dimethylethyl [(1 S)-I-( {4-[ 1 -(ethylo.xy)ethenyl]phenyl ) methj,1)-3 - hydroxypropyl]carbamate: [00398] To a solution of 1,1-dimethylethyl {(1 S)-l-[ (4-bromophenyl)methyl)-3- hydroxypropyl tcarbamate (20 g, 58 mmol) in dioxane (500 mL) was added tributyl[l- (ethyloxy)ethenyl]stannane (39 mL, 116 mmol) and PdCh(PPh3)z. The resulting solution was heated at 100 °C for 5 h. The reaction was then concentrated and the residue purified by flash chromatography (47.5% EtOAc, 47.5% hexanes, 5% triethylamine) to give 15 g (77%) of 1,1- dimethylethyl [( I S(at)- 1 -( (4- [ 1 -(ethyloxy )ethenyl ] phenyl ) inethyl)-3 -hj/droxjpropj/I] carbamate as a brown solid. 1,1 -Dimethylethyl ((1S)-1-[4-(bromoacetyl)phenyl]methyl -3-hydroxypropyl)carbamate: [00399] To a cooled (0 °C) solution of 1,1-dimethylethyl [(1S)-1-({4-[1- (ethyloxy)ethenyl]phenyl J methyl)-3-hydroxypropyl]carbamate (IS g, 44 mmol) in tetrahydrofuran (450 mL) and water (150 mL) was added N-bromosuccinamide. The resulting solution was allowed to wann to room temperature and maintained for 90 minutes. The reaction was then concentrated and diluted with ethyl acetate (1 L). The resulting solution was washed with water (1 L) and brine (500 mL), dried (MgSO(at)) and concentrated to give 19.5 g ((at)100%) of l,l-dimethylethyl «1S)-1-[4-(bromoacetyl)phenyl]methyl}-3- hydroxypropyl)carbamate as a slightly yellow solid. ESMS [M+H]+: 386.2. 1,1 -Dimethylethyl [(1S)-3-hydroxy-1-({4-[8-(1-hydrotyethyl)imidazo[1,2-a]p5n-idin-2- yl]phenyl } methyl)propyl] carbamate [00400] A mixture of 1,1-dimethylethyl (( I §- 1 - ([4-(bromoacetyl)phenyl]methyl ) -3- hydroxypropyl) carbamate (1.00 g, 2.59 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.358 g, 2.59 mmol), and solid sodium bicarbonate (0.272 g, 3.24 mmol) in isopropanol (25 mL) was heated at reflux for 3.5 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried (Na2SO4), and concentrated. The resulting pale yellow solid was used in the next reaction without further purification. MS(ES+) m/e 426 [M+H] +. 3-Chloro-N [(1,5(at)-3-hydroxy-1-({4-[(at)-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2- yl ] phenyl } methyl)propyl ]-4-[ (l-methylethyl)oxy ]benzamide [00(at)101] A mixture of 1,1-dimethylethyl [(IS)-3-h(at),,droxy-l-((4-[S-(l- hydro;yethyl)iinidazo[ I ,?-a]ppidin-2-yl]phenyl )methyl)propj/I]carbamate (1.08 g, 2.54 mmol) and 4M HCI in 1,4-dioxane (8.0 mL, 32 mmol) was stirred at room temperature for 30 minutes. The reaction was concentrated to dryness,redissolved in DMF (25 mL), and to this solution was added N,N-diisopropylethylamine (1.64 g, 12.7 mmol) and pentafluorophenyl 3-chloro-4 [(1-methylethyl)oxy]benzoate (0.963 g, 2.54 mmol). The mixture was stirred for 3.0 h at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water and saturated sodium chloride, dried, (Na2S04), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2% MeOH:EtOAc) to give the title compound (0.7 g, 53%) as a pale yellow powder. MS(ES+) m/e 522 [M+H](at). Scheme E: 1,1-Dimethylethyl [(1Sj-?-(4-bromophenyl)-1-(hydro(at)ymethyl)ethyl]carbamate: [00402] To a solution of 4-bromo-N- 3;[(1,1-dimethylethyl)oxy]carbony=1(at)-L- phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0 °C was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stirred for an additional 2 h at 0 °C. The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stirred at RT for half an hour. Lithium aluminium salts crashed out of solution which were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%). ESMS [M+H]+: 331.2. 1,1-Dimethylethyl {(15)-2-(4-bromophenyl)-l-[(l,3-dioxo-l,3-dihydro-2(at)-isoindol-2- yl) methyl]ethyl} carbamate: [00403] To a solution of 1,1-dimethylethyl [(1S) -2-( 4-bromophenyl)-1- (hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0 °C was added dropwise diisopropyl azodicarboxylate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to warm to RT over 5h. The reaction was then concentrated in vacuo and product was tritarated out of solution usingl acetate (500 mL), The precipitate was filtered, washed with ethyl acetate (3 x 100 mL), and dried to afford the title product as a white solid (57%). ESMS [M+H]+: 460.4. 1,1-Dimethylethyl {(1,S)-?-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-?H isoindol- 2-yl) methyl]ethyl}carbamate: [00404] A solution of 1,1-dimethylethyl (( l s(at)-?-(4-bromophenyl)- I -[( 1 ,3 -dioxo- 1 ,3 - dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (21.7 7 mmol), 1-ethoxy(at)inyltri-n-butylin (43.5 mmol), and trans-dichlorobis(triphenylphospine)palladium(II) (5 mol%) were stirred in anhydrous dioxane (300 mL) at 100 °C for 3h. The reaction was then concentrated in vacuo and redissolved in a solution of tetrahydrofuran and water (3:1, 400mL) and treated with N- bromosuccinimide (108.8 mmol) and stirred at RT for half an hour. The reaction solution was then concentrated to dryness and redissolved in ethyl acetate (150 mL) and precipate formed upon addition of hexanes (350 mL). The precipitate was filtered and dried to afford the title product as yellow solid (71%). ESMS [M+H]+: 502.4. 1,1-Dimethylethyl [(1S(at)-2-(1,3-dioxo-1,3-dihydro-2H isoindol-2-yl)-1-({4-[S-(1- hydroxyethyl)imidazo[ 1,2-a]py(at)(at)idin-?-yl]phenyl (at) methyl)ethyl]carbamate: [00405] A mixture of 1,1-dimethylethyl{(1S)-?-{4-(bromoacetyl)phenyl]-1-[(1,3- dioxo- 1 ,3.dihj/dro-2H-isoindol.?.yl)methyl]ethj,I) carbainate j (1.90 g, 3.79 mmol), 1-(2- amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (NazSO4), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid. MS(ES+) m/e 541 [M+H]+. 3 -Chloro-iN°-[( I S(at)-2-( 1 ,3-dioxo- 1 , 3 -dihj/dro-2H-isoindol-2-yll- 1 -( (4- [8-( 1 - hydroxyethyl)imidazo[ 1,2-a] pyridin-2-yl ]phenyl } me.thyl)ethyl]-4-[( 1- methylethyl) oxy]benzamide: [00406] A mixture of 1,1-dimethylethyl [(1S(at)-2-(1,3-dioxo-1,3-dihydro-2H isoindol-2- yl)- 1 -( (4-[8-(1 -hydro;yethyl)imidazo[ 1 ,2-a]pyridin-2-yl]phenyl ) methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4M HCI in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness,redissolved in DMF (30 mL), and to this solution was added N,N-diisopropylethylamine (2.14 g, 16.55 mmol) and pentafluorophenyl 3-chloro-4 [(l-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na2S04), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS(ES+) mle 637 [M+H] +. (at)'(at)'-[(1 S(at)-2-Amino-1-( {4-[8-(1-hydroxyethyl)imidazo[ 1,2-a]pyridin-2- yl ] phenyl ) methyl)ethyl]-:(at)-chloro-4-[( 1-methylethyl)oxy]benzamide: [00407] A mixture of 3-chloro-l'(at)'-[(1S1-(at)-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yll-1- ({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1- methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57°C overnight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound(1.67 g, 100%) as a pale yellow powder. MS(ES+) m/e 507 [M+H]+. 3-Chloro-N-[(1S(at)-(at)-[(ur,N dimethylglycyl)amino]-1-({4-[8-(1-hydro?:yethyl)imidazo[1,?- a]pyuidin-2-yl]phenyl } methyl)ethyl]-4-[( 1-methylethyl)oxy]benzamide; [00408] A mixture ofN [(1,5(at)-2-amino-1-( f 4-[S-(1-hydroxyethyl)imidazo[1,2- a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.912 g, 1, (at)0 mmol), EDCI (0.69 g, 3.6 mmol), N,N diisopropylethylamine (0.466 g, 3.6 mmol), and N, N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (NazSO(at)), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH: CH2Cl2) to give the title compound ( 0.515 g, 48%) as a pale yellow solid. MS (ES+) m/e 592 [M+H]+. 1,1-Dimethylethyl {(1S(at)-?-[4-(8-bromoimidazo[1,2-a]p(at)n'idin-2-yl)phenyl]-1-[(1,3-dioxo-1,3- dihydro-2H-isoindol-2 yl) methyl]ethyl carbamate: [00409] A solution of 1,1-dimethylethyl {(1,5(at)-?-[4-(bromoacetyl)phenyl]-1-[(1,3- dioxo- 1 ,3 -dihydro-2H-isoindol-2-yl)inethyl]ethj/I ) carbamate (6.9 mmol), 3-bromo-2- pyridinamine (8.4 mmol), and sodium bicarbonate (10.4 mmol) in isopropanol (70 mL) were stirred at 80 °C for 18 h. The reaction was then cooled to RT and a precipitate formed which was filtered, washed with cold hexanes (3 x 100 mL), and dried to afford the title compound as light gray solid (72%). ESMS [M+H]+: 576.2. 1,1-Dimethylethyl ((1,5(at)-2-(1,3-dioao-1,3-dihydro-2H-isoindol-2-yl)-1-[4-(S- methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl} ethyl)carbamate: [00410] Following the procedure described above with 3-methyl-2-pyridinamine, instead of 3-bromo-2-pyridinamine, provided the title product as a light pink solid. ESMS [M+H]+: 511.0. N- {(1S'(at)-2-[4-(R-Bromoimidazo[1,2-a]pyridin-2-yl)phe.nyl]-1-[(1,3-dioxo-1,3-dihydro-?H isoindol-2-yl)methyl] ethyl ; -3-chloro-4-[( 1-methylethyl)oxy]benzamide: [00411] A solution of 1,1-dimethylethyl {(1,S(at)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2- yl)phenj,I]- I -[( 1 ,3-dio;o-1 ,3-dihj/dro-2H-I;oindol-2 y1)methyl]ethyl}carbamate (3.5 mmol) and hydrogen chloride in 1,4- dioxane (20 mL, 4.0M) stirred for Ih at RT. The reaction was concentrated to dryness and redissolved in N, N-dimethylformamide (35 mL). Added to the solution was diisopropylethylamine (10.5 mmol) and pentafluorophenyl 3-chloro-4-[(1- methylethyl)oxy]benzoate (3.8 mmol), which was stirred at RT for half an hour. The reaction was dissolved in ethyl acetate (80 mL) and washed with water (3 x 50 mL) and brine (1 x 50 mL). To the separated organic layer was added hexanes (150 mL) upon which a.precipitate was formed, filtered, and dried to afford the title compound as an off white solid (65%). ESMS [M+H]+: 672.2. 3-Chloro-(at)'(at)r ((1S1-2-(1,3-dioxo-1,3-dihydro-2H isoindol-2-yl)-1-2-a]pyridin-2-yl)phenyl]methyl } ethyl)-3-chloro-=4-[(1- inethylethyl)oxy]benzamide and N,V-dimethylglycine provided the title product as a white solid. ESMS [M+H]+: 563.2. Scheme F: 2-Bromo-1-(4-iodophenyllethanone; [00418] A solution of 1-(4-iodophenyl)ethanone (55.9 mmol) in dioxane (160 mL) was cooled to 10 °C. Bromine (1.1 equiv, 61.6 mmol) was added dropwise to the reaction mixture. After 10 min, the cooling bath was removed and the reaction mixture was stirred at room temperature. After 1.5 h, the reaction mixture was concentrated in vacuo, poured into water (100 mL), and extracted with (3 x 100 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to a tan solid (18.2 g) which was used directly in the next step. 2-(4-Iodophenj,1)-8-methylimidazo[ 1 ,2-a]pyridine: [00419] A mixture of crude 2-bromo-1-(4-iodophenyl)ethanone (18.2 g), 2-amino-3- picoline (1.1 equiv, 61.6 mmol), and sodium bicarbonate (1.3 equiv, 72.8 mmol) in isopropanol (160 mL) was heated at 80 °C for 16 h. After concentrating the reaction mixture in vacuo, water (100 mL) was added and the resultant tan slurry was filtered, rinsing with water (2 x 50 mL). The brown solid was recrystallized from hot isopropanol and further dried in vacuo to provide the title product as a brown solid (13.2 g, 71%). ESMS [M+H]+: 335.0. Scheme G: 4-(4-Bromophenyl)-N,1-dimethyl-N (methylo(at)cy)-1H-imidazole-?-carboxamide:(at) [00420] To a solution of ethyl 4-(4-bromophenyl)-1-methyl-1H imidazole-3- carboxylate (1.66 g, 5.37 7 mmol) in MeOH (38 mL) was added IN NaOH solution (19 mL). The reaction turned cloudy white and was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and pumped under high vacuum overnight to give the sodium salt of 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylic acid as a white solid. The sodium salt of 4-( 4-bromophenyl)-I-methyl-IH-imidazole-2-carboxylic acid was dissolved in anhydrous CH2Cl2 (40 mL) under nitrogen at-15°C (ice/methanol bath) and N- methylmorpholine (1.1 equiv, 5.91 mmol) was added followed by isobutyl chloroformate (1.1 equiv, 5.91 mmol). The reaction mixture was stirred at-15°C for 15 minutes and then N,O- dimethylhydroxylamine hydrochloride (1.0 equiv, 5.37 mmol) was added. The reaction was allowed to warm to room temperature and was stirred for 17 hours. The reaction was quenched with H20 (10mL). The product was extracted using EtOAc (3 x 30 mL) and the combined organic layers were washed with brine (20 mL), dried over MgS04, and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 20-100% EtOAc/hexanes) afforded the title compound as a tan solid (32%). ESMS [M+H] +: 324.2. Scheme H: 1,1 -Dimethylethyl (4R)-4-( ([(1 , -dimethylethyt)oxy]carbonyt} amino)-5-hydroxypentanoate: [00421] Triethylamine (11,49 mL, 82.4 mmol) and ethyl chloroformate (8.27 mL, 86.5 mmol) were added successively by syringe to N t-BOC-D-glutamic acid 5-te(at)°t-buty-1 ester (25 g, 82.4 mmol) in THF (588 mL) at <0 °C (ice-salt bath). After stirring in the cold bath for 40 min, solids were filtered and were washed with THF (150 mL). The filtrate was transferred to a 250-mL addition funnel and added to a solution of sodium borohydride (8.42 g, 222.5 mmol) in H20 (114 mL) at 0 °C over 1 hour. The reaction mixture was maintained at 0 °C for 1.5 h and then stirred for 16 h (0°C to room temperature). After the bulk of solvents were removed by rotary evaporation, the concentrate was quenched with ice water (50 mL) and 1 N HCI (50 mL). After extraction with EtOAc (4 x 100 mL), the extracts were washed with 100mL; 0.5 M citric acid, saturated NaHC03, H2O, and brine and concentrated in vacuo to give the title compound, which was used directly in the next step. ESMS [M+H]+ = 290.4, [2M+H]+ = 579.4. (Literature prep: J. Med. Chem, 1999,42(1), 95-108 for other isomer). 1,1-dimethylethyl (4R)-4 -( ( [( 1,1-dimethylethyl)oxyJcarbonyl ] amino)-5-iodopentanoate: [00422] To a solution of crude 1,1-dimethylethyl (4R) -4-([(1,1- dimethylethyl)oxy]carbonyl}amino)-5-hydroxypentanoate (23.8 g, 82.4 mmol), triphenylphosphine (32.42 g, 123.6 mmol) and imidazole (8.41 g, 123.6 mmol) in 515 mL anhydrous CH2Cl2 under N2 at 0°C was added iodine over 15 min portionwise. The ice bath was removed and the reaction was allowed to wann to room temperature and stirred over 30 minutes. The reaction was quenched with 200 mL H2O. The aqueous layer was extracted with diethyl ether (2 x 150 mL). The combined organic layers were washed with sat. aq. Na2SO3 solution (2 x 25 mL) and brine (25 mL), dried over MgSO(at), and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF'-, 80, 5% - 50% EtOAc/Hex) afforded the title compound as a white solid (25.34 g, 77%). ESMS [M+H]+= 400.4. 1,1-dimethylethyl (4R)-4-( ([(1 , 1 -dimethj/lethyl)oxj/]carbonyl j amino)-j-[4-(8- methylimidazo[ 1,2-a]pyridin-2-yl)phenyl]pentanoate: [00423] A flask containing zinc dust (6.0 equiv, 325 mesh, Strem) was heated with a heat gun while evacuating and filling with nitrogen (3 times). Under nitrogen, degassed DMF (14 mL) was added via syringe followed by 1,2-dibromoethane (0.35 equiv). The grey reaction mixture was stirred in an oil bath at 100°C for 15 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.25 equiv) was added to the mixture via syringe and the reaction was stirred at room temperature for 30 minutes. A solution of 1,1-dimethylethyl (4R)-4-( ( [( 1 , 1 -dimethj/lethj/I)oxy]carbonj/I ) amino)-5-iodopentanoate (2,0 g, 1.2 equiv) in degassed DMF (14 mL) was added to the reaction mixture via cannula. The flask containing the solution was rinsed with degassed DMF (4 mL) and cannulated into the reaction mixture. The reaction was stirred at room temperature for 1 hour. Then, tris(dibenzylideneacetone)dipalladium (0) (2.5 mol%), tri-o-tolylphosphine (10 mol%) and 2- (4-iodophenyll-(at)-methylimidazo[1,2-a]pyridine (1.4 g, 1.0 equiv) were added through the top all at once, The reaction mixture was stirred at room temperature for 17 hours. The reaction was diluted with EtOAc (40 mL) and filtered through CeliteNo.. The filtrate was washed with H(at)O (20 mL) and brine (20 mL), and the organic layer was dried over MgS04 and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 5-90% EtOAc/hexanes) afforded the title compound as a white solid (90%). ESMS [M+H]+ = 480.4. 1,1 -dimethylethyl (4R)-4-( [(1,1 1 -dimethylethyl)o;y]carbonyl) } amino )-5-[ 4-(1-methyl-2- [methyl(methyloxy)amino]carbonyl}-1H imidazol-4-yl)phenyl]pentanoate: [00424] Following the procedure described above using 4-(4-bromophenyl)-N,1- dimethyl-N-(methyloxy)-lH-imidazole-2-carboxamide provided the title compound as a solid (82%). ESMS [M+H]+ = 517.2. (4R)-4-[( {3-chloro-4-[(1-methylethyl)oxy]phenyl ; carbonyl)amino ]-5-[ 4-(8- methylimidazo[ 1 ,2-a]pyridin-2 -yl)phenj4] pentanoi acid: [00425] To a solution of 1, 1 -dimethylethyl (4R) -4-([(1,1- dimethylethyl)oxy]carbonyl; amino)-s-[4-(8-methylimidazo[1,2-a]p5(at)-idin-2- yl) phenyl]pentanoate (1.35 g, 2.82 mmol) in CH2Cl2 (14 mL) was added trifluoroacetic acid (10 mL) followed by triethylsilane (2.5 equiv, 7.04 nunol), The reaction was stirred for 45 minutes at room temperature and then concentrated in vacuo. DMF (35 mL) was added to the residue followed by diisopropylamine (14.7 mL, 84.51 nunol) under nitrogen. The reaction was stirred for 5 minutes and pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (1.1 equiv, 3.10 mmol) was added. The reaction was stirred for 45 minutes and then concentrated in vacuo. Ethyl acetate (50mL) was added to the residue and it was washed with H2O (30 mL). The aqueous layer was extracted with EtOAc (20 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 25-100% EtOAc/hexanes) provided the title compound as a white foamy solid (61%). ESMS [M+H]+ = 520.2. (4R)-4-[ ({3-chloro-4-[ (l-methylethyl)oxy]phenyl} carbonyl)amino ]-5-[ 4-( 1-methyl-2- [methyl(methyloxy)amino]carbonyl}-1H-imidazol-4-yl)phenyl]pentanoic acid: [00426] Following the procedure described above with 1,1-dimethylethyl (4R) -4- (;[(1,1-dimethylethyl)oay]carbonyl; amino)-5-[ 4-(1-methyl-2- [methyl(methyloxy)amino ] carbonyl } -1 H-imidazol-4-yl)pheny1]pentanoate and foregoing purification provided the title compound as a solid. ESMS [M+H]+ = 557.2. (4R)-5-[4-(2-acetyl-i -methyl-lH-imidazol-4-yl)phenjl]-4-[( (3-chloro-4-[(1 - methj4ethyl)oxy]phenjfi ) carbonj4)amino]pentanoic acid: [00427] To a solution of crude (4R)-4-[({3-chloro-4-[(1- methylethyl)oxy]phenyl} carbonyl)amino]-5- [4-( 1-methyl-2- (at)[methyl(methyloxy)amino]carbonyl;-lHimidazol-4-yl)phenyl]pentanoic acid (3.IS mmol) in anhydrous THF (16 mL) under nitrogen at 0°C was added methylmagnesium bromide (10.6 mL, 10 equiv, 3.0 M in ether) dropwise by syringe. The reaction was stirred for 30 minutes at 0°C and then carefully quenched with sat. aq. NH4CI solution (10 mL), followed by IN HCI solution (60 mL) such that the pH of the aqueous layer ~5.5. The product was extracted with EtOAc (4 x 40 mL) and the combined organic layers were dried over MgS04 and concentrated in vacuo to give the title compound, which was used directly in the next reaction. ESMS [M+H]+ = 512.4. (at)V ((1R)-4-Amino-1-[4-(S-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-4-oxobutyl)-3- dfloro-4-[j l -methylethyl)oxy]benzamide: [00=t28] To a solution of-(4Rl-4-[({3-chloro-4-[(1- methylethyl)oxy]phenyl } carbonyl)amino]-5-[4-(8-methylimidazo[ 1,2-a]pyridin-2- yl)phenyl]pentanoic acid (900 mg, 1.73 mmol) in anhydrous THF (12.4 mL) at 0°C under nitrogen was added triethylamine (242 uL, 1.73 mmol) followed by ethyl chloroformate (174 uL, 1.82 mmol). The reaction was stirred for 40 mins at 0°C and then the solids were filtered and washed with 5 mL THF. The filtrate was added to a flask containing NH40H (5 mL) at room temperature and the reaction mixture was stirred for 1 hour. The product was extracted from the reaction mixture with EtOAc (50mL). The aqueous layer was extracted with EtOAc (20 mL) and then acidified with IN HCI solution (30 mL) and re-extracted with EtOAc (10 mL). The combined organic layers were dried over MgS04 and concentrated in vacuo to give a white solid. Purification by recrystallization from hot isopropanol afforded the title compound as a white solid (90%). ESMS [M+H]+ = 519.4. u(at) ((1R)-1-[4-(2-acetyl-1-methyl-1H imidazol-4-yl)phenyl]methyl;-4-amino-4-oxobutyl)-3- chloro-4-[( 1-methylethyl)oxy]benzamide: [00429] Following the procedure described in above with (4R)-5-[4-(2-acetyl-1- methyl-1H-imidazol-4-yl)phenyl]-4-[( {3-chloro-4-[(1- methylethyl) oxy]phenyl}carbonyl)amino]pentanoic acid and purification by Gilsin reverse phase HPLC provided the title compound as a white solid. ESMS [M+H] + = 511.2. Scheme I: (3S)-4-[ 4-(2-acetyl-I-methyl-IH-imidazol-4-yl)phenyl]-3-[ ( {3-chloro-4-[(1- methylethyl)oxy]phenyl;?carbonyl)amino]butyl dimethyl phosphate: [00430] To a solution of N-((IS)-1-([4-(2-acet(at),1-1-methvl-IH-imidazol-4- yl )phenyl) methyl } -3-hydroxypropyl)-3 -chloro-4-[ (I -methylethyl)oxy]benzamide (500 mg, 1.04 mmol) in dry CH2CI2 (10 mL) under N2, was added dimethyl chlorophosphate (748 mg, 5. IS mmol) followed by DNIAP (660 mg, 5.41 mmol) at rt. After 30 min, TLC (95: 5 EtOAc/MeOH) showed -50% conversion, so an additional portion of dimethyl chlorophosphate (748 mg, 5.18 mmol) and DMAP (660 mg, 5.41 mmol) were added. After an additional 30 min, the reaction was quenched with saturated aqueous NH4CI and diluted with CH2Cl2. The aqueous layer was back-extracted with CH2Cl2 and the combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% EtOAc; isocratic on Analogix) to give 475 mg (77%) of the title compound as a pale yellow oil. LC/MS (ES) m/e 592.4 (M + H) +. Note that the product was contaminated with ~1eq of the starting dimethyl chlorophosphate/dimethyl hydrogenphosphate reagent and carried on as is. (3S)-4-[ 4-(2-acetyl-l-methyl-lH-imidazol-4-yl)phenyl]-3-[( {3-chloro-4-[(1- methylethyl)oxy]phenyl}carbonyl)amino]butyl dihydrogen phosphate: [00431] A yellow solution of (3S1-4-[4-('2-acetyl- I -methyl-1H-imidazol-4-yl)phenyl]- 3-[(i3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]butyl dimethyl phosphate (475 mg, 0.804 mmol) in 30% HBr in AcOH was placed in a pre-heated (60 ° C) bath for 10 min, then immediately allowed to cool to rt, The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DNISO (6 mL), filtered and purified by Gilson reverse phase HPLC (MeCN/H2O with 0.1% TFA). The MeCN of the clean fractions was removed under reduced pressure and the remaining aqueous solution was frozen and lyophilyzed ovemight to give 84 mg (19%) of the title compound as a yellow powder. LC/MS (ES) m/e 564.2 (M + H)+. (3S(at)-3-[( (3-chloro-4-[(1 -inethylethj/I)oxy]phenyl) carbonyl)amino]-4-[4-(8- methylimidazo[ 1,2-a] pyridin-2-yl)phenyl]butyl dihydrogen phosphate: [00432] Following the procedures described above, except substituting 3-chloro-N- (( 1 S)-3-hydroxy-l- [4-(S-methylimidazo[ 1,2-a]pyridin-2-yl)phenyl]methyl(at) propyl)-4-[( 1- methylethyl)oxy]benzamide for N ((1S1-1-[4-(2-acetyl-1-methyl-1H imidazol-4- yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide and potassium tert-butoxide for DMAP, the title compound was prepared as a white powder (35% yield). LC/MS (ES) m/e 563 (M + H)+. Scheme J: 3-Cjlano-N-[(I§-1-(j4-[8-j3,5-dimethj,1-4-iso;azolyl)imidazo[I,?-a]pyfdin-?- yl]phenyl a methyl)-3-hydroxypropyl ]-4-[( 1-methylethyl)oxy]benzamide: [00433] To a solution ofN-((1,5(at)-1- f [4-(8-bromoimidazo[1,2-a]pyridin-2- yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(l -methylethyl)oxy]benzamide (200 mg, 0.366 mmol) in dry DMF (2 mL) were added 3,5-dimethyl-isoxazole-4-boronic acid (63 mg, 0.439 mmol), tetrakistriphenylphosphine palladium(O) (21 mg, 0.018 mmol) and 2.0M aqueous K2CO3 (0.46 mL) successively at rt. The reaction mixture was purged with argon and heated to 100 °C, stirred for 22 h, cooled to rt, filtered and purified directly by reverse phase HPLC (MeCN/H2O with 0.1% TFA). The clean fractions were adjusted to pH -8 with saturated aqueous NaHC03 and extracted with 3% MeOH/EtOAc (3 X 30 mL). The extracts were dried (Na2S04), filtered and concentrated under reduced pressure to give 45 mg (22%) of the title compound as an off-white solid. LC/MS (ES) m/e 564.2 (M + H)+. Scheme K: 3-chloro-N-«IS)-1- [3-chloro-4-(8-methyIimidazo[ 1 ,2-a ]pyridin-2-yl)phenyl]methyl} -3- hydroxvpropyl)-4-[(l -methylethyl)oxy]benzamide: [00434] Following the procedures described in the literature (J. Org. Chem. 2003,68, 4215; J Org. Chem. 2002, 67, 1738; J. Am. Chem. Soc. 1972,94, 6203), as well as the procedures above, the title compound was prepared as a white solid. LC/MS (ES) m/e 526 (M + H)+. |
| 100% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 16h; | 2 [00180] To a solution of methyl 3-cyano-4-hydroxybenzoate (82 g, 463 mmol; /. Med.Chem, 2002, 45, 5769) in dimethylformamide (800 mL) was added 2-iodopropane (93 niL, 926 mmol) and potassium carbonate (190 g, 1.4 mol). The resulting mixture was heated at 500C for 16 h, at which time it was allowed to cool to room temperature. The reaction was filtered and the mother liquor diluted with 0.5 N sodium hydroxide (1 L). The resulting mixture was extracted with ether (2 x 1 L) and the organics washed with 1 N HCl (1 L) and brine (700 mL), dried (MgSO4) and concentrated to give 100 g (-100%) of methyl 3-cyano-4-[(l- methylethyl)oxy]benzoate as a yellow solid. |
| With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 12h; Inert atmosphere; | 1.6; 4 To a solution of methyl 4-hydroxy-3-iodobenzoate (12.5 g, 0.045 mol) (Description 1) in DMF (45 mL) was added sodium cyanide (0.22 g, 0.0045 mol) and copper(l) cyanide (4.48 g, 0.05 mol). The reaction mixture was then flushed with nitrogen and heated at 120°C for 24 h, cooled to RT, filtered and the filtrate poured into ethyl acetate (200 mL). The filtrate was then washed with iron(lll) chloride solution (3 x 70 mL) (prepared from iron(lll) chloride (25 g) in concentrated hydrochloric acid (42 mL) and diluted with 200 mL water). It was then washed with water, dried over sodium sulfate and concentrated to afford a brown solid (12.8 g). This materia. was then dissolved in DMF (45 mL) and treated with 2-iodopropane (24.6 g, 0.145 mol) and potassium carbonate (28.6 g, 0.207 mol) and the reaction mixture stirred under nitrogen at 90°C for 12 h. After cooling, the reaction mixture was poured into ice- water (200 mL) and extracted with ethyl acetate (3 x 70 mL). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with petroleum ether : ethyl acetate (30:1 ) to afford the title compound as a clear oil (3.7 g). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 14h; | 17.3 Step 3: Methyl 3-cyano-4-isopropoxybenzoate (85). To as stirred solution of 84 (6.2 g, 34 mmol) in DMF (25 mL) was added 2-bromopropane (6.34 g, 52 mmol) and K2CO3 (14 g, 103 mmol). The resulting reaction mixture was heated to 90° C. for 14 h. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with DCM. The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give 85 (7.0 g, 91%) as a thick oil. |
| 91% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 14h; | 6.3 Step 3: Methyl 3-cyano-4-isopropoxybenzoate (40). Step 3: Methyl 3-cyano-4-isopropoxybenzoate (40). To as stirred solution of compound 39 (6.2 g, 34 mmol) in DMF (25 mL) was added 2-bromopropane (6.34 g, 52 mmol) and K2C03 (14 g, 103 mmol) and the resulting mixture was heated to 90 °C for 14 h. After cooling to RT, the reaction mixture was diluted with water (200 mL) and extracted with DCM. The combined organic layers were dried over Na2S04, concentrated, and purified by column chromatography to give 40 (7.0 g, 91%) as a thick oil. |
| 1.6 g | With potassium carbonate In N,N-dimethyl-formamide at 80℃; | 1.B Preparation of Methyl 3-cyano-4-(propan-2-yloxy)benzoate Methyl 3-cyano-4-(propan-2-yloxy)benzoate: To a solution of methyl 3-cyano-4- hydroxybenzoate (2 g, 11.29 mmol, 1.00 equiv) in DMF (20 mL) was added potassium carbonate (4.67 g, 33.79 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80 °C. The reaction mixture was cooled. The solids were filtered out. The pH value of the solution was adjusted to 9 with sodium hydroxide (0.5 Mol/L). The resulting solution was extracted with ether (2 x 25 mL), and the organic layers were combined. HC1 (1 moL/L) was employed to adjust the pH value to 3. The resulting solution was extracted with ethyl acetate (2 x 25 mL), and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.6 g of methyl 3-cyano-4-(propan-2-yloxy)benzoate as white oil |
| With potassium carbonate In N,N-dimethyl-formamide; acetonitrile at 80℃; Large scale; | 3 50L reaction pot, add the previous step pure product (1.09kg, 6.15mol),Isopropyl bromide (lL, 10.65 mol), carbon(2. lkg, 15.19 mol), acetonitrile / N, N-dimethylformamide (5 L / 1 L) and stirred at 80 ° C overnight.After cooling to room temperature, 8L of water was added and the mixture was completely dissolved in potassium carbonate. Ethyl acetate (5 L) was added and the aqueous phase was separated. The organic phase was washed twice with water.The combined aqueous phase and ethyl acetate were extracted three times. The organic phases were combined, dried and dried to give a yellow oil (about 2.5 kg). The yield was 85% in two steps and 97.5% by HPLC | |
| With potassium carbonate In N,N-dimethyl-formamide; acetonitrile at 80℃; Large scale; | 3 3) 50L reaction kettle, add the previous step pure product (1.09kg, 6.15mol), isopropyl bromide (1L, 10.65mol),Potassium carbonate (2.1 kg, 15.19 mol) and acetonitrile / N, N-dimethylformamide (5 L / 1 L) were stirred overnight at 80 ° C. After cooling to room temperature,Water 8L was added until the potassium carbonate was completely dissolved. Ethyl acetate 5L was added to separate the aqueous phase and the organic phase was washed twice with water. The combined aqueous, BThe mixture was extracted with ethyl acetate three times. The combined organic phases were dried and dried to give a yellow oil (ca. 2.5 kg) which was directly reacted next. | |
| With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 3 Synthesis of Intermediate 36 3.6 g (20.3 mmol) of intermediate 35, 9.9 g (81.3 mmol) of 2-bromopropane and 11.2 g (81.3 mmol) of potassium carbonate were suspended in 36 ml of N,N-dimethylformamide, and reacted at 90° C. for 2 h. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was added with 30 ml of water and 30 ml of ethyl acetate, and separated into layers. The organic phase was washed with water for 3 times, dried and rotary evaporated to dryness to give a crude product (2.6 g) as a yellow oily substance. Yield: 58.1%. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: pyridine / 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran / 0 - 20 °C 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 18 h / 100 °C / Inert atmosphere |
Tags: 156001-68-2 | Methyl 3-cyano-4-hydroxybenzoate | Fluorinated Building Blocks | Aryls | Esters | Nitriles | Benzene Compounds | Phenols | Organic Building Blocks | By Structure

A380369 [406719-76-4]
Methyl 4-cyano-2-methoxybenzoate
Similarity: 0.86
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