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Structure of 4892-02-8 * Storage: {[proInfo.prStorage]}
* 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 potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.283333 h; Inert atmosphere
Intermediate 6: Ethyl-3-hydroxybenzo[6]thiophene-2-carboxylate To a solution of methyl-2-mercaptobenzoate (1.63 mL, 1 1.9 mmol) and ethyl bromoacetate (1.32 mL, 1 1.9 mmol) in dry tetrahydrofuran (130 mL) at 0 °C was added potassium fert-butoxide (5.14 g, 71.3 mmol) gradually over 2 min. The reaction mixture was stirred and allowed to warm to room temperature over 15 min, quenched with 2 M hydrochloric acid to pH 2 and diluted with 75 mL water. The product was immediately extracted with 3 χ 75 mL portions of ethyl acetate. The organic layers were combined, washed with 75 mL brine, dried over magnesium sulfate and concentrated under reduced pressure to give desired product as a yellow solid (2.32 g, 88percent). 3) 10.21 (IH, s), 7.94 (IH), 7.74 (IH), 7.50 (IH), 7.41 (IH), 4.43 (2H), 1.43 (3H).
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1959 - 1970
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 1, p. 371 - 375
3
[ 67-56-1 ]
[ 147-93-3 ]
[ 4892-02-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
With sulfuric acid In water at 5℃; Reflux
Example 1: Preparation of methyl 2-[6-(1-bromo-ethyl)-5-fluoropyrimidin-4-yl-sulfanyl]benzoate (Preparation of compound of formula 2 with substitution of -CO2CH3 at the ortho position); Step 1) Preparation of methyl 2-mercaptobenzoate A mixed solution of 40g of 2-mercaptobenzoic acid and 600mL of methanol was cooled to 5.box. and 42mL of sulfuric acid was added dropwise thereto over 10 minutes. After being refluxed for 14 hours, the reaction liquid was concentrated under reduced pressure. The concentrate was diluted with 400mL of methylene chloride and 400mL of purified water and then the organic layer was separated. The organic layer was successively washed with 200mL of a saturated sodium bicarbonate solution and 400mL of brine and then dried over anhydrous sodium sulfate. After the organic layer was concentrated, the resulting residue was subjected to fractional distillation (118.box./7mmHg) to afford 42g (yield: 96percent) of the title compound as a clear oil. 1H-NMR (200MHz, CDCl3) δ (ppm): 8.01 (d,1H), 7.30 (d,2H), 7.14 (m,1H), 4.68 (s,SH), 3.91 (S,3H)
95%
Reflux
General procedure: To a solution of thiosalicilic acid 1 (15.4 g, 100 mmol) in methanol (600 mL) neat 98percent H2SO4 (10 mL) was added and the reaction mixture was heated at reflux for 72 h (TLC inn-hexanes/AcOEt 7:3), poured into cold H2O (500 mL) and the organics were extracted from acidic (by diluted HCl) water (pH<3) in CHCl3 (3 x 500 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness in vacuo. After flash chromatographic purification of the crude (n-hexane/ethyl acetate 7:3), methyl 2-mercaptobenzoate (3) was isolated as a colorless solid (15.9 g, 95percent). ESI-MS (m/z): 167 [M-H]+;. 1H and 13C NMR data were similar to those of the alreadydescribed compound. To a solution of 3 (15.9 g, 95.0 mmol) in CCl4(100 mL) at 0 °C, neat Br2 (7.82 g, 50.0 mmol) in CCl4 (250 mL) was added dropwise in 30 min. The reaction mixture was stirred at rt for additional 30 min while a colorless precipitate formed and was filtered to give the title compound 4 (28.5 g, 90percent).
94%
for 48 h; Reflux
Step 3: Methyl 2-mercaptobenzoate (18c)To a solution of 2-mercaptobenzoic acid (34 g, 220 mmol) in dry MeOH (150 mL) was added cone. H2S04 (4 mL) and the reaction was refluxed for 48 h. The solution was concentrated under reduced pressure and the residue was diluted with DCM and then sat. NaHC03 solution. The organic phase was washed with brine, dried over Na2S04 and concentrated under reduced pressure to give compound 18c (35 g, 94percent) as a yellow oil.
89.6%
With sulfuric acid In water for 48 h; Heating / reflux
Acid 1 (170.0 g, 1.1 mol), H2SO4 (20 mL, 0.37 mol) and anhydrous MeOH (300 mL) were refluxed for 2 days. The solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with CH2Cl2 (3.x.1000 mL). The organic layers were combined, washed with aq. NaHCO3 (2.x.300 mL), water (2.x.250 mL), brine (500 mL) and dried over Na2SO4 to afford crude compound 2 (165.0 g, 89.6percent). This was used without further purification.
64%
for 72 h; Heating / reflux
o-Mercaptobenzoic acid (9.9 g, 64.2 mmol) was dissolved in methanol (300 ml) and concentrated sulfuric acid (0.5 ml) added. The reaction mixture was refluxed for 72 h. Chloroform (300 ml) was added and the resultant mixture extracted with water (two-100 ml aliquots) and 1percent sodium hydroxide (two-100 ml aliquots). The combined aqueous layers were added to chloroform (75 ml), ice (100 ml) and concentrated hydrochloric acid (8 ml). Chloroform (150 ml) was added, the layers separated, the organic layer dried (MgSO4) and filtered. The solvent was evaporated and the residue rectified at reduced pressure affording clean o-mercapto methyl benzoate (6.9 g, 41.0 mmol, 64percent), b.p. 103-108° C./2.7 Torr. l.r. (liquid film) 1710 cm-1. 1H n.m.r. (270 MHz) δ7.99, d, 1H; 7.29, d, 1H; 7.14, m, 2H; 4.68, s, 1H; 3.90, s, 3H. 13C n.m.r. δ167.09, 138.27, 132.45, 131.65, 130.86, 125.74, 124.62, 52.19. m/z 168 (21percent, M+), 136 (100percent), 108 (35percent).
Reference：
[1] Patent: EP2444398, 2012, A2, . Location in patent: Page/Page column 9
[2] Tetrahedron, 2017, vol. 73, # 13, p. 1745 - 1761
[3] Patent: WO2013/64231, 2013, A1, . Location in patent: Page/Page column 62
[4] Journal of Medicinal Chemistry, 2018,
[5] Patent: US2007/167497, 2007, A1, . Location in patent: Page/Page column 28
[6] Chemical Biology and Drug Design, 2015, vol. 85, # 2, p. 145 - 152
[7] Chemische Berichte, 1987, vol. 120, p. 1151 - 1174
[8] Journal of Medicinal Chemistry, 1993, vol. 36, # 10, p. 1387 - 1392
[9] European Journal of Medicinal Chemistry, 1999, vol. 34, # 11, p. 895 - 901
[10] Australian Journal of Chemistry, 2000, vol. 53, # 1, p. 1 - 5
[11] Patent: US2003/220524, 2003, A1, . Location in patent: Page/Page column 25
[12] Tetrahedron Asymmetry, 2010, vol. 21, # 2, p. 241 - 246
[13] Chemische Berichte, 1899, vol. 32, p. 1156
[14] Justus Liebigs Annalen der Chemie, 1907, vol. 351, p. 413
[15] Canadian Journal of Chemistry, 1965, vol. 43, p. 3221 - 3231
[16] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 2, p. 269 - 272
[17] Journal of the American Chemical Society, 1980, vol. 102, p. 2519
[18] Biological and Pharmaceutical Bulletin, 2000, vol. 23, # 2, p. 254 - 256
[19] Synthetic Communications, 2006, vol. 36, # 10, p. 1419 - 1429
[20] Australian Journal of Chemistry, 2008, vol. 61, # 7, p. 484 - 499
[21] Journal of Organic Chemistry, 2008, vol. 73, # 20, p. 8057 - 8068
[22] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7193 - 7196
[23] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5031 - 5034
[24] Medicinal Chemistry Research, 2013, vol. 22, # 3, p. 1305 - 1312
[25] Patent: US2013/90328, 2013, A1, . Location in patent: Paragraph 0102; 0103
[26] Patent: WO2013/53658, 2013, A1, . Location in patent: Page/Page column 15
4
[ 7283-41-2 ]
[ 4892-02-8 ]
Yield
Reaction Conditions
Operation in experiment
85%
With oxalyl dichloride In methanol for 6 h; Reflux
To a methanol solution (50mL) of 6 (5.00g, 32.5mmol), SOCl2 was added slowly and the mixture was stirred at 0°C for 1h. The obtained mixture was then heated to reflux for 6h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50mL), and washed with saturated NaHCO3 (50mL×2) and brine, dried with anhydrous Na2SO4. The crude product was purified by silica gel chromatography (petroleum ether–ethyl acetate=40:1 v/v as the eluent) to afford compound 7 as a colorless liquid (4.62g, 85percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 374 - 380
[2] Patent: US5104882, 1992, A,
5
[ 152766-18-2 ]
[ 4892-02-8 ]
Reference：
[1] Synlett, 2001, # 12, p. 1956 - 1958
1.1 Step 1) Preparation of methyl 2-mercaptobenzoate
Example 1: Preparation of methyl 2-[6-(1-bromo-ethyl)-5-fluoropyrimidin-4-yl-sulfanyl]benzoate (Preparation of compound of formula 2 with substitution of -CO2CH3 at the ortho position); Step 1) Preparation of methyl 2-mercaptobenzoate A mixed solution of 40g of 2-mercaptobenzoic acid and 600mL of methanol was cooled to 5 and 42mL of sulfuric acid was added dropwise thereto over 10 minutes. After being refluxed for 14 hours, the reaction liquid was concentrated under reduced pressure. The concentrate was diluted with 400mL of methylene chloride and 400mL of purified water and then the organic layer was separated. The organic layer was successively washed with 200mL of a saturated sodium bicarbonate solution and 400mL of brine and then dried over anhydrous sodium sulfate. After the organic layer was concentrated, the resulting residue was subjected to fractional distillation (118 /7mmHg) to afford 42g (yield: 96%) of the title compound as a clear oil. 1H-NMR (200MHz, CDCl3) δ (ppm): 8.01 (d,1H), 7.30 (d,2H), 7.14 (m,1H), 4.68 (s,SH), 3.91 (S,3H)
95%
With sulfuric acid Reflux;
4.2.1.1. Synthesis of dimethyl 2,2'-disulfanediyldibenzoate (4). Route 2.
General procedure: To a solution of thiosalicilic acid 1 (15.4 g, 100 mmol) in methanol (600 mL) neat 98% H2SO4 (10 mL) was added and the reaction mixture was heated at reflux for 72 h (TLC inn-hexanes/AcOEt 7:3), poured into cold H2O (500 mL) and the organics were extracted from acidic (by diluted HCl) water (pH<3) in CHCl3 (3 x 500 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness in vacuo. After flash chromatographic purification of the crude (n-hexane/ethyl acetate 7:3), methyl 2-mercaptobenzoate (3) was isolated as a colorless solid (15.9 g, 95%). ESI-MS (m/z): 167 [M-H]+;. 1H and 13C NMR data were similar to those of the alreadydescribed compound. To a solution of 3 (15.9 g, 95.0 mmol) in CCl4(100 mL) at 0 °C, neat Br2 (7.82 g, 50.0 mmol) in CCl4 (250 mL) was added dropwise in 30 min. The reaction mixture was stirred at rt for additional 30 min while a colorless precipitate formed and was filtered to give the title compound 4 (28.5 g, 90%).
94%
With sulfuric acid for 48h; Reflux;
18.3 Step 3: Methyl 2-mercaptobenzoate (18c)
Step 3: Methyl 2-mercaptobenzoate (18c)To a solution of 2-mercaptobenzoic acid (34 g, 220 mmol) in dry MeOH (150 mL) was added cone. H2S04 (4 mL) and the reaction was refluxed for 48 h. The solution was concentrated under reduced pressure and the residue was diluted with DCM and then sat. NaHC03 solution. The organic phase was washed with brine, dried over Na2S04 and concentrated under reduced pressure to give compound 18c (35 g, 94%) as a yellow oil.
91%
With sulfuric acid at 0℃; for 18h; Inert atmosphere; Reflux;
89.6%
With sulfuric acid In water for 48h; Heating / reflux;
F.1 Synthesis of N-(1,1-dimethyl-2-morpholin-4-ylethyl)-2-[(pyridin-3-ylmethyl)sulfinyl]benzamide
Acid 1 (170.0 g, 1.1 mol), H2SO4 (20 mL, 0.37 mol) and anhydrous MeOH (300 mL) were refluxed for 2 days. The solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with CH2Cl2 (3×1000 mL). The organic layers were combined, washed with aq. NaHCO3 (2×300 mL), water (2×250 mL), brine (500 mL) and dried over Na2SO4 to afford crude compound 2 (165.0 g, 89.6%). This was used without further purification.
85%
With thionyl chloride at 0℃; for 8h; Reflux;
80%
With hydrogenchloride for 10h; Heating;
75%
With hydrogenchloride for 16h; Heating;
73%
With toluene-4-sulfonic acid In toluene for 48h; Heating;
64%
With sulfuric acid for 72h; Heating;
64%
With sulfuric acid for 72h; Heating / reflux;
o-Mercaptobenzoic acid (9.9 g, 64.2 mmol) was dissolved in methanol (300 ml) and concentrated sulfuric acid (0.5 ml) added. The reaction mixture was refluxed for 72 h. Chloroform (300 ml) was added and the resultant mixture extracted with water (two-100 ml aliquots) and 1% sodium hydroxide (two-100 ml aliquots). The combined aqueous layers were added to chloroform (75 ml), ice (100 ml) and concentrated hydrochloric acid (8 ml). Chloroform (150 ml) was added, the layers separated, the organic layer dried (MgSO4) and filtered. The solvent was evaporated and the residue rectified at reduced pressure affording clean o-mercapto methyl benzoate (6.9 g, 41.0 mmol, 64%), b.p. 103-108° C./2.7 Torr. l.r. (liquid film) 1710 cm-1. 1H n.m.r. (270 MHz) δ7.99, d, 1H; 7.29, d, 1H; 7.14, m, 2H; 4.68, s, 1H; 3.90, s, 3H. 13C n.m.r. δ167.09, 138.27, 132.45, 131.65, 130.86, 125.74, 124.62, 52.19. m/z 168 (21%, M+), 136 (100%), 108 (35%).
43%
With sulfuric acid for 24h; Inert atmosphere; Reflux;
With hydrogenchloride
With sulfuric acid
With sulfuric acid for 18h; Heating;
With hydrogenchloride
With sulfuric acid Heating;
With thionyl chloride Heating;
With hydrogenchloride for 22h; Heating;
Acidic conditions;
With sulfuric acid for 18h; Reflux; Inert atmosphere;
Preparation of methyl 3-hydroxybenzo[b]thiophene-2-carboxylate 3a.
A suspension of thiosalicylic acid (7.71 g, 50 mmol) in a mixture of methanol and sulfuric acid (95:5, 125 mL) was refluxed under nitrogen for 18 h. The reaction mixture was evaporated under reduced pressure and water (100 mL) was added. Subsequently, solid NaHCO3 was added until pH ~9 and the mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The residue was dissolved in THF (100 mL). Next, methyl chloroacetate (6.51 g, 60 mmol), N,N-diisopropylethylamine (7.75 g, 60 mmol) and potassium iodide (0.33 g, 2 mmol) were added and the reaction mixture was stirred for 2 days at room temperature. Upon completion of the reaction according to TLC analysis, the precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was treated with 1 N NaOH (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with 1 N HCl (2 × 50 mL), dried over MgSO4 and evaporated. The crude oil was crystallized from diethyl ether/hexane to afford 2.
With sulfuric acid for 6h; Reflux;
With sulfuric acid In methanol at 0℃; for 18h; Inert atmosphere; Reflux;
Step 1. Preparation of Methyl 2-sulfanylbenzoate
To a cooled solution of concentrated sulfuric acid (72 g) in methanol (1.5 L) at 0° C., was added 2-sulfanylbenzoic acid (300 g, 1.95 mol) in portions under argon atmosphere. After being refluxed with stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with water (800 mL), basified with a saturated aqueous solution of sodium bicarbonate to about pH 7, and extracted with dichloromethane (600 mL*3). The combined organic layers were washed with brine (800 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 300 g of methyl 2-sulfanylbenzoate (yield was 90%) as a light yellow oil, which was used for the next step without further purification.
With sulfuric acid at 0℃; for 18h; Inert atmosphere; Reflux; Large scale;
1.1 Step 1. Preparation of Methyl 2-sulfanylbenzoate
Step 1. Preparation of Methyl 2-sulfanylbenzoateTo a cooled solution of concentrated sulfuric acid (72 g) in methanol (1.5 L) at 0 °C, was added 2-sulfanylbenzoic acid (300 g, 1.95 mol) in portions under argon atmosphere. After being refluxed with stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with water (800 mL), basified with a saturated aqueous solution of sodiumbicarbonate to about pH 7, and extracted with dichloromethane (600 mL x 3). The combined organic layers were washed with brine (800 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 300 g of methyl 2-sulfanylbenzoate (yield was 90%) as a light yellow oil, which was used for the next step without further purification.
With cobalt(II)phthalocyanine-tetra-sodium sulfonate In water at 60℃; for 12h; Schlenk technique;
97%
With pyridinium chlorochromate In dichloromethane at 20℃; for 0.9h;
97%
With chlorosulphuric acid; silica gel; sodium nitrite In dichloromethane at 20℃; for 0.0333333h;
97%
With manganese(II)carbonate; 3,4,5-trihydroxybenzoic acid; oxygen; sodium carbonate In water at 80℃; for 4h; Schlenk technique; Green chemistry;
96%
With tetramethylammonium chlorochromate In acetonitrile for 0.8h; Heating;
96%
With benzyltriphenylphosphonium peroxodisulfate In acetonitrile for 0.8h; Heating;
96%
With 1-butyl-4-aza-1-azoniabicyclo[2.2.2]octane dichromate In acetonitrile for 0.8h; Heating;
95%
With bromine In tetrachloromethane at 0 - 20℃; for 1h;
4.2.1.1. Synthesis of dimethyl 2,2'-disulfanediyldibenzoate (4). Route 2.
General procedure: To a solution of thiosalicilic acid 1 (15.4 g, 100 mmol) in methanol (600 mL) neat 98% H2SO4 (10 mL) was added and the reaction mixture was heated at reflux for 72 h (TLC inn-hexanes/AcOEt 7:3), poured into cold H2O (500 mL) and the organics were extracted from acidic (by diluted HCl) water (pH<3) in CHCl3 (3 x 500 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness in vacuo. After flash chromatographic purification of the crude (n-hexane/ethyl acetate 7:3), methyl 2-mercaptobenzoate (3) was isolated as a colorless solid (15.9 g, 95%). ESI-MS (m/z): 167 [M-H]+;. 1H and 13C NMR data were similar to those of the alreadydescribed compound. To a solution of 3 (15.9 g, 95.0 mmol) in CCl4(100 mL) at 0 °C, neat Br2 (7.82 g, 50.0 mmol) in CCl4 (250 mL) was added dropwise in 30 min. The reaction mixture was stirred at rt for additional 30 min while a colorless precipitate formed and was filtered to give the title compound 4 (28.5 g, 90%).
94%
With Oxone; silica gel In acetonitrile at 20℃;
93%
With formic acid; 5-ethyl-10-(2-hydroxylethyl)-3,7,8-trimethylisoalloxazin-5-ium triflate; oxygen; triethylamine In acetonitrile at 60℃; for 4h;
91%
With dipotassium peroxodisulfate; 1-n-butyl-3-methylimidazolim bromide at 65 - 70℃; for 0.166667h;
90%
With piperazinium dichromate In chloroform for 8h; Heating;
89%
With nicotinic acid hydrobromide perbromide at 20℃; for 0.25h; Neat (no solvent);
85%
With air In water; acetonitrile for 10h; Ambient temperature; mushroom tyrosinase;
58%
With tetra-O-acetyl riboflavin; iodine In <i>tert</i>-butyl alcohol at 26℃; for 24h; Darkness; Green chemistry;
Dioctyl Disulfide (3a): Typical Procedure
General procedure: A mixture of octane-1-thiol (2a; 73.1 mg, 0.50 mmol), flavin 1a(13.6 mg, 0.025 mmol), I2 (6.35 mg, 0.025 mmol), and t-BuOH(1.0 mL) was stirred at 26 °C (water bath) for 8 h under air (1atm, balloon) in the dark. The solvent was then evaporated andthe residue was purified by column chromatography (silica gel,CHCl3) to give a colorless oil: yield: 70.7 mg (97%).
With ethanol; iron(III) chloride
Multi-step reaction with 2 steps
1.1: Na / methanol
1.2: 40 percent / acetone / 1 h / 20 °C
2.1: Na / methanol
2.2: 21 percent / acetone / 1 h / 20 °C
Multi-step reaction with 2 steps
1.1: SO2Cl2 / CH2Cl2 / 0.5 h / Heating
1.2: 74 percent / pyridine / CH2Cl2 / 20 °C
2.1: Na / methanol
2.2: 20 percent / acetone / 1 h / 20 °C
With potassium carbonate In acetonitrile at 20℃; for 1h;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
13.A
To a solution of methyl thiosalicylate (4.0 g, 23.8 mmol) in DMF (25 mL) is added K2CO3 (4.0 g, 28.94 mmol) followed by methyl iodide (2.3 mL, 36.9 mmol). The resulting mixture is stirred at ambient temperature for 1 h. The mixture is diluted with EtOAc and washed with 1 N HCI (3x) and water (1x). The organic phase is dried over MgSO4, filtered and concentrated to afford 2-methylsulfanylbenzoic acid methyl ester.
With triethylamine In N,N-dimethyl-formamide for 1h;
90%
With trimethylamine In tetrahydrofuran at 0 - 20℃; for 2.16667h;
3.1
Example 3; (1S,3'R,4'S,5'S,6'R)-8-[(4-ethylphenyl)methyl]-3,3',4,4',5',6'-hexahydro-6'-hydroxymethyl-spiro[2-oxa-9-thiafluorene-1,2'-[2H]pyran]-3',4',5'-triol; 1) Synthesis of methyl 2-(3-ethoxycarbonyl-2-oxo-propylsulfanyl)-benzoate; [Show Image] Under a nitrogen stream, trimethylamine (10.0 mL, 72.0 mmol) and ethyl 4-chloro-3-oxo-acetate (4.9 mL, 36.0 mmol) were added dropwise at 0°C to a solution (100 mL) of methyl 2-mercapto-benzoate (5.0 g, 30.0 mmol) in THF, and the resultant solution was stirred for 10 minutes. After further stirring for 2 hours at room temperature, the reaction solution was filtered through Celite. Solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution = ethyl acetate:n-hexane (1:2)), to thereby obtain the titled compound (8.02 g, 90%). 1H-NMR (CDCl3) δ: 1.25 (3H, t, J = 7.1 Hz), 3.67 (2H, s), 3.89 (2H, s), 3.93 (3H, s), 4.17 (2H, q, J = 7.1 Hz), 7.18-7.31 (2H, m), 7.42-7.49 (1H, m), 7.98-8.01 (1H, m).
Stage #1: Methyl thiosalicylate With lithium aluminium hydride In tetrahydrofuran at 20℃; for 3h; Inert atmosphere;
Stage #2: With hydrogenchloride In tetrahydrofuran; water monomer; ethyl acetate at 0℃; Inert atmosphere;
With lithium aluminium hydride
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 3.5h;
With potassium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere;
150.150-1 Example 150-1: Synthesis of methyl 2-(benzylthio)benzoate
Methyl 2-mercapto benzoate (818 μl, 5.94 mmol) in DMF (15 ml) solution of Potassium carbonate(904 mg, 6.54 mmol), was added at room temperature (1-bromoethyl) benzene (1.56 ml, 13.08 mmol). After stirring overnight at 90 ° C. argon, concentrated to dryness, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.533 g, 100%).
91%
With diguanidine carbonate In acetone Heating;
With potassium carbonate In N,N-dimethyl-formamide Reflux;
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;
113
To a mixture of 5-chloro-2-nitrofluorobenzene (176 mg, 1 mmol) and methyl thiosalicylate (275 μL, 2 mmol) in DMF (5 mL) was added Cs2CO3 (652 mg, 2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2, washed with water, dried (Na2SO-O, concentrated and flash chromatographed (SiO2, heptane:toluene, 1:10-1:4) to give 300 mg (92%) of the title compound (189JO09). 1H NMR (CDCl3) δ 8.15 (d, 1 H J = 2.4 Hz), 7.94 (m, 1 H), 7.53-7.46 (m, 3 H), 7.34 (dd, 1 H, 2.4, 8.6 Hz), 6.95 (d, 1 H, J = 8.8 Hz), 3.82 (s, 3 H).
73%
With caesium carbonate In N,N-dimethyl-formamide at 40 - 60℃; for 2h;
4
A solution of 4-chloro-l-fluoro-2-nitrobenzene (2.00 g, 0.011 mol) and methyl 2-mercaptobenzoate (3.13 mL, 0.023 mol) in DMF (25 mL) was added Cs2CO3 (7.43 g, 0.023 mol) and the resulting mixture was stirred for 2 hours at 40 0C. The reaction mixture was cooled to room temperature, diluted with DCM, washed with water, dried (Na2SO3), filtered and evaporated to give crude product. Purification by flash chromatography (ethyl EPO acetate/heptane 1:4) gave 2.6 g (73 %) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.15 (IH, m ), 7.94 (IH, m), 7.50 (3H, m), 7.34 (IH, ddd, J = 8.8, 2.8, 0.4 Hz ), 6.95 (IH, d, J = 8.4 Hz), 3.82 (3H, s).
In N,N-dimethyl-formamide at 40℃; for 2h;
With sodium hydroxide In methanol at 20℃; for 2h;
52
Methyl 2-((4-Chloro-2-nitrophenyl)thio)benzoate To a solution of 4-chloro-1-fluoro-2-nitrobenzene (1.1 g, 6.0 mmol) in MeOH (10 ml) was added methyl 2-mercaptobenzoate (1.0 g, 6.0 mmol) and 4M NaOH (1.5 ml, 6.0 mmol) and the reaction was stirred at room temperature for 2 hours, diluted with H2O, and the resulting suspension was filtered and washed with H2O to yield Intermediate 21 as a yellow solid (2.0 g, crude). The crude product was used in the next reaction without further purification.
With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 0.5h;
Methyl 2-mercaptobenzoate (4.67 ml, 34 mmol) was added during 30 min to a mixture of <strong>[367-80-6]ethyl 4-flouro-3-nitrobenzoate</strong> (6.60 g, 30.9 mmol) and Cs2CO3 (10.06 g, 30.9 mol) in DMF (60 mL) at 40 0C. The reaction mixture was diluted with EtOAc, water after additional 15 min (full conversion according to TLC). The aqueous phase was extracted once with EtOAc and the combined organic phases were washed twice with water followed by brine and then dried (Na2SO4). Filtration and concentration of the organic phase at reduce pressure gave a yellow crystalline residue. Recrystallization from EtO Ac/heptane gave 10.3 g (92%) of the titled compound as yellow crystals. 1H NMR (400 MHz, CDCl3) delta 8.82 (d, IH, J = 1.9 Hz), 7.94 (m, 2H), 7.62-7.57 (m, 3H), 6.92 (d, IH, J = 8.6 Hz), 4.38 (q, 2H, J = 7.2 EPO <DP n="55"/>Hz), 3.78 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3); delta 166.8, 164.6, 145.5, 144.1, 137.6, 136.3, 133.4, 133.0, 131.5, 131.3, 130.5, 129.8, 128.1, 126.9, 61.9, 52.7, 14.5.
92%
With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 0.5h;
Methyl 2-mercaptobenzoate (4.67 ml, 34 mmol) was added during 30 min to a mixture of <strong>[367-80-6]ethyl 4-flouro-3-nitrobenzoate</strong> (6.60 g, 30.9 mmol) and Cs2CO3 (10.06 g, 30.9 mol) in DMF (60 mL) at 40 C. The reaction mixture was diluted with EtOAc, water after additional 15 min (full conversion according to TLC). The aqueous phase was extracted once with EtOAc and the combined organic phases were washed twice with water followed by brine and then dried (Na2SO4). Filtration and concentration of the organic phase at reduce pressure gave a yellow crystalline residue. Recrystallization from EtO Ac/heptane gave 10.3 g '(92%) of the titled compound as yellow crystals. 1H <n="85"/>NMR (400 MHz, CDCl3) delta 8.82 (d, 1H, J = 1.9 Hz), 7.94 (m, 2H), 7.62-7.57 (m, 3H), 6.92 (d, 1H, J - 8.6 Hz), 4.38 (q, 2H, J = 7.2 Hz), 3.78 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3); delta 166.8, 164.6, 145.5, 144.1, 137.6, 136.3, 133.4, 133.0, 131.5, 131.3, 130.5, 129.8, 128.1, 126.9, 61.9, 52.7, 14.5.
73%
With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 2h;
A solution of <strong>[367-80-6]ethyl 4-flouro-3-nitrobenzoate</strong> (2.50 g, 11.7 mmol) and methyl 2-mercaptobenzoate (3.95 g, 23.5 mol) in DMF (20 mL) was added Cs2CO3 (7.6 g, 23.5 mol) and the resulting mixture was stirred at 40" C for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water, dried (Na2SO3), filtered and evaporated to give crude product. Recrystallization from EtO Ac/heptane gave 3.1O g (73%) of the title compound as yellow crystals. 1H NMR (400 MHz, CDCl3): delta 8.82 (d, IH, J = 1.9 Hz), 7.94 (m, 2H), 7.62-7.57 (m, 3H), 6.92 (d, IH, J = 8.6 Hz), 4.38 (q, 2H, J = 7.2 Hz), 3.78 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3): delta 166.8, 164.6, 145.5, 144.1, 137.6, 136.3, 133.4, 133.0, 131.5, 131.3, 130.5, 129.8, 128.1, 126.9, 61.9, 52.7, 14.5;
With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 0.666667h;
Examples 2 (Compounds 18-20)[0090] Compounds 18-20 of the invention were synthesized according to the following methods.[0091] To Ethyl 4-fluoro-3-nitrobenzoate (about 1 eq.) and Cs:Ctheta3 (about 1 eq.) in DMF (10.1 ml) methyl 2-mercaptobenzoate (about I eq.) dissolved in DMF (10.1 ml) was added at 40 C during 40 min.. The mixture was diluted with EtOAc and water. The water phase was extracted with EtOAc and the combined organics were dried and concentrated. The obtained crude was recrystallized from EtOAc/Heptane to give ( 13) was dissolved in THF (60 ml) followed by addition of IM lithium hydroxide (20 ml). The two phase system was stirred at 60 C for 24h. The reaction mixture was allowed to cool to room temperature and the aqueous phase treated with 2M HCl and a formed precipitate was filtered, washed with water and dried under reduced pressure. The crude product (14) was was taken up in MeOH (10 ml) and Pd/C (5%. wet) and platinum oxide was added. Hydrogen was added the reaction chamber evacuated and refilled with hydrogen several times. The mixture was stirred for 16h at room temperature under argon atmosphere. The mixture was filtered through celite and washed with MeOH and concentrated to give crude 3-amino-4-(2- carboxyphenylthio)benzoic acid ( 15) that was used in the next step without any further purification. To a mixture of 3-amino-4-(2-carboxypheny]thio)benzoic acid in THF 1 ,1 '- carbonyldiimidazole (10 eq) was added and the mixture stirred at room temperature for 18h. 2M HCl solution was added until pH 2 was obtained. A white precipitate was filtered off and washed with water to give ] l -oxo-10.1 l -dihydrodibenzo[b,fj[1.4]thiazepine-8-carboxylic acid (16). 1 l -oxo-10.1 l -dihydrodibenzo[b.fJ[l ,4]thiazepine-8-carboxylic acid (54 mg) was dissolved in toluene and SOCl2 (thionyl chloride, excess) was added dropwise followed by 2 drops of DMF. The mixture was stirred at 90 C for 6h. The mixture was cooled to room temperature and the mixture concentrated and thereafter diluted with toluene and concentrated. The crude product (1 7) ( 1.0 mmol) dissolved in DCM (4 ml) was added to the appropriate hydroxylamine hydrochloride (O-methylhydroxylamine hydrochloride, compound 18; O-ethylhydroxylamine hydrochloride, compound 19; and N, O- dimethylhydroxylamine. compound 20:) (2.5 mmol) in DCM (2 ml) at 0 C. Shaken for 4 h at room temperature. The reaction mixture was filtered through AI2O3 (acidic), eluating with DCM/EtOAc. The filtrate was concentrated at reduce pressure and the obtained imidoylchloride used in the next step without any further purification.[0092] Piperazine (100 ul) in toluene (1 ml) was added to the imidoylchloride (0.03 mmol) and the mixture was shaken for Ih at 100 C. The volatile material was removed at reduced pressure and the crude product was purified by preparative HPLC-MS to give one of the desired compound 18. 19. or 20.
With triethylamine; In toluene; for 24h;Heating / reflux;
Example 172 2-(1H-Indol-3-yl)-4H-1,3-benzothiazine-4-one 3-Cyanoindole (1.00g, 7.0mmol) and methyl thiosalicylate (1.20 g, 7.0 mmol) were dissolved in toluene (10 ml), and triethylamine (1.5 ml, 10.4 mmol) was added thereto.. The reaction mixture was refluxed for 24 hrs.. The solvent was evaporated.. The residue was recrystallized from ethanol to give the titled compound (0.38 g, 20 %) as pale yellow crystals. mp. 276.5-277.0 C IR(KBr): 1626, 1591, 1516, 1493, 1454, 1439, 1356, 1329, 1300, 1261, 1242, 1143, 1107, 1086, 1068, 908, 817, 729 cm-1.1H-NMR (CDCl3) δ: 7.28-7.31 (2H, m), 7.53-7.56 (1H, m), 7.61-7.66 (1H, m), 7.71-7.75 (2H, m), 8.31 (1H, d, J = 7.6 Hz), 8.49-8.51 (1H, m), 8.55 (1H, d, J = 3.0 Hz), 12.41 (1H, br s).
With triethylamine; In toluene; for 15h;Heating / reflux;
Example 347 2-(2-Methyl-1,3-thiazol-4-yl)-4H-1,3-benzothiazin-4-one <strong>[21917-76-0]2-Methyl-1,3-thiazole-4-carbonitrile</strong> (0.46 g, 3.7 mmol) and methyl thiosalicylate (1.26 g, 7.4 mmol) were dissolved in toluene (6 ml), and triethylamine (3.0 ml, 21. mmol) was added thereto.. The mixture was refluxed for 15 hrs.. After cooling, the precipitates were collected by filtration and recrystallized from ethanol to give the titled compound (0.75 g, 78 %) as white crystals. mp. 219.0-220.0 C1H-NMR (CDCl3) delta: 2.83 (3H, s), 7.55-7.70 (3H, m), 8.44 (1H, s), 8.55 (1H, m). IR(KBr): 3098, 1645, 1574, 1531, 1288, 1159, 740 cm-1.
With triethylamine; In toluene; for 8h;Heating / reflux;
Example 138 2-(4-Methyl-2-pyridyl)-4H-1,3-benzothiazine-4-one A mixture of methyl thiosalicylate (1.15 g, 6.8 mmol), 2-cyano-4-methylpyridine (0.81 g, 6.8 mmol), triethylamine (1.50 ml, 10.8 mmol) and toluene (2.0 ml) was refluxed for 8 hrs.. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (1.11 g, 64 %). mp. 199.7-199.9 C IR (KBr): 1659, 1574, 1537, 1300, 1281 cm-11H-NMR (CDCl3) delta: 2.48 (3H, s), 7.36 (1H, d, J=4.2Hz), 7.60-7.72 (3H, m), 8.41 (1H, s), 8.54-8.60 (2H, m).
With triethylamine; In toluene; for 1h;Heating / reflux;
Example 242 6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-s-pyridinecarbonitrile 2,6-Pyridinecarbonitrile (1.00 g, 7.7 mmol) and methyl thiosalicylate (1.54 g, 9.1 mmol) were dissolved in toluene (6 ml), and triethylamine (3.0 ml, 21.5 mmol) was added thereto.. The mixture was refluxed for 1 hr.. After cooling, the precipitates were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (1.07 g, 52 %) as pale yellow crystals. mp. 263.7-264.2 C1H-NMR (CDCl3) delta: 7.74 (1H, m), 7.82 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.32-8.37 (3H, m), 8.60 (1H, m). IR(KBr): 3078, 2241, 1666, 1572, 1537, 1439, 1302, 1097, 995, 815, 742 cm-1.
With triethylamine; In toluene; for 8h;Heating / reflux;
Example 70 2-(2-Methoxy-4-pyridyl)-4H-1,3-benzothiazine-4-one 2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in tetrahydrofuran (1 ml), and 12 % lithium methylate in methanol (1.0 g, 3.2 mmol) was added thereto.. The reaction mixture was refluxed for 6 hrs, combined with water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated under reduced pressure to give a mixture (0.30 g) containing <strong>[72716-86-0]2-methoxyisonicotinonitrile</strong>.. This mixture and methyl thiosalicylate (1.0 g, 5.9 mmol) were dissolved in toluene (3.0 ml), and triethylamine (1.0 ml, 7.2 mmol) was added thereto.. The reaction mixture was refluxed for 8 hrs, subjected to a silica gel (60 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) to give the titled compound (0.05 g, 8 %) as white crystals. mp. 148.8-150.5 C IR(KBr): 1662, 1525, 1448, 1387, 1315 cm-1.1H-NMR (CDCl3) delta: 4.01 (3H, s), 7.46 (1H, s), 7.56-7.74 (4H, m), 8.35 (1H, d, J = 5.4 Hz), 8.56 (1H, dd, J = 7.5, 1.8 Hz).
0.864 g (16 mmol) of sodium methoxide is dissolved in 15 ml of absolute methanol, 2.52 g (15 mmol) of methyl thiosalicylate are added and 2.53 g (15 mmol) of 2,4,6-trimethylbenzyl chloride are then slowly added dropwise. The mixture is stirred at room temperature overnight, concentrated and admixed with water, and the crystals are filtered off with suction, washed with cleaner's naphtha and dried in the air. [1151] Yield: 2.98 g (66.1% of theory), melting point: 115-1 18 C.
66.1%
With sodium methylate; In methanol; at 20℃;
0.864 g (16 mmol) of sodium methoxide is dissolved in 15 ml of absolute methanol, 2.52 g (15 mmol) of methyl thiosalicylate are added and 2.53 g (15 mmol) of 2,4,6-trimethylbenzyl chloride are then slowly added dropwise. The mixture is stirred at room temperature overnight, concentrated and admixed with water, and the crystals are filtered off with suction, washed with cleaner's naphtha and dried in the air. [01209] Yield: 2.98 g (66.1% of theory), melting point: 115-118 C.
With triethylamine; In toluene; for 2.5h;Heating / reflux;
Example 143 2-(4-Cyano-2-pyridyl)-4H-1,3-benzothiazine-4-one A mixture of methyl thiosalicylate (0.65 g, 3.9 mmol), <strong>[29181-50-8]2,4-dicyanopyridine</strong> (0.50 g, 3.9 mmol), triethylamine (0.81 ml, 5.8 mmol) and toluene (2.0 ml) was refluxed for 2.5 hrs.. After cooling, the precipitated crystals were collected by filtration and recrystallized from acetone-chloroform to give the titled compound (0.54 g, 53 %). mp. 283.4-283.6 C IR (KBr): 1655, 1589, 1570, 1529, 1460, 1396 cm-11H-NMR (CDCl3) delta: 7.63-7.78 (4H, m), 8.57 (1H, d, J = 7.5 Hz), 8.80 (1H, s), 8.93 (1H, d, J = 4.8 Hz).
With triethylamine; In toluene; for 6.5h;Heating / reflux;
Reference Example 36 2-(6-Chloro-2-pyridyl)-4H-1,3-benzothiazine-4-one A mixture of methyl thiosalicylate (0.65 g, 3.9 mmol), 2-cyano-6-chloropyridine (0.54 g, 3.9 mmol), triethylamine (1.00 ml, 7.2 mmol) and toluene (2.0 ml) was refluxed for 6.5 hrs.. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.39 g, 37 %). mp. 224.3-225.0 C IR (KBr): 1664, 1535, 1429, 1298 cm-11H-NMR (CDCl3) delta: 7.51-7.74 (4H, m), 7.88 (1H, t, J = 7.8 Hz), 8.48 (1H, d, J = 7.8 Hz), 8.55 (1H, d, J = 7.8 Hz).
With triethylamine; In toluene; for 18.0h;Heating / reflux;
Example 284 2-[2-(Methylthio)-6-pyrimidinyl]-4H-1,3-benzothiazine-4-one <strong>[1124-75-0]6-Cyano-2-methylthiopyrimidine</strong> (1.37 g, 9.06 mmol) and methyl thiosalicylate (3.05 g, 18.1 mmol) were dissolved in toluene (30 ml), and triethylamine (3.80 ml, 27.2 mmol) was added thereto.. The mixture was refluxed for 18 hrs.. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (1.40 g, 54 %) as pale yellow crystals. mp. 223.5-224.0 C1H-NMR (CDCl3) delta: 2.70 (3H, s), 7.62-7.76 (3H, m), 8.03(1H, d, J = 5.0 Hz), 8.54-8.57 (1H, m), 8.78 (1H, d, J = 5.0 Hz). IR(KBr): 1655, 1533, 1412, 1346, 1284, 1203, 1093, 748 cm-1.
With triethylamine; In toluene; for 2h;Heating / reflux;
Example 348 2-(1,3-thiazol-2-yl)-4H-1,3-benzothiazin-4-one <strong>[1452-16-0]1,3-Thiazole-2-carbonitrile</strong> (0.32 g, 2.9 mmol) andmethyl thiosalicylate (0.98 g, 5.8 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 2 hrs.. After cooling, the precipitates were collected by filtration and recrystallized from diisopropyl ether-ethanol to give the titled compound (0.51 g, 70 %) as yellow crystals. mp. 229.1-229.8 C1H-NMR (CDCl3) delta: 7.60 (1H, m), 7.63 (1H, m), 7.68 (1H, m), 7.73 (1H, m), 8.10 (1H, m), 8.55 (1H, d, J = 7.8 Hz). IR(KBr): 3126, 1666, 1655, 1535, 1292, 866, 736 cm-1.
3 Example 3
Example 3 2-(2-Quinolinyl)-4H-1,3-benzothiazine-4-one The titled compound was obtained by the reaction of methyl thiosalicylate (1.00 g, 5.9 mmol) and 2-quinolinecarbonitrile (0.95 g, 6.2 mmol) in accordance with the method described in Example 1 (1.54 g, 89 %). mp. 262.7-263.4 °C (recrystallized from chloroform) IR (KBr): 3055, 1651, 1593, 1570, 1529, 1440, 1292, 1097, 929, 837, 740 cm-1.1H-NMR (CDCl3) δ: 7.63-7.70 (4H, m), 7.81 (1H, m), 7.90 (1H, d), 8.23 (1H, d), 8.34 (1H, d), 8.58-8.62 (2H, m).
Methyl 3-(4-oxo-4H-1,3-benzothiazin-2-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With triethylamine; In xylene; at 145℃; for 22h;
EXAMPLE 21 Methyl 3-(4-oxo-4H-1,3-benzothiazin-2-yl)benzoate A mixture of <strong>[13531-48-1]methyl 3-cyanobenzoate</strong> (967 mg, 6.00 mmol), methyl thiosalicylate (1.51 g, 8.98 mmol), triethylamine (1.5 ml, 11 mmol) and xylene (6 mL) was stirred at 145°C for 22 hours under a nitrogen flow. After the reaction mixture was allowed to cool, the crystals were taken by filtration and recrystallized from methanol to give the title compound (519 mg, 29percent). Melting point: 164.3-164.4°C 1H-NMR (CDCl3) delta: 3.98 (3H, s), 7.56-7.74 (4H, m), 8.30 (1H, dt, J = 7.8, 1.4 Hz), 8.44 (1H, ddd, J = 8.0, 2.0, 1.3 Hz), 8.53-8.58 (1H, m), 8.83 (1H, t, J = 1.5 Hz). Elemental analysis: as C16H11NO3S Calcd.: C, 64.63; H, 3.73; N, 4.71 Found: C, 64.62; H, 3.64; N, 4.70
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h;
To a mixture of 5-chloro-2-nitrofluorobenzene (176 mg, 1 mmol) and methyl thiosalicylate (275 uL, 2 mmol) in DMF (5 mL) was added Cs2CO3 (652 mg, 2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with CH2C12, washed with water, dried (Na2S04), concentrated and flash chromatographed SiO2, heptane: toluene, 1: 10-1: 4) to give 300 mg (92%) of the title compound (189JO09). lH NMR (CDC13) 6 8.15 (d, 1 H J= 2.4 Hz), 7.94 (m, 1 H), 7.53- 7.46 (m, 3 H), 7.34 (dd, 1 H, 2.4, 8. 6 Hz), 6.95 (d, 1 H, J = 8.8 Hz), 3. 82 (s, 3 H).
92%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a mixture of 5-chloro-2-nitrofluorobenzene (176 mg, 1 mmol) and methyl thiosalicylate (275 muL, 2 mmol) in DMF (5 mL) was added Cs2CO3 (652 mg, 2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2, washed with water, dried (Na2SO4), concentrated and flash chromatographed (SiO2, heptane:toluene, 1:10-1:4) to give 300 mg (92%) of the title compound (189JO09). 1H NMR (CDCl3) delta 8.15 (d, 1 H J= 2.4 Hz), 7.94 (m, 1 H), 7.53-7.46 (m, 3 H), 7.34 (dd, 1 H, 2.4, 8.6 Hz), 6.95 (d, 1 H, J= 8.8 Hz), 3.82 (s, 3 H).
With copper(l) iodide; potassium carbonate In 1,2-dimethoxyethane at 20 - 80℃; for 1h; Inert atmosphere; Microwave irradiation;
75%
With potassium carbonate In 1,2-dimethoxyethane at 20 - 80℃; for 1h; microwave irradiation;
1; 7.B; 10 Methyl 2-(4-nitrophenylthio)benzoate 8a
Method B: Synthesis of 2-(4-Nitrophenylthio)-N-(2-methoxyphenyl)benzamide (1) Vif inhibitor 1 and a Vif inhibitor 1-analog was synthesized according procedure outlined in Scheme 10. The key step in the reaction scheme is the copper catalyzed coupling reaction of substituted iodobenzenes 6 with methyl thiosalicylate 7 under microwave irradiations. The resulting esters 8 were hydrolyzed to obtain the acids 9 in excellent yields. Treatment of the acids 9 with oxalyl chloride and the reaction of the resulting acid chlorides with o-anisidine 11 provided 2-(4-nitrophenylthio)-N-(2-methoxyphenyl)benzamide 1 and 2-(2-chloro-4-nitrophenylthio)-N-(2-methoxyphenyl)benzamide 12b. Reaction of the acid chlorides 9 with various other amines could provide analogs of Vif inhibitor 1. Scheme 10: (a) K2CO3, Cu(I)I (cat.), 1,2-DME, microwave (150 Wt power), 80° C., 30 min (2×); (b) Ba(OH)2.8H2O, MeOH, 80° C., 2 h; (c) (OCOCl)2, CH2Cl2, r. t, 4 h; (d) Et3N, CH2Cl2, 0° C. to r. t. overnight.; General Procedure for the Coupling Reaction Substituted iodobenzene 6 (1.0 mmol), Cu(I) iodide (20 mg, 0.1 mmol), and K2CO3 (0.276 g, 2.0 mmol) were added to a 10 mL reaction vessel with Teflon-lined septum. The tube was evacuated and backfilled with dry N2 (3 cycles). 1,2-Dimethoxyetane (1 mL) was added by syringe at room temperature followed by methyl thiosalicylate 7 (1 mmol). The reaction vessel was heated in a microwave reactor (CEM, Explorer) at 80° C. and 150 Wt power for 30 min (2×). The reaction mixture was then allowed to reach room temperature. Ethyl acetate (approx. 10 mL) was added; the reaction mixture was filtered and concentrated. The crude product was purified by flash column chromatography on silica, eluting with 15% EtO Ac in hexanes.; Methyl 2-(4-nitrophenylthio)benzoate 8a Above general procedure provided methyl 2-(4-nitrophenylthio)benzoate 8a as pale yellow crystalline solid in 75% yield; 1H NMR (400 MHz, CDCl3) δ 8.15 (m, 2H), 7.95 (dd, J=7.6, 1.6 Hz, 1H), 7.47 (m, 2H), 7.39 (ddd, J=8.8, 7.6, 1.6 Hz, 1H), 7.32 (ddd, J=8.8, 7.6, 1.6 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.82, 146.93, 144.95, 136.71, 132.71, 131.88 (2 C), 131.72, 131.25, 131.07, 127.30, 124.42 (2 C), 52.56; MS (ESI): m/z 312.50 (M+Na)+.
50%
Stage #1: Methyl thiosalicylate With sodium hydride In dimethyl sulfoxide at 20℃; for 0.5h; Glovebox; Inert atmosphere; Sealed tube;
Stage #2: p-nitrobenzene iodide With p-phenylpyridine; potassium methanolate; bis(pinacol)diborane In dimethyl sulfoxide at 25℃; for 24h; Glovebox; Inert atmosphere; Sealed tube;
With caesium carbonate In N,N-dimethyl-formamide at 20 - 70℃;
56
5-Bromo-2-fluoronitrobenzene (1.23 mL; 10.0 mmol) and Cs2CO3 (3.58 g; 11.0 mmol) was mixed in 30 mL DMF and heated to 700C. A solution of methyl 2- mercaptobenzoate (1.5 mL mg; 10.9 mmol) in 30 mL DMF was added dropwise over 15 min. The heating was turned of and the mixture left stirring overnight at room temperature. Water and ethyl acetate was added and the aqueous layer extracted twice with ethyl acetate/heptane. After separation of the phases, the organic phase was washed twice with water, before drying over sodium sulphate, filtration and concentration in vacuo. Purification was done by silica EPO gel column chromatography (0-30 % ethyl acetate in heptane) to afford the title compound as a yellow solid (3.61 g; 98%).[0272] 1H NMR (400 MHz, CDCl3) δ 8.30 (d, IH, J= 2.4), 7.95 - 7.92 (m, IH), 7.54 - 7.45 (m, 4H), 6.86 (d, IH, J= 8.4), 4.82 (s, 3H). HPLC tR = 4.97 min.
98%
With caesium carbonate In N,N-dimethyl-formamide at 20 - 70℃;
56
5-Bromo-2-fluoronitrobenzene (1.23 mL; 10.0 mmol) and Cs2CO3 (3.58 g; 11.0 mmol) was mixed in 30 mL DMF and heated to 7O°C. A solution of methyl 2-mercaptobenzoate (1.5 mL mg; 10.9 mmol) in 30 mL DMF was added dropwise over 15 min. The heating was turned of and the mixture left stirring overnight at room temperature. Water and ethyl acetate was added and the aqueous layer extracted twice with ethyl acetate/heptane. After separation of the phases, the organic phase was washed twice with water, before drying over sodium sulphate, filtration and concentration in vacuo. Purification was done by silica gel column chromatography (0-30 % ethyl acetate in heptane) to afford the title compound as a yellow solid (3.61 g; 98%).[0353] 1H NMR (400 MHz, CDCl3) δ 8.30 (d, 1H, J = 2.4), 7.95 - 7.92 (m,1H), 7.54 - 7.45 (m, 4H), 6.86 (d, 1H, J- 8.4), 4.82 (s, 3H). HPLC tκ = 4.97 min.
(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-6-iodo-1,3-dihydro-2H-indol-2-one[ No CAS ]
[ 4892-02-8 ]
methyl 2-[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 2.5h;
483 Methyl 2-[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate
EXAMPLE 483 Methyl 2-[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate A 25 mL reaction vessel was charged with (3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-6-iodo-1,3-dihydro-2H-indol-2-one (100 mg, 0.23 mmol), methyl thiosalicylate (77 mg, 0.46 mmol), PdCl2(dppf)-CH2Cl2 (19 mg, 0.023 mmol), cesium carbonate (225 mg, 0.69 mmol) and 8 mL of anhydrous DMF. The mixture was purged with nitrogen and heated in 90° C. bath for 2.5 hours. The mixture was cooled to room temperature, diluted with 50 mL of water and extracted with EtOAc (3*50 mL). The organic layers were combined, washed with saturated NaHCO3 (50 mL), brine (2*50 mL), dried over Na2SO4, and concentrated to give a brown oil. Purification of the oily mixture by silica gel chromatography eluted with 1-10% MeOH/CHCl3 provided methyl 2-[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate as a brown solid. Yield: 60 mg, 55%. 1H NMR (500 MHz, d6-DMSO) δ ppm 1.70 (s, 6 H) 3.48 (br s, 4 H) 3.71 (br s, 4 H) 3.87 (s, 3 H) 6.23 (s, 1 H) 6.77 (d, J=8.30 Hz, 1 H) 6.83 (d, J=1.46 Hz, 1 H) 7.03 (dd, J=7.81, 1.46 Hz, 1 H) 7.16-7.19 (m, 1 H) 7.35-7.38 (m, 1 H) 7.52 (d, J=7.81 Hz, 1 H) 7.89 (d, J=7.81 Hz, 1 H) 10.08 (s, 1 H) LR MS (ES+): 479 (M+1)
With caesium carbonate In N,N-dimethyl-formamide at 20 - 40℃; for 4h;
99%
With caesium carbonate In N,N-dimethyl-formamide at 20 - 40℃; for 4h;
6.1 Preparation of Methyl 4-(2-(methoxycarbonyl)phenylthio)-3-nitrobenzoate
A solution of methyl 4-fluoro-3-nitrobenzoate (12.1 g, 60.9 mmol) and methyl 2-mercaptobenzoate (9.21 mL, 66.9 mmol) in DMF (6.00 mL) was treated with Cs2C03 (19.8 g, 60.9 mmol) at room temperature. The reaction mixture was stirred at 40 °C for 4 hr and then cooled to room temperature. Ice water was added to induce the precipitation. The precipitate was filtered, washed with water, and dried to give 21.0 g (99%) of the title compound as a yellow solid which was used directly in the next reaction without further purification. 1H NMR (400 MHz, DMSO-J6) δ ppm 8.63 (d, 7=2.0 Hz, 1 H), 8.04 (dd, 7=8.4, 1.8 Hz, 1 H), 7.87 - 7.99 (m, 1 H), 7.57 - 7.77 (m, 3 H), 7.05 (d, 7=8.6 Hz, 1 H), 3.88 (s, 3 H), 3.71 (s, 3 H); LCMS RT = 6.19 min, m/z 365.0 [M+Na+] ; HRMS (ESI) m/z calcd for Ci6Hi3NNa06S [M+Na+] 371.0387, found 371.0393
93%
With caesium carbonate In N,N-dimethyl-formamide at 20 - 60℃; for 2h; Inert atmosphere;
1 Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) thio)-3-nitrobenzoate (3):
[00077] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate 2 (30 g, 150.67 mmol) in DMF (300 mL) under inert atmosphere were added cesium carbonate (58.76 g, 180.8 mmol) and methyl 2-mercaptobenzoate 1 (22.6 mL, 165.47 mmol) at RT; heated to 55-60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (1500 mL) and the precipitated solid was filtered to obtain the crude. The crude was washed with water (500 mL), hexane (200 mL) and dried in vacuo to afford compound 3 (48.8 g, 93%) as yellow solid. TLC: 20% EtOAc/ hexanes (R 0.4); 1H NMR (CDC13, 400 MHz): ö 8.85 (s, 1H), 7.99-7.92 (m, 2H), 7.66-7.56 (m, 3H), 6.93 (d, J 8.6 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H).
93%
With caesium carbonate In N,N-dimethyl-formamide at 55 - 60℃; for 2h; Inert atmosphere;
4 Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) thio)-3-nitrobenzoate (24):
[00076] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate 12 (30 g, 150.67 mmol) in DMF (300 mL) under inert atmosphere were added cesium carbonate (58.76 g, 180.8 mmol) and methyl 2-mercaptobenzoate 1 (22.6 mL, 165.47 mmol) at RT; heated to 55-60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (1500 mL) and the precipitated solid was filtered to obtain the crude. The crude was washed with water (500 mL), hexane (200 mL) and dried in vacuo to afford compound 24 (48.8 g, 93%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); NMR (CDC13, 400 MHz): δ 8.85 (s, 1H), 7.99-7.92 (m, 2H), 7.66-7.56 (m, 3H), 6.93 (d, J = 8.6 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H).
93%
With caesium carbonate In N,N-dimethyl-formamide at 55 - 60℃; for 2h; Inert atmosphere;
1; 2 ynthesis of methyl 4-((2-(methoxycarbonyl) phenyl) thio)-3-nitrobenzoate (3):
To a stirred solution of methyl 4-fluoro-3-nitrobenzoate 2 (30 g, 150.67 mmol) inDMF (300 mL) under inert atmosphere were added cesium carbonate (58.76 g, 180.8 mmol) and methyl 2-mercaptobenzoate 1 (22.6 mL, 165.47 mmol) at RT; heated to 55-60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (1500 mL) and the precipitated solid was filtered to obtain the crude. The crude was washed with water (500 mL), hexane (200 mL) and dried in vacuo to affordcompound 3 (48.8 g, 93%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); ‘H NMR (CDC13, 400 MHz): ö 8.85 (s, 1H), 7.99-7.92 (m, 2H), 7.66-7.56 (m, 3H), 6.93 (d, J = 8.6 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H).
92.96%
With caesium carbonate In water; N,N-dimethyl-formamide at 0 - 20℃; for 5h;
3.1 methyl 4-((2-(methoxycarbonyl) phenyl) thio)-3-nitrobenzoate(3-3)
To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (300 g, 1.0 eq.) and methylthiosalicylate (278.7 g, 1.1 eq.) in DMF (1.8 L) was added Cs2CO3 (589 g, 1.2 eq.) inbatches at 0 to 5 °C. The reaction mixture was stirred at 0 to 5 °C for 30 mm, warmed to room temperature over 2 h, and stirred at room temperature for 2 h. The reaction mixture was cooled to 10-15 °C, diluted with water (26 V) and stirred for 30 mm. The solids were collected by filtration, washed with water (20 V) and n-heptane (10 V), and dried under reduced pressure below 50 °C. The dry solids were suspended in n-heptane (10 V) at 90-95°C to form a slurry and cooled to 35 - 40 °C. The solids were collected by filtration, washed with n-heptane (5 V), and dried under reduced pressure for 8 h to yield the title compound 3-3. Yield: (92.96 %), Purity: 99.01 %. TLC: 20% EtOAc/ hexanes (Rj: 0.4); 1H NMR (CDC13, 400 MHz): 8.85 (s, 1H), 7.99-7.92 (m, 2H), 7.66-7.56 (m, 3H), 6.93 (d, J= 8.6 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H); LCMS-ESI m/z: 348 [M+H]
87%
With caesium carbonate In N,N-dimethyl-formamide at 40℃; for 2h;
4.2.1. Methyl-4-((2-(methoxycarbonyl)phenyl)thio)-3-nitro-benzoate (46)
A mixture of methyl 4-fluoro-3-nitrobenzoate 45 (14. 1 g, 0.0706 mol) and methyl 2-mercaptobenzoate 44 (10 mL, 0.0727 mol) was dissolved in 120 mL of anhydrous DMF. Finely ground Cs2CO3 (30.9 g, 0.950 mol) was added at rt. After mixing for 30 min, the suspension was stirred at 40 °C for 2 h. After cooling to rt, the mixture was diluted with CH2Cl2 (200 mL) and washed with water (50 mL) and brine (50 mL) and dried (Na2SO4). The crude product was recrystallized from EtOAc/hexanes to afford 21.42 g (87%) of long yellow needles 46, mp 177-178 °C; 1H NMR (500 MHz, CDCl3) δ 9.22 (s, 1H); 8.12 (dt, J = 3.8, 5.2 Hz, 1H); 8.09 (d, J = 10.6 Hz, 1H); 7.71-6.59 (m, 3H), 6.81 (d, J = 10.7 Hz, 1H), 3.08 (s, 3H), 2.89 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.1, 187.0, 162.1, 161.3, 152.8, 150.9, 147.5, 147.0, 145.1, 144.4, 143.9, 142.7, 140.1, 139.5, 41.0, 40.9; HREIMS [M+Na]+ m/z: 370.0389 (calcd for C16H13NNaO6S, 370.0361).
Stage #1: Methyl thiosalicylate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: ethyl bromide In N,N-dimethyl-formamide for 1h;
1.1.1
Step 1: Synthesis of 2-ethylsulfanyl-benzoic acid methyl ester (2).[00369] To a solution of 2-mercaptobenzoic acid methyl ester (1, 1.00 g, 5.95 mmol) in anhydrous dimethylformamide (6 mL) was added K2CO3 (1.00 g, 7.24 mmol). The reaction mixture was stirred for 15 min at room temperature, ethyl bromide (662 μ, 8.93 mmol) was added and the reaction was stirred for 1 h. The mixture was poured onto ice (25 g) and extracted with diethyl ether (2 x 25 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (1.11 g, 95%) as a yellow oil.
95%
Stage #1: Methyl thiosalicylate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: ethyl bromide In N,N-dimethyl-formamide for 1h;
4.1 Step 1: Synthesis of 2-ethylsulfanyl-benzoic acid methyl ester (27)
To a solution of 2-mercaptobenzoic acid methyl ester (26) (1.00 g, 5.95 mmol) in anhydrous dimethylformamide (6 mL) was added K2CO3 (1.00 g, 7.24 mmol). The reaction mixture was stirred for 15 min at room temperature, ethyl bromide (662 μ, 8.93 mmol) was added and the reaction was stirred for 1 h. The mixture was poured onto ice (25 g) and extracted with diethyl ether (2 x 25 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (1.11 g, 95%) as a yellow oil.
With potassium carbonate In N,N-dimethyl-formamide Reflux;
Step 2) Preparation of methyl 2-(6-ethyl-5-fluoropyrimidin-4-yl-sulfanyl)benzoate A mixed solution of 31.7g of methyl 2-mercaptobenzoate prepared in Step 1) and 300mL of tetrahydrofuran was cooled to 5 and 5.0g of sodium hydride was added dropwise thereto over 10 minutes. After being stirred at 5 for 30 minutes, 30g of <strong>[137234-74-3]4-chloro-6-ethyl-5-fluoropyrimidine</strong> was added dropwise over 20 minutes. The temperature during addition was maintained below 20 . The temperature of the reaction liquid was elevated to 25 , followed by stirring for 30 minutes. The resulting mixture was concentrated under reduced pressure and diluted with 300mL of ethyl acetate. The organic layer was successively washed with 200mL of a saturated ammonium chloride solution and 200mL of purified water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 52.5g (yield: 96%) of the title compound as an oil. 1H-NMR (200MHz, CDCl3) delta (ppm): 8.52 (d,1H), 8.01 (m,1H), 7.65-7.50 (m,3H), 3.82 (s,3H), 2.83 (q,2H), 1.32 (t,3H)
With copper(l) iodide; potassium carbonate; In ethylene glycol; isopropyl alcohol; at 20 - 80℃; for 68h;Inert atmosphere;
To an oven-dried seal tube, was added <strong>[14192-12-2]2,5-diiodobenzoic acid</strong> 6b (74.8 mg, 0.2 mmol), CuI (3.8 mg, 0.02 mmol) and K2CO3 (55.2 mg, 0.4 mmol). The reaction tube was evacuated and backfilled with argon. 2-Propanol (1.0 mL), ethylene glycol (22.3 muL) and thiol 5 (30 muL, 0.22 mmol) were added by syringes at room temperature. The tube was heated to 80 oC and stirred for 68 h. The reaction mixture was then allowed to reach room temperature. The reaction mixture was then filtered and concentrated in vacuo. The crude product was purified using CombiFlash automated chromatography system (methanol / methylene chloride, 0% to 10%) to afford the desired product 7b as white solid.
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;
To a cooled solution of methyl 2-sulfanylbenzoate (200 g, 1.19 mol) in tetrahydrofuran and N,N-dimethylformamide (2 L, V/V=1/1) was added 2-chloroethanamine hydrochloride (138 g, 1.19 mol) at 0 C. followed by sodium hydride (143 g, 3.57 mol, 60% in mineral oil) in portions. After being stirred at room temperature overnight, the reaction mixture was poured into ice-water and extracted with ethyl acetate (900 mL*4). The organic layers were combined, washed with brine (900 mL*3), dried over sodium sulfate and concentrated in vacuo. The residue was stirred in a mixture solution of ethyl acetate and petroleum ether (300 mL, V/V=1/1) for 1 hour. The solid was collected by filtration and dried in vacuo to afford 100 g of 3,4-dihydro-1,4-benzothiazepin-5(2H)-one (yield was 47%).
100 g
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;
Step 2. Preparation of 3,4-Dihydro-l,4-benzothiazepin-5(2H)-oneTo a cooled solution of methyl 2-sulfanylbenzoate (200 g, 1.19 mol) in tetrahydrofuran and N,N- dimethylformamide (2 L, V/V = 1/1) was added 2-chloroethanamine hydrochloride (138 g, 1.19 mol) at 0 C followed by sodium hydride (143 g, 3.57 mol, 60%> in mineral oil) in portions. After being stirred at room temperature overnight, the reaction mixture was poured into ice- water and extracted with ethyl acetate (900 mL x 4). The organic layers were combined, washed with brine (900 mL x 3), dried over sodium sulfate and concentrated in vacuo. The residue was stirred in a mixture solution of ethyl acetate and petroleum ether (300 mL, V/V = 1/1) for 1 hour. The solid was collected by filtration and dried in vacuo to afford 100 g of 3,4-dihydro-l ,4- benzothiazepin-5(2H)-one (yield was 47%).
With sodium hydroxide; In water; dimethyl sulfoxide; at 20℃; for 1.5h;
Intermediate 25: 2- [(4-A'-Boc-piperi Methyl thiosalicylate (168 mg, 1.00 mmol) was dissolved in DMSO (1 mL) and 50% NaOH(aq) (0.5 mL). l-Boc-4-bromopiperidine (264 mg, 1.00 mmol) was added and the mixture stirred at room temperature for 90 min after which time TLC analysis (ethyl acetate) revealed partial consumption of starting material (R/0.89) and a major product (R/0.41). The reaction mixture was diluted with ethyl acetate (30 mL) and the organic phase washed with 2 x 30 mL HC1 solution (2 M) then with brine (30 mL). The organic phase was dried (Na2S04) and the solvents removed under reduced pressure to afford a runny pale yellow oil. The crude was re-dissolved in DCM and purified using a 24G GraceResolv column (using 1% AcOH in the column solvents) to afford 2-[(4- piperidinyl)thio] salicylic acid as a white solid (99 mg, yield: 29%). Vppm (400 MHz, CDC13): 8.12 (1H), 7.51-7.42 (2H), 7.34-7.26 (1H), 4.10-3.97 (2H), 3.39 (1H), 2.97 (2H), 2.04-1.99 (2H), 1.62 (2H), 1.44 (9H).
General procedure: To a stirred solution of benzoic acid derivative 5 (300 mg, 2.18 mmol) in CH2Cl2 was added an amine (266 mg, 3.27 mmol) followed by the coupling agents; HOBT (442 mg, 3.27 mmol) and EDCI (630 mg, 3.27 mmol) and then Hunig’s base (1.14 mL, 6.54 mmol). The reaction was stirred at room temperature over night, then quenched with saturated NaHCO3 solution and CH2Cl2, then dried over Na2SO4. The solvents were removed by rotary evaporation, no further purification was needed. To a stirred solution of the aniline 6 (260mg, 1.58mmol) in CH2Cl2 at 0C under nitrogen was added AlMe3 (2 mL, 1 M in THF) dropwise and the reaction was slowly warmed to room temperature. The mixture was stirred continuously for an additional 30 min. Methyl thiosalicylate (130 μL, 0.790 mmol) was added and the reaction was heated to 60 C and then heated under reflux overnight. The reaction was quenched with HCl (5% aq) and CH2Cl2 was added (50 mL). The organic layer was separated and washed with saturated NaHCO3 solution, then brine, and dried over Na2SO4. The solvents were removed by rotary evaporation. The products were purified by flash chromatography or reverse phase HPLC and lyophilized to provide thiols 4 which were determined to be >95% pure by HPLC-UV, HPLC-MS, and 1H NMR. A solution of PIFA in CH2Cl2 was added to 0C solution of the benzamide (250mg, 0.833mmol) and TFA (0.185mL, 16M) in CH2Cl2. The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the product isolated by flash chromatography or reverse phase HPLC and lyophilized to provide the final compounds (2) which were determined to be >95% pure by HPLC-UV, HPLC-MS, and 1H NMR.
General procedure: To a stirred solution of benzoic acid derivative 5 (300 mg, 2.18 mmol) in CH2Cl2 was added an amine (266 mg, 3.27 mmol) followed by the coupling agents; HOBT (442 mg, 3.27 mmol) and EDCI (630 mg, 3.27 mmol) and then Hunig?s base (1.14 mL, 6.54 mmol). The reaction was stirred at room temperature over night, then quenched with saturated NaHCO3 solution and CH2Cl2, then dried over Na2SO4. The solvents were removed by rotary evaporation, no further purification was needed. To a stirred solution of the aniline 6 (260mg, 1.58mmol) in CH2Cl2 at 0C under nitrogen was added AlMe3 (2 mL, 1 M in THF) dropwise and the reaction was slowly warmed to room temperature. The mixture was stirred continuously for an additional 30 min. Methyl thiosalicylate (130 muL, 0.790 mmol) was added and the reaction was heated to 60 C and then heated under reflux overnight. The reaction was quenched with HCl (5% aq) and CH2Cl2 was added (50 mL). The organic layer was separated and washed with saturated NaHCO3 solution, then brine, and dried over Na2SO4. The solvents were removed by rotary evaporation. The products were purified by flash chromatography or reverse phase HPLC and lyophilized to provide thiols 4 which were determined to be >95% pure by HPLC-UV, HPLC-MS, and 1H NMR. A solution of PIFA in CH2Cl2 was added to 0C solution of the benzamide (250mg, 0.833mmol) and TFA (0.185mL, 16M) in CH2Cl2. The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the product isolated by flash chromatography or reverse phase HPLC and lyophilized to provide the final compounds (2) which were determined to be >95% pure by HPLC-UV, HPLC-MS, and 1H NMR.
methyl 2-((2-chloro-5-nitropyridin-4-yl)thio)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate; In acetonitrile; at 0 - 25℃; for 2h;
1002711 To a stirred suspension of Fl (290 mg, 1.50 rnmol) and potassium carbonate (312 mg, 2.26 mmol) in acetonitrile (5.5 mL) was added a solution of methyl thiosalicylate (253 mg, 1.50 mmol) in acetonitrile (2 mL) at 0 °C. The mixture was stirred 0 °C for 1 h and then at room temperature for 1 h. Water was added to the reaction mixture and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and then the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (25percent ethyl acetate-hexane) to provide the title compound M14 (473 mg, 97percent) as a yellow solid. LRMS (ESI) 325 [M + Hj
methyl 4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-5-nitrobenzoate[ No CAS ]
methyl 4-((2-(methoxycarbonyl) phenyl)thio)-2-methyl-3-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[000151] To a stirred solution of <strong>[321-21-1]4-fluoro-2-methylbenzoic acid</strong> 83 (10 g, 64.51 mmol) in acetic acid (50 mL) under inert atmosphere was added fuming nitric acid (50 mL) at RT and heated to 80 C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL). The precipitate was filtered and dried in vacuo to afford mixture of compounds 84 and 89 (5.3 g, 40%) as white solid. TLC: 70% EtOAc/ hexanes (R 0.4); 1H NMR (DMSO-d6, 400 MHz): oe 13.30 (br s, 2H), 8.52 (d, J 8.0 Hz, 2H), 8.10 (dd, J= 8.9 5.9, Hz, 1H), 7.60 (d, J= 12.5 Hz, 2H), 7.56 (t, J 9.3 Hz, 1H), 2.63 (s, 6H), 2.48 (s, 3H); (?H NMR showed mixture of compounds 84 and 89 in the ratio of 2: 1). [000152] To a stirred solution of compound 84 and 89 (10 g) in MeOH (100 mL) under argon atmosphere was conc. sulfuric acid (20 mL) at 0 C and heated to reflux for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compounds 90 & 91 (6 g) as colorless thick syrup. TLC: 30% EtOAc/ hexane (R 0.5); 1H NMR (DMSO-d6, 500 MHz): oe 8.51 (d, J=7.8 Hz, 1H), 8.09 (dd, J= 8.8, 5.6 Hz, 0.5H), 7.63 (d, J 12.4 Hz, 1H),7.58 (t,J 9.1 Hz, 0.5H), 3.87 (s, 4.5H), 2.62 (s, 3H), 2.45 (s, 1.5H); (?HNMR showed mixture of compounds 90: 91 in the ratio of 2: 1). [000153] To a stirred solution of compounds 90 and 91(11 g) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1(10.4 g, 61.97 mmol), cesium carbonate (18.5 g, 56.81 mmol) at 0 C; heated to 80 C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture of compounds 93 and 92 (12 g) as a yellow solid. TLC: 20% EtOAc/ hexanes (R 0.2); LC-MS: 12.57% + 81.14%; 370.8 (M+1); (column; X-Select CSH C18, (50 X 3.0 mm, 3.5 .im); RT 2.77 mm. 0.05% Aq. TFA: ACN; 0.8 mL/min); RT 4.05, 4.14 mm.
To a stirred solution of <strong>[321-21-1]4-fluoro-2-methylbenzoic acid</strong> 16 (10 g, 64.51 mmol) in acetic acid (50 mL) under inert atmosphere was added fuming nitric acid (50 mL) at RT and heated to 80 C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL). The precipitate was filtered anddried in vacuo to afford mixture of compounds 17 and 18 (5.3 g, 40%) as white solid. TLC: 70%EtOAc/ hexanes(R 0.4); ?H NMR (DMSO-d6, 400 MHz): oe 13.30 (br s, 2H), 8.52 (d, J = 8.0Hz, 2H), 8.10 (dd, J= 8.9 5.9, Hz, 1H), 7.60 (d, J= 12.5 Hz, 2H), 7.56 (t, J= 9.3 Hz, 1H), 2.63(s, 6H), 2.48 (s, 3H); (?H NMR showed mixture of compounds 17 & 18 in the ratio of 2: 1)._To a stirred solution of compound 17 & 18 (10 g) in MeOH (100 mL) under argon atmosphere was conc. sulfuric acid (20 mL) at 0 C and heated to reflux for 48 h. The reactionwas monitored by TLC; after completion of the reaction, the reaction mixture was diluted withwater (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compounds 19& 20 (6 g) as a colorless, thick syrup. TLC: 30% EtOAc/ hexane (R 0.5); ?H NMR (DMSO-d6,500 MHz): oe 8.51 (d, J=7.8 Hz, 1H), 8.09 (dd, J= 8.8, 5.6 Hz, 0.5H), 7.63 (d, J= 12.4 Hz, 1H),7.58 (t, J = 9.1 Hz, 0.5H), 3.87 (s, 4.5H), 2.62 (s, 3H), 2.45 (s, 1.5H); (?H NMR showed mixture of compounds 19: 20 in the ratio of 2: 1)._To a stirred solution of compounds 19 & 20 (11 g) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 7 (10.4 g, 61.97 mmol), cesium carbonate (18.5 g, 56.81 mmol) at 0 C; heated to 80 C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed withwater (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compounds 21 & 22 (12 g) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf:0.2); LC-MS: 12.57% + 81.14%; 370.8 (M+1) (column; X-Select CSH C18, (50 x 3.0 mm, 3.5 jim); RT 2.77 mm. 0.05% Aq. TFA: ACN; 0.8 mL/min); RT 4.05, 4.14 mm.
methyl 5-amino-4-((2-(methoxycarbonyl) phenyl) thio)-2-methylbenzoate[ No CAS ]
methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) thio)-2-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%; 30%
[000151] To a stirred solution of <strong>[321-21-1]4-fluoro-2-methylbenzoic acid</strong> 83 (10 g, 64.51 mmol) in acetic acid (50 mL) under inert atmosphere was added fuming nitric acid (50 mL) at RT and heated to 80 C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL). The precipitate was filtered and dried in vacuo to afford mixture of compounds 84 and 89 (5.3 g, 40%) as white solid. TLC: 70% EtOAc/ hexanes (R 0.4); 1H NMR (DMSO-d6, 400 MHz): oe 13.30 (br s, 2H), 8.52 (d, J 8.0 Hz, 2H), 8.10 (dd, J= 8.9 5.9, Hz, 1H), 7.60 (d, J= 12.5 Hz, 2H), 7.56 (t, J 9.3 Hz, 1H), 2.63 (s, 6H), 2.48 (s, 3H); (?H NMR showed mixture of compounds 84 and 89 in the ratio of 2: 1). [000152] To a stirred solution of compound 84 and 89 (10 g) in MeOH (100 mL) under argon atmosphere was conc. sulfuric acid (20 mL) at 0 C and heated to reflux for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compounds 90 & 91 (6 g) as colorless thick syrup. TLC: 30% EtOAc/ hexane (R 0.5); 1H NMR (DMSO-d6, 500 MHz): oe 8.51 (d, J=7.8 Hz, 1H), 8.09 (dd, J= 8.8, 5.6 Hz, 0.5H), 7.63 (d, J 12.4 Hz, 1H),7.58 (t,J 9.1 Hz, 0.5H), 3.87 (s, 4.5H), 2.62 (s, 3H), 2.45 (s, 1.5H); (?HNMR showed mixture of compounds 90: 91 in the ratio of 2: 1). [000153] To a stirred solution of compounds 90 and 91(11 g) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1(10.4 g, 61.97 mmol), cesium carbonate (18.5 g, 56.81 mmol) at 0 C; heated to 80 C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture of compounds 93 and 92 (12 g) as a yellow solid. TLC: 20% EtOAc/ hexanes (R 0.2); LC-MS: 12.57% + 81.14%; 370.8 (M+1); (column; X-Select CSH C18, (50 X 3.0 mm, 3.5 .im); RT 2.77 mm. 0.05% Aq. TFA: ACN; 0.8 mL/min); RT 4.05, 4.14 mm.
63%; 30%
To a stirred solution of <strong>[321-21-1]4-fluoro-2-methylbenzoic acid</strong> 16 (10 g, 64.51 mmol) in acetic acid (50 mL) under inert atmosphere was added fuming nitric acid (50 mL) at RT and heated to 80 C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL). The precipitate was filtered anddried in vacuo to afford mixture of compounds 17 and 18 (5.3 g, 40%) as white solid. TLC: 70%EtOAc/ hexanes(R 0.4); ?H NMR (DMSO-d6, 400 MHz): oe 13.30 (br s, 2H), 8.52 (d, J = 8.0Hz, 2H), 8.10 (dd, J= 8.9 5.9, Hz, 1H), 7.60 (d, J= 12.5 Hz, 2H), 7.56 (t, J= 9.3 Hz, 1H), 2.63(s, 6H), 2.48 (s, 3H); (?H NMR showed mixture of compounds 17 & 18 in the ratio of 2: 1)._To a stirred solution of compound 17 & 18 (10 g) in MeOH (100 mL) under argon atmosphere was conc. sulfuric acid (20 mL) at 0 C and heated to reflux for 48 h. The reactionwas monitored by TLC; after completion of the reaction, the reaction mixture was diluted withwater (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts weredried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compounds 19& 20 (6 g) as a colorless, thick syrup. TLC: 30% EtOAc/ hexane (R 0.5); ?H NMR (DMSO-d6,500 MHz): oe 8.51 (d, J=7.8 Hz, 1H), 8.09 (dd, J= 8.8, 5.6 Hz, 0.5H), 7.63 (d, J= 12.4 Hz, 1H),7.58 (t, J = 9.1 Hz, 0.5H), 3.87 (s, 4.5H), 2.62 (s, 3H), 2.45 (s, 1.5H); (?H NMR showed mixture of compounds 19: 20 in the ratio of 2: 1)._To a stirred solution of compounds 19 & 20 (11 g) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 7 (10.4 g, 61.97 mmol), cesium carbonate (18.5 g, 56.81 mmol) at 0 C; heated to 80 C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed withwater (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compounds 21 & 22 (12 g) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf:0.2); LC-MS: 12.57% + 81.14%; 370.8 (M+1) (column; X-Select CSH C18, (50 x 3.0 mm, 3.5 jim); RT 2.77 mm. 0.05% Aq. TFA: ACN; 0.8 mL/min); RT 4.05, 4.14 mm._To a stirred solution of compound 21 & 22 (14 g, crude) in MeOH (500 mL) under inert atmosphere was added Pd/C (1.4 g, 50% wet) at RT and stirred under hydrogen atmospherein an autoclave (6 kg/ cm2 pressure) for 18 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (100 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was recrystallized with EtOH (20 mL) and further purified through silica gel column chromatography column chromatography using 10% EtOAc/ hexanes to afford compound 23 (8 g, 63%) and 24 (3 g, 30%) as sticky off-white solids. TLC: 30% EtOAc/ hexanes (R 0.4); ?H NMR (DMSOd 6, 400 MHz) (23): oe 7.94 (d, J = 7.1 Hz, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.33-7.26 (m, 2H), 7.22 (dt, J= 7.6, 1.1 Hz, 1H), 6.67 (dd, J= 8.2, 0.8 Hz, 1H), 5.41 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H),2.33 (s, 3H). ?H NMR (DMSO-d6, 400 MHz) (24): oe 7.94 (dd, J = 7.8, 1.4 Hz, 1H), 7.42-7.38 (m, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.22 (td, J=7.5, 1.0 Hz, 1H), 6.67 (dd, J= 8.1, 0.8 Hz, 1H), 5.41 (s, 2H), 3.88 (s, 2H), 3.82 (s, 3H), 2.33 (s, 3H).
methyl 2-fluoro-4-((2-(methoxycarbonyl) phenyl) thio)-5-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 10℃; for 2h;Inert atmosphere;
[000119] To a stirred solution of methyl 2, 4-difluoro-5-nitrobenzoate 51(9.0 g, 41.45 mmol) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1(6.97 g, 41.45 mmol), cesium carbonate (14.82 g, 45.60 mmol) at 0 C; warmed to 10 C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (800 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried under sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 52 (11 g, 73%) as an off-white solid. TLC: 10% EtOAc/ hexanes (R 0.4); 1H NMR (DMSO-d6,400 MHz): oe 8.69 (d, J= 6.8 Hz, 1H), 8.04-7.92 (m, 1H), 7.81-7.69 (m, 3H), 6.60 (d,J= 11.5 Hz, 1H), 3.88 (s, 3H), 3.73 (s, 3H).
methyl 2-methoxy-4-((2-(methoxycarbonyl) phenyl)thio)-5-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 2.0h;Inert atmosphere;
[000137] To a stirred solution of compound 72 (200 mg, 0.81 mmol) in DMF (4 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1 (151 mg, 0.89 mmol), cesium carbonate (318 mg, 0.97 mmol) at RT; heated to 80 C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 73 (200 mg, 61%) as yellow solid. TLC: 20% EtOAc/ hexanes (R 0.4); 1H-NMR (CDC13, 400 MHz): oe 8.80 (s, 1H), 7.94-7.92 (m, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.6 1-7.59 (m, 2H), 6.30 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.52 (s, 3H).
methyl 2-[(2-chloro-3-formylpyridin-4-yl)sulfanyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.69%
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 2h;
To a stirred solution of methyl 2-sulfanylbenzoate(5g, 29.72mmol) in DMF (50m1) was added Cs2CO3 (19.369 g, 59.45 mmol) followed by <strong>[134031-24-6]2,4-dichloropyridine-3-carbaldehyde</strong> (5.23 1 g 29.72 mmol) and heated at 70C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude, thus obtained was purifiedby silica gel column chromatography using ethyl acetate in n-hexane (0-8%) as eluting solvent to afford methyl 2-[(2-chloro-3-formylpyridin-4-yl)sulfanyl]benzoate (6.1 g, 66.69 %) as light yellow solid. LC-MS: 307.9 [M+H] .
methyl 2-[(5-fluoro-3-formylpyridin-2-yl)sulfanyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 0.5h;
To a stirred solution of methyl 2-sulfanylbenzoate (2.5 g, 14.86 mmol) in DMF (30 ml)were added Cs2CO3 (7.267 g, 22.29 mmol) followed by <strong>[851484-95-2]2-chloro-5-fluoropyridine-3-carbaldehyde</strong> (2.37 1 g, 14.86 mmol) and heated at 70C for 30 mm. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude thus obtained, was purified by silica gel column chromatography using ethyl acetate in n-hexane (0-6%) as an eluting solvent to afford methyl 2-[(5-fluoro-3-formylpyridin-2-yl)sulfanyl]benzoate (2.65 g, 61%) as off white solid. LC-MS: 292.0 [M+Hf?.
methyl 2-(2-formyl-4-isopropenylphenyl)sulfanylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 3h; Inert atmosphere; Cooling with ice;
9H-fluoren-9-ylmethyl N- [[2-(2-formylphenyl)sulfanyl-5-isopropyl- phenylimethylicarbamate
To an ice-cooled solution of 2-fluoro-5-isopropenyl-benzaldehyde (1.3 g, 7.92 mmol) and methyl thiosalicylate (1.59 g, 9.51 mmol) in DMF (30 mL) under argon atmosphere was addedpotassium carbonate (2.73 g, 19.81 mmol) and the reaction mixture was heated at 60 °C for 3 h. Then the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The organic layer was washed with brine (40 mL x 3), dried over sodium sulfate and concentrated under reduced pressure to get crude compound which was purified by flash- chromatography (30% ethyl acetate in hexane) to afford methyl 2-(2-formyl-4-isopropenyl-phenyl)sulfanylbenzoate (2.2 g, 89%) as pale yellow solid. MS found: 313.1(M+H).
89%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 3h; Cooling with ice; Inert atmosphere;
To an ice-cooled solution of 2-fluoro-5-isopropenyl-benzaldehyde (1.3 g, 7.92 mmol) and methyl thiosalicylate (1.59 g, 9.51 mmol) in DMF (30 mL) under argon atmosphere was added potassium carbonate (2.73 g, 19.81 mmol) and the reaction mixture was heated at 60 °C for 3 h. Then the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The organic layer was washed with brine (40 mL x 3), dried over sodium sulfate and concentrated under reduced pressure to get crude compound which was purified by flash- chromatography (30% ethyl acetate in hexane) to afford methyl 2-(2-formyl-4-isopropenyl- phenyl)sulfanylbenzoate (2.2 g, 89%) as pale yellow solid. MS found: 313.1(M+H).
methyl 2-((4-bromo-2-chloro-6-formylphenyl)thio)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77.8%
With potassium carbonate; In N,N-dimethyl-formamide; at 22℃; for 0.5h;
To a solution of <strong>[1280786-80-2]5-bromo-3-chloro-2-fluorobenzaldehyde</strong> (1.19 g, 5 mmol, Eq: 1) in DMF (12 ml) was added at 22 C methyl 2-mercaptobenzoate (867 mg, 709 jil, 5 mmol, Eq: 1) followed by potassium carbonate (691 mg, 5 mmol, Eq: 1) and stirred at 22 C for 5 mm to give nearly complete conversion. After total 30 minutes the thick suspension was quenched withwater (25 ml) and extracted with ethyl acetate (2 x 25 ml). The organic layers - containing solid - were combined, the solid was filtered, washed with ethyl acetate (2 x 6 ml) and dried in HV to give methyl 2-((4-bromo-2-chloro-6-formylphenyl)thio)benzoate (1.5 g, 3.89 mmol, 77.8 % yield) as light yellow solid.GC-MS: mlz = 325.9 (M + H - HCOOMe)+ for monoisotopic mass 383.92 for P1
methyl 2-(2-chloro-6-formylphenyl)sulfanylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.17%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a suspension of 3-Chloro-2-fluoro-benzaldehyde (2.8 g, 16.64 mmol) and K2C03 (4.5 g, 33.29 mmol) in DMF (15 mL) was added 2-Mercapto-benzoic acid methyl ester (7.9 g, 49.93mmol) and the reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with (3 x 100 mL) ethyl acetate. Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the crude compound which was purified by silica gel column chromatography (20 % ethyl acetate and hexane) to afford methyl 2-(2-chloro-6-formyl-phenyl)sulfanylbenzoate (4.4 g, 86.17%) as white solid. LC-MS: 307.2 [M+H].
86.17%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a suspension of 3-Chloro-2-fluoro-benzaldehyde (2.8 g, 16.64 mmol) and K2CO3 (4.5 g, 33.29 mmol) in DMF (15 mL) was added 2-Mercapto-benzoic acid methyl ester (7.9 g, 49.93 mmol) and the reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with (3 x 100 mL) ethyl acetate. Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the crude compound which was purified by silica gel column chromatography (20 % ethyl acetate and hexane) to afford methyl 2-(2- chloro-6-formyl-phenyl)sulfanylbenzoate (4.4 g, 86.17%) as white solid. LC-MS: 307.2 [M+H]+.
methyl 2-[2-formyl-6-(trifluoromethyl)phenyl]sulfanylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.67%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;
To a solution of 2-Fluoro-3-trifluoromethyl-benzaldehyde (2.0 g, 10.41 mmol) in DMF (4 mL) was added K2C03 (2.8 g, 20.82 mmol) followed by 2-Mercapto-benzoic acid methyl ester (2.62 g, 15.61 mmol) and the reaction mixture was stirred for 6 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (70 mL). Organic layer was dried over sodiumsulphate and concentrated under reduced pressure to obtain methyl 2- [2-formyl-6- (trifluoromethyl)phenyl]sulfanylbenzoate (3.0 g, 84.67%) as off white solid. LC-MS: 341.0 (M+H).
methyl 2-[2-formyl-5-(trifluoromethyl)phenyl]sulfanylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.67%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;
To a solution of 2-Fluoro-4-trifluoromethyl-benzaldehyde (2.0 g, 10.4 immol) in DMF (4 mL) was added K2C03 (2.8 g, 20.82 mmol) followed by 2-Mercapto-benzoic acid methyl ester (2.62 g, 15.61 mmol) and the reaction mixture was stirred for 6 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (70 mL). Organic layer was dried over sodiumsulphate and concentrated under reduced pressure to obtain methyl 2- [2-formyl-5- (trifluoromethyl)phenyl] sulfanylbenzoate (3.0 g, 84.67 %) as off white solid. LC-MS: 341.1 (M+H).
84.67%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;
To a solution of 2-Fluoro-4-trifluoromethyl-benzaldehyde (2.0 g, 10.41mmol) in DMF (4 mL) was added K2CO3 (2.8 g, 20.82 mmol) followed by 2-Mercapto-benzoic acid methyl ester (2.62 g, 15.61 mmol) and the reaction mixture was stirred for 6 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (70 mL). Organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain methyl 2-[2-formyl-5-(trifluoromethyl)phenyl]sulfanylbenzoate (3.0 g, 84.67 %) as off white solid. LC-MS: 341.1 (M+H).
methyl 2-[2-formyl-4-(trifluoromethyl)phenyl]sulfanylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98.78%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;
To a solution of 2-fluoro-5-trifluoromethyl-benzaldehyde (2.0 g, 10.4 immol) in DMF (4 mL) was added K2C03 (2.8 g, 20.82 mmol) followed by 2-Mercapto-benzoic acid methyl ester (2.67g, 15.61 mmol) and the reaction mixture was stuffed for 4 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). Combined organic layer wasdried over sodium sulphate and concentrated under reduced pressure to obtain methyl 2-[2- formyl-4-(trifluoromethyl)phenyl]sulfanylbenzoate (3.5 g, 98.78%) as off white solid. LC-MS:340.7 (M+H).
methyl 2-[6-chloro-2-formyl-3-(trifluoromethyl)phenyl]sulfanylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With potassium carbonate; In N,N-dimethyl-formamide; at 25.0℃; for 0.5h;
To a stirred solution of methyl 2-mercapto-benzoic acid methyl ester (2g, 11.89 mmol) and<strong>[186517-27-1]2,3-dichloro-6-(trifluoromethyl)benzaldehyde</strong> (2.89g, 1 1.889mmo1) in DMF (2OmL) was added K2C03 (1.64g, 11.89 mmol) and reaction mass was stirred at 25C for 30 mm. Reaction mixture was diluted with ethyl acetate and washed with water. The separated organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure.The crude thus obtained was purified by normal silica column using 0-5% ethyl acetate in hexane to get methyl 2- [6-chloro-2-formyl-3- (trifluoromethyl)phenyl] sulfanylbenzoate (2. 3g, 51%) as a white solid. MS found: 375 (M+H).
51%
With potassium carbonate; In N,N-dimethyl-formamide; at 25.0℃; for 0.5h;
To a stirred solution of methyl 2-mercapto-benzoic acid methyl ester (2g, 11.89 mmol) and <strong>[186517-27-1]2,3-dichloro-6-(trifluoromethyl)benzaldehyde</strong> (2.89g, 11.889mmol) in DMF (20mF) was added K2CO3 (1.64g, 11.89 mmol) and reaction mass was stirred at 25C for 30 min. Reaction mixture was diluted with ethyl acetate and washed with water. The separated organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude thus obtained was purified by normal silica column using 0-5% ethyl acetate in hexane to get methyl 2-[6-chloro-2-formyl-3-(trifluoromethyl)phenyl]sulfanylbenzoate (2.3g, 51%) as a white solid. MS found: 375 (M+H).
methyl 2-(3,6-difluoro-2-formylphenyl)sulfanylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 0.5h;
To a stirred solution of methyl 2-Mercapto-benzoic acid methyl ester (1.37g, 8.l53mmol) and 2-chloro-3 ,6-difluorobenzaldehyde (1.43 g, 8.1 53mmol) in DMF (1 2mL) was added K2C03(1. 12g, 8. l53mmol) and reaction mass was stirred at 25C for 30 mm. Reaction mixture was diluted with ethyl acetate and washed with water. The separated organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure.The crude thus obtained was purified by normal silica column using 0-2% ethyl acetate in hexane to get methyl 2-(3,6-difluoro-2-formyl-phenyl)sulfanylbenzoate (lg, 40%) as a yellow solid. MS found: 309.3 (M+H).
methyl 2-[4-chloro-2-formyl-6-(trifluoromethyl)phenyl]sulfanylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;
9H-fluoren-9-ylmethyl N-[[5-chloro-2-(2-formylphenyl)sulfanyl-3-(trifluoromethyl)phenyl]methyl] carbamate
To a suspension of 5-Chloro-2-fluoro-3-trifluoromethyl-benzaldehyde (1.5 g, 6.62 mmol) and K2C03 (1.8 g, 13.24 mmol) in DMF (15 mL) was added 2-Mercapto-benzoic acid methyl ester (1.1 g, 6.62 mmol) added and the reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with (3 x 250 mL) ethyl acetate. Combined organiclayer was dried over sodium sulphate and concentrated under reduced pressure to get crude compound which was purified by silica gel (100-200 mesh) column chromatography (20 % ethyl acetate and hexane) to get methyl 2-[4-chloro-2-formyl-6- (trifluoromethyl)phenyl]sulfanylbenzoate (2.3 g, 93%) as brown solid.
93%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;
To a suspension of 5-Chloro-2-fluoro-3-trifluoromethyl-benzaldehyde (1.5 g, 6.62 mmol) and K2CO3 (1.8 g, 13.24 mmol) in DMF (15 mL) was added 2-Mercapto-benzoic acid methyl ester (1.1 g, 6.62 mmol) added and the reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with (3 x 250 mL) ethyl acetate. Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to get crude compound which was purified by silica gel (100-200 mesh) column chromatography (20 % ethyl acetate and hexane) to get methyl 2-[4-chloro-2-formyl-6- (trifluoromethyl)phenyl]sulfanylbenzoate (2.3 g, 93%) as brown solid.
General procedure: Method A: To a stirred suspension of chlorophosphine gold(l) compound VII (0.32 mmol) in EtOH (1 mL) at 0C was slowly added the appropriate thiol III (0.32 mmol) as a solution in aqueous K2CO3 (10% w/v, 1 mL). The reaction mixture was then stirred at 0C for 1 h before it was diluted with water (5 mL) and extracted with DCM (4 x 15 mL). The combined organic extracts were passed through a phase separator cartridge (Biotage) and the solvent evaporated to provide the title compound I. Method L: As method A except MeOH was used as the reaction solvent.
methyl 2-((4-bromo-3-methyl-2-nitrophenyl)thio)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;
To a stirring solution of compound 8-2 (5.1 g, 21.79 mmol) in DMF (80 mL) under argon atmosphere were added cesium carbonate (10.62 g, 32.67 mmol), methyl 2- mercaptobenzoate 1 (4.03 g, 23.97 mmol) at RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL), the precipitated solid was filtered, washed with hexane (100 mL)and diethyl ether (100 mL) and dried in vacuo to afford compound 8-3 (7.0 g, 84%) as an off- white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.3); 1H NMR (DMSO-d6, 400 MHz): 8.09-7.85 (m, 2H), 7.55-7.46 (m, 2H), 7.34 (td, J= 7.6, 1.1 Hz, 1H), 6.81 (dd, J= 8.2, 0.8 Hz, 1H),3.87 (s, 3H), 2.35 (s, 3H); LC-MS: 98.98%; 383.2 (M+2) (Column; X-select CSH C-18 (50 x 3.0mm, 2.5 um); RT 4.99 mm. 2.5 mM Aq. NH4OAc : ACN, 0.8 mL/min)
N-(2-(1H-indol-3-yl)ethyl)-2-mercaptobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: tryptamine With trimethylaluminum In hexane; dichloromethane at 20℃; for 1h; Cooling with ice; Inert atmosphere;
Stage #2: Methyl thiosalicylate In hexane; dichloromethane at 20℃; for 12h;
10 N-(2-(1H-indol-3-yl)ethyl)-2-mercaptobenzamide (new tryptamine derivative 10):
Add tryptophan (0.30mmol) to the 10mL reaction bottle (A is tryptophan hydrochloride, need to add water and dichloromethane, adjust the pH of the aqueous phase to 13, extract and dry), add the solvent dichloromethane under argon 3.0mL. Under ice bath, slowly add trimethylaluminum AlMe3 (1.6M in n-hexane, 0.47mL), remove the ice bath, stir at room temperature for 60min, and slowly drop methyl thiosalicylate (0.30mmol) at room temperature Stir for 12h. After the reaction was monitored by TLC, a 3 mol/L hydrochloric acid aqueous solution was added under ice bath until the solution became clear and no bubbles were generated. Dichloromethane was added to dilute (10 mL) and extracted with water. The organic phase was collected and spin-dried, and the organic phase was dried over anhydrous magnesium sulfate. Purification by silica gel column chromatography (V/V PE:EA=2:1) gave a light yellow solid in 60% yield.
Stage #1: tryptamine With trimethylaluminum In dichloromethane; toluene at 0 - 20℃; for 0.5h;
Stage #2: Methyl thiosalicylate In dichloromethane; toluene for 12h; Reflux;
With trimethylaluminum In dichloromethane at 0 - 20℃; for 12h;
With trimethylaluminum In dichloromethane at 0 - 20℃;
4.3. general procedure for the preparation of compounds and the characterization data of new compounds
General procedure: For compounds with oxygen or nitrogen atoms substituted at 14position, the synthetic procedure is shown as follows: a test tubeequipped with a magnetic stir bar was charged with tryptamine (1 mmol), 2-(phenylamino)benzoic acid (1 mmol), EDCl (1.2 mmol), HOBt(1.2 mmol), triethylamine (2.5 mmol) and DCM (10 mL). The resultingmixture was stirred for 10 h at room temperature, then added 25 mL ofwater and 10 mL of saturated brine solution and extracted with DCM for3 times (3 × 25 mL). The combined organic extracts were concentratedand the resulting residue was purified by column chromatography onsilica gel (petroleum ether/ethyl acetate = 3/1) to give intermediates aswhite solid. For compounds with sulfur atom substituted at 14 position,a test tube equipped with a magnetic stir bar was charged with tryptamine(1.2 mmol), methyl 2-mercaptobenzoate (1 mmol), AlMe3 (1.2mmol), DCM (10 mL) at 0 C. The resulting mixture was moved to roomtemperature and stirred for 12 h, then quenched with HCl (5 M) aqueoussolution, and extracted with DCM for 3 times (3 × 25 mL), the combinedorganic extracts were concentrated and the resulting residue was purifiedby column chromatography on silica gel (petroleum ether/ethylacetate = 2/1) to give intermediates as white solid. The next step is thata mixture of the above intermediates (0.1 mmol) was triethyl orthoformate(0.30 mmol), BF3•Et2O (0.05 mmol, 0.5 eq) and DMF (1.0 mL)were added and stirred at 100 C for 5 h under an argon atmosphere.Then, the mixture was added 25 mL of water and 10 mL of saturatedbrine solution and extracted with ethyl acetate for 3 times (3 × 25 mL).The extract was dried over anhydrous Na2SO4 and concentrated underreduced pressure. The crude product was purified by column chromatography(petroleum ether/ ethyl acetate = 4/1) to afford the productsas white solid. (compounds 1-3 were obtained at 135 C; compounds 4 -5 were obtained at room temperature in DCM.)
With trimethylaluminum; triethylamine; In hexane; dichloromethane; at 0 - 40℃;Inert atmosphere;
Add tri-<strong>[7436-22-8]deuterated methylamine hydrochloride</strong> (2.2g, 31.18mmol, 2.0eq.) and dichloromethane (150mL) into the reaction flask. The reaction system was replaced with nitrogen three times, and then the reaction system was cooled with an ice water bath. Under this cooling condition, triethylamine (3.14g, 31.18mmol, 2.0eq.) and a n-hexane solution of trimethylaluminum (15.6mL, 2M, 31.18mmol, 2.0eq.) were sequentially added dropwise to the reaction system. After the addition was completed, the reaction temperature was raised to room temperature, and the reaction mixture was stirred at room temperature for 1 hour, and then methyl 2-mercaptobenzoate (2.62 g, 15.59 mmol, 1.0 eq.) was added dropwise thereto. The reaction temperature was raised to 40C and stirred at this temperature overnight. Then the reaction system was cooled with an ice-water bath, and 5M hydrochloric acid solution (30 mL) was added dropwise to the reaction mixture under this cooling condition to quench the reaction. After separating the organic layer, the aqueous layer was extracted and washed with dichloromethane three times (30 mL each time). The organic layer and the dichloromethane extraction and washing liquid were combined and concentrated. The obtained residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate=20:80-50:50) to obtain N-(trideuteromethyl)-2-mercaptobenzamide (2.3g, 86.7%).
With calcium hydroxide In N,N-dimethyl-formamide at 80℃; for 1h; Sealed tube;
General Methylation Procedure A (DMF Conditions)
General procedure: A 10-mL glass reaction tube fitted with a resealable Teflon valve wasequipped with a magnetic stir bar and charged with the heteroatomnucleophile substrate (1.0 mmol, 1.0 equiv), Ca(OH)2 (100 mg, 1.35mmol, 1.35 equiv), TMP (0.20 mL, 1.7 mmol, 1.7 equiv), and DMF (1.0mL). The flask was sealed and stirred at 80 °C (or at RT for some thiolsubstrates) until TLC indicated complete conversion. The reaction wasthen worked up as described below. Workup Procedure A After complete conversion, 1 N HCl (5 mL) was added and the mixturewas extracted with CH2Cl2 (10 mL). The organic phase was separated,washed with H2O (20 mL), dried over Na2SO4, filtered, and then concentratedin vacuo. The resulting residue was purified by silica gelcolumn chromatography to afford the desired methylated product.Workup Procedure B After complete conversion, petroleum ether (5 mL) was added, andthe solid was smashed into fine particles using a spatula and sonicatedfor 5 min. The resulting residue was then directly subjected to silicagel column chromatography to afford the desired methylated product.Workup Procedure C After complete conversion, CH2Cl2 (5 mL) was added, and the mixturewas filtered through a pad of Celite, washed with H2O (10 mL), andextracted with EtOAc (5 × 20 mL). The organic phase was separated,dried over Na2SO4, filtered, and concentrated in vacuo. The resultingresidue was purified by silica gel column chromatography to affordthe desired methylated product.
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