Structure of 55289-05-9
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| CAS No. : | 55289-05-9 |
| Formula : | C9H10O3 |
| M.W : | 166.17 |
| SMILES Code : | O=C(OC)C1=CC=CC(O)=C1C |
| English Name : | Methyl 3-hydroxy-2-methylbenzoate |
| MDL No. : | MFCD09038292 |
| InChI Key : | PJSKJGYGIBLIAS-UHFFFAOYSA-N |
| Pubchem ID : | 12488879 |
| Num. heavy atoms | 12 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.22 |
| Num. rotatable bonds | 2 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 44.71 |
| TPSA ? Topological Polar Surface Area: Calculated from |
46.53 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.89 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.78 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.49 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.64 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.68 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.69 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.23 |
| Solubility | 0.979 mg/ml ; 0.00589 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.38 |
| Solubility | 0.7 mg/ml ; 0.00421 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.28 |
| Solubility | 0.876 mg/ml ; 0.00527 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 |
-6.05 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) |
1.4 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With hydrogenchloride Heating; | |
| 100% | With thionyl chloride In methanol for 1h; Reflux; | Thionyl chloride (26.2 g, 0.22 mol) was added dropwise to a solution of 3-hydroxy-2-methylbenzoic acid (20 g, 0.13 mol) in methanol (60 mL) at 0°C. The reaction was refluxed for 1 hour, and the solvent removed to give methyl ester (22.3 g, quantitative yield). The ester (22.3 mol, 0.13 mol) was dissolved in DCM (100 mL) and cooled to 0°C. Imidazole (26.5 g, 0.39 mol) and TBDMSC1 (24.2 g, 0.16 mol) were added while keeping the internal temperature between 0-5°C, and the reaction was stirred for 1 hour at 0°C. The mixture was poured into water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica chromatography (petroleum ether/ethyl acetate= 100: 1) to give TBS-protected methyl ester (47) (37.9 g, quantitative yield). A mixture of TBS -protected methyl ester (37.9 g, 0.13 mol) and NBS (26.7 g, 0.15 mol) in CC14 (200 mL) was degassed and purged with N2. AIBN (2.3 g, 14 mmol) was added and the reaction was refluxed overnight. After cooling, the precipitate was filtered and washed with CC14 (50 mL). The filtrate was concentrated, and the residue suspended in water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (52 g, quantitative yield), which was used without further purification. 1H NMR (400 MHz, CDCI3): δ 7.51 (dd, 1H), 7.23 (m, 1H), 7.00 (dd, 1H), 5.02 (s, 2H), 3.93 (s, 3H), 1.26 (s, 9H), 0.31 (s, 6H). |
| 100% | With thionyl chloride at 0℃; Reflux; | 1 Methyl 2-(bromomethyl)-3-(fe/7-butyldimethylsilyloxy)benzoate Thionyl chloride (26.2 g, 0.22 mol) was added dropwise to a solution of 3-hydroxy-2- methylbenzoic acid (20 g, 0.13 mol) in methanol (60 mL) at 0°C. The reaction was refluxed for 1 hour, and the solvent was removed to give the corresponding methyl ester (22.3 g, quantitative yield). The ester (22.3 mol, 0.13 mol) was dissolved in DCM (100 mL) and cooled to 0°C. Imidazole (26.5 g, 0.39 mol) and fert-butyldimethylsilyl chloride (TBDMSC1) (24.2 g, 0.16 mol) were added while keeping the internal temperature between 0-5°C, and the reaction was stirred for 1 hour at 0°C. The mixture was poured into water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica chromatography (100: 1 petroleum ethenEtOAc) to give TBS-protected methyl ester (Int-4) (37.9 g, quantitative yield). A mixture of Int-4 (37.9 g, 0.13 mol) and N-bromosuccinimide (NBS) (26.7 g, 0.15 mol) in CCl4 (200 mL) was degassed and purged with N2. Azobisisobutyronitrile (AIBN) (2.3 g, 14 mmol) was added and the reaction was refluxed overnight. After allowing the reaction to cool to room temperature, the precipitate was filtered and washed with CCI4 (50 mL). The filtrate was concentrated, and the residue was suspended in water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (52 g, quantitative yield), which was used without further purification. (0369) [0125] NMR (400 MHz, CDCh): d 7.51 (dd, 1H), 7.23 (m, 1H), 7.00 (dd, 1H), 5.02 (s, 2H), (0370) 3.93 (s, 3H), 1.26 (s, 9H), 0.31 (s, 6H). |
| 98% | With thionyl chloride at 50℃; | xxxiv.a Methyl 3-hydroxy-2-methylbenzoate 189 To a solution of 3-hydroxy-2-methylbenzoic acid (10.0 g, 65.7 mmol) in MeOH (100 mL) was added SOC (15.6 g, 131.5 mmol) slowly and the mixture was stirred at 50 C overnight. The reaction mixture was concentrated and the residue dissolved in DCM (100 mL). The organic solution was washed with saturated aqueous NaHCOa, dried (Na2SO.i) and concentrated to give the title compound (10.7 g, 98%) as a white solid. LCMS-C: RT 1.98 min; m/z 167.1 [M+H] |
| 98% | With sulfuric acid at 90℃; | 28.1 Step 1 : 3-Hydroxy-2-methylbenzoic acid (3.0 g, 19.7 mmol) was heated in methanol (30 ml) at 90 °C overnight in the presence of 0.5 ml H2S04. After cooling to room temperature, methanol was removed on the rotary evaporator and 1 M HC1 was added (100 ml). The aqueous phase was extracted with EtOAc (x3) and the combined organic phase was washed with brine, dried (Na2S04), filtered and concentrated to afford 3.2 g (98% yield) of methyl 3-hydroxy-2-methylbenzoate as a solid. 1H NMR (400 MHz, CDC13) d 7.39 (dd, 1H), 7.08 (t, 1H), 6.93 (d, 1H), 5.43 (s, 1H), 3.88 (s, 3H), 2.43 (s, 3H). |
| 97% | With sulfuric acid for 15 - 48h; Heating / reflux; | 15.1; 34.1 STEP 1 : A solution of 3-hydroxy-2-methylbenzoic acid (5 g, 33 mmol) and sulfuric acid (500 μl) in methanol (20 mL) was stirred at reflux for 15 hours. The reaction mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. The aqueous portion was extracted with ethyl acetate and the combined organic portion was washed with saturated sodium bicarbonate, brine, and then was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (5.46 g, 100%) of methyl 3-hydroxy-2-methylbenzoate. 1H NMR (400 MHz, DMSOd6): 9.71 (s, IH), 7.20-7.17 (m, IH), 7.11-7.07 (m, IH), 7.01-6.97 (m, IH), 3.79 (s, 3H), 2.28 (s, 3H). MS (EI) for C9Hi0O3: 166 (MH+).; STEP 1 : A solution of 3-hydroxy-2-methylbenzoic acid (5 g, 33 mmol) and concentrated sulfuric acid (3 mL) in methanol (300 mL) was stirrred at reflux for 48 hours. The mixture was cooled to room temperature and the pH was adjusted to 7 using solid sodium bicarbonate. Some methanol was evaporated and residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic portion was washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded 5.3 g, 32 mmol (97%) of methyl 3-hydroxy-2- methylbenzoate. 1H NMR (400 MHz, CDCl3): 7.41 (d, IH), 7.13-7.09 (m, IH), 6.94 (d, IH), 3.89 (s, 3H), 2.46 (s, 3H). MS (EI) for C9Hi0O3: 167 (MH+). |
| 96% | With sulfuric acid for 18h; Reflux; | |
| 95% | With thionyl chloride at 0 - 70℃; for 10h; | |
| 93% | With sulfuric acid for 6h; Reflux; | Methyl 5-hydroxy-2-methylbenzoate (10b). General procedure: A solution of 5-hydroxy-2- methylbenzoic acid(0.5 g, 3.29 mmol), concentrated sulfuric acid (27 μL,0.5 mmol) in methanol (5 mL) was refluxed for 6 h under stirring. The solventwas removed under reduced pressure. The residue was diluted with DCM (30 mL), washedwith saturated sodium bicarbonate aqueous solution, brine, dried over anhydroussodium sulfate, concentrated to give title compound as a white solid (0.43 g, 78%yield), which was used in the following step without any further purification. |
| 93% | With thionyl chloride at 0 - 70℃; for 3h; | 19 [0279] To a solution of 3-hydroxy-2-methylbenzoic acid (100.0 g, 660 mmol) in dry MeOH (700 mL) at 0 oC was added thionyl chloride (156.0 g, 1316 mmol). The reaction was heated to 70 oC for 3 hrs. The reaction was cooled to RT and the solvent was evaporated. The residue was diluted with water and extracted with EtOAc. Workup and purification with EtOAc in petroleum ether from 0% to 8% to give methyl 3-hydroxy-2- methylbenzoate (102 g, 93% yield) as a white solid. |
| 93% | With sulfuric acid for 48h; Reflux; | |
| 91% | With acetyl chloride at 0 - 20℃; for 18h; | 103 Example 103 5-(S)-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic-acid; 3-Hydroxy-2-methylbenzoic acid (0.5 g, 3.2 mmol) was dissolved in HPLC grade methanol (5 ml) and cooled to 0° C. under nitrogen. Acetyl chloride (5 ml) was added dropwise. Once the addition was complete, the ice bath was removed and the reaction mixture allowed warming to room temperature over a period of 18 hours. The reaction was complete by tlc (Rf=0.5, 1:1 ethyl acetate/hexanes) and quenched with saturated sodium bicarbonate. The reaction mixture was concentrated, diluted with dichloromethane and water and the layers separated. The aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo, which afforded 0.5 g (91%) of 3-hydroxy-2-methylbenzoic acid methyl ester as a solid.1H-NMR (CDCl3) δ 7.39 (dd, 1H, J=8.1 Hz and J=1.5 Hz), 7.09 (t, 1H, J=8.1 Hz), 6.92 (dd, 1H, J=8.1 Hz and J=1.2 Hz), 5.11 (bs, 1H), 3.87 (s, 3H), 2.43 (s, 3H).3-Hydroxy-2-methylbenzoic acid methyl ester (0.5 g, 3.01 mmol) in dichloromethane (15 ml) and N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was cooled to 0° C. under nitrogen. Chloromethyl methyl ether (0.46 ml, 6.02 mmol) was added dropwise and the reaction allowed warming to room temperature over a period of 18 hours. The reaction was judged to be 50% complete by tlc (1:2 ethyl acetate/hexanes, 12) and therefore, N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was added, the reaction mixture cooled to 0° C. and chloromethyl methyl ether (0.46 ml, 6.02 mmol) added once more. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water and the layers separated. The aqueous layer was extracted once with dichloromethane and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (20% ethyl acetate/hexanes) affording 0.44 g (69%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil.1H-NMR (CDCl3) δ 7.46 (dd, 1H, J=7.6 Hz and J=1.2 Hz), 7.21 (dd, 1H, J=8 Hz and J=1.2 Hz), 7.18 (d, 1H, J=8 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.48 (s, 3H), 2.46 (s, 3H).To a mixture of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (0.44 g, 2.09 mmol) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (0.39 g, 2.19 mmol) and 1,1'-azo bis(cyclohexane-carbonitrile) (0.051 g, 0.21 mmol). The mixture was heated at reflux for 3 hours, at which time the reaction was judged complete by tlc (1:4 ethyl acetate/hexanes). The reaction mixture was cooled to room temperature and concentrated in vacuo to a solid. The solid was recrystallized from hexane leaving 0.44 g (82%) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid.1H-NMR (CDCl3) δ 7.58 (dd, 1H, J=6.8 Hz and J=2.4 Hz), 7.33-7.29 (m, 2H), 5.30 (s, 2H), 5.07 (s, 2H), 3.94 (s, 3H), 3.52 (s, 3H).To a stirred mixture of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.24 g, 0.67 mmol) in acetonitrile (30 ml) was added N,N-diisopropylethylamine (0.16 ml, 0.93 mmol) under nitrogen. 2-Bromo-methyl-3-methoxymethoxy-benzoic acid methyl ester (0.16 g, 0.55 mmol) dissolved in acetonitrile, was added via syringe pump at a rate of 0.3 ml/hour. Once the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. Tlc analysis (1:1 ethyl acetate/hexanes) indicated the reaction to be complete. The volatiles were removed in vacuo and the resultant oil dissolved in ethyl acetate/water. The layers were separated and the aqueous layer extracted with ethyl acetate (3×). The organic layers were combined, dried (MgSO4), filtered and the solvebt evaporated in vacuo, which afforded 0.34 g (100%) of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester, which was used without further purification in the next step.1H-NMR (CDCl3) δ 7.51 (d, 1H, J=6.8 Hz), 7.42 (t, 2H, J=7.6 Hz, 7.23-7.17 (m, 5H), 5.93 (s, 2H), 5.25 (s, 2H), 4.23 (s, 2H), 4.12 (q, 1H, J=7.2 Hz), 3.94 (m, 1H), 3.85 (q, 1H, J=6.4 Hz), 3.66 (d, 1H, J=16.4 Hz), 3.50 (s, 3H), 3.48-3.46 (m, 1H), 3.20 (dd, 1H, J=14 Hz and J=6 Hz), 2.94-2.87 (m, 1H), 2.60 (m, 1H), 1.49 (s, 9H), 1.36 (d, 3H, J=6.4 Hz);LC-MS: m/z: 564.1 [M+H]+.To a solution of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.34 g, 0.60 mmol) in dichloromethane (10 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.35 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water (2×20 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:1) as eluent. The obtained residue was then subjected to chromatotron purification (1% methanol/dichloromethane) and later to another flash chromatography (20% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) to obtain 210 mg (50%) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.1H-NMR (CDCl3) δ 12.50 (s, 1H), 7.51 (dd, 1H, J=6.8 Hz and J=1.2 Hz), 7.42 (t, 2H, J=8 Hz), 7.25-7.17 (m, 5H), 5.23 (s, 2H), 4.24 (q, 2H, J=16.8 Hz), 4.08 (d, 1H, J=16.8 Hz), 4.01 (dd, 1H, J=14 Hz and J=8.8 Hz), 3.89 (d, 1H, J=17.6 Hz), 3.82 (q, 1H, J=6.8 Hz), 3.56 (q, 1H, J=6.4 Hz), 3.51 (s, 3H), 2.28 (dd, 1H, J=14 Hz and J=6.4), 2.98-2.92 (m, 1H), 2.69 (d, 1H, J=17.2), 1.56 (s, 9H), 1.54 (s, 9H), 1.38 (d, 3H, J=6.8 Hz);LC-MS: m/z: 692.5 [M+H]+.To a solution of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.16 g, 0.23 mmol) in formic acid (10% in methanol, 5 ml total) was added 10% palladium on carbon (85 mg, source: Avacado) and the reaction mixture allowed to stir at room temperature. After 6 hours, tlc (1:1 ethyl acetate/hexanes) analysis indicated reaction complete. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude product was purified via flash chromatography (gradient: 3% isopropyl alcohol/dichloromethane to 5% isopropyl alcohol/dichloromethane (in 1% increments of isopropyl alcohol)) to provide 0.11 g (82%) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.1H-NMR (CDCl3) δ 12.50 (bs, 1H), 7.48 (dd, 1H, J=7.6 Hz and J=0.8 Hz), 7.38 (t, 1H, J=8 Hz), 7.22 (dd, 1H, J=8 Hz and J=0.8 Hz); 5.24 (s, 2H), 4.50 (q, 2H, J=17.3 Hz), 4.02-3.90 (m, 2H), 3.74 (ddd, 2H, J=34 Hz, J=13.6 Hz and J=5.6 Hz), 3.49 (s, 3H), 3.24 (m, 1H), 2.97 (ddd, 1H, J=20 Hz, J=4.4 Hz and J=2.8 Hz), 2.50 (m, 1H), 1.59 (s, 9H), 1.51 (s, 9H);LC-MS: m/z: 587.8 [M+H]+.2-(tert-Butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.11 g, 0.18 mmol) was dissolved in neat trifluoroacetic acid (4 ml) and stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and the resultant solid washed with dichloromethane several times affording 100 mg (83%) of the title compound as a solid trifluoroaceatet.1H-NMR (DMSO-d6) δ 12.29 (bs, 1H), 10.13 (s, 1H), 9.29 (bs, 1H), 9.10 (bs, 1H), 7.32 (t, 1H, J=7.6 Hz), 7.17 (d, 1H, J=7.2 Hz), 7.01 (d, 1H, J=8 Hz), 4.52 (d, 1H, J=17.2 Hz), 4.40-4.22 (m, 3H), 4.05 (dd, 1H, J=14.4 Hz and J=9.6 Hz), 3.90 (bs, 1H), 3.69 (dm, 1H), 3.22 (dm, 1H), 2.80 (dm,LC-MS: m/z: 432.2 [M+H]+. |
| 91.56% | With thionyl chloride at 80℃; for 2h; | 104.1 Step 1: Slowly add thionyl chloride (15.64g, 131.45mmol) to a solution of 3-hydroxy-2-methylbenzoic acid 21a (10g, 65.73mmol) in methanol (100mL).The reaction solution was stirred at 80°C for 2 hours.The reaction solution was spin-dried to obtain a gray solid intermediate 21b (10.0g, 91.56%). |
| 91.56% | With sulfuryl dichloride at 80℃; for 2h; | 21.1 Step 1: 3-hydroxy-2-methylbenzoic acid methyl ester (intermediate 21b) To a solution of 3-hydroxy-2-methylbenzoic acid 21a (10 g, 65.73 mmol) in methanol (100 mL), dichlorothionyl (15.64 g, 131.45 mmol) was slowly added. The reaction solution was stirred at 80°C for 2 hours. The reaction solution was spin-dried to obtain a gray solid intermediate 21b (10.0 g, 91.56%). |
| 90% | With sulfuric acid for 6h; Reflux; Inert atmosphere; | |
| 88.7% | With sulfuric acid at 65℃; for 17h; Inert atmosphere; | |
| 87% | Stage #1: methanol With acetyl chloride at 0 - 20℃; for 1h; Stage #2: 3-hydroxy 2-methylbenzoic acid at 20℃; for 42h; | 73 Example 73 5-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid; Acetyl chloride (5.4 ml, 5.96 g, 76 mmol) was added dropwise to methanol (15 ml) at 0° C. in a sealed 50 ml round-bottom flask. This solution was allowed to warm to room temperature for 1 hour while stirring. To this solution 3-hydroxy-2-methyl-benzoic acid (519 mg, 3.4 mmol) was added and the solution was stirred at room temperature for 42 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and solid sodium bicarbonate. The volatiles were removed in vacuo and the basic aqueous solution was then extracted with dichloromethane (4×40 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording 493 mg (87%) of 3-hydroxy-2-methyl-benzoic acid methyl ester as a solid.1H-NMR (300 MHz, CDCl3): δ 7.43 (d, 1H, J=9 Hz), 7.12 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 5.05 (bs, 1H), 3.90 (s, 3H), 2.47 (s, 3H).To a solution of the above methyl ester (256 mg, 1.54 mmol) and N,N-diisopropylethylamine (530 μl, 3.0 mmol) in dichloromethane (8 ml) at 0° C. methyloxymethyl chloride (175 μl, 2.3 mmol) was added dropwise. The solution was allowed slowly to warm to room temperature and stired for 24 hours. The solution was diluted with dichloromethane (12 ml), washed with water (20 ml), brine (20 ml), dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (4:1) as eluent, which afforded 269 mg (85%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil.1H-NMR (300 MHz, CDCl3): δ 7.48 (d, 1H, J=8 Hz), 7.24-7.15 (m, 2H), 5.22 (s, 2H), 3.90 (s, 3H), 3.50 (s, 3H), 2.47 (s, 3H).In a 25 ml round-bottom flask, N-bromosuccinimide (236 mg, 1.3 mmol) and azobis(cyclohexanecarbonitrile) (33 mg, 0.14 mmol) were added to a solution of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (265 mg, 1.26 mmol) in carbon tetrachloride (6.5 ml). The reaction was heated to reflux with stirring for 3.5 hours. The volatiles were removed in vacuo and the residue purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (9:1) as eluent, which afforded 364 mg (100%) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid.1H-NMR (300 MHz, CDCl3): δ 7.55 (dd, 1H, J=6, 3 Hz), 7.29 (d, 2H, J=3 Hz), 5.27 (s, 2H), 5.05 (s, 2H), 3.91 (s, 3H), 3.50 (s, 3H).In a 100 ml round-bottom flask, 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (298 mg, 0.74 mmol) and N,N-diisopropylethylamine (195 μl, 1.12 mmol) were dissolved in acetonitrile (40 ml). 2-Bromomethyl-3-methoxymethoxy-benzoic acid methyl ester (193 mg, 0.67 mmol) in acetonitrile (5 ml) was slowly added to the amine solution via gastight syringe over 24 hours, followed by stirring at room temperature for an additional 36 hours. The solution was concentrated in vacuo, the residue redissolved in ethyl acetate (25 ml), and washed with saturated aqueous sodium bicarbonate (25 ml) and brine (25 ml). The organic phase was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 345 mg (81%) of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.1H-NMR (300 MHz, CDCl3): δ 7.67 (d, 1H, J=8 Hz), 7.57-7.38 (m, 5H), 7.14 (d, 2H, J=8 Hz), 6.96 (m, 2H), 6.77 (d, 2H, J=9 Hz), 6.20 (d, 2H, J=6 Hz), 5.96 (s, 2H), 4.69-2.58 (m, 17H), 1.55 (s, 9H).In a 50, ml round-bottom flask a solution of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (338 mg, 0.58 mmol) in dichloromethane (20 ml) was treated with imidazol-1-yl-oxo-acetic acid tert-butyl ester (575 mg, 2.9 mmol). After stirring for 18 hours at room temperature, the mixture was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 310 mg (75%) of 2-(tert-Butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.1H-NMR (300 MHz, CDCl3): δ 12.57 (s, 1H), 7.53 (d, 1H, J=8 Hz), 7.43 (t, 1H, J=8 Hz), 7.26 (d, 1H, J=8 Hz), 7.13 (d, 2H, J=9 Hz), 6.78 (d, 2H, J=9 Hz), 5.28 (s, 2H), 4.47 (q, 2H, J=18 Hz), 4.02-3.44 (m, 11H), 2.97 (dd, 1H, J=18 Hz and J=5 Hz), 2.76 (dd, 1H, J=17 Hz and J=5 Hz), 1.63 (s, 9H), 1.59 (s, 9H).10% Pd/C (145 mg, 50% by weight) was added to a mixture of 2-(tert-butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (283 mg, 0.40 mmol) in 10% formic acid and methanol (10 ml). After stirring at room temperature for 18 hours, more Pd/C (141 mg, 50% by weight) was added to the reaction mixture. After stirring at room temperature for an additional 20 hours, the catalyst was removed via fitration through celite. Fresh Pd/C (255 mg) and ammonium formate (1.0 g) were added to the residue (253 mg, 0.36 mmol) dissolved in 10% formic acid in methanol (10 ml). The solution was heated to 40° C. for 48 hours. Catalyst was removed via filtration through celite and liberal washing with methanol. Purification by chromatotron (ethyl acetate/triethylamine (99:1)) afforded 63 mg (27%) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A and 46 mg (19%) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester B.A: 1H-NMR (300 MHz, CDCl3): δ 12.54 (s, 1H), 7.50 (d, 1H, J=8 Hz), 7.41 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 5.27 (s, 2H), 4.52 (dd, 2H, J=30 Hz and J=19 Hz), 4.08-3.90 (m, 2H), 3.86-3.67 (m, 2H), 3.51 (s, 3H), 3.27 (m, 1H), 2.99 (dd, 1H, J=18 Hz and J=4 Hz), 2.53 (dd, 1H, J=18. Hz and J=11 Hz), 1.61 (s, 9H), 1.53 (s, 9H).LC-MS (APCI+) m/z: 588 [M+H]+; Rt=1.32 min.B: 1H-NMR (300 MHz, CDCl3): δ 12.56 (s, 1H), 7.50 (d, 1H, J=7 Hz), 7.41 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 5.27 (s, 2H), 4.50 (dd, J=28 Hz and J=18 Hz), 3.93-3.68 (m, 4H), 3.51 (s, 1H), 3.51 (s, 3H), 3.31 (m, 1H), 2.88 (dd, 1H, J=18 Hz and J=4 Hz), 2.68 (dd, 1H, J=19 Hz and J=9 Hz), 2.46 (s, 3H), 1.61 (s, 9H), 1.54 (s, 9H).LC-MS (APCI+) m/z: 602 [M+H]+; Rt=1.35 min.2-(tert-Butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A (63 mg, 0.11 mmol) was dissolved in 30% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring. After 24 hours the precipitate was filtered off and washed with diethyl ether, affording 57 mg (90%) of the title compound as a solid trifluoroacetate.1H-NMR (300 MHz, DMSO-d6): δ 12.30 (s, 1H), 10.17 (s, 1H), 9.23 (s, 2H, J=5 Hz and J=7 Hz), 7.34 (t, 1H, J=6 Hz), 7.19 (d, 1H, J=5 Hz), 7.03 (d, 1H, J=6 Hz), 5.76 (s, 2H), 4.53 (d, 1H, J=13 Hz), 4.43-4.22 (m, 3H), 4.07 (m, 1H), 3.91 (m, 1H), 3.70 (m, 1H), 3.10 (m, 1H), 2.82 (dd, 1H, J=14 Hz and J=8 Hz). |
| 87% | With sulfuric acid at 62℃; for 17h; | 1.1 3-Hydroxy-2-methyl-benzoic acid methyl ester 3-Hydroxy-2-methylbenzoic acid (105 g, 690 mmol) was added to MeOH (800 mL) in a 2 L three neck round bottom flask equipped with condenser, thermometer and stirring bar followed by the addition of MeOH (250 ml). H2SO4 (10 mL, 180 mmol) was added to above solution. The reaction mixture was stirred at 62° C. for 17 hours. The solvent was removed in vacuo. The residue (200 mL) was added to water (600 mL) slowly at room temperature and a white solid was formed. The suspension was stirred in an ice bath for 30 minutes and filtered. The solid was washed with water (5*250 mL) and dried to give 3-hydroxy-2-methyl-benzoic acid methyl ester as a white solid (100 g, 87% yield). The compound was used in the next step without further purification: LCMS MH=167; 1H NMR (DMSO-d6) δ 2.28 (s, 3H, CH3), 3.80 (s, 3H, CH3), 6.96-7.03 (m, 1H, Ar), 7.09 (t, J=7.8 Hz, 1H, Ar), 7.14-7.24 (m, 1H, Ar), 9.71 (s, 1H, OH). |
| 87% | With sulfuric acid In methanol at 62℃; for 17h; | 6.4 6.4 Preparation of 3-(4-((4-(morpholinomethyl)benzyl)- oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-Hydroxy-2-methyl-benzoic acid methyl ester 3-Hydroxy-2-methylbenzoic acid (105 g, 690 mmol) was added to MeOH (800 mL) in a 2L three neck round bottom flask equipped with condenser, thermometer and stirring bar followed by the addition of MeOH (250mL). H2S04 (10 mL, 180 mmol) was added to above solution. The reaction mixture was stirred at 62°C for 17 hours. The solvent was removed in vacuo. The residue (200 mL) was added to water (600 mL) slowly at room temperature and a white solid was formed. The suspension was stirred in an ice bath for 30 minutes and filtered. The solid was washed with water (5 x 250 mL) and dried to give 3- hydroxy-2-methyl-benzoic acid methyl ester as a white solid (100g, 87% yield). The compound was used in the next step without further purification: LCMS MH = 167; 1H NMR (DMSO-d6) δ 2.28 (s, 3H, CH3), 3.80 (s, 3H, CH3), 6.96 - 7.03 (m, 1H, Ar), 7.09 (t, J = 7.8 Hz, 1H, Ar), 7.14 - 7.24 (m, 1H, Ar), 9.71 (s, 1H, OH) |
| 87% | With sulfuric acid at 62℃; for 17h; | 6.1.1 6.1.1 3-Hydroxy-2-methyl-benzoic acid methyl ester [00145j 3-Hydroxy-2-methylbenzoic acid (105 g, 690 mmol) was added to MeOH (800 mL) in a 2L three neck round bottom flask equipped with condenser, thermometer and stirring bar followed by the addition of MeOH (250m1). H2504 (10 mL, 180 mmol) was added to above solution. The reaction mixture was stirred at 62°C for 17 hours. The solvent was removed in vacuo. The residue (200 mL) was added to water (600 mL) slowly at room temperature and a white solid was formed. The suspension was stirred in an ice bath for 30 minutes and filtered. The solid was washed with water (5 x 250 mL) and dried to give 3- hydroxy-2-methyl-benzoic acid methyl ester as a white solid (bOg, 87% yield). The compound was used in the next step without further purification: LCMS MH = 167; ‘H NMR (DMSO-d6) ö 2.28 (s, 3H, CH3), 3.80 (s, 3H, CH3), 6.96 - 7.03 (m, 1H, Ar), 7.09 (t, J= 7.8 Hz, 1H, Ar), 7.14 - 7.24 (m, 1H, Ar), 9.71 (s, 1H, OH). |
| 87% | With sulfuric acid at 62℃; for 17h; | 6.1.1 (1) 3-Hydroxy-2-methyl-benzoic acid methyl ester 3 -Hydroxy -2-methylbenzoic acid (105 g, 690 mmol) was added to MeOH (800 mL) in a 2L three neck round bottom flask equipped with condenser, thermometer and stirring bar followed by the addition of MeOH (250ml). H2SO4 (10 mL, 180 mmol) was added to above solution. The reaction mixture was stirred at 62°C for 17 hours. The solvent was removed in vacuo. The residue (200 mL) was added to water (600 mL) slowly at room temperature and a white solid was formed. The suspension was stirred in an ice bath for 30 minutes and filtered. The solid was washed with water (5 x 250 mL) and dried to give 3- hydroxy-2-methyl-benzoic acid methyl ester as a white solid (100g, 87% yield). The compound was used in the next step without further purification: LCMS MH = 167; ’H NMR (DMSO-de) 5 2.28 (s, 3H, CH3), 3.80 (s, 3H, CH3), 6.96 - 7.03 (m, 1H, Ar), 7.09 (t, J= 7.8 Hz, 1H, Ar), 7.14 - 7.24 (m, 1H, Ar), 9.71 (s, 1H, OH). |
| 87% | With sulfuric acid at 62℃; for 17h; | 6.1.1 (1) 3-Hydroxy-2-methyl-benzoic acid methyl ester 3 -Hydroxy -2-methylbenzoic acid (105 g, 690 mmol) was added to MeOH (800 mL) in a 2L three neck round bottom flask equipped with condenser, thermometer and stirring bar followed by the addition of MeOH (250ml). H2SO4 (10 mL, 180 mmol) was added to above solution. The reaction mixture was stirred at 62°C for 17 hours. The solvent was removed in vacuo. The residue (200 mL) was added to water (600 mL) slowly at room temperature and a white solid was formed. The suspension was stirred in an ice bath for 30 minutes and filtered. The solid was washed with water (5 x 250 mL) and dried to give 3- hydroxy-2-methyl-benzoic acid methyl ester as a white solid (100g, 87% yield). The compound was used in the next step without further purification: LCMS MH = 167; ’H NMR (DMSO-de) 5 2.28 (s, 3H, CH3), 3.80 (s, 3H, CH3), 6.96 - 7.03 (m, 1H, Ar), 7.09 (t, J= 7.8 Hz, 1H, Ar), 7.14 - 7.24 (m, 1H, Ar), 9.71 (s, 1H, OH). |
| 86% | With sulfuric acid at 60℃; Inert atmosphere; | 1.1 Step 1 Step 1 3-Hydroxy-2-methylbenzoic acid (250 g, 1.32 mole) was added to methanol (2500 mL, 10*) in a jacketed bottom drop three neck flask under nitrogen. Sulfuric acid (48.3 g, 0.49 mole) was added to the above solution. The mixture was heated to 60° C. and stirred for 8 to 17 hours. Once conversion was >98%, the mixture was atmospherically distilled to 3* volume. The residue was cooled to 20° C. and slowly added to water (500 mL, 2*) over at least 30 minutes. Seeds (2 g, 0.01*) were added and the mixture was agitated at 20° C. for at least 1 hour. Water (1500 mL, 6*) was added at 20° C. over at least 3 hours and the mixture was agitated at 20° C. for at least one additional hour. The solid was filtered, and washed three times with 9:1 water:methanol (500 mL, 2* each) until pH≧3. The solid was dried under vacuum at 35 to 45° C. until KF≦0.1% to give methyl 3-hydroxy-2-methylbenzoate (235.3 g, 86% yield); 1H NMR (DMSO-d6, 300 MHz) δ 9.68 (s, 1H), 7.18 (dd, J=7.5, 1.2 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 7.00 (dd, J=8.1, 1.2 Hz, 1H), 3.80 (s, 3H), 2.29 (s, 3H) ppm. |
| 86% | With thionyl chloride at 0 - 20℃; | |
| 84% | With thionyl chloride at 20 - 50℃; for 2h; | 114 Example 114 4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-ethoxy-6-methyl-3,4-dihydro-1,4-benzoxazebin-5(2H)-one To a solution of 3-hydroxy-2-methylbenzoic acid (3.80 g, 25.0 mmol) in methanol (3.0 mL) at 0° C. was added thionyl chloride (3.00 mL, 41.2 mmol) dropwise. The reaction was allowed to warm to room temperature and was then heated at 50° C. for 2 hours. The solvent was removed under vacuum and the resulting solids were dissolved in ethyl acetate and washed with NaHCO3 (sat. aq.). The ethyl acetate layer was dried over Na2SO4, filtered, and concentrated under vacuum to give methyl 3-hydroxy-2-methylbenzoate (114a, 3.49 g, 84% yield) as a light tan solid. |
| 84% | With thionyl chloride at 0 - 70℃; for 2h; | 8 Synthesis of Intermediate 9 To a solution of SMI (46 g, 0.3 mol) in MeOH (300 mL) at 0°C was added SOCh (59 g, 0.5 mol) and the mixture was heated at 70 °C for 2 h. The mixture was then concentrated to afford product 9.1 (42 g, 84%) as a brown solid. TLC: Rf= 0.65 (DCM: MeOH = 20:1, v/v, 254 nm). 'H NMR: 'H NMR (400 MHz, DMSO-r/r,) (FID No CJP- 0147-055-HNMR) 59.69 (m, 1H), 7.18 - 7.16 (m, 1H), 7.07 (t, J= 8Hz, 1H), 7.00-6.98 (m, 1H), 3.79 (s, 3H), 2.27 (s, 3H). |
| 82% | With sulfuric acid at 70℃; for 20h; | 5.1 Methyl 3-hydroxy-2-methylbenzoate (5b) 3-Hydroxy-2-methylbenzoic acid 5a (5 g, 33 mmol) was dissolved in methanol (50 mL) and concentrated sulfuric acid (980 mg, 9.9 mmol) was added. The mixture was heated to 70°C and stirred for 20 hours. After cooling to room temperature, concentrated to about 10 mL, then the residue was slowly added to cold water (100 mL), then adjusted to pH=4 with saturated sodium bicarbonate solution and stirred for 20 minutes. The precipitate was collected by filtration to give the target product 5b (4.48 g, 82%). |
| 80.4% | With sulfuric acid at 60℃; for 17h; | 1; 2 Methyl 3-hydroxy-2-methyl-benzoate Four batches (200 g each) were run in parallel. To a solution of 3-hydroxy-2-methyl-benzoic acid (200 g, 1.31 mol) in methanol (4.0 L) was added concentrated sulfuric acid (47.7 g, 486 mmol). The reaction mixture was stirred at 60 °C for 17 h. The reaction mixture was concentrated to 800 mL. The resulting mixture was cooled to 20 °C and slowly poured into water (400 mL) over 30 mins. Water (1200 mL) was added at 20 °C over 3 h and the resulting mixture was stirred at 20 °C for 1 h. The precipitated solid was collected by vacuum filtration (four batches combined) and was washed three times with water/methanol (1000 mL, 9: 1) until pH > 3. The solid was dried under vacuum at 45 °C to give methyl 3-hydroxy-2-methyl- benzoate (700 g, 80.4% yield) as a gray solid. fiT NMR: 400 MHz DMSO-ifc d: 9.70 (s, 1H), 7.18 (t, J= 6.8 Hz, 1H), 7.09 (t, J= 7.6 Hz, 1H), 7.00 (t, J= 6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H |
| 80.4% | Stage #1: methanol; 3-hydroxy 2-methylbenzoic acid With sulfuric acid at 60℃; for 17h; Stage #2: With water at 20℃; for 4.5h; | 2 Methyl 3-hydroxy-2-methyl-benzoate Methyl 3-hydroxy-2-methyl-benzoate Four batches (200 g each) were run in parallel. To a solution of 3-hydroxy-2-methyl-benzoic acid (200 g, 1.31 mol) in methanol (4.0 L) was added concentrated sulfuric acid (47.7 g, 486 mmol). The reaction mixture was stirred at 60° C. for 17 h. The reaction mixture was concentrated to 800 mL. The resulting mixture was cooled to 20° C. and slowly poured into water (400 mL) over 30 mins. Water (1200 mL) was added at 20° C. over 3 h and the resulting mixture was stirred at 20° C. for 1 h. The precipitated solid was collected by vacuum filtration (four batches combined) and was washed three times with water/methanol (1000 mL, 9:1) until pH >3. The solid was dried under vacuum at 45° C. to give methyl 3-hydroxy-2-methyl-benzoate (700 g, 80.4% yield) as a gray solid. 1H NMR: 400 MHz DMSO-d6 δ: 9.70 (s, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 7.00 (t, J=6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H). |
| With sulfuric acid | ||
| With sulfuric acid at 62℃; for 17h; | 6.1.1 6.1.1 3-Hydroxy-2-methyl-benzoic acid methyl ester 6.1.1 3-Hydroxy-2-methyl-benzoic acid methyl ester 3-Hydroxy-2-methylbenzoic acid (105 g, 690 mmol) was added to MeOH (800 mL) in a 2 L three neck round bottom flask equipped with condenser, thermometer and stirring bar followed by the addition of MeOH (250 ml). H2SO4 (10 mL, 180 mmol) was added to above solution. The reaction mixture was stirred at 62° C. for 17 hours. The solvent was removed in vacuo. The residue (200 mL) was added to water (600 mL) slowly at room temperature and a white solid was formed. The suspension was stirred in an ice bath for 30 minutes and filtered. The solid was washed with water (5*250 mL) and dried to give 3-hydroxy-2-methyl-benzoic acid methyl ester as a white solid (100 g, 87% yield). The compound was used in the next step without further purification: LCMS MH=167; 1H NMR (DMSO-d6) δ 2.28 (s, 3H, CH3), 3.80 (s, 3H, CH3), 6.96-7.03 (m, 1H, Ar), 7.09 (t, J=7.8 Hz, 1H, Ar), 7.14-7.24 (m, 1H, Ar), 9.71 (s, 1H, OH). |
|
| With sulfuric acid Inert atmosphere; Reflux; | 2.1 Synthesis of methyl 3-hydroxy-2-methylbenzoate To a 1L 3-necked round bottom flask equipped with a condenser and magnetic stirrer was added 3-Hhydroxy 2-methyl benzoic acid (15.2 g, 100 mmol) and anhydrous MeOH (400 ml). To this, 7 ml of conc. H2S04 was added and the mixtdre was refluxed overnight under argon. LCMS showed complete conversion to the product. The reaction mixture was collected and the solvent was removed under vacuum. The crude mixture was diluted with ethyl acetate. After aqueous work up and extraction with ethyl acetate, the mixture was purified using an ISCO system (120 g silica gel column, hexane:ethyl acetate solvent mixture) to give the methyl benzoate derivative (major peak, eluted with -12% EtOAc in hexane) in 84% isolated yield. ‘H NMR (400 MHz, CDC13) ö 7.57 (dd, J= 7.8, 1.0 Hz, 1H), 7.26 (t, J= 7.9 Hz, 1H). 7.10 (dd, J 8.0, 0.9 Hz, IH), 5.49 (s, IH), 4.06 (s, 3H), 2.62 (s, 3H). | |
| With thionyl chloride at 60℃; | 4.1.1. General procedure for intermediate 1 General procedure: 3-Hydroxybenzoic acid (10 mmol) and anhydrous methanol (20 mL) were added to a 100 mL dry eggplant-shaped flask. With stirring, thionyl chloride (25 mmol) was added dropwise 5-12 h at 60 °C, and the reaction progress was tracked using TLC. After the reaction completion, excess thionyl chloride was removed under reduced pressure, and the system was slowly poured into 100 mL of icewater. The mixture was extracted with ethyl acetate (30 mL 3),the combined organic layer was dried over Na2SO4, concentrated under vaccum. The crude product 1 was used in the next step without further purification. | |
| With sulfuric acid at 60℃; for 17h; | 1; 2 Methyl 3-hydroxy-2-methyl-benzoate Four batches (200 g each) were run in parallel. To a solution of 3-hydroxy-2-methyl-benzoic acid (200 g, 1.31 mol) in methanol (4.0 L) was added concentrated sulfuric acid (47.7 g, 486 mmol). The reaction mixture was stirred at 60° C. for 17 h and was concentrated to 800 mL. The resulting mixture was cooled to 20° C. and slowly poured into water (400 mL) over 30 mins. Water (1200 mL) was added at 20° C. over 3 h and the resulting mixture was stirred at 20° C. for 1 h. The precipitated solid was collected by vacuum filtration (four batches combined) and was washed three times with water/methanol (1000 mL, 9:1) or until the filtrate has pH >3. The solid was dried under vacuum at 45° C. to give methyl 3-hydroxy-2-methyl-benzoate (700 g, 80.4% yield) as a gray solid. 1H NMR: 400 MHz DMSO-d6 δ: 9.70 (s, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 7.00 (t, J=6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H). | |
| 700 g | With sulfuric acid at 60℃; for 17h; | 1 Methyl 3-hydroxy-2-methyl-benzoate Four batches (200 g each) were run in parallel. To a solution of 3-hydroxy-2-methyl-benzoic acid (200 g, 1.31 mol) in methanol (4.0 L) was added concentrated sulfuric acid (47.7 g, 486 mmol). The reaction mixture was stirred at 60° C. for 17 h. The reaction mixture was concentrated to 800 mL. The resulting mixture was cooled to 20° C. and slowly poured into water (400 mL) over 30 mins. Water (1200 mL) was added at 20° C. over 3 h and the resulting mixture was stirred at 20° C. for 1 h. The precipitated solid was collected by vacuum filtration (four batches combined) and was washed three times with water/methanol (1000 mL, 9:1) or until the filtrate had pH >3. The solid was dried under vacuum at 45° C. to give methyl 3-hydroxy-2-methyl-benzoate (700 g, 80.4% yield) as a gray solid. 1H NMR: 400 MHz DMSO-d6 δ: 9.70 (s, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 7.00 (t, J=6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H). |
| 700 g | With sulfuric acid at 60℃; for 17h; | 6.1 6.1 Methyl 3-hydroxy-2-methyl-benzoate. Four batches (200 g each) were run in parallel. To a solution of 3-hydroxy-2-methyl-benzoic acid (200 g, 1.31 mol) in methanol (4.0 L) was added concentrated sulfuric acid (47.7 g, 486 mmol). The reaction mixture was stirred at 60° C. for 17 h. The reaction mixture was concentrated to 800 mL. The resulting mixture was cooled to 20° C. and slowly poured into water (400 mL) over 30 mins. Water (1200 mL) was added at 20° C. over 3 h and the resulting mixture was stirred at 20° C. for 1 h. The precipitated solid was collected by vacuum filtration (four batches combined) and was washed three times with water/methanol (1000 mL, 9:1) or until the filtrate had pH >3. The solid was dried under vacuum at 45° C. to give methyl 3-hydroxy-2-methyl-benzoate (700 g, 80.4% yield) as a gray solid. 1H NMR: 400 MHz DMSO-d6 δ: 9.70 (s, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 7.00 (t, J=6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H). |
| 700 g | With sulfuric acid at 60℃; for 17h; | 6.1 Methyl 3-hydroxy-2-methyl-benzoate Methyl 3-hydroxy-2-methyl-benzoate Four batches (200 g each) were run in parallel. To a solution of 3-hydroxy-2-methyl-benzoic acid (200 g, 1.31 mol) in methanol (4.0 L) was added concentrated sulfuric acid (47.7 g, 486 mmol). The reaction mixture was stirred at 60° C. for 17 h. The reaction mixture was concentrated to 800 mL. The resulting mixture was cooled to 20° C. and slowly poured into water (400 mL) over 30 mins. Water (1200 mL) was added at 20° C. over 3 h and the resulting mixture was stirred at 20° C. for 1 h. The precipitated solid was collected by vacuum filtration (four batches combined) and was washed three times with water/methanol (1000 mL, 9:1) or until the filtrate had pH >3. The solid was dried under vacuum at 45° C. to give methyl 3-hydroxy-2-methyl-benzoate (700 g, 80.4% yield) as a gray solid. 1H NMR: 400 MHz DMSO-d6 δ: 9.70 (s, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 7.00 (t, J=6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H). |
| at 85 - 100℃; | 1.2; 2.2; 3; 4; 6.2; 7.2 The reaction solution is heated to 85-100°C,Atmospheric distillation to recover methanol, after recovering 1400-1600 g of methanol,Add 1200g of water, stand for stratification, separate the oil layer and collect.The water layer is extracted with 1000ml MIBK,Separate the organic layer and concentrate and combine with the oil layer,425 g of crude methyl 3-hydroxy-2-methylbenzoate was obtained (HPLC: methyl 3-hydroxy-2-methylbenzoate 42.8%, methyl 3-methoxy-2-methylbenzoate 51.4% ),Direct methylation reaction. | |
| 3.84 g | With sulfuric acid for 48h; Reflux; | 1 methyl 3-hydroxy-2-methylbenzoate (FW-279) 3.80 g (25.0 mmol) 3-hydroxy-2-methylbenzoic acid was dissolved in 50 ml of dry MeOH and five drops of cone. H2SO4 were added. Refluxing over 48 h led to complete conversion. After cooling to ambient temperature, the solvent was evaporated, sat. aq. NaHCO3was added to the residue and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and volatiles were evaporated. Yield: 3.84 g (23.1 mmol, 92 %) of an amorphic solid.1H NMR (200 MHz, CDCI3) δ 7.41 (d, J = 7.7 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1 H), 5.48 (bs, 1H), 3.90 (s, 3H), 2.45 (s, 3H).13C NMR (50 MHz, CDCI3) δ 168.91 , 154.55, 131.88, 126.30, 125.69, 122.71, 118.60, 52.22, 12.72. |
| 3.84 g | With sulfuric acid for 48h; Reflux; | 1 methyl 3-hydroxy-2-methylbenzoate (FW-279) 3.80 g (25.0 mmol) 3-hydroxy-2-methylbenzoic acid was dissolved in 50 ml of dry MeOH and five drops of cone. H2SO4 were added. Refluxing over 48 h led to complete conversion. After cooling to ambient temperature, the solvent was evaporated, sat. aq. NaHCO3was added to the residue and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and volatiles were evaporated. Yield: 3.84 g (23.1 mmol, 92 %) of an amorphic solid.1H NMR (200 MHz, CDCI3) δ 7.41 (d, J = 7.7 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1 H), 5.48 (bs, 1H), 3.90 (s, 3H), 2.45 (s, 3H).13C NMR (50 MHz, CDCI3) δ 168.91 , 154.55, 131.88, 126.30, 125.69, 122.71, 118.60, 52.22, 12.72. |
| 93 % | With thionyl chloride In N,N-dimethyl-formamide at 0℃; Inert atmosphere; Reflux; | 1.A Step A. Under nitrogen protection, 3-hydroxy-2-methylbenzoic acid (, 30.0 g, 197 mmol) was dissolved in anhydrous methanol (400 mL), and DMF (2 mL) and thionyl chloride (70.3 g, 591 mmol) were added dropwise at 0°C. After the dropwise addition was completed, the reaction solution was heated to reflux and reacted overnight. Then the reaction solution was cooled down to room temperature (25°C) and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (250 mL). The mixture was washed successively with saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL) and saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 3-hydroxy-2-methylbenzoate as a gray solid (30.5 g, yield: 93%). 1H NMR (CDCl3, 300 MHz): δ 7.41 (dd, J = 8.1, 1.2 Hz, 1H), 7.10 (td, J = 7.8, 0.6 Hz, 1H), 6.94 (dd, J =8.1, 1.2 Hz, 1H),5.25 (s, 1H), 3.89 (s, 3H), 2.45 (s, 3H). |
| 93 % | With thionyl chloride In N,N-dimethyl-formamide at 0℃; Inert atmosphere; Reflux; | 1.A Step A. Under nitrogen protection, 3-hydroxy-2-methylbenzoic acid (, 30.0 g, 197 mmol) was dissolved in anhydrous methanol (400 mL), and DMF (2 mL) and thionyl chloride (70.3 g, 591 mmol) were added dropwise at 0°C. After the dropwise addition was completed, the reaction solution was heated to reflux and reacted overnight. Then the reaction solution was cooled down to room temperature (25°C) and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (250 mL). The mixture was washed successively with saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL) and saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 3-hydroxy-2-methylbenzoate as a gray solid (30.5 g, yield: 93%). 1H NMR (CDCl3, 300 MHz): δ 7.41 (dd, J = 8.1, 1.2 Hz, 1H), 7.10 (td, J = 7.8, 0.6 Hz, 1H), 6.94 (dd, J =8.1, 1.2 Hz, 1H),5.25 (s, 1H), 3.89 (s, 3H), 2.45 (s, 3H). |
| 93 % | With thionyl chloride In N,N-dimethyl-formamide at 0℃; Inert atmosphere; Reflux; | 1.A Step A. Under nitrogen protection, 3-hydroxy-2-methylbenzoic acid (, 30.0 g, 197 mmol) was dissolved in anhydrous methanol (400 mL), and DMF (2 mL) and thionyl chloride (70.3 g, 591 mmol) were added dropwise at 0°C. After the dropwise addition was completed, the reaction solution was heated to reflux and reacted overnight. Then the reaction solution was cooled down to room temperature (25°C) and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (250 mL). The mixture was washed successively with saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL) and saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 3-hydroxy-2-methylbenzoate as a gray solid (30.5 g, yield: 93%). 1H NMR (CDCl3, 300 MHz): δ 7.41 (dd, J = 8.1, 1.2 Hz, 1H), 7.10 (td, J = 7.8, 0.6 Hz, 1H), 6.94 (dd, J =8.1, 1.2 Hz, 1H),5.25 (s, 1H), 3.89 (s, 3H), 2.45 (s, 3H). |
| 91.56 % | With thionyl chloride at 80℃; | 21.1 Step 1: Methyl 3-hydroxy-2-methylbenzoate (compound 21b) To a solution of 3-hydroxy-2-methylbenzoic acid (compound 21a) (10 g, 65.73 mmol) in methanol (100 mL) was slowly added thionyl dichloride (15.64 g, 131.45 mmol).The reaction solution was stirred at 80°C for 2 hours. The reaction solution was spun to dryness to obtain gray solid 21b (10.0 g, 91.56%). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94% | With bromine In dichloromethane at -45℃; for 2h; | |
| 92% | With carbon dioxide; bromine In dichloromethane; acetonitrile at 45℃; for 2h; | 114 To a solution of methyl 3-hydroxy-2-methylbenzoate (114a, 3.557 g, 21.40 mmol) in dichloromethane (100 mL) in a dry ice/acetonitrile bath (˜-45° C.) was added bromine (1.15 mL, 22.5 mmol) dropwise. The reaction was stirred at -45° C. for 2 hours before Na2S2O3 (sat. aq., 2 mL) was added. The reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The dichloromethane layer was concentrated under vacuum, and the resulting crude product was purified by column chromatography (0-40% ethyl acetate/heptane) to give methyl 6-bromo-3-hydroxy-2-methylbenzoate (114b, 4.8 g, 92% yield) as a white solid. |
| 83% | With bromine In dichloromethane at -45℃; |
| With bromine | ||
| With bromine In dichloromethane at -45℃; for 2h; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sulfuric acid; sodium nitrite | ||
| 4.27 g | With sulfuric acid; sodium nitrite In water at 20℃; for 2h; Reflux; | |
| 198 g | With sulfuric acid; water; sodium nitrite In methanol at 65 - 100℃; for 3h; | 1.5; 2.5; 3.5 5) Preparation of 2-methyl-3-hydroxybenzoic acid methyl ester: 270g of methanol was injected into the reaction flask. Methyl 2-methyl-3-aminobenzoate 193g, Turn on the stirring, slowly add 172g of sulfuric acid, and control the temperature to about 65 °C. A solution of 87 g of sodium nitrite and 155 g of water was added dropwise. After the addition was completed within 2 hours, the temperature was kept for 1 hour, and the methanol was recovered by heating to 100 ° C. 60 g of water was added and stirred for 0.5 hours, and the aqueous layer was separated into waste water to obtain an oil layer of 198 g, the content was >98%, and the yield was >95%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | With potassium carbonate In acetone Heating; | |
| With sodium hydroxide at 40℃; for 5h; | 1.6; 2.6; 3.6 Methylation: 96 g of methyl 2-methyl-3-hydroxybenzoate and 81 g of dimethyl sulfate were sequentially added to the reaction flask. 173 g of liquid caustic soda was added dropwise under controlled temperature <40 ° C for 4 hours, and the temperature was kept for 1 hour, and HPLC 2-methyl-3-hydroxybenzoic acid methyl ester <1%. Hydrolysis: 200 g of water and 84 g of 30% liquid alkali were added, and the temperature was raised to 85 ° C and stirred for 1 hr. The process controlled pH=13, otherwise the liquid base was added, and HPLC 2-methyl-3-methoxybenzoic acid methyl ester <1%. Cooled to room temperature, sodium hypochlorite 10g, hydrosulfite (sodium dithionite) 10g, activated carbon 6g, stirred for 15min, Filtered, the filtrate was 152g mass fraction of 30% sulfuric acid adjusted pH = 4 by suction filtration. The filter cake was washed three times with 50 ml of water to obtain 105 g of wet product, and the content of 82.5 g was dried at 89%. The crude product was put into a four-necked bottle and 240 g of mass fraction was 85%. The methanol was heated to reflux, kept for 1 h, slowly cooled to 30-35 ° C, and filtered to obtain a wet product. Drying 93g, content > 98%, yield > 95%; | |
| With sodium hydroxide at 30 - 40℃; for 1h; | 1.3; 2.3; 3; 4; 6.3; 7.3 (3) Methylation 100 g of crude methyl 3-hydroxy-2-methylbenzoate obtained in step (2),Add dimethyl sulfate (58.5 g, 1.8 eq.),Warm up to 30-35°C,Add 30% sodium hydroxide solution (103.0 g, 3.0 eq.) dropwise,Control the temperature not to exceed 40°C, after the addition, continue to stir for 1 hour until the reaction is complete.Set aside for stratification and separate the oil layer,After washing with water, 101 g of crude methyl 3-methoxy-2-methylbenzoate was obtained.Vacuum distillation, control vacuum degree <100Pa, gas phase temperature 106-110, collect product 75g (GC:99.6%) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With potassium carbonate In acetonitrile Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With potassium carbonate In acetonitrile Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 78% | Stage #1: 2-methyl-3-nitro-benzoic acid methyl ester With hydrogen In ethanol at 20℃; Stage #2: With sulfuric acid; sodium nitrite Heating; Further stages.; | |
| Multi-step reaction with 2 steps 1: H2 / Pd-C / aq. ethanol; 2-methoxy-ethanol 2: aq. NaNO2, H2SO4 | ||
| Multi-step reaction with 2 steps 1: palladium on activated charcoal; hydrogen / methanol / 0.5 h / 60 °C / 3750.38 Torr / Autoclave 2: sulfuric acid; sodium nitrite; water / methanol / 3 h / 65 - 100 °C |
| Multi-step reaction with 3 steps 1.1: platinum on carbon; hydrogen / methanol / 80 - 90 °C / 9750.98 - 11251.1 Torr / Autoclave 2.1: tert.-butylnitrite / 1.5 h / 10 - 60 °C 2.2: 64 - 66 °C 3.1: 85 - 100 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1.1: 92 percent / H2SO4 / Heating 2.1: H2 / Pd/C / ethanol / 20 °C 2.2: 78 percent / NaNO2; H2SO4 / Heating | ||
| Multi-step reaction with 3 steps 1.1: 98 percent / H2 / Pd/C / ethanol / 20 °C 2.1: NaNO2; H2SO4 / H2O / 0 °C 2.2: 99 percent / aq. H2SO4 / Heating 3.1: 100 percent / hydrogen chloride / Heating | ||
| Multi-step reaction with 3 steps 1: H2SO4 2: H2 / Pd-C / aq. ethanol; 2-methoxy-ethanol 3: aq. NaNO2, H2SO4 |
| Multi-step reaction with 3 steps 1: sulfuric acid / 6 h / Reflux 2: palladium on activated charcoal; hydrogen / methanol / 0.5 h / 60 °C / 3750.38 Torr / Autoclave 3: sulfuric acid; sodium nitrite; water / methanol / 3 h / 65 - 100 °C | ||
| Multi-step reaction with 3 steps 1: platinum on carbon; hydrogen / methanol / 70 - 80 °C / 7500.75 - 9750.98 Torr / Autoclave 2: nitrosylsulfuric acid / 0 - 66 °C 3: 85 - 100 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: aq. H2SO4 2: H2SO4 |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With caesium carbonate In acetone for 14h; Heating / reflux; | 2 3-[2-((2R)-4-Benzoyl-2-methyl-piperazin-1-yl)-1-methyl-2-oxo-ethoxy]-2-methyl-benzoic acid methyl ester EXAMPLE 2 3-[2-((2R)-4-Benzoyl-2-methyl-piperazin-1-yl)-1-methyl-2-oxo-ethoxy]-2-methyl-benzoic acid methyl ester Cesium carbonate (0.39 g, 1.2 mmol) was added portionwise to a solution of 1-[(2R)-4-benzoyl-2-methyl-piperazin-1-yl]-2-bromo-propan-1-one (Preparation 3) (0.41 g, 1.2 mmol) and 3-hydroxy-2-methyl-benzoic acid methyl ester (Tet Lett. (2000), 41(11), 1741) (0.2 g, 1.2 mmol) in acetone (10 ml) and the mixture heated under reflux for 14 hours. The cooled reaction mixture was evaporated to dryness under reduced pressure and the residue partitioned between dichloromethane (50 ml) and water (10 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (3*30 ml), the combined organic extracts were dried (MgSO4) and solvent evaporated under reduced pressure to afford the title compound as a white solid (0.5 g). 1H NMR (400 MHz, CDCl3): δ: 7.50-7.30 (6H, m), 7.15 (1H, m), 6.95 (1H, m), 4.95 (1H, m), 4.80-2.80 (7H, m), 3.90 (3H, s), 2.40 (3H, s), 1.65 (3H, d), 1.20 (3H, br s) ppm. LRMS (APCI+): m/z [M+H]+ 425. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With copper diacetate; triethylamine In dichloromethane at 20℃; for 48h; Molecular sieve; | 1.4.2 The 3-hydroxy-2-methylbenzoic acid methyl ester obtained in step 1 (0.20 g, 1.2 mmol) is dissolved in 5 mL of CH2C12 over powdered 4A molecular sieves. 4-tert-Butylphenylboronic acid (0.64 g, 3.6 mmol) is then added, followed by Cu (OAc) 2 (0.22 g, 1.2 mmol) and NEt3 (0.84 mL, 6.0 mmol). The reaction mixture is stirred for 48 hours at room temperature. The heterogeneous mixture is filtered and the product is purified by flash chromatography over silicagel eluting with EtOAc/hexanes (1: 3). The title compound is isolated as pale orange oil. H- 1 NMR (CDCl3) : 7.62 (1H, d), 7.30 (2H, d), 7.18 (1H, t), 7.06 (1H, d), 6. 82 (2H, d), 3.92 (3H, s), 2.48 (3H, s), 1.30 (9H, s). LC/MS m/z: (M+H) + calcd for ClsH2203 299, found 299. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | 155.a a a 3-Hydroxy-2-methylbenzoic acid methyl ester By using 3-hydroxy-2-methylbenzoic acid, the title compound was obtained by similar procedures to those of Example 3a (yield: 97%). 1H-NMR (CDCl3): δ2.46 (s, 3H), 3.89 (s, 3H), 6.94 (d, J=8.3 Hz, 1H), 7.11 (t, J=8.3 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H). | |
| 94% | With sulfuric acid In methanol for 72h; Reflux; | |
| With dichlorosulfoxide In methanol | 27.1 Step 1 Step 1 To a methanol solution (25 mL) at 0° C. was dropwise added thionyl chloride (9.6 mL, 0.13 mol). After 15 minutes, 3-hydroxy-2-methylbenzoic acid (4 g, 0.033 mol) was added and the resulting mixture was stirred at room temperature for 24 hours. Volatile was removed under vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and saturated sodium chloride solution, and was dried over sodium sulfate. After concentration, the crude product was recrystallized from dichloromethane and hexane to gave 3.48 g of methyl 3-hydroxy-2-methylbenzoate. |
| In methanol; dichlorosulfoxide; toluene | 1.ii (ii) (ii) Preparation of methyl 2-methyl-3-hydroxybenzoate. Crude 2-methyl-3-hydroxybenzoic acid (7.63 g) was dissolved in methanol (18.45 g) in a 300 ml round bottom flask and 99% thionyl chloride (9.8 g, 82 mmole) was added dropwise with stirring. The resulting homogeneous solution was heated in an oil bath for 10 minutes at 46-70°C and 65 minutes at 70-85°C bath temperature. The slowly refluxing mixture was evaporated to 8.22 g of brown oil, 1.81 g of toluene was added and the mixture was evaporated again to give methyl 2-methyl-3-hydroxybenzoate (8.15 g) as a brown solid, m.p. 66.8-73.2°C. | |
| With sulfuric acid In methanol Reflux; | 31.i To a solution of 3-hydroxy-2-methylbenzoic acid (5.05 g) in methanol (100 mL) was added conc. sulfuric acid (2 mL) and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=10:90→20:80). The object fraction was concentrated under reduced pressure. The residue was filtered with hexane to give the title compound (4.18 g) as a white powder. 1H-NMR (CDCl3) δ: 2.45 (3H, s), 3.89 (3H, s), 5.11 (1H, s), 6.93 (1H, d, J = 7.8 Hz), 7.10 (1H, t, J = 7.8 Hz), 7.41 (1H, dd, J = 1.4 Hz, 7.8 Hz) | |
| With chloro-trimethyl-silane In methanol at 20℃; for 16h; | 1.4.1 3-Hydroxy-2-methylbenzoic acid (1.0 g, 6.58 mmol) is dissolved in 40 mL of MeOH. Chlorotrimethylsilane (2.5 mL, 19.7 mmol) is added and the resulting solution is stirred for 16 hours at room temperature. The reaction mixture is concentrated under reduced pressure and the resulting residue is purified by silicagel chromatography eluting with EtOAc/hexanes (1: 1). The title compound is obtained as a pale yellow solid. LC/MS m/z : (M+H) + calcd for CgH1003 167, found 167. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | In methanol at 0 - 20℃; for 18h; | 39 5-(S)-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid 3-Hydroxy-2-methylbenzoic acid (0.5 g, 3.2 mmol) was dissolved in HPLC grade methanol (5 ml) and cooled to 0 °C under nitrogen. Acetyl chloride (5 ml) was added dropwise. Once the addition was complete, the ice bath was removed and the reaction mixture allowed warming to room temperature over a period of 18 hours. The reaction was complete by tlc (Rf=0.5,1:1 ethyl acetate/hexanes) and quenched with saturated sodium bicarbonate. The reaction mixture was concentrated, diluted with dichloromethane and water and the layers separated. The aqueous layer was extracted with dichloromethane (3x). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo, which afforded 0.5 g (91 %) of 3-hydroxy-2-methylbenzoic acid methyl ester as a solid. 1H-NMR (CDCl3) δ 7.39 (dd, 1H, J = 8.1 Hz and J = 1.5 Hz), 7.09 (t, 1H, J = 8.1 Hz), 6.92 (dd, 1H, J = 8.1 Hz and J = 1.2 Hz), 5.11 (bs, 1H), 3.87 (s, 3H), 2.43 (s, 3H). 3-Hydroxy-2-methylbenzoic acid methyl ester (0.5 g, 3.01 mmol) in dichloromethane (15 ml) and N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was cooled to 0 °C under nitrogen. Chloromethyl methyl ether (0.46 ml, 6.02 mmol) was added dropwise and the reaction allowed warming to room temperature over a period of 18 hours. The reaction was judged to be 50 % complete by tlc (1:2 ethyl acetate/hexanes, I2) and therefore, N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was added, the reaction mixture cooled to 0 °C and chloromethyl methyl ether (0.46 ml, 6.02 mmol) added once more. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water and the layers separated. The aqueous layer was extracted once with dichloromethane and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (20 % ethyl acetate/hexanes) affording 0.44 g (69 %) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil. 1H-NMR (CDCl3) δ 7.46 (dd, 1H, J = 7.6 Hz and J = 1.2 Hz), 7.21 (dd, 1H, J = 8 Hz and J = 1.2 Hz), 7.18 (d, 1H, J = 8 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.48 (s, 3H), 2.46 (s, 3H). To a mixture of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (0.44 g, 2.09 mmol) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (0.39 g, 2.19 mmol) and 1,1'-azo bis(cyclohexane-carbonitrile) (0.051 g, 0.21 mmol). The mixture was heated at reflux for 3 hours, at which time the reaction was judged complete by tlc (1:4 ethyl acetate/hexanes). The reaction mixture was cooled to room temperature and concentrated in vacuo to a solid. The solid was recrystallized from hexane leaving 0.44 g (82 %) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid. 1H-NMR (CDCl3) δ 7.58 (dd, 1H, J= 6.8 Hz and J= 2.4 Hz), 7.33-7.29 (m, 2H), 5.30 (s, 2H), 5.07 (s, 2H), 3.94 (s, 3H), 3.52 (s, 3H). To a stirred mixture of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.24 g, 0.67 mmol) in acetonitrile (30 ml) was added N,N-diisopropylethylamine (0.16 ml, 0.93 mmol) under nitrogen. 2-Bromo-methyl-3-methoxymethoxy-benzoic acid methyl ester (0.16 g, 0.55 mmol) dissolved in acetonitrile, was added via syringe pump at a rate of 0.3 ml/hour. Once the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. Tlc analysis (1:1 ethyl acetate/hexanes) indicated the reaction to be complete. The volatiles were removed in vacuo and the resultant oil dissolved in ethyl acetate/water. The layers were separated and the aqueous layer extracted with ethyl acetate (3x). The organic layers were combined, dried (MgSO4), filtered and the solvebt evaporated in vacuo, which afforded 0.34 g (100 %) of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester, which was used without further purification in the next step. 1H-NMR (CDCl3) δ 7.51 (d, 1H, J = 6.8 Hz), 7.42 (t, 2H, J = 7.6 Hz), 7.23-7.17 (m, 5H), 5.93 (s, 2H), 5.25 (s, 2H), 4.23 (s, 2H), 4.12 (q, 1H, J = 7.2 Hz), 3.94 (m, 1H), 3.85 (q, 1H, J = 6.4 Hz), 3.66 (d, 1H, J =16.4 Hz), 3.50 (s, 3H), 3.48-3.46 (m, 1H), 3.20 (dd, 1H, J = 14 Hz and J = 6 Hz), 2.94-2.87 (m, 1H), 2.60 (m, 1H), 1.49 (s, 9H), 1.36 (d, 3H, J = 6.4 Hz); LC-MS: m/z: 564.1 [M+H]+. To a solution of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.34 g, 0.60 mmol) in dichloromethane (10 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.35 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water (2 x 20 ml) and brine (2 x 25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:1) as eluent. The obtained residue was then subjected to chromatotron purification (1% methanol/dichloromethane) and later to another flash chromatography (20 % ethyl acetate/hexanes to 25 % ethyl acetate/hexanes) to obtain 210 mg (50 %) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6, 7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil. 1H-NMR (CDCl3) δ 12.50 (s, 1H), 7.51 (dd, 1H, J = 6.8 Hz and J = 1.2 Hz), 7.42 (t, 2H, J = 8 Hz), 7.25-7.17 (m, 5H), 5.23 (s, 2H), 4.24 (q, 2H, J = 16.8 Hz), 4.08 (d, 1H, J = 16.8 Hz), 4.01 (dd, 1H, J = 14 Hz and J = 8.8 Hz), 3.89 (d, 1H, J =17.6 Hz), 3.82 (q, 1H, J = 6.8 Hz), 3.56 (q, 1H, J = 6.4 Hz), 3.51 (s, 3H), 2.28 (dd, 1H, J = 14 Hz and J = 6.4), 2.98-2.92 (m, 1H), 2.69 (d, 1H, J = 17.2), 1.56 (s, 9H), 1.54 (s, 9H), 1.38 (d, 3H, J = 6.8 Hz); LC-MS: m/z: 692.5 [M+H]+. To a solution of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.16 g, 0.23 mmol) in formic acid (10 % in methanol, 5 ml total) was added 10% palladium on carbon (85 mg, source: Avacado) and the reaction mixture allowed to stir at room temperature. After 6 hours, tic (1:1 ethyl acetate/hexanes) analysis indicated reaction complete. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude product was purified via flash chromatography (gradient: 3% isopropyl alcohol/dichloromethane to 5 % isopropyl alcohol/dichloromethane (in 1% increments of isopropyl alcohol)) to provide 0.11 g (82 %) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil. 1H-NMR (CDCl3) δ 12.50 (bs, 1H), 7.48 (dd, 1H, J = 7.6 Hz and J = 0.8 Hz), 7.38 (t, 1H, J = 8 Hz), 7.22 (dd, 1H, J = 8 Hz and J = 0.8 Hz), 5.24 (s, 2H), 4.50 (q, 2H, J = 17.3 Hz), 4.02-3.90 (m, 2H), 3.74 (ddd, 2H, J = 34 Hz, J = 13.6 Hz and J = 5.6 Hz), 3.49 (s, 3H), 3.24 (m, 1H), 2.97 (ddd, 1H, J = 20 Hz, J = 4.4 Hz and J = 2.8 Hz), 2.50 (m, 1H), 1.59 (s, 9H), 1.51 (s,9H); LC-MS: m/z: 587.8 [M+H]+. 2-(tert-Butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.11 g, 0.18 mmol) was dissolved in neat trifluoroacetic acid (4 ml) and stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and the resultant solid washed with dichloromethane several times affording 100 mg (83 %) of the title compound as a solid trifluoroaceatet. 1H-NMR (DMSO-d6) δ 12.29 (bs, 1H), 10.13 (s, 1H), 9.29 (bs, 1H), 9.10 (bs, 1H), 7.32 (t, 1H, J = 7.6 Hz), 7.17 (d, 1H, J = 7.2 Hz), 7.01 (d, 1H, J = 8 Hz), 4.52 (d, 1H, J = 17.2 Hz), 4.40-4.22 (m, 3H), 4.05 (dd, 1H, J = 14.4 Hz and J = 9.6 Hz), 3.90 (bs, 1H), 3.69 (dm, 1H), 3.22 (dm, 1H), 2.80 (dm, 1H); LC-MS: m/z: 432.2 [M+H]+. |
| 87% | In methanol at 0 - 20℃; for 43h; | 8 Acetyl chloride (5.4 ml, 5.96 g, 76 mmol) was added dropwise to methanol (15 ml) at 0 °C in a sealed 50 ml round-bottom flask. This solution was allowed to warm to room temperature for 1 hour while stirring. To this solution 3-hydroxy-2-methyl-benzoic acid (519 mg, 3.4 mmol) was added and the solution was stirred at room temperature for 42 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and solid sodium bicarbonate. The volatiles were removed in vacuo and the basic aqueous solution was then extracted with dichloromethane (4 x 40 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording 493 mg (87 %) of 3-hydroxy-2-methyl-benzoic acid methyl ester as a solid. 1H-NMR (300 MHz, CDCl3): δ 7.43 (d, 1H, J = 9 Hz), 7.12 (t, 1H, J= 8 Hz), 6.95 (d, 1H, J = 8 Hz), 5.05 (bs, 1H), 3.90 (s, 3H), 2.47 (s, 3H). To a solution of the above methyl ester (256 mg, 1.54 mmol) and N,N-diisopropylethylamine (530 µl, 3.0 mmol) in dichloromethane (8 ml) at 0 °C methyloxymethyl chloride (175 µl, 2.3 mmol) was added dropwise. The solution was allowed slowly to warm to room temperature and stired for 24 hours. The solution was diluted with dichloromethane (12 ml), washed with water (20 ml), brine (20 ml), dried (MgSO4) filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (4:1) as eluent, which afforded 269 mg (85 %) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil. 1H-NMR (300 MHz, CDCl3): δ 7.48 (d, 1H, J = 8 Hz), 7.24-7.15 (m, 2H), 5.22 (s, 2H), 3.90 (s, 3H), 3.50 (s, 3H), 2.47 (s, 3H). In a 25 ml round-bottom flask, N-bromo succinimide (236 mg, 1.3 mmol) and azobis(cyclohexanecarbonitrile) (33 mg, 0.14 mmol) were added to a solution of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (265 mg, 1.26 mmol) in carbon tetrachloride (6.5 ml). The reaction was heated to reflux with stirring for 3.5 hours. The volatiles were removed in vacuo and the residue purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (9:1) as eluent, which afforded 364 mg (100 %) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid. 1H-NMR (300 MHz, CDCl3): δ 7.55 (dd, 1H, J = 6,3 Hz), 7.29 (d, 2H, J = 3 Hz), 5.27 (s, 2H), 5.05 (s, 2H), 3.91 (s, 3H), 3.50 (s, 3H). In a 100 ml round-bottom flask, 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (298 mg, 0.74 mmol) and N,N-diisopropylethylamine (195 µl, 1.12 mmol) were dissolved in acetonitrile (40 ml). 2-Bromomethyl-3-methoxymethoxy-benzoic acid methyl ester (193 mg, 0.67 mmol) in acetonitrile (5 ml) was slowly added to the amine solution via gastight syringe over 24 hours, followed by stirring at room temperature for an additional 36 hours. The solution was concentrated in vacuo, the residue redissolved in ethyl acetate (25 ml), and washed with saturated aqueous sodium bicarbonate (25 ml) and brine (25 ml). The organic phase was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 345 mg (81 %) of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid. 1H-NMR (300 MHz, CDCl3): δ 7.67 (d, 1H, J = 8 Hz), 7.57-7.38 (m, 5H), 7.14 (d, 2H, J = 8 Hz), 6.96 (m, 2H), 6.77 (d, 2H, J = 9 Hz), 6.20 (d, 2H, J = 6 Hz), 5.96 (s, 2H), 4.69-2.58 (m, 17H), 1.55 (s, 9H). In a 50 ml round-bottom flask a solution of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (338 mg, 0.58 mmol) in dichloromethane (20 ml) was treated with imidazol-1-yl-oxo-acetic acid tert-butyl ester (575 mg, 2.9 mmol). After stirring for 18 hours at room temperature, the mixture was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 310 mg (75 %) of 2-(tert-Butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid. 1H-NMR (300 MHz, CDCl3): δ 12.57 (s, 1H), 7.53 (d, 1H, J = 8 Hz), 7.43 (t, 1H, J = 8 Hz), 7.26 (d, 1H, J = 8 Hz), 7.13 (d, 2H, J = 9 Hz), 6.78 (d, 2H, J = 9 Hz), 5.28 (s, 2H), 4.47 (q, 2H, J = 18 Hz), 4.02-3.44 (m, 11H), 2.97 (dd, 1H, J = 18 Hz and J = 5 Hz), 2.76 (dd, 1H, J = 17 Hz and J = 5 Hz), 1.63 (s, 9H), 1.59 (s, 9H). 10 % Pd/C (145 mg, 50 % by weight) was added to a mixture of 2-(tert-butoxyoxalylamino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (283 mg, 0.40 mmol) in 10 % formic acid and methanol (10 ml). After stirring at room temperature for 18 hours, more Pd/C (141 mg, 50 % by weight) was added to the reaction mixture. After stirring at room temperature for an additional 20 hours, the catalyst was removed via fitration through celite. Fresh Pd/C (255 mg) and ammonium formate (1.0 g) were added to the residue (253 mg, 0.36 mmol) dissolved in 10 % formic acid in methanol (10 ml). The solution was heated to 40 °C for 48 hours. Catalyst was removed via filtration through celite and liberal washing with methanol. Purification by chromatotron (ethyl acetate/triethylamine (99:1)) afforded 63 mg (27 %) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A and 46 mg (19 %) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester B. A: 1H-NMR (300 MHz, CDCl3): δ 12.54 (s, 1H), 7.50 (d, 1H, J = 8 Hz), 7.41 (t, 1H, J = 8 Hz), 7.25 (d, 1H, J = 8 Hz), 5.27 (s, 2H), 4.52 (dd, 2H, J = 30 Hz and J = 19 Hz), 4.08-3.90 (m, 2H), 3.86-3.67 (m, 2H), 3.51 (s, 3H), 3.27 (m, 1H), 2.99 (dd, 1H, J = 18 Hz and J = 4 Hz), 2.53 (dd, 1H, J =18 Hz and J = 11 Hz), 1.61 (s, 9H), 1.53 (s, 9H). LC-MS (APCI+) m/z: 588 [M+H]+; Rt = 1.32 min.B: H-NMR (300 MHz, CDCl3): δ 12.56 (s, 1H), 7.50 (d, 1H, J = 7 Hz), 7.41 (t, 1H, J = 8 Hz), 7.25 (d, 1H, J = 8 Hz), 5.27 (s, 2H), 4.50 (dd, J = 28 Hz and J = 18 Hz), 3.93-3.68 (m, 4H), 3.51 (s, 1H), 3.51 (s, 3H), 3.31 (m, 1H), 2.88 (dd, 1H, J = 18 Hz and J = 4 Hz), 2.68 (dd, 1H, J =19 Hz and J = 9 Hz), 2.46 (s, 3H), 1.61 (s, 9H), 1.54 (s, 9H). LC-MS (APCI+) m/z: 602 [M+H]+; Rt = 1.35 min. 2-(tert-Butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A (63 mg, 0.11 mmol) was dissolved in 30 % trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring. After 24 hours the precipitate was filtered off and washed with diethyl ether, affording 57 mg (90 %) of the title compound as a solid trifluoroacetate. 1H-NMR (300 MHz, DMSO-d6): δ12.30 (s, 1H), 10.17 (s, 1H), 9.23 (s, 2H, J = 5 Hz and J = 7 Hz), 7.34 (t, 1H, J = 6 Hz), 7.19 (d, 1H, J = 5 Hz), 7.03 (d, 1H, J = 6 Hz), 5.76 (s, 2H), 4.53 (d, 1 H, J = 13 Hz), 4.43-4.22 (m, 3H), 4.07 (m, 1H), 3.91 (m, 1H), 3.70 (m, 1H), 3.10 (m, 1H), 2.82 (dd, 1H, J = 14 Hz and J = 8 Hz). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Cooling with ice; | 2.80.1 Step 1 Dissolve methyl 3-hydroxy-2-methylbenzoate (20.54g, 123.56mmol, 1.0eq) in 200mL DMF, ice bath for 15 minutes, add sodium hydride (5.93g, 148.27mmol, 1.2eq) After that, MOMCl (11.94g, 148.27mmol, 1.2eq) was added and reacted at room temperature for one hour.After the return of the reaction, saturated ammonium chloride was added to quench the reaction, extracted with ethyl acetate three times, washed with saturated ammonium chloride three times, dried, concentrated under reduced pressure, and purified by column chromatography to obtain 25.98g of yellow oil with a yield of 100%. |
| 85% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 24h; | 8 5-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid Acetyl chloride (5.4 ml, 5.96 g, 76 mmol) was added dropwise to methanol (15 ml) at 0 °C in a sealed 50 ml round-bottom flask. This solution was allowed to warm to room temperature for 1 hour while stirring. To this solution 3-hydroxy-2-methyl-benzoic acid (519 mg, 3.4 mmol) was added and the solution was stirred at room temperature for 42 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and solid sodium bicarbonate. The volatiles were removed in vacuo and the basic aqueous solution was then extracted with dichloromethane (4 x 40 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording 493 mg (87 %) of 3-hydroxy-2-methyl-benzoic acid methyl ester as a solid. 1H-NMR (300 MHz, CDCl3): δ 7.43 (d, 1H, J = 9 Hz), 7.12 (t, 1H, J= 8 Hz), 6.95 (d, 1H, J = 8 Hz), 5.05 (bs, 1H), 3.90 (s, 3H), 2.47 (s, 3H). To a solution of the above methyl ester (256 mg, 1.54 mmol) and N,N-diisopropylethylamine (530 µl, 3.0 mmol) in dichloromethane (8 ml) at 0 °C methyloxymethyl chloride (175 µl, 2.3 mmol) was added dropwise. The solution was allowed slowly to warm to room temperature and stired for 24 hours. The solution was diluted with dichloromethane (12 ml), washed with water (20 ml), brine (20 ml), dried (MgSO4) filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (4:1) as eluent, which afforded 269 mg (85 %) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil. 1H-NMR (300 MHz, CDCl3): δ 7.48 (d, 1H, J = 8 Hz), 7.24-7.15 (m, 2H), 5.22 (s, 2H), 3.90 (s, 3H), 3.50 (s, 3H), 2.47 (s, 3H). In a 25 ml round-bottom flask, N-bromo succinimide (236 mg, 1.3 mmol) and azobis(cyclohexanecarbonitrile) (33 mg, 0.14 mmol) were added to a solution of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (265 mg, 1.26 mmol) in carbon tetrachloride (6.5 ml). The reaction was heated to reflux with stirring for 3.5 hours. The volatiles were removed in vacuo and the residue purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (9:1) as eluent, which afforded 364 mg (100 %) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid. 1H-NMR (300 MHz, CDCl3): δ 7.55 (dd, 1H, J = 6,3 Hz), 7.29 (d, 2H, J = 3 Hz), 5.27 (s, 2H), 5.05 (s, 2H), 3.91 (s, 3H), 3.50 (s, 3H). In a 100 ml round-bottom flask, 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (298 mg, 0.74 mmol) and N,N-diisopropylethylamine (195 µl, 1.12 mmol) were dissolved in acetonitrile (40 ml). 2-Bromomethyl-3-methoxymethoxy-benzoic acid methyl ester (193 mg, 0.67 mmol) in acetonitrile (5 ml) was slowly added to the amine solution via gastight syringe over 24 hours, followed by stirring at room temperature for an additional 36 hours. The solution was concentrated in vacuo, the residue redissolved in ethyl acetate (25 ml), and washed with saturated aqueous sodium bicarbonate (25 ml) and brine (25 ml). The organic phase was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 345 mg (81 %) of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid. 1H-NMR (300 MHz, CDCl3): δ 7.67 (d, 1H, J = 8 Hz), 7.57-7.38 (m, 5H), 7.14 (d, 2H, J = 8 Hz), 6.96 (m, 2H), 6.77 (d, 2H, J = 9 Hz), 6.20 (d, 2H, J = 6 Hz), 5.96 (s, 2H), 4.69-2.58 (m, 17H), 1.55 (s, 9H). In a 50 ml round-bottom flask a solution of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (338 mg, 0.58 mmol) in dichloromethane (20 ml) was treated with imidazol-1-yl-oxo-acetic acid tert-butyl ester (575 mg, 2.9 mmol). After stirring for 18 hours at room temperature, the mixture was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 310 mg (75 %) of 2-(tert-Butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid. 1H-NMR (300 MHz, CDCl3): δ 12.57 (s, 1H), 7.53 (d, 1H, J = 8 Hz), 7.43 (t, 1H, J = 8 Hz), 7.26 (d, 1H, J = 8 Hz), 7.13 (d, 2H, J = 9 Hz), 6.78 (d, 2H, J = 9 Hz), 5.28 (s, 2H), 4.47 (q, 2H, J = 18 Hz), 4.02-3.44 (m, 11H), 2.97 (dd, 1H, J = 18 Hz and J = 5 Hz), 2.76 (dd, 1H, J = 17 Hz and J = 5 Hz), 1.63 (s, 9H), 1.59 (s, 9H). 10 % Pd/C (145 mg, 50 % by weight) was added to a mixture of 2-(tert-butoxyoxalylamino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (283 mg, 0.40 mmol) in 10 % formic acid and methanol (10 ml). After stirring at room temperature for 18 hours, more Pd/C (141 mg, 50 % by weight) was added to the reaction mixture. After stirring at room temperature for an additional 20 hours, the catalyst was removed via fitration through celite. Fresh Pd/C (255 mg) and ammonium formate (1.0 g) were added to the residue (253 mg, 0.36 mmol) dissolved in 10 % formic acid in methanol (10 ml). The solution was heated to 40 °C for 48 hours. Catalyst was removed via filtration through celite and liberal washing with methanol. Purification by chromatotron (ethyl acetate/triethylamine (99:1)) afforded 63 mg (27 %) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A and 46 mg (19 %) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester B. A: 1H-NMR (300 MHz, CDCl3): δ 12.54 (s, 1H), 7.50 (d, 1H, J = 8 Hz), 7.41 (t, 1H, J = 8 Hz), 7.25 (d, 1H, J = 8 Hz), 5.27 (s, 2H), 4.52 (dd, 2H, J = 30 Hz and J = 19 Hz), 4.08-3.90 (m, 2H), 3.86-3.67 (m, 2H), 3.51 (s, 3H), 3.27 (m, 1H), 2.99 (dd, 1H, J = 18 Hz and J = 4 Hz), 2.53 (dd, 1H, J =18 Hz and J = 11 Hz), 1.61 (s, 9H), 1.53 (s, 9H). LC-MS (APCI+) m/z: 588 [M+H]+; Rt = 1.32 min.B: H-NMR (300 MHz, CDCl3): δ 12.56 (s, 1H), 7.50 (d, 1H, J = 7 Hz), 7.41 (t, 1H, J = 8 Hz), 7.25 (d, 1H, J = 8 Hz), 5.27 (s, 2H), 4.50 (dd, J = 28 Hz and J = 18 Hz), 3.93-3.68 (m, 4H), 3.51 (s, 1H), 3.51 (s, 3H), 3.31 (m, 1H), 2.88 (dd, 1H, J = 18 Hz and J = 4 Hz), 2.68 (dd, 1H, J =19 Hz and J = 9 Hz), 2.46 (s, 3H), 1.61 (s, 9H), 1.54 (s, 9H). LC-MS (APCI+) m/z: 602 [M+H]+; Rt = 1.35 min. 2-(tert-Butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A (63 mg, 0.11 mmol) was dissolved in 30 % trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring. After 24 hours the precipitate was filtered off and washed with diethyl ether, affording 57 mg (90 %) of the title compound as a solid trifluoroacetate. 1H-NMR (300 MHz, DMSO-d6): δ12.30 (s, 1H), 10.17 (s, 1H), 9.23 (s, 2H, J = 5 Hz and J = 7 Hz), 7.34 (t, 1H, J = 6 Hz), 7.19 (d, 1H, J = 5 Hz), 7.03 (d, 1H, J = 6 Hz), 5.76 (s, 2H), 4.53 (d, 1 H, J = 13 Hz), 4.43-4.22 (m, 3H), 4.07 (m, 1H), 3.91 (m, 1H), 3.70 (m, 1H), 3.10 (m, 1H), 2.82 (dd, 1H, J = 14 Hz and J = 8 Hz). |
| 69% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 23h; | 39 5-(S)-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid 3-Hydroxy-2-methylbenzoic acid (0.5 g, 3.2 mmol) was dissolved in HPLC grade methanol (5 ml) and cooled to 0 °C under nitrogen. Acetyl chloride (5 ml) was added dropwise. Once the addition was complete, the ice bath was removed and the reaction mixture allowed warming to room temperature over a period of 18 hours. The reaction was complete by tlc (Rf=0.5,1:1 ethyl acetate/hexanes) and quenched with saturated sodium bicarbonate. The reaction mixture was concentrated, diluted with dichloromethane and water and the layers separated. The aqueous layer was extracted with dichloromethane (3x). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo, which afforded 0.5 g (91 %) of 3-hydroxy-2-methylbenzoic acid methyl ester as a solid. 1H-NMR (CDCl3) δ 7.39 (dd, 1H, J = 8.1 Hz and J = 1.5 Hz), 7.09 (t, 1H, J = 8.1 Hz), 6.92 (dd, 1H, J = 8.1 Hz and J = 1.2 Hz), 5.11 (bs, 1H), 3.87 (s, 3H), 2.43 (s, 3H). 3-Hydroxy-2-methylbenzoic acid methyl ester (0.5 g, 3.01 mmol) in dichloromethane (15 ml) and N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was cooled to 0 °C under nitrogen. Chloromethyl methyl ether (0.46 ml, 6.02 mmol) was added dropwise and the reaction allowed warming to room temperature over a period of 18 hours. The reaction was judged to be 50 % complete by tlc (1:2 ethyl acetate/hexanes, I2) and therefore, N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was added, the reaction mixture cooled to 0 °C and chloromethyl methyl ether (0.46 ml, 6.02 mmol) added once more. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water and the layers separated. The aqueous layer was extracted once with dichloromethane and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (20 % ethyl acetate/hexanes) affording 0.44 g (69 %) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil. 1H-NMR (CDCl3) δ 7.46 (dd, 1H, J = 7.6 Hz and J = 1.2 Hz), 7.21 (dd, 1H, J = 8 Hz and J = 1.2 Hz), 7.18 (d, 1H, J = 8 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.48 (s, 3H), 2.46 (s, 3H). To a mixture of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (0.44 g, 2.09 mmol) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (0.39 g, 2.19 mmol) and 1,1'-azo bis(cyclohexane-carbonitrile) (0.051 g, 0.21 mmol). The mixture was heated at reflux for 3 hours, at which time the reaction was judged complete by tlc (1:4 ethyl acetate/hexanes). The reaction mixture was cooled to room temperature and concentrated in vacuo to a solid. The solid was recrystallized from hexane leaving 0.44 g (82 %) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid. 1H-NMR (CDCl3) δ 7.58 (dd, 1H, J= 6.8 Hz and J= 2.4 Hz), 7.33-7.29 (m, 2H), 5.30 (s, 2H), 5.07 (s, 2H), 3.94 (s, 3H), 3.52 (s, 3H). To a stirred mixture of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.24 g, 0.67 mmol) in acetonitrile (30 ml) was added N,N-diisopropylethylamine (0.16 ml, 0.93 mmol) under nitrogen. 2-Bromo-methyl-3-methoxymethoxy-benzoic acid methyl ester (0.16 g, 0.55 mmol) dissolved in acetonitrile, was added via syringe pump at a rate of 0.3 ml/hour. Once the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. Tlc analysis (1:1 ethyl acetate/hexanes) indicated the reaction to be complete. The volatiles were removed in vacuo and the resultant oil dissolved in ethyl acetate/water. The layers were separated and the aqueous layer extracted with ethyl acetate (3x). The organic layers were combined, dried (MgSO4), filtered and the solvebt evaporated in vacuo, which afforded 0.34 g (100 %) of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester, which was used without further purification in the next step. 1H-NMR (CDCl3) δ 7.51 (d, 1H, J = 6.8 Hz), 7.42 (t, 2H, J = 7.6 Hz), 7.23-7.17 (m, 5H), 5.93 (s, 2H), 5.25 (s, 2H), 4.23 (s, 2H), 4.12 (q, 1H, J = 7.2 Hz), 3.94 (m, 1H), 3.85 (q, 1H, J = 6.4 Hz), 3.66 (d, 1H, J =16.4 Hz), 3.50 (s, 3H), 3.48-3.46 (m, 1H), 3.20 (dd, 1H, J = 14 Hz and J = 6 Hz), 2.94-2.87 (m, 1H), 2.60 (m, 1H), 1.49 (s, 9H), 1.36 (d, 3H, J = 6.4 Hz); LC-MS: m/z: 564.1 [M+H]+. To a solution of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.34 g, 0.60 mmol) in dichloromethane (10 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.35 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water (2 x 20 ml) and brine (2 x 25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:1) as eluent. The obtained residue was then subjected to chromatotron purification (1% methanol/dichloromethane) and later to another flash chromatography (20 % ethyl acetate/hexanes to 25 % ethyl acetate/hexanes) to obtain 210 mg (50 %) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6, 7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil. 1H-NMR (CDCl3) δ 12.50 (s, 1H), 7.51 (dd, 1H, J = 6.8 Hz and J = 1.2 Hz), 7.42 (t, 2H, J = 8 Hz), 7.25-7.17 (m, 5H), 5.23 (s, 2H), 4.24 (q, 2H, J = 16.8 Hz), 4.08 (d, 1H, J = 16.8 Hz), 4.01 (dd, 1H, J = 14 Hz and J = 8.8 Hz), 3.89 (d, 1H, J =17.6 Hz), 3.82 (q, 1H, J = 6.8 Hz), 3.56 (q, 1H, J = 6.4 Hz), 3.51 (s, 3H), 2.28 (dd, 1H, J = 14 Hz and J = 6.4), 2.98-2.92 (m, 1H), 2.69 (d, 1H, J = 17.2), 1.56 (s, 9H), 1.54 (s, 9H), 1.38 (d, 3H, J = 6.8 Hz); LC-MS: m/z: 692.5 [M+H]+. To a solution of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.16 g, 0.23 mmol) in formic acid (10 % in methanol, 5 ml total) was added 10% palladium on carbon (85 mg, source: Avacado) and the reaction mixture allowed to stir at room temperature. After 6 hours, tic (1:1 ethyl acetate/hexanes) analysis indicated reaction complete. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude product was purified via flash chromatography (gradient: 3% isopropyl alcohol/dichloromethane to 5 % isopropyl alcohol/dichloromethane (in 1% increments of isopropyl alcohol)) to provide 0.11 g (82 %) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil. 1H-NMR (CDCl3) δ 12.50 (bs, 1H), 7.48 (dd, 1H, J = 7.6 Hz and J = 0.8 Hz), 7.38 (t, 1H, J = 8 Hz), 7.22 (dd, 1H, J = 8 Hz and J = 0.8 Hz), 5.24 (s, 2H), 4.50 (q, 2H, J = 17.3 Hz), 4.02-3.90 (m, 2H), 3.74 (ddd, 2H, J = 34 Hz, J = 13.6 Hz and J = 5.6 Hz), 3.49 (s, 3H), 3.24 (m, 1H), 2.97 (ddd, 1H, J = 20 Hz, J = 4.4 Hz and J = 2.8 Hz), 2.50 (m, 1H), 1.59 (s, 9H), 1.51 (s,9H); LC-MS: m/z: 587.8 [M+H]+. 2-(tert-Butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.11 g, 0.18 mmol) was dissolved in neat trifluoroacetic acid (4 ml) and stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and the resultant solid washed with dichloromethane several times affording 100 mg (83 %) of the title compound as a solid trifluoroaceatet. 1H-NMR (DMSO-d6) δ 12.29 (bs, 1H), 10.13 (s, 1H), 9.29 (bs, 1H), 9.10 (bs, 1H), 7.32 (t, 1H, J = 7.6 Hz), 7.17 (d, 1H, J = 7.2 Hz), 7.01 (d, 1H, J = 8 Hz), 4.52 (d, 1H, J = 17.2 Hz), 4.40-4.22 (m, 3H), 4.05 (dd, 1H, J = 14.4 Hz and J = 9.6 Hz), 3.90 (bs, 1H), 3.69 (dm, 1H), 3.22 (dm, 1H), 2.80 (dm, 1H); LC-MS: m/z: 432.2 [M+H]+. |
| 69% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 23 - 24h; | 73; 103 Example 73 5-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid; Acetyl chloride (5.4 ml, 5.96 g, 76 mmol) was added dropwise to methanol (15 ml) at 0° C. in a sealed 50 ml round-bottom flask. This solution was allowed to warm to room temperature for 1 hour while stirring. To this solution 3-hydroxy-2-methyl-benzoic acid (519 mg, 3.4 mmol) was added and the solution was stirred at room temperature for 42 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and solid sodium bicarbonate. The volatiles were removed in vacuo and the basic aqueous solution was then extracted with dichloromethane (4×40 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording 493 mg (87%) of 3-hydroxy-2-methyl-benzoic acid methyl ester as a solid.1H-NMR (300 MHz, CDCl3): δ 7.43 (d, 1H, J=9 Hz), 7.12 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 5.05 (bs, 1H), 3.90 (s, 3H), 2.47 (s, 3H).To a solution of the above methyl ester (256 mg, 1.54 mmol) and N,N-diisopropylethylamine (530 μl, 3.0 mmol) in dichloromethane (8 ml) at 0° C. methyloxymethyl chloride (175 μl, 2.3 mmol) was added dropwise. The solution was allowed slowly to warm to room temperature and stired for 24 hours. The solution was diluted with dichloromethane (12 ml), washed with water (20 ml), brine (20 ml), dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (4:1) as eluent, which afforded 269 mg (85%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil.1H-NMR (300 MHz, CDCl3): δ 7.48 (d, 1H, J=8 Hz), 7.24-7.15 (m, 2H), 5.22 (s, 2H), 3.90 (s, 3H), 3.50 (s, 3H), 2.47 (s, 3H).In a 25 ml round-bottom flask, N-bromosuccinimide (236 mg, 1.3 mmol) and azobis(cyclohexanecarbonitrile) (33 mg, 0.14 mmol) were added to a solution of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (265 mg, 1.26 mmol) in carbon tetrachloride (6.5 ml). The reaction was heated to reflux with stirring for 3.5 hours. The volatiles were removed in vacuo and the residue purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (9:1) as eluent, which afforded 364 mg (100%) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid.1H-NMR (300 MHz, CDCl3): δ 7.55 (dd, 1H, J=6, 3 Hz), 7.29 (d, 2H, J=3 Hz), 5.27 (s, 2H), 5.05 (s, 2H), 3.91 (s, 3H), 3.50 (s, 3H).In a 100 ml round-bottom flask, 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (298 mg, 0.74 mmol) and N,N-diisopropylethylamine (195 μl, 1.12 mmol) were dissolved in acetonitrile (40 ml). 2-Bromomethyl-3-methoxymethoxy-benzoic acid methyl ester (193 mg, 0.67 mmol) in acetonitrile (5 ml) was slowly added to the amine solution via gastight syringe over 24 hours, followed by stirring at room temperature for an additional 36 hours. The solution was concentrated in vacuo, the residue redissolved in ethyl acetate (25 ml), and washed with saturated aqueous sodium bicarbonate (25 ml) and brine (25 ml). The organic phase was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 345 mg (81%) of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.1H-NMR (300 MHz, CDCl3): δ 7.67 (d, 1H, J=8 Hz), 7.57-7.38 (m, 5H), 7.14 (d, 2H, J=8 Hz), 6.96 (m, 2H), 6.77 (d, 2H, J=9 Hz), 6.20 (d, 2H, J=6 Hz), 5.96 (s, 2H), 4.69-2.58 (m, 17H), 1.55 (s, 9H).In a 50, ml round-bottom flask a solution of 2-amino-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (338 mg, 0.58 mmol) in dichloromethane (20 ml) was treated with imidazol-1-yl-oxo-acetic acid tert-butyl ester (575 mg, 2.9 mmol). After stirring for 18 hours at room temperature, the mixture was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (1:1) as eluent, which afforded 310 mg (75%) of 2-(tert-Butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.1H-NMR (300 MHz, CDCl3): δ 12.57 (s, 1H), 7.53 (d, 1H, J=8 Hz), 7.43 (t, 1H, J=8 Hz), 7.26 (d, 1H, J=8 Hz), 7.13 (d, 2H, J=9 Hz), 6.78 (d, 2H, J=9 Hz), 5.28 (s, 2H), 4.47 (q, 2H, J=18 Hz), 4.02-3.44 (m, 11H), 2.97 (dd, 1H, J=18 Hz and J=5 Hz), 2.76 (dd, 1H, J=17 Hz and J=5 Hz), 1.63 (s, 9H), 1.59 (s, 9H).10% Pd/C (145 mg, 50% by weight) was added to a mixture of 2-(tert-butoxyoxalyl-amino)-6-(4-methoxy-benzyl)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (283 mg, 0.40 mmol) in 10% formic acid and methanol (10 ml). After stirring at room temperature for 18 hours, more Pd/C (141 mg, 50% by weight) was added to the reaction mixture. After stirring at room temperature for an additional 20 hours, the catalyst was removed via fitration through celite. Fresh Pd/C (255 mg) and ammonium formate (1.0 g) were added to the residue (253 mg, 0.36 mmol) dissolved in 10% formic acid in methanol (10 ml). The solution was heated to 40° C. for 48 hours. Catalyst was removed via filtration through celite and liberal washing with methanol. Purification by chromatotron (ethyl acetate/triethylamine (99:1)) afforded 63 mg (27%) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A and 46 mg (19%) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester B.A: 1H-NMR (300 MHz, CDCl3): δ 12.54 (s, 1H), 7.50 (d, 1H, J=8 Hz), 7.41 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 5.27 (s, 2H), 4.52 (dd, 2H, J=30 Hz and J=19 Hz), 4.08-3.90 (m, 2H), 3.86-3.67 (m, 2H), 3.51 (s, 3H), 3.27 (m, 1H), 2.99 (dd, 1H, J=18 Hz and J=4 Hz), 2.53 (dd, 1H, J=18. Hz and J=11 Hz), 1.61 (s, 9H), 1.53 (s, 9H).LC-MS (APCI+) m/z: 588 [M+H]+; Rt=1.32 min.B: 1H-NMR (300 MHz, CDCl3): δ 12.56 (s, 1H), 7.50 (d, 1H, J=7 Hz), 7.41 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 5.27 (s, 2H), 4.50 (dd, J=28 Hz and J=18 Hz), 3.93-3.68 (m, 4H), 3.51 (s, 1H), 3.51 (s, 3H), 3.31 (m, 1H), 2.88 (dd, 1H, J=18 Hz and J=4 Hz), 2.68 (dd, 1H, J=19 Hz and J=9 Hz), 2.46 (s, 3H), 1.61 (s, 9H), 1.54 (s, 9H).LC-MS (APCI+) m/z: 602 [M+H]+; Rt=1.35 min.2-(tert-Butoxyoxalyl-amino)-5-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester A (63 mg, 0.11 mmol) was dissolved in 30% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring. After 24 hours the precipitate was filtered off and washed with diethyl ether, affording 57 mg (90%) of the title compound as a solid trifluoroacetate.1H-NMR (300 MHz, DMSO-d6): δ 12.30 (s, 1H), 10.17 (s, 1H), 9.23 (s, 2H, J=5 Hz and J=7 Hz), 7.34 (t, 1H, J=6 Hz), 7.19 (d, 1H, J=5 Hz), 7.03 (d, 1H, J=6 Hz), 5.76 (s, 2H), 4.53 (d, 1H, J=13 Hz), 4.43-4.22 (m, 3H), 4.07 (m, 1H), 3.91 (m, 1H), 3.70 (m, 1H), 3.10 (m, 1H), 2.82 (dd, 1H, J=14 Hz and J=8 Hz).; Example 103 5-(S)-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic-acid3-Hydroxy-2-methylbenzoic acid (0.5 g, 3.2 mmol) was dissolved in HPLC grade methanol (5 ml) and cooled to 0° C. under nitrogen. Acetyl chloride (5 ml) was added dropwise. Once the addition was complete, the ice bath was removed and the reaction mixture allowed warming to room temperature over a period of 18 hours. The reaction was complete by tlc (Rf=0.5, 1:1 ethyl acetate/hexanes) and quenched with saturated sodium bicarbonate. The reaction mixture was concentrated, diluted with dichloromethane and water and the layers separated. The aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo, which afforded 0.5 g (91%) of 3-hydroxy-2-methylbenzoic acid methyl ester as a solid.1H-NMR (CDCl3) δ 7.39 (dd, 1H, J=8.1 Hz and J=1.5 Hz), 7.09 (t, 1H, J=8.1 Hz), 6.92 (dd, 1H, J=8.1 Hz and J=1.2 Hz), 5.11 (bs, 1H), 3.87 (s, 3H), 2.43 (s, 3H).3-Hydroxy-2-methylbenzoic acid methyl ester (0.5 g, 3.01 mmol) in dichloromethane (15 ml) and N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was cooled to 0° C. under nitrogen. Chloromethyl methyl ether (0.46 ml, 6.02 mmol) was added dropwise and the reaction allowed warming to room temperature over a period of 18 hours. The reaction was judged to be 50% complete by tlc (1:2 ethyl acetate/hexanes, 12) and therefore, N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was added, the reaction mixture cooled to 0° C. and chloromethyl methyl ether (0.46 ml, 6.02 mmol) added once more. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water and the layers separated. The aqueous layer was extracted once with dichloromethane and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (20% ethyl acetate/hexanes) affording 0.44 g (69%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil.1H-NMR (CDCl3) δ 7.46 (dd, 1H, J=7.6 Hz and J=1.2 Hz), 7.21 (dd, 1H, J=8 Hz and J=1.2 Hz), 7.18 (d, 1H, J=8 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.48 (s, 3H), 2.46 (s, 3H).To a mixture of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester (0.44 g, 2.09 mmol) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (0.39 g, 2.19 mmol) and 1,1'-azo bis(cyclohexane-carbonitrile) (0.051 g, 0.21 mmol). The mixture was heated at reflux for 3 hours, at which time the reaction was judged complete by tlc (1:4 ethyl acetate/hexanes). The reaction mixture was cooled to room temperature and concentrated in vacuo to a solid. The solid was recrystallized from hexane leaving 0.44 g (82%) of 2-bromomethyl-3-methoxymethoxy-benzoic acid methyl ester as a solid.1H-NMR (CDCl3) δ 7.58 (dd, 1H, J=6.8 Hz and J=2.4 Hz), 7.33-7.29 (m, 2H), 5.30 (s, 2H), 5.07 (s, 2H), 3.94 (s, 3H), 3.52 (s, 3H).To a stirred mixture of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.24 g, 0.67 mmol) in acetonitrile (30 ml) was added N,N-diisopropylethylamine (0.16 ml, 0.93 mmol) under nitrogen. 2-Bromo-methyl-3-methoxymethoxy-benzoic acid methyl ester (0.16 g, 0.55 mmol) dissolved in acetonitrile, was added via syringe pump at a rate of 0.3 ml/hour. Once the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. Tlc analysis (1:1 ethyl acetate/hexanes) indicated the reaction to be complete. The volatiles were removed in vacuo and the resultant oil dissolved in ethyl acetate/water. The layers were separated and the aqueous layer extracted with ethyl acetate (3×). The organic layers were combined, dried (MgSO4), filtered and the solvebt evaporated in vacuo, which afforded 0.34 g (100%) of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester, which was used without further purification in the next step.1H-NMR (CDCl3) δ 7.51 (d, 1H, J=6.8 Hz), 7.42 (t, 2H, J=7.6 Hz, 7.23-7.17 (m, 5H), 5.93 (s, 2H), 5.25 (s, 2H), 4.23 (s, 2H), 4.12 (q, 1H, J=7.2 Hz), 3.94 (m, 1H), 3.85 (q, 1H, J=6.4 Hz), 3.66 (d, 1H, J=16.4 Hz), 3.50 (s, 3H), 3.48-3.46 (m, 1H), 3.20 (dd, 1H, J=14 Hz and J=6 Hz), 2.94-2.87 (m, 1H), 2.60 (m, 1H), 1.49 (s, 9H), 1.36 (d, 3H, J=6.4 Hz);LC-MS: m/z: 564.1 [M+H]+.To a solution of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.34 g, 0.60 mmol) in dichloromethane (10 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.35 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water (2×20 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:1) as eluent. The obtained residue was then subjected to chromatotron purification (1% methanol/dichloromethane) and later to another flash chromatography (20% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) to obtain 210 mg (50%) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.1H-NMR (CDCl3) δ 12.50 (s, 1H), 7.51 (dd, 1H, J=6.8 Hz and J=1.2 Hz), 7.42 (t, 2H, J=8 Hz), 7.25-7.17 (m, 5H), 5.23 (s, 2H), 4.24 (q, 2H, J=16.8 Hz), 4.08 (d, 1H, J=16.8 Hz), 4.01 (dd, 1H, J=14 Hz and J=8.8 Hz), 3.89 (d, 1H, J=17.6 Hz), 3.82 (q, 1H, J=6.8 Hz), 3.56 (q, 1H, J=6.4 Hz), 3.51 (s, 3H), 2.28 (dd, 1H, J=14 Hz and J=6.4), 2.98-2.92 (m, 1H), 2.69 (d, 1H, J=17.2), 1.56 (s, 9H), 1.54 (s, 9H), 1.38 (d, 3H, J=6.8 Hz);LC-MS: m/z: 692.5 [M+H]+.To a solution of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.16 g, 0.23 mmol) in formic acid (10% in methanol, 5 ml total) was added 10% palladium on carbon (85 mg, source: Avacado) and the reaction mixture allowed to stir at room temperature. After 6 hours, tlc (1:1 ethyl acetate/hexanes) analysis indicated reaction complete. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude product was purified via flash chromatography (gradient: 3% isopropyl alcohol/dichloromethane to 5% isopropyl alcohol/dichloromethane (in 1% increments of isopropyl alcohol)) to provide 0.11 g (82%) of 2-(tert-butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.1H-NMR (CDCl3) δ 12.50 (bs, 1H), 7.48 (dd, 1H, J=7.6 Hz and J=0.8 Hz), 7.38 (t, 1H, J=8 Hz), 7.22 (dd, 1H, J=8 Hz and J=0.8 Hz); 5.24 (s, 2H), 4.50 (q, 2H, J=17.3 Hz), 4.02-3.90 (m, 2H), 3.74 (ddd, 2H, J=34 Hz, J=13.6 Hz and J=5.6 Hz), 3.49 (s, 3H), 3.24 (m, 1H), 2.97 (ddd, 1H, J=20 Hz, J=4.4 Hz and J=2.8 Hz), 2.50 (m, 1H), 1.59 (s, 9H), 1.51 (s, 9H);LC-MS: m/z: 587.8 [M+H]+.2-(tert-Butoxyoxalyl-amino)-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.11 g, 0.18 mmol) was dissolved in neat trifluoroacetic acid (4 ml) and stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and the resultant solid washed with dichloromethane several times affording 100 mg (83%) of the title compound as a solid trifluoroaceatet.1H-NMR (DMSO-d6) δ 12.29 (bs, 1H), 10.13 (s, 1H), 9.29 (bs, 1H), 9.10 (bs, 1H), 7.32 (t, 1H, J=7.6 Hz), 7.17 (d, 1H, J=7.2 Hz), 7.01 (d, 1H, J=8 Hz), 4.52 (d, 1H, J=17.2 Hz), 4.40-4.22 (m, 3H), 4.05 (dd, 1H, J=14.4 Hz and J=9.6 Hz), 3.90 (bs, 1H), 3.69 (dm, 1H), 3.22 (dm, 1H), 2.80 (dm,LC-MS: m/z: 432.2 [M+H]+. |
| With N-ethyl-N,N-diisopropylamine In dichloromethane | 39 5-(S)-4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid 3-Hydroxy-2-methylbenzoic acid methyl ester (0.5 g, 3.01 mmol) in dichloromethane (15 ml) and N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was cooled to 0° C. under nitrogen. Chloromethyl methyl ether (0.46 ml, 6.02 mmol) was added dropwise and the reaction allowed warming to room temperature over a period of 18 hours. The reaction was judged to be 50% complete by tlc (1:2 ethyl acetate/hexanes, 12) and therefore, N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was added, the reaction mixture cooled to 0° C. and chloromethyl methyl ether (0.46 ml, 6.02 mmol) added once more. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water and the layers separated. The aqueous layer was extracted once with dichloromethane and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (20% ethyl acetate/hexanes) affording 0.44 g (69%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil. 1H-NMR (CDCl3) δ7.46 (dd, 1H, J=7.6 Hz and J=1.2 Hz), 7.21 (dd, 1H, J=8 Hz and J=1.2 Hz), 7.18 (d, 1H, J=8 Hz), 5.21 (s, 2H), 3.88 (s, 3H), 3.48 (s, 3H), 2.46 (s, 3H). | |
| With potassium carbonate In acetone at 0 - 20℃; for 6h; |


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