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[ CAS No. 603-80-5 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 603-80-5
Chemical Structure| 603-80-5
Chemical Structure| 603-80-5
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Product Details of [ 603-80-5 ]

CAS No. :603-80-5 MDL No. :MFCD00671541
Formula : C8H8O3 Boiling Point : -
Linear Structure Formula :- InChI Key :RIERSGULWXEJKL-UHFFFAOYSA-N
M.W : 152.15 Pubchem ID :252023
Synonyms :

Calculated chemistry of [ 603-80-5 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 40.39
TPSA : 57.53 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.19 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.78
Log Po/w (XLOGP3) : 1.46
Log Po/w (WLOGP) : 1.4
Log Po/w (MLOGP) : 1.32
Log Po/w (SILICOS-IT) : 1.19
Consensus Log Po/w : 1.23

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.04
Solubility : 1.39 mg/ml ; 0.0091 mol/l
Class : Soluble
Log S (Ali) : -2.27
Solubility : 0.809 mg/ml ; 0.00532 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.57
Solubility : 4.13 mg/ml ; 0.0272 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.01

Safety of [ 603-80-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 603-80-5 ]

* 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.

  • Upstream synthesis route of [ 603-80-5 ]
  • Downstream synthetic route of [ 603-80-5 ]

[ 603-80-5 ] Synthesis Path-Upstream   1~28

  • 1
  • [ 603-80-5 ]
  • [ 917-54-4 ]
  • [ 69976-81-4 ]
Reference: [1] Patent: US2012/225876, 2012, A1, . Location in patent: Page/Page column 53-54
  • 2
  • [ 603-80-5 ]
  • [ 55289-05-9 ]
Reference: [1] Patent: US2003/212094, 2003, A1,
[2] Patent: US2002/52397, 2002, A1,
[3] Patent: EP984009, 2000, A1,
[4] Patent: EP2103620, 2009, A1, . Location in patent: Page/Page column 54
[5] Patent: WO2005/77903, 2005, A2, . Location in patent: Page/Page column 48-49
  • 3
  • [ 67-56-1 ]
  • [ 603-80-5 ]
  • [ 55289-05-9 ]
YieldReaction ConditionsOperation in experiment
100% With thionyl chloride In methanol for 1 h; 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).
98% at 50℃; 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, 98percent) as a white solid. LCMS-C: RT 1.98 min; m/z 167.1 [M+H]
97% for 15 - 48 h; Heating / reflux 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, 100percent) 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 (97percent) 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+).
93% for 6 h; Reflux 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, 78percentyield), which was used in the following step without any further purification.
91% at 0 - 20℃; for 18 h; 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.x.). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo, which afforded 0.5 g (91percent) 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 50percent 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 (20percent ethyl acetate/hexanes) affording 0.44 g (69percent) 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 (82percent) 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.x.). The organic layers were combined, dried (MgSO4), filtered and the solvebt evaporated in vacuo, which afforded 0.34 g (100percent) 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 (1percent methanol/dichloromethane) and later to another flash chromatography (20percent ethyl acetate/hexanes to 25percent ethyl acetate/hexanes) to obtain 210 mg (50percent) 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 (10percent in methanol, 5 ml total) was added 10percent 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: 3percent isopropyl alcohol/dichloromethane to 5percent isopropyl alcohol/dichloromethane (in 1percent increments of isopropyl alcohol)) to provide 0.11 g (82percent) 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 (83percent) 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]+.
87%
Stage #1: at 0 - 20℃; for 1 h;
Stage #2: at 20℃; for 42 h;
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.x.40 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording 493 mg (87percent) 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 (85percent) 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 (100percent) 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 (81percent) 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 (75percent) 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).10percent Pd/C (145 mg, 50percent 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 10percent formic acid and methanol (10 ml). After stirring at room temperature for 18 hours, more Pd/C (141 mg, 50percent 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 10percent 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 (27percent) 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 (19percent) 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 30percent 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 (90percent) 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% at 62℃; for 17 h; 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, 87percent 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 17 h; 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, 87percent 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% at 62℃; for 17 h; [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, 87percent 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).
86% at 60℃; Inert atmosphere 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 >98percent, 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≦0.1percent to give methyl 3-hydroxy-2-methylbenzoate (235.3 g, 86percent 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.
84% at 20 - 50℃; for 2 h; 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, 84percent yield) as a light tan solid.

Reference: [1] Tetrahedron Letters, 2000, vol. 41, # 11, p. 1741 - 1745
[2] Patent: WO2018/85247, 2018, A1, . Location in patent: Paragraph 00338
[3] Patent: WO2016/34673, 2016, A1, . Location in patent: Page/Page column 108
[4] Patent: WO2009/55077, 2009, A1, . Location in patent: Page/Page column 385; 401
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 13, p. 3141 - 3147
[6] Patent: US7115624, 2006, B1, . Location in patent: Page/Page column 164-166
[7] Patent: US7115624, 2006, B1, . Location in patent: Page/Page column 128-130
[8] Patent: US2014/45844, 2014, A1, . Location in patent: Paragraph 0281; 0282
[9] Patent: WO2014/39960, 2014, A1, . Location in patent: Page/Page column 60; 61
[10] Patent: WO2015/179276, 2015, A1, . Location in patent: Paragraph 00145
[11] Patent: US2014/46058, 2014, A1, . Location in patent: Paragraph 0249; 0250
[12] Patent: US2014/179667, 2014, A1, . Location in patent: Paragraph 0926; 0927
[13] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2435 - 2447
[14] Patent: US2014/45843, 2014, A1, . Location in patent: Paragraph 0411
[15] Patent: WO2014/144380, 2014, A1, . Location in patent: Paragraph 0458
  • 4
  • [ 603-80-5 ]
  • [ 75-36-5 ]
  • [ 55289-05-9 ]
YieldReaction ConditionsOperation in experiment
91% at 0 - 20℃; for 18 h; 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 percent) 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 percent 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 percent ethyl acetate/hexanes) affording 0.44 g (69 percent) 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 percent) 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 percent) 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 (1percent methanol/dichloromethane) and later to another flash chromatography (20 percent ethyl acetate/hexanes to 25 percent ethyl acetate/hexanes) to obtain 210 mg (50 percent) 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 percent in methanol, 5 ml total) was added 10percent 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: 3percent isopropyl alcohol/dichloromethane to 5 percent isopropyl alcohol/dichloromethane (in 1percent increments of isopropyl alcohol)) to provide 0.11 g (82 percent) 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 percent) 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% at 0 - 20℃; for 43 h; 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 percent) 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 percent) 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 percent) 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 percent) 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 percent) 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 percent Pd/C (145 mg, 50 percent 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 percent formic acid and methanol (10 ml). After stirring at room temperature for 18 hours, more Pd/C (141 mg, 50 percent 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 percent 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 percent) 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 percent) 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 percent 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 percent) 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).
Reference: [1] Patent: EP1214324, 2006, B1, . Location in patent: Page/Page column 59-60
[2] Patent: EP1214324, 2006, B1, . Location in patent: Page/Page column 32-33
  • 5
  • [ 603-80-5 ]
  • [ 55289-05-9 ]
Reference: [1] Patent: US6133303, 2000, A,
  • 6
  • [ 603-80-5 ]
  • [ 75-36-5 ]
  • [ 55289-05-9 ]
Reference: [1] Patent: US6410556, 2002, B1,
  • 7
  • [ 603-80-5 ]
  • [ 144-55-8 ]
  • [ 75-36-5 ]
  • [ 330191-68-9 ]
  • [ 55289-05-9 ]
Reference: [1] Patent: US6410556, 2002, B1,
  • 8
  • [ 603-80-5 ]
  • [ 55289-16-2 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2435 - 2447
  • 9
  • [ 52130-17-3 ]
  • [ 603-80-5 ]
YieldReaction ConditionsOperation in experiment
69% With sulfuric acid; sodium nitrite In methanol; dichloromethane; water Alternative Preparation for 2-Methyl-3-hydroxybenzoic acid
To a cold (0° C.) suspension of 0.54 g (3.3 mmol) of 2-methyl-3-aminobenzoic acid in 5 mL of water containing 0.65 mL of concentrated sulfuric acid, was added 0.25 g (3.6 mmol) of solid sodium nitrite.
After approximately 15 minutes the reaction mixture was poured into 20 mL of warm water containing 4 mL of concentrated sulfuric acid.
The resultant reaction mixture was heated slowly to 90° C., resulting in gas evolution.
After the gas evolution ceased, the solution was cooled to room temperature and extracted with ethyl acetate.
The organic layers were combined, washed with 0.5N hydrochloric acid, dried and concentrated under reduced pressure.
The crude residue was purified by rapid filtration through silica gel (eluent of 5percent methanol in methylene chloride) to yield 350 mg of a white solid (m.p. 137-138° C.).
Yield: 69percent. 1 H NMR (CDCl3): δ 8.18 (br.s, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.13 (t, J=7.9 Hz, 1H), 6.93 (d, J=7.9 Hz, 1H), 2.46 (s, 3H).
Analysis for C8 H8 O3: Calcd: C, 63.15; H, 5.29; Found: C, 63.32; H, 5.36.
69% With sulfuric acid; sodium nitrite In methanol; dichloromethane; water Alternative Preparation for 2-Methyl-3-hydroxybenzoic acid
To a cold (0° C.) suspension of 0.54 g (3.3 mmol) of 2-methyl-3-aminobenzoic acid in 5 mL of water containing 0.65 mL of concentrated sulfuric acid, was added 0.25 g (3.6 mmol) of solid sodium nitrite.
After approximately 15 minutes the reaction mixture was poured into 20 mL of warm water containing 4 mL of concentrated sulfuric acid.
The resultant reaction mixture was heated slowly to 90° C., resulting in gas evolution.
After the gas evolution ceased, the solution was cooled to room temperature and extracted with ethyl acetate.
The organic layers were combined, washed with 0.5N hydrochloric acid, dried and concentrated under reduced pressure.
The crude residue was purified by rapid filtration through silica gel (eluent of 5percent methanol in methylene chloride) to yield 350 mg of a white solid (m.p. 137°-138° C.).
Yield: 69percent.
1 H NMR (CDCl3): δ8.18 (br.s, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.13 (t, J=7.9 Hz, 1H), 6.93 (d, J=7.9 Hz, 1H), 2.46 (s, 3H).
Analysis for C8 H8 O3: Calcd: C, 63.15; H, 5.29; Found: C, 63.32; H, 5.36.
69% With sulfuric acid; sodium nitrite In methanol; dichloromethane; water PREPARATION 1
2-Methyl-3-hydroxybenzoic acid
To a cold (0° C.) suspension of 0.54 g (3.3 mmol) of 2-methyl-3-aminobenzoic acid in 5 mL of water containing 0.65 mL of concentrated sulfuric acid, was added 0.25 g (3.6 mmol) of solid sodium nitrite.
After approximately 15 minutes the reaction mixture was poured into 20 mL of warm water containing 4 mL of concentrated sulfuric acid.
The resultant reaction mixture was heated slowly to 90° C. resulting in gas evolution After the gas evolution ceased, the solution was cooled to room temperature and extracted with ethyl acetate.
The organic layers were combined, washed with 0.5N hydrochloric acid, dried and concentrated under reduced pressure.
The crude residue was purified by rapid filtration through silica gel (eluent of 5percent methanol in methylene chloride) to yield 350 mg of a white solid (m.p. 137°-138° C.). Yield: 69percent.
1 H NMR (CDCl3): δ8.18 (br.s, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.13 (t, J=7.9 Hz, 1H), 6.93 (d, J=7.9 Hz, 1H), 2.46 (s, 3H).
Analysis for C8 H8 O3: Calcd: C, 63.15; H, 5.29; Found: C, 63.32; H, 5.36.
Reference: [1] Patent: US6335/459, 2002, B1, . Location in patent: Page column 29
[2] Patent: US6335459, 2002, B1, . Location in patent: Page column 29
[3] Tetrahedron Letters, 2000, vol. 41, # 11, p. 1741 - 1745
[4] Patent: US5952343, 1999, A,
[5] Patent: US5484926, 1996, A,
[6] Patent: US5527829, 1996, A,
[7] Bulletin de la Societe Chimique de France, 1973, p. 3427 - 3432
[8] Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3979 - 3985
[9] Steroids, 2000, vol. 65, # 3, p. 117 - 123
  • 10
  • [ 170240-13-8 ]
  • [ 603-80-5 ]
YieldReaction ConditionsOperation in experiment
79% With potassium <i>tert</i>-butylate In toluene; <i>tert</i>-butyl alcohol Example 3
Preparation of 3-Hydroxy-2-methylbenzoic Acid
The cycloadduct (1.05 g) from Example 2, 1.80 g of potassium tert-butoxide and 9 mL of tert-butanol were combined and refluxed a total of 9 hours.
The reaction mixture was poured into water.
Toluene was added.
The toluene phase was washed twice with dilute sodium hydroxide solution.
The combined aqueous phases were acidified with HCl, then extracted several times with n-butyl acetate.
The n-butyl acetate was stripped, and the product dried in a vacuum oven to give 0.87 g of 3-hydroxy-2-methylbenzoic acid, 94percent purity, 79percent yield.
79% With potassium <i>tert</i>-butylate In toluene; <i>tert</i>-butyl alcohol EXAMPLE 3
Preparation of 3-Hydroxy-2-methylbenzoic Acid
The cycloadduct (1.05 g) from Example 2, 1.80 g of potassium tert-butoxide and 9 mL of tert-butanol were combined and refluxed a total of 9 hours.
The reaction mixture was poured into water.
Toluene was added.
The toluene phase was washed twice with dilute sodium hydroxide solution.
The combined aqueous phases were acidified with HCl, then extracted several times with t-butyl acetate.
The n-butyl acetate was stripped, and the product dried in a vacuum oven to give 0.87 g of 3-hydroxy-2-methylbenzoic acid, 94percent purity, 79percent yield.
Reference: [1] Patent: EP1008583, 2000, A1,
[2] Patent: US6288260, 2001, B1,
  • 11
  • [ 60-29-7 ]
  • [ 7664-93-9 ]
  • [ 18583-89-6 ]
  • [ 603-80-5 ]
YieldReaction ConditionsOperation in experiment
94.4% With sodium nitrite In water; acetic acid Step 1
3-Hydroxy-2-methylbenzoic acid
A solution of 20.6 g (0.125 mol) of methyl 3-amino-2-methylbenzoate in 150 mL of HOAc and 25 mL of conc. H2 SO4 was cooled in ice and diazotized by the dropwise addition of a solution of 8.7 g (0.125 mol) of NaNO2 in 50 mL of H2 O.
After stirring for 15 minutes, the diazonium solution was added dropwise to a boiling solution of 200 mL of 50percent H2 SO4, and the refluxing continued for 15 minutes after the addition was complete.
The mixture was diluted with H2 O and extracted twice with Et2 O.
The Et2 O was washed 5 times with H2 O, then with saturated NaCl.
Drying over MgSO4 and removal of the solvent under reduced pressure left 17.98 g (94.4percent yield) of the product as a tan solid, mp 137-140° C.
The structure was confirmed by NMR spectroscopy.
Reference: [1] Patent: US6133303, 2000, A,
  • 12
  • [ 55289-06-0 ]
  • [ 603-80-5 ]
Reference: [1] Patent: US6124500, 2000, A,
[2] Patent: US6124500, 2000, A,
[3] Patent: EP984009, 2000, A1,
  • 13
  • [ 52130-17-3 ]
  • [ 603-80-5 ]
YieldReaction ConditionsOperation in experiment
36% With hydrogenchloride; sulfuric acid; urea; sodium nitrite In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water Part A
Preparation of 3-Hydroxy-2-methylbenzoic Acid
A one-necked 100 mL round-bottomed flask (magnetic stirring) was charged with 1.0 gram (6.6 mM) 3-amino-2-methylbenzoic acid.
A warm mixture of 2.3 mL conc. sulfuric acid in 4.3 mL water was added to the flask, the resulting slurry was cooled below 15° C. in an ice bath, and 6.6 grams of ice was added.
The reaction mixture was treated via subsurface addition with a solution of 0.6 gram (8.6 mM) sodium nitrite in 6.6 mL ice water with the reaction temperature maintained at 0-5° C. during the addition.
After stirring at 0-5° C. for 30 min., a few crystals of urea were added to decompose the excess nitrite.
The reaction mixture was then poured into a room temperature solution of 23.8 grams (102.3 mM) copper (II) nitrate hemipentahydrate in 200 mL water.
With vigorous stirring, the reaction mixture was treated with 0.9 gram (6.0 mM) copper (I) oxide.
The reaction mixture foamed and changed from turquoise blue to dark green in color.
Reaction was left stirring for 30 min.
The reaction mixture was extracted with diethyl ether (3*), and the organic extracts were combined.
The organic extracts were concentrated to approximately one-fourth the original volume, then extracted with 25 mL 1N sodium hydroxide solution.
The layers were separated, and the dark-red aqueous layer was acidified to pH=2 using 1N hydrochloric acid solution.
The acidified aqueous layer was then extracted with diethyl ether (3*), and the ether extracts were combined, dried (MgSO4), and concentrated to yield a reddish-colored oil.
Purification by flash chromatography on silica gel using a gradient of 0-7percent methanol/methylene chloride afforded 0.39 grams (36percent) of a yellow solid.
36% With hydrogenchloride; sulfuric acid; urea; sodium nitrite In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water Part A
Preparation of 3-Hydroxy-2-methylbenzoic Acid
A one-necked 100 mL round-bottomed flask (magnetic stirring) was charged with 1.0 gram (6.6 mM) 3-amino-2-methylbenzoic acid.
A warm mixture of 2.3 mL conc. sulfuric acid in 4.3 mL water was added to the flask, the resulting slurry was cooled below 15° C. in an ice bath, and 6.6 grams of ice was added.
The reaction mixture was treated via subsurface addition with a solution of 0.6 gram (8.6 mM) sodium nitrite in 6.6 mL ice water with the reaction temperature maintained at 0-5° C. during the addition.
After stirring at 0-5° C. for 30 min., a few crystals of urea were added to decompose the excess nitrite.
The reaction mixture was then poured into a room temperature solution of 23.8 grams (102.3 mM) copper (II) nitrate hemipentahydrate in 200 mL water.
With vigorous stirring, the reaction mixture was treated with 0.9 gram (6.0 mM) copper (I) oxide.
The reaction mixture foamed and changed from turquoise blue to dark green in color.
Reaction was left stirring for 30 min.
The reaction mixture was extracted with diethyl ether (3*), and the organic extracts were combined.
The organic extracts were concentrated to approximately one-fourth the original volume, then extracted with 25 mL 1N sodium hydroxide solution.
The layers were separated, and the dark-red aqueous layer was acidified to pH=2 using 1N hydrochloric acid solution.
The acidified aqueous layer was then extracted with diethyl ether (3*), and the ether extracts were combined, dried (MgSO4), and concentrated to yield a reddish-colored oil.
Purification by flash chromatography on silica gel using a gradient of 0-7percent methanol/methylene chloride afforded 0.39 grams (36percent) of a yellow solid.
Reference: [1] Patent: US6046190, 2000, A,
[2] Patent: US5968942, 1999, A,
[3] Patent: US6143747, 2000, A,
  • 14
  • [ 131-27-1 ]
  • [ 603-80-5 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 148
[2] Journal of the American Chemical Society, 1936, vol. 58, p. 749,753
[3] Tetrahedron Letters, 1981, vol. 22, # 19, p. 1843 - 1844
[4] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 149
  • 15
  • [ 7499-08-3 ]
  • [ 603-80-5 ]
Reference: [1] Patent: US6124500, 2000, A,
  • 16
  • [ 7499-08-3 ]
  • [ 603-80-5 ]
Reference: [1] Patent: US6124500, 2000, A,
  • 17
  • [ 91-20-3 ]
  • [ 603-80-5 ]
Reference: [1] Patent: WO2016/144909, 2016, A1, . Location in patent: Page/Page column 25
  • 18
  • [ 1975-50-4 ]
  • [ 603-80-5 ]
Reference: [1] Tetrahedron Letters, 2000, vol. 41, # 11, p. 1741 - 1745
[2] Bulletin de la Societe Chimique de France, 1973, p. 3427 - 3432
  • 19
  • [ 489-78-1 ]
  • [ 603-80-5 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 148
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 149
  • 20
  • [ 38251-40-0 ]
  • [ 603-80-5 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 148
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 149
  • 21
  • [ 55289-04-8 ]
  • [ 603-80-5 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2435 - 2447
  • 22
  • [ 3260-87-5 ]
  • [ 603-80-5 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2435 - 2447
  • 23
  • [ 6654-64-4 ]
  • [ 603-80-5 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 148
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 149
  • 24
  • [ 75-15-0 ]
  • [ 7446-70-0 ]
  • [ 24487-91-0 ]
  • [ 603-80-5 ]
  • [ 860732-72-5 ]
  • [ 860731-27-7 ]
Reference: [1] Journal of the American Chemical Society, 1936, vol. 58, p. 749,753
  • 25
  • [ 603-80-5 ]
  • [ 71887-28-0 ]
Reference: [1] European Journal of Inorganic Chemistry, 2011, # 7, p. 1112 - 1120
  • 26
  • [ 603-80-5 ]
  • [ 1149388-19-1 ]
Reference: [1] Patent: WO2014/144380, 2014, A1,
[2] Patent: WO2016/34673, 2016, A1,
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Reference: [1] Patent: WO2013/66714, 2013, A1,
[2] Patent: WO2013/90271, 2013, A1,
[3] Patent: WO2013/66718, 2013, A2,
[4] Patent: WO2013/28474, 2013, A1,
[5] Patent: WO2014/15495, 2014, A1,
[6] Patent: WO2014/18764, 2014, A1,
[7] Patent: WO2014/99633, 2014, A2,
[8] Patent: WO2014/126944, 2014, A2,
[9] Patent: WO2015/17305, 2015, A1,
[10] Patent: WO2015/65866, 2015, A1,
[11] Patent: WO2015/96035, 2015, A1,
[12] Patent: WO2015/100147, 2015, A1,
[13] Patent: WO2016/65582, 2016, A1,
[14] Patent: WO2016/122994, 2016, A1,
[15] Patent: EP2744499, 2016, B1,
[16] Patent: WO2016/127358, 2016, A1,
[17] Patent: US9493474, 2016, B2,
[18] Patent: WO2016/60941, 2016, A1,
[19] Patent: WO2013/66717, 2013, A1,
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Reference: [1] Patent: WO2015/179276, 2015, A1,
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