* 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.
With hydrogenchloride; sodium carbonate; sodium nitrite In water at 0 - 100℃; for 19 h;
Methyl 4-amino-2-methylbenzoate (1 ) (4.14 g, 25.1 mmol) was suspended in cone. HCI (20 ml.) and H20 (100 ml.) and stirred at 0°C. A solution of sodium nitrite (1 .73 g, 25.1 mmol) in H20 (50 ml.) was slowly added to the suspension such that the (0587) temperature was maintained at 0-5°C. The mixture was made basic by the addition of aq. Na2C03 and added dropwise to a stirring mixture of potassium cyanide (1 .88 g, (0588) 28.8 mmol) and copper (I) cyanide (2.58 g, 28.8 mmol) in H20 (200 ml.) at 0-5°C. The mixture was stirred at 0-5°C for 0.5 h, then was warmed to RT and stirred for 18 h. The mixture was stirred at 100°C for 0.5 h and then cooled to RT and treated with 10percent aq. FeC solution (250 ml_). The product was extracted with EtOAc (600 ml.) and the organic solution was washed with brine (500 ml_), dried over Na2S04, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (120 g cartridge, 0-10percent EtOAc in isohexane) to afford a red solid. The product was recrystallised from isohexane/EtOAc to give the title compound (2) (2.58 g, 59percent) as an orange solid: 1 H NMR (400 MHz, CDCI3) δ: 7.97 (1 H, dd), 7.58 - 7.50 (2H, m), 3.93 (3H, s), 2.62 (3H, s)
Intermediate 7; Methyl 4-amino-2-methylbenzoate; To a solution of methyl 2-methyl-4-nitrobenzoate (Intermediate 5) (3.25 g, 16.6 mmol) in ethanol was added Pd/C 10percent (catalytic quantity) and ammonium formate (10.5 g, 0.17 mmol). The mixture was stirred at 400C for 2 hours. The mixture was filtered on celite, washed with diethyl ether. The filtrate was evaporated and the residue was diluted with diethyl ether, washed with water. The organic phase was dried over Na2SC>4, filtered and evaporated to give the title compound as brown oil (2.8 g, quantitative yield). NMR1H NMR (300 MHz), CDCI3 δ: 7.74 (d, 1 H, J=9.20 Hz), 6.41 (m, 2H), 3.75 (s, 3H), 2.47 (s, 3H).
Reference：
[1] Patent: WO2009/47240, 2009, A1, . Location in patent: Page/Page column 29
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 942 - 945
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 946 - 949
[4] Bulletin de la Societe Scientifique de Bretagne, 1956, vol. 31, p. Sonderheft S.9,41
[5] Patent: WO2006/7542, 2006, A1, . Location in patent: Page/Page column 24
4
[ 67-56-1 ]
[ 103204-69-9 ]
[ 6933-47-7 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: for 3 h; Reflux Stage #2: With sodium hydroxide In waterCooling with ice
4-Acetamido-2-methylbenzoic acid (46 g, 238 mmol) is initially charged in methanol (460 ml), and concentrated sulphuric acid (63 g, 643 mmol) is added. The reaction mixture is heated under reflux for 3 h, cooled, carefully added to ice-water and made alkaline using 5N aqueous sodium hydroxide solution. Extraction with ethyl acetate, drying of the organic phase over sodium sulphate and removal of the solvent under reduced pressure gives ethyl 4-amino-2-methylbenzoate (38.3 g, 232 mmol, 94percent) which is used without further purification for the next step.
Step 1. Synthesis of methyl 4-amino-2-methylbenzoate To a solution of 4-amino-2-methylbenzoic acid (1.00 g, 6.60 mmol) in 18 mL of methanol was treated concentrated HCl (2.30 mL, 27.6 mmol) in one portion at r.t. The reaction mixture was refluxed overnight then directly concentrated to give a crude product, which was partitioned between ethyl acetate (50 mL) and saturated NaHCO3(aq) (20 mL). The organic layer was washed with brine (10 mL), dried over MgSO4 and concentrated to give the desired product (930 mg, 85percent). 1H NMR (CDCl3, 400 MHz) δ 7.83-7.80 (m, 1H), 6.51-6.48 (m, 2H), 4.15 (br s, 2H), 3.83 (s, 3H), 2.55 (s, 3H).
With sodium periodate; iodine In N,N-dimethyl-formamide at 50℃; for 2 h;
Intermediate 9; methyl 4-amino-5-iodo-2-methylbenzoate; To a solution of methyl 4-amino-2-methylbenzoate (Intermediate 7) (2.9 g, 16.6 mmol) in DMF (15 ml) was added sodium periodate (1.45 g, 6.6 mmol) and iodine (3.4 g, 13.3 mmol). The reaction mixture was stirred at 500C for 2 hours. The mixture was poured into cold water with NaHSO3 (0.5 g). After stirring, the mixture was left overnight. The precipitate was filtered, washed with water and diluted with dichloromethane. This solution was dried over Na2SO4, filtered and evaporated to give the title compound as orange solid (4.1 g, 85percent). NMR1H NMR (300 MHz), CDCI3 δ: 8.20 (s, 1 H), 6.47 (s, 1 H), 3.75 (s, 3H), 2.42 (s, 3H).
65%
Stage #1: With sodium periodate; iodine In N,N-dimethyl-formamide at 50℃; for 3 h; Stage #2: With sodium hydrogen sulfite In water; N,N-dimethyl-formamide for 3 h;
To a mixture of 136 methyl 4-amino-2-methylbenzoate (15.0 g, 85.86 mmol) in 30 DMF (80 mL) was added 137 sodium periodate (7.36 g, 34.42 mmol) and 138 iodine (17.6. g, 68.84 mmol). The reaction mixture was stirred at 50° C. for 3 hours. The mixture was poured into a solution of 139 NaHSO3 (2.6 g) in 86 water (200 mL). After stirring for 3 h, the mixture was extracted with DCM (300 mL×3). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by chromatography on silica gel (2percent-30percent 32 EtOAc in 60 pet. ether) to give 18A (16.15 g, 65percent yield) as a yellow 140 solid: 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 6.47 (s, 1H), 3.75 (s, 3H), 2.42 (s, 3H) ; ESI m/z 292.0 [M+H]+
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 942 - 945
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 946 - 949
[3] Patent: WO2009/47240, 2009, A1, . Location in patent: Page/Page column 30
[4] Patent: US2018/291002, 2018, A1, . Location in patent: Paragraph 0462; 0463
[5] Patent: US2004/142940, 2004, A1, . Location in patent: Page/Page column 42
[6] Patent: WO2006/7542, 2006, A1, . Location in patent: Page/Page column 24
With ammonium formate;palladium 10% on activated carbon; In ethanol; at 40℃; for 2h;
Intermediate 7; Methyl 4-amino-2-methylbenzoate; To a solution of <strong>[62621-09-4]methyl 2-methyl-4-nitrobenzoate</strong> (Intermediate 5) (3.25 g, 16.6 mmol) in ethanol was added Pd/C 10% (catalytic quantity) and ammonium formate (10.5 g, 0.17 mmol). The mixture was stirred at 400C for 2 hours. The mixture was filtered on celite, washed with diethyl ether. The filtrate was evaporated and the residue was diluted with diethyl ether, washed with water. The organic phase was dried over Na2SC>4, filtered and evaporated to give the title compound as brown oil (2.8 g, quantitative yield). NMR1H NMR (300 MHz), CDCI3 delta: 7.74 (d, 1 H, J=9.20 Hz), 6.41 (m, 2H), 3.75 (s, 3H), 2.47 (s, 3H).
With iron(III) chloride; water; hydrazine; In ethanol; for 3h;Heating / reflux; Charcoal;
Example 1: Synthesis of PDZ domain inhibitor (2-(l-HydroxypentvD-3-(2-phenvlethvl)-6-methvl)indole-5-carboxylic acid [Formula (I); Table 1A, compound 11; [0067] The general scheme for this synthesis was (Scheme D):; [0068] Methyl (4-amino-5-iodo-2-methyl)benzoate (4); A mixture of 2-iodo-5-nitrotoluene (1,10 g), triethylamine (16 mL), palladium acetate (68 mg), methanol (20 mL) and DMF (10 mL) was stirred at 90C overnight under carbon monoxide atmosphere (1 atm). The reaction mixture was diluted with ethyl acetate (200 mL), washed with water twice (100 mL each) followed by brine (100 mL), dried (Na2S04), and evaporated. The residue was filtered through a short pad of silica gel and evaporated to give 2 as a crude oil. A mixture of 2, ethanol (140 mL), water (2 mL), hydrazine monohydrate (3.8 mL), ferric trichloride (0.17 g) and charcoal (0.1 g) was stirred under reflux for 3 hours. The reaction mixture was filtrated, diluted with ethyl acetate (200 mL), washed with water twice (100 mL each) followed by brine (100 mL), dried (Na2S04), and evaporated. The residue was filtered through a short pad of silica gel and evaporated to give 3 as a crude oil. To a mixture of 3, methanol (33 mL), calcium carbonate (10 g), iodine monochloride solution (33 mL, 1M in dichloromethane) was added slowly at 4C and stirred overnight at the ambient temperature. The reaction mixture was filtrated, diluted with ethyl acetate (200 mL), washed with aqueous sodium sulfite solution (100 mL), followed by brine (100 mL), dried (Na2SC>4), and evaporated. The residue was purified by column chromatography (silica gel 0.2 L, eluent: 10% ethyl acetate in hexanes) and evaporated to give 4 (4.30 g) as pale brown crystals. *H NMR (CDC13, 400 MHz) 8 8.28 (s, 1H), 6.54 (s, 1H), 4,39 (broad s, 2H), 3.84 (s, 3H), 2.50 (s, 3H).
4-methanesulphonylamino-2-methyl-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine;dmap; In dichloromethane; for 1 - 16h;
4.22 4-Methanesulphonylamino-2-methyl-benzoic acid methyl ester; <n="48"/>Methanesulfonyl chloride was added to a solution of <strong>[6933-47-7]4-amino-2-methyl-benzoic acid methyl ester</strong> in dichloromethane, pyridine and a catalytic amount of DMAP. After 1-16 hrs the mixture was concentrated to near dryness and the product crystallized from added ethanol. This product was hydrolyzed in 2.5 M LiOH (5 ml_), THF (14 ml_), MeOH (7 ml.) in a microwave oven at 110 0C for 30 min. After cooling, the solution was acidified with aq. HCI and extracted with ethyl acetate, dried with Na2SO4 and concentrated to dryness.
With sodium periodate; iodine; In N,N-dimethyl-formamide; at 50℃; for 2h;
Intermediate 9; methyl 4-amino-5-iodo-2-methylbenzoate; To a solution of methyl 4-amino-2-methylbenzoate (Intermediate 7) (2.9 g, 16.6 mmol) in DMF (15 ml) was added sodium periodate (1.45 g, 6.6 mmol) and iodine (3.4 g, 13.3 mmol). The reaction mixture was stirred at 500C for 2 hours. The mixture was poured into cold water with NaHSO3 (0.5 g). After stirring, the mixture was left overnight. The precipitate was filtered, washed with water and diluted with dichloromethane. This solution was dried over Na2SO4, filtered and evaporated to give the title compound as orange solid (4.1 g, 85%). NMR1H NMR (300 MHz), CDCI3 delta: 8.20 (s, 1 H), 6.47 (s, 1 H), 3.75 (s, 3H), 2.42 (s, 3H).
65%
To a mixture of 136 methyl 4-amino-2-methylbenzoate (15.0 g, 85.86 mmol) in 30 DMF (80 mL) was added 137 sodium periodate (7.36 g, 34.42 mmol) and 138 iodine (17.6. g, 68.84 mmol). The reaction mixture was stirred at 50 C. for 3 hours. The mixture was poured into a solution of 139 NaHSO3 (2.6 g) in 86 water (200 mL). After stirring for 3 h, the mixture was extracted with DCM (300 mL×3). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by chromatography on silica gel (2%-30% 32 EtOAc in 60 pet. ether) to give 18A (16.15 g, 65% yield) as a yellow 140 solid: 1H NMR (400 MHz, CDCl3) delta 8.20 (s, 1H), 6.47 (s, 1H), 3.75 (s, 3H), 2.42 (s, 3H) ; ESI m/z 292.0 [M+H]+
With sodium periodate; iodine; In DMF (N,N-dimethyl-formamide); at 50℃; for 4h;
To a solution of methyl 5-methyl-4-aminobenzoate (1.1 g, 6.7 mmol) in 4 mL DMF was added NaIO4 (573 mg, 2.68 mmol) and iodine (1.35 g, 5.3 mmol). The mixture was warmed at 50 C. for 4 h. It was then cooled and diluted with water and the product was extracted with ethyl acetate. The organic layer was dried with Na2SO4 and concentrated. The residue was purified by column chromatography using 10% EtOAc and hexane to give 2.2 g of product as brown solids. M+H+(292).
With Iodine monochloride; calcium carbonate; In methanol; dichloromethane; at 4 - 20℃;
Example 1: Synthesis of PDZ domain inhibitor (2-(l-HydroxypentvD-3-(2-phenvlethvl)-6-methvl)indole-5-carboxylic acid [Formula (I); Table 1A, compound 11; [0067] The general scheme for this synthesis was (Scheme D):; [0068] Methyl (4-amino-5-iodo-2-methyl)benzoate (4); A mixture of 2-iodo-5-nitrotoluene (1,10 g), triethylamine (16 mL), palladium acetate (68 mg), methanol (20 mL) and DMF (10 mL) was stirred at 90C overnight under carbon monoxide atmosphere (1 atm). The reaction mixture was diluted with ethyl acetate (200 mL), washed with water twice (100 mL each) followed by brine (100 mL), dried (Na2S04), and evaporated. The residue was filtered through a short pad of silica gel and evaporated to give 2 as a crude oil. A mixture of 2, ethanol (140 mL), water (2 mL), hydrazine monohydrate (3.8 mL), ferric trichloride (0.17 g) and charcoal (0.1 g) was stirred under reflux for 3 hours. The reaction mixture was filtrated, diluted with ethyl acetate (200 mL), washed with water twice (100 mL each) followed by brine (100 mL), dried (Na2S04), and evaporated. The residue was filtered through a short pad of silica gel and evaporated to give 3 as a crude oil. To a mixture of 3, methanol (33 mL), calcium carbonate (10 g), iodine monochloride solution (33 mL, 1M in dichloromethane) was added slowly at 4C and stirred overnight at the ambient temperature. The reaction mixture was filtrated, diluted with ethyl acetate (200 mL), washed with aqueous sodium sulfite solution (100 mL), followed by brine (100 mL), dried (Na2SC>4), and evaporated. The residue was purified by column chromatography (silica gel 0.2 L, eluent: 10% ethyl acetate in hexanes) and evaporated to give 4 (4.30 g) as pale brown crystals. *H NMR (CDC13, 400 MHz) 8 8.28 (s, 1H), 6.54 (s, 1H), 4,39 (broad s, 2H), 3.84 (s, 3H), 2.50 (s, 3H).
4-Acetamido-2-methylbenzoic acid (46 g, 238 mmol) is initially charged in methanol (460 ml), and concentrated sulphuric acid (63 g, 643 mmol) is added. The reaction mixture is heated under reflux for 3 h, cooled, carefully added to ice-water and made alkaline using 5N aqueous sodium hydroxide solution. Extraction with ethyl acetate, drying of the organic phase over sodium sulphate and removal of the solvent under reduced pressure gives ethyl 4-amino-2-methylbenzoate (38.3 g, 232 mmol, 94%) which is used without further purification for the next step.
Intermediate 7.5.1 4-Amino-2-methyl-benzoic acidTo a stirred solution of 4-acetylamino-2-methyl-benzoic acid (25.5 g) in methanol (250 ml) was added cone. H2S04 (19 ml) dropwise and the reaction heated to reflux. After 2.5 h, the reaction was cooled to rt. NaHC03 (aq) was added until alkaline and the obtained mixture was extracted with EtOAc. The organic extracts were washed with NaOH(aq) (2 M) 3 times, then dried and concentrated affording 17.6 g of the title compound.ESI mass spectrum: [M+H]+ = 166
Synthesis Example 7.5Intermediate 7.5.14-Amino-2-methyl-benzoic acidTo a stirred solution of 4-acetylamino-2-methyl-benzoic acid (25.5 g) in methanol (250 ml) was added conc. H2SO4 (19 ml) dropwise and the reaction heated to reflux. After 2.5 h, the reaction was cooled to rt. NaHCO3 (aq) was added until alkaline and the obtained mixture was extracted with EtOAc. The organic extracts were washed with NaOH(aq) (2 M) 3 times, then dried and concentrated affording 17.6 g of the title compound.ESI mass spectrum: [M+H]+=166
With hydrogenchloride; In methanol; water; at 70℃; for 2h;
4-Amino-2-methyl-benzoic acid methyl ester (P3 building block for Example 15.5) EPO <DP n="118"/>4-Acetylamino-2-methyl-benzoic acid methyl ester was kept in cone. HCI/MeOH 1 :1 in a microwave oven at 70 deg C for 2 hrs. After cooling the solid was collected, dried in a vacuum and used in the next step.
With hydrogenchloride; methanol; water; at 70℃; for 2h;Microwave irradiation;
4.21 4-Amino-2-methyl-benzoic acid methyl ester; 4-Acetylamino-2-methyl-benzoic acid methyl ester was kept in cone. HCI/MeOH 1 :1 in a microwave oven at 70 0C for 2 hrs. After cooling the solid was collected and dried under vacuum. Hydrolysation of the methyl ester as described fo the preparation of 4.17 gave the title compound.
(1) The same procedure as in Reference Example 1 (1) and Reference Example 1 (2) is repeated, except that <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> is substituted for the 3-fluoro-4-methylaniline, to obtain methyl 4-(2,2-diethoxyethylthio)-2-methylbenzoate. NMR (CDCl3) delta value: 1.20 (6H, t, J=7.0 Hz), 2.57 (3H, s), 3.18 (2H, d, J=5.4 Hz), 3.3-3.8 (4H, m), 3.86 (3H, s), 4.67 (1H, t, J=5.4 Hz), 7.0-7.3 (2H, m), 7.7-7.9 (1H, m)
EXAMPLE 66Part A: A solution of 4-Amino-2-methyl-benzoic acid methyl ester (0.33 g; 2 mmol; prepared from commercially available 4-nitro-2-methyl-benzoic acid) and 8- methanesulfonyl-6-bromo-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1/-/-pyrazol-4-yl]- imidazo[1 , 2-a]pyrazine (0.472 g; 1.0 mmol) was treated with LiHMDS (1 M in THF; 2 mL) at RT. The resulting burgundy solution was stirred at RT for 20 minutes and then <n="160"/>quenched with saturated aqueous NH4CI solution. Standard work up as described for Example 65 and flash silicagel chromatography (25% EtOAc in CH2CI2) provided the title compound as pale yellow foam (0.48 g; 86%).NMR (400 MHz, CDCI3): 8.18 (s, 1 H), 8 (d, 1 H), 7.9 (s, 1 H), 7.85 (d, 1 H), 7.78 (s, 1 H), 7.7 (s, 1 H), 7.62 (s, 1 H), 7.58 (s, 1 H), 5.5 (s, 2H), 3.9 (s, 3H), 3.65 (t, 2H), 2.6 (s, 3H), 0.98 (t, 2H), 0.0 (s, 9H). Mass CaIc. for C24H29BrN6O3Si 556.13; Obsd MH+ (CI-MS) 557 / 559 (m/z).
With hydrogen iodide; sodium nitrite; In water; dimethyl sulfoxide; at 35.0℃;
A mixture of 4-amino-2-methyl-benzoic acid methyl ester (1 eq) and NaNCh in DMSO(2 eq .in DMSO) was treated dropwise with a solution of 57 % aqueous HI (10 eq.) in DMSO at 35 0C with stirring. The mixture was stirred at 35 0C for 10 minutes or until the reaction went to completion (monitored by LCMS), and then it was transferred to a solution containing K2CO3 (500 nig) in 2 mL of water. The reaction mixture is extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhyd. magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The crude product was then purified by flash chromatography to give the corresponding iodo derivative.
rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid[ No CAS ]
[ 6933-47-7 ]
rac-4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methyl-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃;
Example 295; Preparation of rac 4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methyl-benzoic acid methyl ester To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 235 mg, 0.62 mmol) was added followed by the addition of DIPEA(0.30 mL, 1.72 mmol) and 4-amino-2-methyl-benzoic acid (Aldrich, 114 mg, 0.69 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 102 mg.MS (ES+) m/z Calcd: [(M+H)+]: 614, found: 614
Synthesis 184-(3,5-Dichloro-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-019)Step (i): Methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (3)1A solution of 3,5-dichloro-4-ethoxybenzoic acid (1) (285 mg, 1.21 mmol) and DIPEA (1.05 mL, 6.05 mmol) in DMF (2.5 mL) was added to HATU (690 mg, 1.82 mmol) and the orange mixture was stirred for 5 min prior to the addition of methyl 4-amino-2- methylbenzoate (2) (200 mg, 1.21 mmol) in DMF (1 mL). The resulting dark orange solution was stirred overnight for 18 h. 2 M HCI (10 mL) was added and stirring continued for 10 min, and then the mixture was extracted with diethyl ether. The organic layer was washed with water (3 x 15 mL), dried over MgS04, filtered and the solvent was evaporated in vacuo. The yellow residue was purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to afford methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2- methylbenzoate (3) (267 mg, 56%): m/z 380 (M-H)" (ES"). 1H NMR (400 MHz, CDCI3) delta: 7.97 (1 H, s), 7.80 (3H, m), 7.54 (1 H, dd), 7.51 (1 H, d), 4.18 (2H, q), 3.89 (3H, s), 2.63 (3H, s), 1.49 (3H, t).
56%
A solution of 3,5-dichloro-4-ethoxybenzoic acid (1) (285 mg, 1.21 mmol) and DIPEA (1.05 mL, 6.05 mmol) in DMF (2.5 mL) was added to HATU (690 mg, 1.82 mmol) and the orange mixture was stirred for 5 min prior to the addition of <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (2) (200 mg, 1.21 mmol) in DMF (1 mL). The resulting dark orange solution was stirred overnight for 18 h. 2 M HCl (10 mL) was added and stirring continued for 10 min, and then the mixture was extracted with diethyl ether. The organic layer was washed with water (3*15 mL), dried over MgSO4, filtered and the solvent was evaporated in vacuo. The yellow residue was purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to afford methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (3) (267 mg, 56%): m/z 380 (M-H)- (ES-). 1H NMR (400 MHz, CDCl3) delta: 7.97 (1H, s), 7.80 (3H, m), 7.54 (1H, dd), 7.51 (1H, d), 4.18 (2H, q), 3.89 (3H, s), 2.63 (3H, s), 1.49 (3H, t).
56%
A solution of 143 3,5-dichloro-4-ethoxybenzoic acid (7: R1=Et) (285mg, 1.21mmol) and 144 DIPEA (1.05mL, 6.05mmol) in 35 DMF (2.5mL) was added to 38 HATU (690mg, 1.82mmol) and the orange mixture was stirred for 5min prior to the addition of 145 <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (8: R=R2=Me) (200mg, 1.21mmol) in DMF (1mL). The resulting dark orange solution was stirred for 18h. 2M 117 HCl (10mL) was added and stirring continued for 10min, and then the mixture was extracted with diethyl ether. The organic layer was washed with water (3×15mL), dried over MgSO4, filtered and the solvent was evaporated in vacuo. The yellow residue was purified by silica gel chromatography (40g, 0-100% 45 EtOAc in 136 isohexane) to afford 146 methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (10: R1=Et, R=R2=Me) (267mg, 56%): 1H NMR (400MHz, CDCl3) delta 7.97 (d, J=8.5Hz, 1H), 7.81 (2H, s), 7.83-7.77 (1H, m), 7.59-7.48 (2H, m), 4.18 (2H, q, J=7.0Hz), 3.89 (3H, s), 2.63 (3H, s), 1.49 (3H, t, J=7.0Hz). m/z 380 (M-H)- (ES-).
With trimethylene hydrogen phosphate; triethylamine; In ethyl acetate; at 60℃; for 5h;
A mixture of 3-chloro-5-isopropoxy-4-methoxybenzoic acid (5) (250 mg, 1.02 mmol), <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (6) (177 mg, 1.07 mmol) and TEA (150 muIota_, 1.07 mmol) in EtOAc (2.5 mL) was treated with T3P (50% in EtOAc) (1.63 mL, 2.55 mmol) and the mixture was heated at 60C for 5 h. The mixture was diluted with DCM (5 mL) and washed with 1 M HCI (5 mL) followed by satd. NaHC03 solution (5 mL). The organic solvents were removed in vacuo and the residue purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane to yield methyl 4-(3-chloro-5-isopropoxy-4- methoxybenzamido)-2-methylbenzoate (7) (167 mg, 40%): m/z 392 [M+H]+ (ES+), 390 [M- H]- (ES ). H NMR (400 MHz, CDCI3) delta: 7.98 (1 H, d), 7.78 (1 H, s), 7.59-7.50 (2H, m), 7.40 (2H, dd), 4.67 (1 H, sep), 3.94 (3H, s), 3.89 (3H, s), 2.62 (3H, s), 1.40 (6H, d).
40%
A mixture of 3-chloro-5-isopropoxy-4-methoxybenzoic acid (5) (250 mg, 1.02 mmol), <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (6) (177 mg, 1.07 mmol) and TEA (150 muL, 1.07 mmol) in EtOAc (2.5 mL) was treated with T3P (50% in EtOAc) (1.63 mL, 2.55 mmol) and the mixture was heated at 60 C. for 5 h. The mixture was diluted with DCM (5 mL) and washed with 1M HCl (5 mL) followed by satd. NaHCO3 solution (5 mL). The organic solvents were removed in vacuo and the residue purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane to yield methyl 4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate (7) (167 mg, 40%): m/z 392 [M+H]+ (ES+), 390 [M-H]- (ES-). 1H NMR (400 MHz, CDCl3) delta: 7.98 (1H, d), 7.78 (1H, s), 7.59-7.50 (2H, m), 7.40 (2H, dd), 4.67 (1H, sep), 3.94 (3H, s), 3.89 (3H, s), 2.62 (3H, s), 1.40 (6H, d).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 25 - 60℃; for 20h;
General procedure: Step (viii): Methyl 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoate. A suspension of 217 3-chloro-4-ethoxy 5-isopropoxybenzoic acid (48: R2=iPr, R3=Et) (2.82g, 10.9mmol) and 145 <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (38: R1=Me) (2.16g, 13.1mmol) in 45 ethyl acetate (33mL) was treated with 46 triethylamine (4.56mL, 32.7mmol) followed by 44 T3P (50wt% in ethyl acetate) (17.34mL, 27.3mmol) and the mixture was heated at 60C for 4h and allowed to cool to room temperature for 16h. The reaction mixture was stirred vigorously with an aqueous solution of 218 sodium hydrogencarbonate (50mL) for 10min and separated. The aqueous layer was extracted with dichloromethane (3×100mL) and the combined organic phases were dried (magnesium sulfate), filtered concentrated in vacuo and the residue purified by silica gel chromatography (40g, 0:50:50 to 20:40:40 ethyl acetate:120 dichloromethane:isohexane) to produce 219 methyl 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoate as a beige solid (3.24g, 70% yield).
rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino}-2-methylbenzoic acid[ No CAS ]
rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino}-2-methylbenzoic acid methyl ester[ No CAS ]
In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
To a mixture of <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (208.9 mg, 1.230 mmol) in.N,N-dimethyl formamide (5 mL) was added 1,1'-carbonyldiimidazole (Aldrich, 215 mg, 1.29 mmol). After it was stirred at rt overnight under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-[(Imidazole-1-carbonyl)-amino]-2-methyl-benzoic acid methyl ester (342.0 mg) which was used without further purification.
Methyl 4-amino-2-methylbenzoate (5.0 g, 30 mmol) is initially charged in water (25 ml), concentrated hydrochloric acid (50 ml) is added and the mixture is stirred at room temperature for 30 min. The reaction mixture is cooled to 0 C., and a solution of sodium nitrite (2.72 g, 39.3 mmol) in water (25 ml) is slowly added dropwise. The mixture is stirred at 0 C. for one hour, and tin(II) chloride dihydrate (20.5 g, 90.8 mmol) in concentrated hydrochloric acid (100 ml) is then added dropwise at 0 C. The mixture is stirred initially at 0 C. for 30 min and then at room temperature for 1.5 h. The reaction mixture is diluted with water (50 ml), and the precipitate is filtered off and washed with a little water. The filtrate is poured into ice-water, adjusted to pH 8-9 using semiconcentrated aqueous sodium hydroxide solution and extracted twice with dichloromethane. The organic phases are combined and dried over sodium sulfate. Removal of the solvent under reduced pressure gives methyl 4-hydrazino-2-methylbenzoate (4.1 g, 22.8 mmol, 70%) which is used without further purification for the next step.log P(HCOOH): 0.401H NMR (DMSO-d6): 7.67 (d, 1H, J=8.8 Hz), 7.19 (s, 1H), 6.61-6.58 (m, 2H), 4.03 (s, 2H), 3.71 (s, 3H), 2.44 (s, 3H)
Intermediate 7.5.2 4-tert-Butoxycarbonylamino-2-methyl-benzoic acid methyl esterTo a stirred solution of intermediate 7.5.1 (1 .5 g) in dioxane (15 ml) at 10C was added a solution of Boc anhydride (2.2 g) in dioxane (15 ml) dropwise and the reaction allowed to warm to rt. After 3 h, dimethylaminopyridine (catalytic amount) was added. After overnight stirring, the mixture was concentrated, and the residue was purified by flash chromatography (dichloromethan with ethanol gradient 0 to 4 %) affording 0.69 g of the title compound. ESI mass spectrum: [M+H]+ = 266
dmap; In 1,4-dioxane; at 10 - 20℃;
Intermediate 7.5.24-tert-Butoxycarbonylamino-2-methyl-benzoic acid methyl esterTo a stirred solution of intermediate 7.5.1 (1.5 g) in dioxane (15 ml) at 10 C. was added a solution of Boc anhydride (2.2 g) in dioxane (15 ml) dropwise and the reaction allowed to warm to rt. After 3 h, dimethylaminopyridine (catalytic amount) was added. After overnight stirring, the mixture was concentrated, and the residue was purified by flash chromatography (dichloromethan with ethanol gradient 0 to 4%) affording 0.69 g of the title compound.ESI mass spectrum: [M+H]+=266
(R)-1-(3-((4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methylphenyl)amino)-3-oxopropyl)piperidin-4-yl [1,1′-biphenyl]-2-ylcarbamate trifluoroacetic acid salt[ No CAS ]
With hydrogenchloride; sodium carbonate; sodium nitrite; In water; at 0 - 100℃; for 19h;
Methyl 4-amino-2-methylbenzoate (1 ) (4.14 g, 25.1 mmol) was suspended in cone. HCI (20 ml.) and H20 (100 ml.) and stirred at 0C. A solution of sodium nitrite (1 .73 g, 25.1 mmol) in H20 (50 ml.) was slowly added to the suspension such that the (0587) temperature was maintained at 0-5C. The mixture was made basic by the addition of aq. Na2C03 and added dropwise to a stirring mixture of potassium cyanide (1 .88 g, (0588) 28.8 mmol) and copper (I) cyanide (2.58 g, 28.8 mmol) in H20 (200 ml.) at 0-5C. The mixture was stirred at 0-5C for 0.5 h, then was warmed to RT and stirred for 18 h. The mixture was stirred at 100C for 0.5 h and then cooled to RT and treated with 10% aq. FeC solution (250 ml_). The product was extracted with EtOAc (600 ml.) and the organic solution was washed with brine (500 ml_), dried over Na2S04, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (120 g cartridge, 0-10% EtOAc in isohexane) to afford a red solid. The product was recrystallised from isohexane/EtOAc to give the title compound (2) (2.58 g, 59%) as an orange solid: 1 H NMR (400 MHz, CDCI3) delta: 7.97 (1 H, dd), 7.58 - 7.50 (2H, m), 3.93 (3H, s), 2.62 (3H, s)
Step 1: A stirred solution of compound 14 (1.0 g, 6.1 mmol) in acetic acid (10 mL) was treated dropwise with a solution of bromine (1.5 mL, 12 mmol) in acetic acid (5 mL). On completion of the addition, the resultant suspension was stirred at room temperature for 30 minutes, then water (50 mL) was added. A thick white ppt formed which was filtered, washed with water (3x50 mL) and air dried. The solid still contained water, so it was dissolved in dichloromethane and the solution was dried by passing through a hydrophobic frit. Evaporation of the solvent under reduced pressure afforded compound 15 as a cream solid (1.90 g). 1H NMR (400MHz, CDC13) delta 8.02 (s, 1H), 6.23 (br. s., 2H), 3.85 (s, 3H), 2.67 (s, 3H)
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 5 - 7℃; for 0.583333h;Cooling with ice;
Methyl-4-amino-2-methyl-benzoate (500 mg, 3.03 mmol) In dimethylformamide (10 mL) was cooled to 5 C in an ice bath, And N-bromosuccinimide (540 mg, 3.03 mmol) was added in portions over a period of 5 minutes, While maintaining the temperature between 5 C and 7 C. The clear pale yellow reaction mixture was stirred in an ice bath for an additional 30 min and then poured into water. Forming a dense white precipitate, to its extraction in diethyl ether. The the ether raises extract separated, washed with water, dried by anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, to produce methyl 4 - amino -3 - bromo -2 - methyl - phenylboronic acid ester and methyl 4 - amino -5 - bromo -2 - methyl - phenylboronic acid ester which can not be separated 60:40 mixture, its directly used for the next step.,
methyl 8-bromo-7-methylquinoline-6-carboxylate[ No CAS ]
methyl 5-bromo-7-methylquinoline-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Methyl-4-amino-2-methyl-benzoate (500 mg, 3.03 mmol) In dimethylformamide (10 mL) was cooled to 5 C in an ice bath, And N-bromosuccinimide (540 mg, 3.03 mmol) was added in portions over a period of 5 minutes, While maintaining the temperature between 5 C and 7 C. The clear pale yellow reaction mixture was stirred in an ice bath for an additional 30 min and then poured into water. Forming a dense white precipitate, to its extraction in diethyl ether. The the ether raises extract separated, washed with water, dried by anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, to produce methyl 4 - amino -3 - bromo -2 - methyl - phenylboronic acid ester and methyl 4 - amino -5 - bromo -2 - methyl - phenylboronic acid ester which can not be separated 60:40 mixture, its directly used for the next step., Methyl 4 - amino -3 - bromo -2 - methyl - phenylboronic acid ester and methyl 4 - amino -5 - bromo -2 - methyl - phenylboronic acid ester 60:40 mixture (200 mg, 0 . 82mmol) in n-butanol (5 ml, 55mmol) for stirring the suspension in concentrated hydrochloric acid (0.2 ml) and tetrachloro-P-benzoquinone (200 mg, 0 . 81mmol) processing. Then the resulting slurry is heated to 100 C, and dropwise added c -2 - activated olefinic ketones (acrolein) (0.1 ml, 1mmol). Continue to heating in addition of 30min, the mixture is then cooled and in distribution between water and methylene chloride. Through evaporation under reduced pressure the dichloromethane layer on the adsorption to the silica gel, and by fast chromatography (silica, ethyl acetate/isohexane gradient elution) separation, provide is amber solid methyl 8 - bromo -7 - methyl - quinoline -6 - methyl ester and methyl 8 - bromo -5 - methyl - quinoline -6 - formic ester which can not be separated 60:40 mixture (155 mg).
methyl 8-(4-methylsulfanylphenyl)-7-methylquinoline-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
190 mg
General procedure: Methyl-4-amino-2-methyl-benzoate (500 mg, 3.03 mmol) In dimethylformamide (10 mL) was cooled to 5 C in an ice bath, And N-bromosuccinimide (540 mg, 3.03 mmol) was added in portions over a period of 5 minutes, While maintaining the temperature between 5 C and 7 C. The clear pale yellow reaction mixture was stirred in an ice bath for an additional 30 min and then poured into water. Forming a dense white precipitate, to its extraction in diethyl ether. The the ether raises extract separated, washed with water, dried by anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure, to produce methyl 4 - amino -3 - bromo -2 - methyl - phenylboronic acid ester and methyl 4 - amino -5 - bromo -2 - methyl - phenylboronic acid ester which can not be separated 60:40 mixture, its directly used for the next step., Methyl 4 - amino -3 - bromo -2 - methyl - phenylboronic acid ester and methyl 4 - amino -5 - bromo -2 - methyl - phenylboronic acid ester 60:40 mixture (200 mg, 0 . 82mmol) in n-butanol (5 ml, 55mmol) for stirring the suspension in concentrated hydrochloric acid (0.2 ml) and tetrachloro-P-benzoquinone (200 mg, 0 . 81mmol) processing. Then the resulting slurry is heated to 100 C, and dropwise added c -2 - activated olefinic ketones (acrolein) (0.1 ml, 1mmol). Continue to heating in addition of 30min, the mixture is then cooled and in distribution between water and methylene chloride. Through evaporation under reduced pressure the dichloromethane layer on the adsorption to the silica gel, and by fast chromatography (silica, ethyl acetate/isohexane gradient elution) separation, provide is amber solid methyl 8 - bromo -7 - methyl - quinoline -6 - methyl ester and methyl 8 - bromo -5 - methyl - quinoline -6 - formic ester which can not be separated 60:40 mixture (155 mg).4-methylsulfanylphenyl) -7-methyl-quinoline-6-carboxylate Methyl-8-bromo-7-methyl-quinoline-6-carboxylate and methyl 8-bromo-5-methyl-quinone in a 20 ml microwave vial (310 mg, 1.14 mmol) in tert-butanol (10 mL) was treated with potassium phosphate (610(610 mg, 2 . 79mmol), 2 - bicyclic hexyl phosphine -2 ', 6' - dimethoxy biphenyl (S - Phos: 90 mg, 0 . 069mmol), tris(dibenzylidene acetone) dipalladium (0) (50 mg, 0 . 053mmol) and 4 - methyl sulfanyl phenyl boronic acid (270 mg, 1 . 61mmol) processing, nitrogen cover. The small on the bottle cap, the reaction mixture through the microwave heating to 100 C sustained 45min. The cooled mixture through hyflo filter, and dichloromethane is used for washing produce yellow filtrate, on the adsorption to the silica gel, and by fast chromatography (silica, ethyl acetate/isohexane gradient elution) purification, provide is amber solid methyl 8 - (4 - methyl sulfanyl-phenyl) -7 - methyl - quinoline -6 - a ester (190 mg).
Step 1. Synthesis of methyl 4-amino-2-methylbenzoate To a solution of <strong>[2486-75-1]4-amino-2-methylbenzoic acid</strong> (1.00 g, 6.60 mmol) in 18 mL of methanol was treated concentrated HCl (2.30 mL, 27.6 mmol) in one portion at r.t. The reaction mixture was refluxed overnight then directly concentrated to give a crude product, which was partitioned between ethyl acetate (50 mL) and saturated NaHCO3(aq) (20 mL). The organic layer was washed with brine (10 mL), dried over MgSO4 and concentrated to give the desired product (930 mg, 85%). 1H NMR (CDCl3, 400 MHz) delta 7.83-7.80 (m, 1H), 6.51-6.48 (m, 2H), 4.15 (br s, 2H), 3.83 (s, 3H), 2.55 (s, 3H).
General procedure: A solution of 143 3,5-dichloro-4-ethoxybenzoic acid (7: R1=Et) (285mg, 1.21mmol) and 144 DIPEA (1.05mL, 6.05mmol) in 35 DMF (2.5mL) was added to 38 HATU (690mg, 1.82mmol) and the orange mixture was stirred for 5min prior to the addition of 145 <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (8: R=R2=Me) (200mg, 1.21mmol) in DMF (1mL). The resulting dark orange solution was stirred for 18h. 2M 117 HCl (10mL) was added and stirring continued for 10min, and then the mixture was extracted with diethyl ether. The organic layer was washed with water (3×15mL), dried over MgSO4, filtered and the solvent was evaporated in vacuo. The yellow residue was purified by silica gel chromatography (40g, 0-100% 45 EtOAc in 136 isohexane) to afford 146 methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (10: R1=Et, R=R2=Me) (267mg, 56%):
3-chloro-4-ethoxy 5-isopropoxybenzoic acid[ No CAS ]
methyl 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 25 - 60℃; for 20h;
Step (viii): Methyl 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoate. A suspension of 217 3-chloro-4-ethoxy 5-isopropoxybenzoic acid (48: R2=iPr, R3=Et) (2.82g, 10.9mmol) and 145 <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (38: R1=Me) (2.16g, 13.1mmol) in 45 ethyl acetate (33mL) was treated with 46 triethylamine (4.56mL, 32.7mmol) followed by 44 T3P (50wt% in ethyl acetate) (17.34mL, 27.3mmol) and the mixture was heated at 60C for 4h and allowed to cool to room temperature for 16h. The reaction mixture was stirred vigorously with an aqueous solution of 218 sodium hydrogencarbonate (50mL) for 10min and separated. The aqueous layer was extracted with dichloromethane (3×100mL) and the combined organic phases were dried (magnesium sulfate), filtered concentrated in vacuo and the residue purified by silica gel chromatography (40g, 0:50:50 to 20:40:40 ethyl acetate:120 dichloromethane:isohexane) to produce 219 methyl 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoate as a beige solid (3.24g, 70% yield). 1H NMR (400MHz, CDCl3) delta 8.0 (1H, d, J=8.4Hz), 7.8 (1H, s), 7.59-7.50 (2H, m), 7.43-7.36 (2H, m), 4.69-4.73 (1H, m), 4.18 (2H, q, J=7.1Hz), 3.92 (3H, s), 2.6 (3H, s), 1.46-1.37 (9H, m). m/z 406 [M+H]+ (ES+), 404 [M-H]- (ES-).
In dichloromethane; at 25℃; for 12h;Alkaline conditions;
General procedure: A solution of (7: R1=cyclopentyloxy) (100mg, 363mumol) in dichloromethane (5 mL), cooled to 0C, was treated with oxalyl chloride (63.6 muL, 727 mumol), followed by a drop of N,N-dimethylformamide. The resultant mixture was stirred for 1h at room temperature. The solvent was evaporated in vacuo and the residue dissolved in dichloromethane (5 mL) and then treated with a solution of methyl 4-aminobenzoate (8: R2=H, R=Me) (54.9mg, 363mumol) and di-isopropylethylamine (190muL, 1.09mmol) in dichloromethane (5mL). The reaction mixture was stirred for 12 h at room temperature and then partitioned between dichloromethane (20 mL) and aqueous 1M hydrochloric acid (20 mL). The phases were separated, and the organic phase was washed successively with water (2×20 mL), and brine (20 mL), dried over magnesium sulfate, filtered and then the solvent was removed in vacuo. The residue was purified by silica gel chromatography (12 g, 0-100 % ethyl acetate/isohexane) to afford methyl 4-[3,5-dichloro-4-(cyclopentyloxy)benzamido]benzoate (10: R1 = cyclopentyloxy, R2 = H, R =Me) (30mg, 20% yield). 1H NMR (400MHz, CDCl3) delta 8.06 (2H, d, J=8.8Hz,), 7.85 (1H, br s), 7.82 (2H, s), 7.71 (2H, d, J=8.8Hz), 5.07-5.03 (1H, m), 3.92 (3H, s), 2.10-1.90 (4H, m), 1.85-1.70 (2H, m), 1.70-1.60 (2H, m).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 25 - 60℃; for 20h;
General procedure: Step (viii): Methyl 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoate. A suspension of 217 3-chloro-4-ethoxy 5-isopropoxybenzoic acid (48: R2=iPr, R3=Et) (2.82g, 10.9mmol) and 145 <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (38: R1=Me) (2.16g, 13.1mmol) in 45 ethyl acetate (33mL) was treated with 46 triethylamine (4.56mL, 32.7mmol) followed by 44 T3P (50wt% in ethyl acetate) (17.34mL, 27.3mmol) and the mixture was heated at 60C for 4h and allowed to cool to room temperature for 16h. The reaction mixture was stirred vigorously with an aqueous solution of 218 sodium hydrogencarbonate (50mL) for 10min and separated. The aqueous layer was extracted with dichloromethane (3×100mL) and the combined organic phases were dried (magnesium sulfate), filtered concentrated in vacuo and the residue purified by silica gel chromatography (40g, 0:50:50 to 20:40:40 ethyl acetate:120 dichloromethane:isohexane) to produce 219 methyl 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoate as a beige solid (3.24g, 70% yield).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 25 - 60℃; for 20h;
General procedure: Step (viii): Methyl 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoate. A suspension of 217 3-chloro-4-ethoxy 5-isopropoxybenzoic acid (48: R2=iPr, R3=Et) (2.82g, 10.9mmol) and 145 <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (38: R1=Me) (2.16g, 13.1mmol) in 45 ethyl acetate (33mL) was treated with 46 triethylamine (4.56mL, 32.7mmol) followed by 44 T3P (50wt% in ethyl acetate) (17.34mL, 27.3mmol) and the mixture was heated at 60C for 4h and allowed to cool to room temperature for 16h. The reaction mixture was stirred vigorously with an aqueous solution of 218 sodium hydrogencarbonate (50mL) for 10min and separated. The aqueous layer was extracted with dichloromethane (3×100mL) and the combined organic phases were dried (magnesium sulfate), filtered concentrated in vacuo and the residue purified by silica gel chromatography (40g, 0:50:50 to 20:40:40 ethyl acetate:120 dichloromethane:isohexane) to produce 219 methyl 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoate as a beige solid (3.24g, 70% yield).
General procedure: A solution of 143 3,5-dichloro-4-ethoxybenzoic acid (7: R1=Et) (285mg, 1.21mmol) and 144 DIPEA (1.05mL, 6.05mmol) in 35 DMF (2.5mL) was added to 38 HATU (690mg, 1.82mmol) and the orange mixture was stirred for 5min prior to the addition of 145 <strong>[6933-47-7]methyl 4-amino-2-methylbenzoate</strong> (8: R=R2=Me) (200mg, 1.21mmol) in DMF (1mL). The resulting dark orange solution was stirred for 18h. 2M 117 HCl (10mL) was added and stirring continued for 10min, and then the mixture was extracted with diethyl ether. The organic layer was washed with water (3×15mL), dried over MgSO4, filtered and the solvent was evaporated in vacuo. The yellow residue was purified by silica gel chromatography (40g, 0-100% 45 EtOAc in 136 isohexane) to afford 146 methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (10: R1=Et, R=R2=Me) (267mg, 56%):
methyl 2-methyl-4-[(E)-o-tolylazo]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tert-butylhypochlorite; sodium iodide; In tetrahydrofuran; at 0℃; for 6h;
To a solution of 2-methylaniline (454.07 mg, 4.24 mmol, 454.07 muL, 1 eq), <strong>[6933-47-7]methyl 4-amino-2-methyl-benzoate</strong> (1 g, 6.05 mmol, 1.43 eq), NaI (2.54 g, 16.95 mmol, 4 eq) in THF (70 mL) was added tert-butyl hypochlorite (1.84 g, 16.95 mmol, 4 eq) at 0 C. The mixture was stirred at 0 C. for 6 h. The reaction mixture was quenched by addition of water (100 mL), extracted with EtOAc (80 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc=1/0 to 5/1, TLC: PE/EtOAc=5/1, Rf=0.62) to yield methyl 2-methyl-4-[(E)-o-tolylazo]benzoate (120 mg, 384.63 umol, 9.1% yield, 86.0% purity) as yellow oil. 1H NMR (400 MHz, CD3OD) delta ppm 8.05 (d, J=8.6 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.62 (dd, J=7.8, 17.3 Hz, 1H), 7.43-7.36 (m, 2H), 7.29-7.26 (m, 1H), 3.92 (s, 3H), 2.75-2.72 (m, 3H), 2.68 (s, 3H); ES-LCMS m/z 269.1 [M+H]+.
tert-butyl 7-amino-2-azaspiro[4.4]nonane-2-carboxylate[ No CAS ]
C21H30N2O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With methanol; nido-decaborane; at 50℃;
General procedure: To a stirred solution of tert-butyl 2-formyl-6-azaspiro[3.4]octane-6-carboxylate (CAS: 203662-55-9) (225 mg, 1.0 mmol) and 2-(3-aminopheny])acetonitrile (CAS: 4623-249) (136 mg, 1.03 mmol) in MeOH (10 mL) at room temperature was added decaborane (43 mg, 0.35 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified bysilica gel chromatography eluted with PE/EtOAc(3/1,v/v) to afford intermediate 119 (340 mg, 99% yield) as a yellow solid. Intermediate 178 was prepared via an analogous reaction protocol as described forthe preparation of intermediate 119, starting from the respective starting materials.
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