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Structure of 1711-06-4 * 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.
In a 1000 ml reaction flask equipped with a thermometer, a stirrer, a condenser, and an exhaust gas absorption device, 540.56 g of m-toluic acid, 573.0 g of thionyl chloride and 1.0 g of N, N-dimethylformamide were charged and heated to 90 ° C, the reaction was stirred 3h, the reaction was completely transparent, excess pressure to remove excess thionyl chloride, m-methyl benzoyl chloride 610.0g, purity 98.2percent, yield 99.3percent o
98.2%
With thionyl chloride; tetra(n-butyl)ammonium hydrogensulfate In 5,5-dimethyl-1,3-cyclohexadiene at 45℃; for 4.5 h; Large scale
m-methyl benzoyl chloride continuous production process is as follows: (1) m-methylbenzoic acid 1360kg, 1453kg thionylchloride and 2720kg xylene were added to the reactor. Then, addition of 2.04kg tetrabutyl ammonium hydrogen sulfate. At 45 deg.C reaction 4h, until no gas evolution. Continue to hold temperature for 0.5 hours, to obtain a reaction solution;(2) The reaction mixture was added tothe distillation column, flow into the tower 4.7kg / min, distillation tower bottoms heated by steam, Temperature controlled at 105 , overhead light component recovery flow 4.2kg / min, light component after condensed by the condenser returned to the reaction vessel; (3) the distillation tower reactor m-methylbenzoyl chloride crude product was added to the thin film evaporator, feed rate of 3.9kg / min, adjust the degree of vacuum to 630mmHg, vacuum distillation at 127 deg.C, to give 1516.5 kg-methyl chloride in a yield of 98.2percent, after testing, chromatography between methyl chloride content of 99.4percent.
98.9%
With thionyl chloride In N,N-dimethyl-formamide at 90℃; for 4 h;
(1) Add 330 g of m-toluic acid to the reaction vessel, add 360 g of thionyl chloride and 5 g of DMF, and stir for 2 h. When there is no obvious gas in the reaction vessel, the temperature is raised to 90 ± 5 ° C. Incubated for 2 h to complete the reaction, and then distilled at 120 ° C excess excess thionyl chloride. M-methyl benzoyl chloride yield of 98.9percent;
Reference：
[1] Patent: CN107417518, 2017, A, . Location in patent: Paragraph 0028
[2] Patent: CN105348085, 2016, A, . Location in patent: Paragraph 0026; 0027; 0028; 0029; 0030
[3] Patent: CN107400052, 2017, A, . Location in patent: Paragraph 0016
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[11] Bulletin des Societes Chimiques Belges, 1966, vol. 75, p. 199 - 229
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4
[ 108-38-3 ]
[ 99-63-8 ]
[ 1711-06-4 ]
Yield
Reaction Conditions
Operation in experiment
65.7%
Stage #1: at 135℃;
The catalyst dissolved in fresh m-xylene added to the oxidation reactor isN-hydroxyphthalimide,Cobalt naphthenate,Metal phthalocyanine having the structure of the general formula (IV) (R1=H, R2=H, M=Co) and metal porphyrin having the structure of the general formula (III) (R1=R2=R3=H, M1=M2=Mn )mixture,The total concentration is 800ppm and the reaction temperature is 135 °C.The reaction pressure is 0.5 MPa, and the oxygen-containing gas is pure oxygen. The operation procedure is the same as in the first embodiment.The difference is that the conversion of meta-xylene is controlled at 36percent.The content of intermediate methyl benzyl alcohol in the initial steaming tower was controlled to be 0.05percent.The mass percentage of each component obtained by HPLC analysis in the reaction solution is shown in Table 1.The quality of the obtained steaming tower bottom liquid,The contents of the methyl benzoic acid in the mixture of the composition and the initial distillation column are shown in Table 2.The above-mentioned preliminary steaming tower bottom liquid is subjected to rectification,At the top of the column, 376.6 g of m-methylbenzoic acid product with a purity of 99.0percent was obtained.In the column, 1718.8 g of a high-boiling tower liquid having an m-methylbenzoic acid content of 86.5 wtpercent was obtained.Taking thionyl chloride as the acid chloride reagent,The high boiling column liquid is subjected to an acid chlorination reaction,Obtaining an acid chloride reaction solution whose main components are m-methylbenzoyl chloride and isophthaloyl chloride,The reaction end point is the content of m-methylbenzoic acid <0.5 wtpercent.The obtained acid chloride reaction solution is subjected to rectification separation,At the top of the column, 1655.4 g of m-methylbenzoyl chloride and 99.0percent of isophthalic acid were obtained in this order.The acid chloride was 277.9 g. Calculated based on the input meta-xylene,The yield of m-methylbenzoic acid was 17.0percent, and the yield of m-methylbenzoyl chloride was 65.7percent.The yield of isophthalic acid chloride is 8.4percent.The total yield of the three was 91.1percent.
25%
Stage #1: at 156℃;
The catalyst dissolved in fresh m-xylene added to the oxidation reactor is a mixture of MnO2 and Co(Ac)2·4H2O.The compound has a total concentration of 150 ppm and a reaction temperature of 156 ° C.The reaction pressure is 1.0 MPa, and the oxygen-containing gas is pure oxygen.The difference is that the conversion of meta-xylene is controlled to 38percent.The content of intermediate methyl benzyl alcohol in the initial steaming tower was controlled to be 0.05percent.The mass percentage of each component obtained by HPLC analysis in the reaction solution is shown in Table 1.The mass and composition of the obtained preliminary steaming tower bottom liquid and the content of methylbenzoic acid in the initial steaming tower overhead mixture are shown in Table 2.The above-mentioned preliminary steaming tower bottom liquid is subjected to rectification,At the top of the column, 555.2 g of m-methylbenzoic acid product with a purity of 99.0percent was obtained.The column kettle obtained 1552.3 g of a high-boiling tower liquid having an m-methylbenzoic acid content of 84.6 wtpercent.The chlorination reaction is carried out by using sulfoxide as the acyl chloride reagent, and the high boiling column liquid is subjected to an acid chlorination reaction.Obtaining an acid chloride reaction solution whose main components are m-methylbenzoyl chloride and isophthaloyl chloride,The reaction end point is the content of m-methylbenzoic acid <0.5 wtpercent.The obtained acid chloride reaction solution is subjected to rectification separation,At the top of the column, 1461.9 g of m-methylbenzoyl chloride and 99.0percent of isophthalic acid were obtained in this order.The acid chloride was 286.7 g. Calculated based on the input meta-xylene,The yield of m-methylbenzoic acid was 71.8percent, and the yield of m-methylbenzoyl chloride was 25.0percent.The yield of isophthaloyl chloride was 58.0percent, and the total yield of the three was 8.7percent.
Reference：
[1] Patent: CN108117486, 2018, A, . Location in patent: Paragraph 18-24; 27; 28
[2] Patent: CN108117486, 2018, A, . Location in patent: Paragraph 18-24; 27; 28
5
[ 620-23-5 ]
[ 1711-06-4 ]
Reference：
[1] Organic Letters, 2015, vol. 17, # 15, p. 3666 - 3669
[2] New Journal of Chemistry, 2017, vol. 41, # 3, p. 931 - 939
[3] Tetrahedron Letters, 2017, vol. 58, # 26, p. 2533 - 2536
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 32, p. 10140 - 10144
8
[ 79-37-8 ]
[ 99-04-7 ]
[ 1711-06-4 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 16, p. 6449 - 6457
[2] Chemistry - A European Journal, 2017, vol. 23, # 50, p. 12149 - 12152
9
[ 625-95-6 ]
[ 100-20-9 ]
[ 1711-02-0 ]
[ 1711-06-4 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 32, p. 10140 - 10144
10
[ 99-04-7 ]
[ 98-88-4 ]
[ 1711-06-4 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 6, p. 1129 - 1132[2] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 6, p. 1275 - 1279
11
[ 933-88-0 ]
[ 874-60-2 ]
[ 1711-06-4 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1989, vol. 25, # 11.2, p. 2139 - 2141[2] Zhurnal Organicheskoi Khimii, 1989, vol. 25, # 11, p. 2372 - 2374
12
[ 141-97-9 ]
[ 1711-06-4 ]
[ 33166-79-9 ]
Yield
Reaction Conditions
Operation in experiment
17%
With sodium hydroxide; ammonium chloride In water; benzene
EXAMPLE 6 Preparation of Ethyl 2-Amino-4-(m-Tolyl)-5-Thiazolecarboxylate To a cold (5° C.) mixture of 137.5 g (1.05 mole) of ethyl acetoacetate, 175 ml. of benzene, 325 ml. of water, and 45.8 ml. of 33percent sodium hydroxide was added simultaneously 221.05 g (1.430 mole) of m-toluoyl chloride and 190 ml. of 33percent sodium hydroxide as described in Example 4. The aqueous solution of sodium salt of ethyl m-toluoylacetoacetate was stirred with 56.3 g of ammonium chloride overnight and worked up as described in Example 4 to give 38.0 g (17percent) of crude ethyl m-toluoylacetate after a Kugelrohr distillation (95°-98° C.) at 0.05 mm Hg).
17%
With sodium hydroxide; ammonium chloride In water; benzene
EXAMPLE 6 Preparation of Ethyl 2-Chloro-4-(m-Tolyl)-5-Thiazolecarboxylate To a cold (5° C.) mixture of 137.5 g (1.05 mole) of ethyl acetoacetate, 175 ml. of benzene, 325 ml. of water, and 45.8 ml. of 33percent sodium hydroxide was added simultaneously 221.05 g (1.430 mole) of m-toluoyl chloride and 190 ml. of 33percent sodium hydroxide as described in Example 4. The aqueous solution of sodium salt of ethyl m-toluoylacetoacetate was stirred with 56.3 g of ammonium chloride overnight and worked up as described in Example 4 to give 38.0 g (17percent) of crude ethyl m-toluoylacetate after a Kugelrohr distillation (95°-98° C. at 0.05 mm Hg).
Reference：
[1] Patent: US4308391, 1981, A,
[2] Patent: US4336389, 1982, A,
13
[ 141-97-9 ]
[ 1711-06-4 ]
[ 33166-79-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1621 - 1630
[2] Chemische Berichte, 1935, vol. 68, p. 227,230
14
[ 109-89-7 ]
[ 1711-06-4 ]
[ 134-62-3 ]
Yield
Reaction Conditions
Operation in experiment
97.5%
With sodium hydroxide In water at 45℃; for 0.05 h;
438.8 g (6 mol) of diethylamine and 1052 g of an aqueous sodium hydroxide solution (19percent) were mixed and stirred.Forming a diethylamine-hydrogen peroxide system, m-methylbenzoyl chloride is an acid chloride system,The two systems were injected into the reactor through a metering pump at a flow rate of 45 ml/min and 35 ml/min, respectively, where n (m-methylbenzoyl chloride): n (diethylamine) = 1:2,Using the microchannel reactor of Figure 2, the temperature is controlled at 45 ° C and the residence time is 180 s.The quantitative collection reaction solution is transferred to a separatory funnel for separation.The organic phase was retained and the aqueous phase was extracted three times with diethyl ether.Drying over anhydrous sodium sulfate, distilling off diethyl ether to give a crude product.After distillation under reduced pressure, fractions of 165 to 175 ° C were collected.A pale yellow liquid was obtained, and the yield of the product calculated by weighing was 97.5percent.Chromatographic detection The purity of the product was 98.3percent.
Reference：
[1] Patent: CN107840805, 2018, A, . Location in patent: Paragraph 0032; 0035; 0038; 0041; 0044; 0047-0050; 0053
[2] Chem.Abstr., 1930, vol. 24, p. 94[3] Chem. Zentralbl., 1929, vol. 100, # II, p. 2324
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 9, p. 1225 - 1228
[5] Journal of the American Chemical Society, 2014, vol. 136, # 29, p. 10258 - 10261
15
[ 1711-06-4 ]
[ 68432-92-8 ]
Reference：
[1] Organic and biomolecular chemistry, 2004, vol. 2, # 12, p. 1732 - 1741
With sodium hydroxide; In water; at 45℃; for 0.05h;
438.8 g (6 mol) of diethylamine and 1052 g of an aqueous sodium hydroxide solution (19%) were mixed and stirred.Forming a diethylamine-hydrogen peroxide system, m-methylbenzoyl chloride is an acid chloride system,The two systems were injected into the reactor through a metering pump at a flow rate of 45 ml/min and 35 ml/min, respectively, where n (m-methylbenzoyl chloride): n (diethylamine) = 1:2,Using the microchannel reactor of Figure 2, the temperature is controlled at 45 C and the residence time is 180 s.The quantitative collection reaction solution is transferred to a separatory funnel for separation.The organic phase was retained and the aqueous phase was extracted three times with diethyl ether.Drying over anhydrous sodium sulfate, distilling off diethyl ether to give a crude product.After distillation under reduced pressure, fractions of 165 to 175 C were collected.A pale yellow liquid was obtained, and the yield of the product calculated by weighing was 97.5%.Chromatographic detection The purity of the product was 98.3%.
With copper(I) thiophene-2-carboxylate; triphenylphosphine; bis(dibenzylideneacetone)-palladium(0); In diethyl ether; at 20℃; for 1h;Schlenk technique; Inert atmosphere;
General procedure: 4.3.1 Benzophenone (3a) 18 To phenylboronic acid (1a, 244 mg, 2 mmol), CuTC (191 mg, 1 mmol), Pd(dba)2 (29 mg, 0.05 mmol), and PPh3 (26.2 mg, 0.1 mmol), were added dry Et2O (30 mL) and benzoyl chloride (2a, 116 muL, 1 mmol) at rt and the reaction was monitored by GC and TLC. After completion of the reaction, the reaction mixture was passed briefly through a Celite pad. Further, the pad was washed with Et2O (2*10 mL). The combined organics were concentrated with a rotary evaporator to give a viscous oil or solid. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc=9:1, Rf=0.47), benzophenone (3a) (142 mg, 0.78 mmol, 78%) was obtained as a white solid.
EXAMPLE 7. Synthesis of 5-f3-Methylbenzamido)-2-Chlorobenzoic Acid(Intermediate 4); [0134] To a stirring solution of <strong>[89-54-3]5-amino-2-chlorobenzoic acid</strong> (880 mg, 5.1 mmol) in anhydrous THF (45 mL), 3-methylbenzoyl chloride (870 mg, 5.6 mmol) was added slowly. The mixture was stirred at room temperature under argon for overnight. The solvent was removed under reduced pressure and re-crystallized from chloroform to afford the title compound as a white solid (1.2 g, 80percent).
<strong>[4727-00-8]O-t-Butyl-L-tyrosine</strong> 1 (2.00 g, 7.8 mmol) was dissolved in H2O (10 mL) containing equimolar amounts of NaOH (0.31 g, 7.8 mmol). The solution was cooled to 0 C., then m-toluoyl chloride (1.04 mL, 7.8 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 2 h. After acidification with 0.25 M phosphate buffer (pH 6.2), the product was extracted from the reaction mixture three times with EtOAc. The combined organic layers were dried (MgSO4), filtered and the solvent was removed in vacuo to yield (S)-3-(4-tert-Butoxy-phenyl)-2-(3-methyl-benzoylamino)-propionic acid 2 (2.17 g, 6.1 mmol, 78%) as a white solid: 1H-NMR (400 MHz, CD3OD) delta=7.51-6.87 (m, 8H), 4.82 (dd, J=5.0, J=9.8, 1H), 3.33-3.28 (m, 1H), 3.09-3.03 (m, 1H), 2.35 (s, 3H), 1.27 (s, 9H). MS calcd. for C21H26NO4 (M+H+) 356.19, found 356.4.
L-p-Iodo-phenylalanine (3.00 g, 10 mmol) was dissolved in H2O (25 mL) containing equimolar amounts of NaOH (0.40 g, 10 mmol). The solution was cooled to 0° C., then m-toluoyl chloride (1.32 mL, 10 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 2 h. After neutralization with 0.5 M HCl, the product was extracted from the reaction mixture three times with EtOAc. The combined organic layers were dried (MgSO4), filtered and the solvent was removed in vacuo to yield (S)-(3-(4-Iodo-phenyl)-2-(3-methyl-benzoylamino)-propionic acid 2 (3.36 g, 82percent): 1H-NMR (400 MHz, CD3OD) delta=7.62-7.05 (m, 8H), 4.82 (dd, J=5.0, J=9.7, 1H), 3.32-3.26 (m, 1H), 3.08-3.03 (m, 1H), 2.36 (s, 3H). MS calcd. for C17H17INO3 (M+H+) 410.22, found 410.2.
With sodium hydroxide; In water; at 20℃; for 12.0h;
(S)-2-Amino-5-phenyl-pentanoic acid 2 (23 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0 C., then m-Toluic acid chloride (16 muL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (S)-2-(3-methyl-benzoylamino)-5-phenyl-pentanoic acid 3 (21 mg, 56%) as a white solid: 1H-NMR (400 MHz, CD3OD) delta=7.83-7.09 (m, 9H), 4.62 (dd, J=5.0, J=9.1, 1H), 2.65 (m, 2H), 2.37 (s, 3H), 2.01-1.67 (m, 4H). MS calcd. for C19H22NO3 (M+H+) 312.16, found 312.4.
4-Fluoro-phenyl glycine 1 (20 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0 C., then m-toluoyl chloride (16 muL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (4-Fluoro-phenyl)-(3-methyl-benzoylamino)-acetic acid 2 (34 mg, 0.12 mmol, quant.) as a white solid: 1H-NMR (400 MHz, CD3OD) delta=7.67-7.08 (m, 8H), 5.66 (s, 1H), 2.38 (s, 3H). MS calcd. for C16H15FNO3 (M+H+) 288.10, found 288.4
3-methyl-N-(5-phenyl-thiazol-2-yl)-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17.7%
In pyridine; at 20℃;
5-Phenyl-thiazol-2-ylamine (35.2 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (10.4 mg, 0.0353 mmol, 17.7 %). ESI-MS M/Z calc. 294.1, found 295.4 (M+1) + Retention time 3.40 minutes.
sodium salt of ethyl m-toluoylacetoacetate[ No CAS ]
[ 141-97-9 ]
[ 1711-06-4 ]
[ 33166-79-9 ]
Yield
Reaction Conditions
Operation in experiment
38.0 g (17%)
With sodium hydroxide; ammonium chloride; In water; benzene;
EXAMPLE 6 Preparation of Ethyl 2-Amino-4-(m-Tolyl)-5-Thiazolecarboxylate To a cold (5 C.) mixture of 137.5 g (1.05 mole) of ethyl acetoacetate, 175 ml. of benzene, 325 ml. of water, and 45.8 ml. of 33% sodium hydroxide was added simultaneously 221.05 g (1.430 mole) of m-toluoyl chloride and 190 ml. of 33% sodium hydroxide as described in Example 4. The aqueous solution of sodium salt of ethyl m-toluoylacetoacetate was stirred with 56.3 g of ammonium chloride overnight and worked up as described in Example 4 to give 38.0 g (17%) of crude ethyl m-toluoylacetate after a Kugelrohr distillation (95-98 C.) at 0.05 mm Hg).
38.0 g (17%)
With sodium hydroxide; ammonium chloride; In water; benzene;
EXAMPLE 6 Preparation of Ethyl 2-Chloro-4-(m-Tolyl)-5-Thiazolecarboxylate To a cold (5 C.) mixture of 137.5 g (1.05 mole) of ethyl acetoacetate, 175 ml. of benzene, 325 ml. of water, and 45.8 ml. of 33% sodium hydroxide was added simultaneously 221.05 g (1.430 mole) of m-toluoyl chloride and 190 ml. of 33% sodium hydroxide as described in Example 4. The aqueous solution of sodium salt of ethyl m-toluoylacetoacetate was stirred with 56.3 g of ammonium chloride overnight and worked up as described in Example 4 to give 38.0 g (17%) of crude ethyl m-toluoylacetate after a Kugelrohr distillation (95-98 C. at 0.05 mm Hg).
EXAMPLE 6 (Reference) Preparation of (+-)-N-(1-carbamoyl-1,2-dimethylpropyl)-m-toluamide To a solution containing 26 g (0.20 mol), (+-)-<strong>[40963-14-2]2-amino-2,3-dimethylbutyramide</strong> and 30.7 ml trimethylamine in 200 ml dry tetrahydrofuran at 0c is added dropwise 26.4 ml (0.20 mol) m -toluoyl chloride. The temperature is kept below 15C. After the addition, stirring is continued for one hour at room temperature. The mixture is poured into 300 ml ice-cold water. The product is collected by filtration, washed with water and air dried to give 52.3 g of crude products. A 4.0 g sample is recrystallized from methylene chloride-hexane to give 2.58 g of analytically pure (+-)-N-(1-carbamoyl-1,2-dimethylpropyl)- m -toluamide, mp 186.5-187.5C. When (+)-<strong>[40963-14-2]2-amino-2,3-dimethylbutyramide</strong> is used in place of the racemic material, the product is (-)-N-(1-carbamoyl-1,2-dimethylpropyl)- m -toluamide, mp 164C-179C, [alpha] [25/D ] = -39.32 (C = 0.0509 g/ml methanol).
Compound 31: Add 30 (1.0 mmol) drop-wise to a solution of 29 (1.0 mmol) and NEt3 (2.0 mmol) in THF 10.0 mL under nitrogen at 0 C. When the reaction is completed, dilute with ethyl acetate. Wash with 1.0 M HCl, aqueous sat. NaHCO3, and brine. Dry with Na2SO4, concentrate, and purify by flash column chromatography to obtain 31.
2,5-bis-(3-methylphenylcarbonyloxy)-3-undecyl-1,4-benzoquinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With pyridine; In dichloromethane; at 15 - 30℃; for 3h;
Example 13: 2,5-Di-0-(3-methylphenylcarbonyl)-3-undecyI-l,4-benzoquinone; Synthesis of Structure No. 13; 2,5-t°-(3-methylphenylcarbonylormu)-3-undecyl-l,4- benzoquinone.To a stirred solution of 2,5-dihydroxy-3-undecyl-l,4-benzoquinone (0.5 g, 1.7 mmole) in dichloromethane (20 mL) was added pyridine (0.55 mL, 6.8 mmole). To this, was added 3-toluoyl chloride (0.654 gm, 4.25 mmole) at 15-20 0C and stirred, allowed to attain 30 0C and stirring was continued for 3 h (TLC). The organic layer was extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to crude which was purified by SiO2 column chromatography (10-20% EtOAc in hexane) to pure mass (0.64 g, 71%).1H NMR (300 MHz, CDCl3) delta: 0.85 (t, 3H, J = 7.5 Hz), 1.0 - 1.5 (m, 18H), 2.3 - 2.5 (m, 8H), 6.75 (s, IH), 7.30 - 7.61 (m, 5H), 7.9 - 8.10 (m, 3H). TOF MS ES: 553 (100, M+ + Na). Mp. 80.4-81.7 C
71%
With pyridine; In dichloromethane; at 15 - 30℃; for 3h;
Synthesis of Structure # 13; 2,5-bis-(3-methylphenylcarbonyloxy)-3-undecyl-1,4-benzoquinone To a stirred solution of <strong>[550-24-3]2,5-dihydroxy-3-undecyl-1,4-benzoquinone</strong> (0.5 g, 1.7 mmole) in dichloromethane (20 mL) was added pyridine (0.55 mL, 6.8 mmole). To this, was added 3-toluoyl chloride (0.654 gm, 4.25 mmole) at 15-20 C. and stirred, allowed to attain 30 C. and stirring was continued for 3 h (TLC). The organic layer was extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to crude which was purified by SiO2 column chromatography (10-20% EtOAc in hexane) to pure mass (0.64 g, 71%). 1H NMR (300 MHz, CDCl3) delta: 0.85 (t, 3H, J=7.5 Hz), 1.0-1.5 (m, 18H), 2.3-2.5 (m, 8H), 6.75 (s, 1H), 7.30-7.61 (m, 5H), 7.9-8.10 (m, 3H). TOF MS ES: 553 (100, M++Na). Mp. 80.4-81.7 C.
Example 24; N-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl)-3-methylbenzamide; Example 24A; N-(6-chloropyrazin-2-yl)-3-methylbenzamide; <strong>[33332-28-4]2-Amino-6-chloropyrazin</strong>e (496.0 mg, 3.83 mmol) was dissolved in pyridine (15 mL). 3-Methylbenzoyl chloride (760 muL, 5.77 mmol) was added to the reaction mixture. The reaction was heated to 100° C. for 16 h then concentrated under vacuum. The residue was partitioned between 1M K2CO3 (50 mL) and CH2Cl2 (4.x.50 mL). The organic extracts were combined, washed with and brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (5percent EtOAc in CH2Cl2, Rf=0.39) to afford the title compound as a white solid (919.0 mg, 97percent). MS m/z 248 (M+H)+.
Example 1-623-Methyl-7V- [4-(4-py ridinyl)-. ,3-thiazol-2-yl] benzamide (100). [0316] 3-Methyl-7V-[4-(4-pyridinyl)-l,3-thiazol-2-yl]benzamide (100). Oxalyl chloride (0.26 mL, 3.0 mmol) was added to a stirred solution of m-toluic acid (0.41 g, 3.0 mmol) and DMF (3 drops) in DCM (30 mL) and the solution stirred at 20 0C for 1 h. A solution of amine 98 (354 mg, 2.0 mmol) was added and the mixture stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between water (70 mL) and EtOAc (70 mL). The organic fraction was washed with water (30 mL), dried and the solvent evapporated. The crude solid was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give benzamide 100 (110 mg, 19%) as a cream powder: mp (MeOH/EtOAc) 201- 202 0C; 1H NMR delta 12.77 (br s, 1 H, CONH), 8.64 (dd, J= 4.6, 1.6 Hz, 2 H, H-2", H-6"), 8.05 (s, 1 H, H-5), 7.98 (br s, 1 H, H-2), 7.92 (br d, J= 6.9 Hz, 1 H, H-6), 7.88 (dd, J= 4.6, 1.6 Hz, 2 H, H-3", H-5"), 7.42-7.48 (m, 2 H, H-4, H-5), 2.41 (s, <n="136"/>3 H, CH3); 13C NMR delta 165.4, 159.0, 150.1 (2), 146.5, 140.9, 137.8, 133.1, 131.7, 128.6, 128.3, 125.2, 119.2 (2), 112.5, 20.7; MS m/z 296.4 (MH+, 100%). Anal, calcd for Ci6Hi3N3OS: C, 65.06; H, 4.44; N, 14.23. Found: C, 65.19 H, 4.56; N, 14.31%.
m-toluic acid (1.98 g, 1.1 equivalent ratio, Aldrich) was dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) at 00C and then thionyl chloride (1.81 g, 1.15 equivalent ratio) was gradually added to the solution. After the mixture solution was stirred for 10 min at 00C, the mixture of l-(3-amino-2-hydroxy-phenyl)-ethanone (2 g, 1 equivalent ratio) dissolved in 15 ml dimethylacetamide (DMAC, Aldrich) was slowly added to the mixture solution, and thermally stirred for 5 hrs at 25C. The reaction mixture was mixed with 40 ml H2O and stirred for 1 hr at 25C. The solid material obtained by filtering the solid material produced was washed with 20 ml H2O and then dried at 600C with hot-wind, obtaining 3.31 g (yield rate: 93%): 1H NMR (400 MHz, DMSO) delta 12.62 (s, IH) 9.58 (s, IH) 7.98 (d, IH7 J = 6.2 Hz) 7.77 (m, 3H) 7.41 (d, 2H, J = 3.8 Hz) 7.01 (t, IH, J= 6.3 Hz) 2.71 (s, 3H) 2.39 (s, 3H).
aluminum (III) chloride; In dichloromethane; for 2h;Reflux;
Example 3; Preparation of 2-(2-hydroxy-3-(m-methyl benzoyl)-5-methyl)benzotriazole; 2-(2-hydroxy-3-(m-methyl benzoyl)-5-methyl)benzotriazole would be anticipated to be made by the following process. 112.5 g 2-(2-hydroxy-5-methyl)benzotriazole, 92.8 g m-methyl benzoyl chloride and 133 g aluminum chloride are dissolved in 1000 ml CH2Cl2. The mixture is refluxed for 2 hours before CH2Cl2 is removed completely from the mixture via distillation. The temperature is then raised to 160 C. and the mixture in molten state is mixed thoroughly with a mechanical agitator for 30 minutes. The heating is then stopped and the mixture is stirred until the temperature dropped to bellow 90 C. At this point, enough water is added into the mixture until no more bubbles from the decomposition of aluminum chloride is detected.500 ml of additional water is then added to the mixture along with 50 g of concentrated HCl. The mixture is then stirred under reflux conditions for another hour before cooling to room temperature. The aqueous layer is then discharged completely and 500 ml water is added to the mixture along with 50 g of 45% NaOH. The mixture is then refluxed for another hour before cooling to room temperature. The aqueous layer is again discharged. 500 ml of water is then added along with another 50 g of concentrated HCl, mixed under reflux, cooled and the aqueous phase separated. The remaining organic phase is then washed with water several times and dried to obtain the 2-(2-hydroxy-3-benzoyl-5-methyl)benzotriazole (compound 3) whose structure would be confirmed by the methods set forth in Example 1.
With triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: To a cooled (0 C) suspension of 1H-indazole-3-carboxylic acid phenylamide 234 (0.42 mmol) and a catalytic amount of Et3N (0.05 mL) in anhydrous CH2Cl2 (1-2 mL), the appropriate aroyl chloride (1.25 mmol) was added. The mixture was stirred for 1-2 h at 0 C and then for 1-3 h at room temperature. The precipitate was filtered off, and the solvent was evaporated in vacuo. Cold water (20 mL) was added, the mixture was neutralized with 0.5 N NaOH, and the precipitate was recovered by vacuum filtration. For compounds 3c, 3e-f, 3k, and 3q, the reaction mixture was extracted with CH2Cl2 (3 × 15 mL) after dilution. The solvent was dried over sodium sulphate to obtain the desired final compounds. Compound 3c was purified by column chromatography using toluene/ethyl acetate 8:2 as eluent.
With triethylamine; In 1,4-dioxane; at 10 - 20℃; for 1h;
General procedure: A mixture of 2-chlorobenzoic acid (1b) (0.61 g, 3.92 mmol) and thionyl chloride (1 mL) was heated for 2 h. The excess of thionyl chloride was recovered under reduced pressure and the residue so obtained was dissolved in dry dioxane (1 mL). The solution was then dropwise added to mixture of <strong>[5004-88-6]2-amino-4,5-dimethoxybenzamide</strong> (2) (0.7 g, 3.57 mmol) and TEA (1.2 mL, 8.92 mmol) in dry dioxane (2 mL) at 10 C. The reaction mixture was stirred at rt for another 1 h and quenched into cold water (50 mL). The precipitate formed was filtered, washed with water and dried to obtain compound 3b (0.85 g, 71%).
3-(2-pyridyl)-5-(3′-toluyl)-1,2,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With pyridine; In toluene;Reflux;
General procedure: The synthesis of 1,2,4-oxadiazoles has been performed by theamidoxime route [35]. The appropriate amidoxime (0.3 g) wasdissolved in 50 mL of toluene in a 250 mL round bottomed flask.Then,1.2 eq. of the appropriate aroyl chloride and 1.2 eq. of pyridinewere added and the reaction mixture was refluxed for 6e8 hmonitoring the reaction by TLC until consumption of starting material. The solvent was removed under vacuum and water wasadded to the residue. Extraction with ethyl acetate and chromatographic separation on silica gel using mixtures of petroleum etherand ethyl acetate as eluent allowed to obtain the desired oxadiazole, further purified by crystallization.
[Preparation Example 1] (Scheme 1) Preparation of 3,5-Dimethyl-1-(3-Methylbenzoyl)piperidine NCR-1) 3,5-Dimethylpiperidine (0.73 g) and triethylamine (2.25 ml) were dissolved in dichloromethane (20 ml). A solution of 3-methylbenzoylchloride (1.00g) in dichloromethane (10 ml) was added dropwise at the freezing point. After stirring for 30 minutes at 0C, the reaction solution was poured into water (100 ml) and extracted with chloroform (50 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and, after filtration, concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (developing solvent: n-hexane/ethyl acetate=4:1) to obtain the subject compound (NCR-1 cis form:trans form=9:1) (0.95 g, yield 63%) as a colorless oil. 1H-NMR (CDCl3, 500MHz, delta; ppm) 0.76-1.86 (10H, m), 2.15-2.23 (0.9H, m), 2.36 (3H, s), 2.44-2.49 (0.9H, m), 3.08 (0.1H, m), 3.20 (0.1H, m), 3.32-3.34 (0.1H, m), 3.63-3.65 (0.9H, m), 7.14 (1H, d, J= 7.3 Hz), 7.19 (1H, d, J= 7.3 Hz), 7.20 (1H, s), 7.26 (1H, t, J = 7.6 Hz); MS (EI) m/z: 231 (M+).
With triethylamine; In dichloromethane; at 0 - 20℃; for 6h;
General procedure: A solution of acid (5 mmol) in SOCl2 (5 mL) was refluxedfor 2 h and cooled to r.t.. The excess of SOCl2 wasremoved under vacuum to give the corresponding acid chloride.The acid chloride was then re-dissolved in 5 mL anhydrousCH2Cl2 and added dropwise to a 20 mL anhydrousCH2Cl2 solution containing PIP-NH2 (5 mmol) and Et3N (10mmol) at 0 C. After stirring for 6 h at r.t., the resultingmixture was washed with brine, dried over MgSO4, filteredand concentrated under reduced pressure. The residue waspurified by flash chromatography to give the desired product.
(R)-methyl 3-methyl-2-(3-methylbenzamido)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h;
(ff)-Methyl-3-methyl-2-(3-methylbenzamido)butanoate To a suspension of (R)-methyl-2-amino-3-methylbutanoate hydrochloride (2.9 g, 17 mmol) in dichloromethane (30 mL) was added N,N-diisopropylethylamine (5.6 g, 40 mmol). To the resulting mixture was added dropwise a solution of 3-methylbenzoyl chloride (3.2 g, 20.6 mmol) in dichloromethane (5 mL) at 0C. The mixture was stirred for 1 hour before the reaction was quenched with ice-water (10 mL). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (3 chi 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate : petroleum ether = 1 :10 to afford (R)-methyl-3-methyl-2-(3-methylbenzamido)butanoate as a yellow oil (3.3 g, 78%). LCMS (ESI): m/z = 250.1 [M+H]+. 1 H-NMR (300 MHz, CDCI3): delta = 1 .01 (t, J = 7.2 Hz, 6H), 2.19-2.36 (m, 1 H), 2.42 (s, 3H), 3.79 (s, 3H), 4.59-4.83 (m, 1 H), 6.55-6.66 (m, 1 H), 7.30-7.38 (m, 2H), 7.56-7.66 (m, 2H).
78%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h;
To a suspension of (R)-methyl-2-amino-3-methylbutanoate hydrochloride (2.9 g, 17 mmol) in 25 dichloromethane (30 ml)was added N,N-diisopropylethylamine (5.6 g, 40 mmol). To theresulting mixture was added dropwisea solution of 3-methylbenzoyl chloride(3.2 g, 20.6 mmol) in dichloromethane (5 ml) at 0C. The mixture was stirred for 1 hour before the reaction was quenched with ice-water (10 ml). The organic layer was collectedand the aqueous layer was extracted with ethyl acetate(3 x20 ml). The combined organiclayers were dried over anhydroussodium sulfate and the solventwas removed under30 reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether= 1:10 to afford (R)-methyl-3-methyl-2-(3-methylbenzamido)butanoate asa yeHow oil (3.3 g. 78%).LCMS (ESI): m/z = 250.1 [M+H(1H-NMR (300 MHz, CDCI3}: 6 = 1.01 (t, J = 7.2 Hz, 6H), 2.19-2.36 (m, 1H), 2.42 (s, 3H), 3. 79(s, 3H}, 5 4.59-4.83 (m, 1H), 6.55-6.66 (m, 1H), 7.30-7.38 (m, 2H), 7 56-7 66 (m, 2H).
(R)-2-cyclohexyl-2-(3-methylbenzamido)acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium hydroxide; In water; at 0℃; for 0.166667h;
(R)-2-Cyclohexyl-2-(3-methylbenzamido)acetic acidTo a solution of <strong>[14328-52-0](R)-2-amino-2-cyclohexylacetic acid</strong> (1DO mg, 0.636mmol) in a 20% aqueous sodiumhydroxide solution (2 ml) was addeddropwise 3-methylbenzoyl chloride (110 mg, 0.709 mmol) at 0C. The mixture was stirred for 10 minutes before the reaction was quenched with ice-water (10 ml). The pHof the mixturewas adjusted to 1 by addition ofa 37% aqueous hydrochloric acid solution. The mixture 15 was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were dried over anhydroussodium sulfate and the solvent was removed under reduced pressure.The residue waspurified by silica gel column chromatography eluting withdichloromethane : methanol = 20:1 to afford (R)-2-cyclohexyl-2- (3-methylbenzamido)acetic acid as a colorless oil (87 mg, 50%).LCMS (ESI): m/z= 276.2 [M+H(
methyl-2-(3-methylbenzamido)-2-(tetrahydro-2H-pyran-4-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With triethylamine; In dichloromethane; for 1.0h;
To a suspension of <strong>[1260637-54-4]methyl-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetate hydrochloride</strong> (210 mg, 1.0 mmol)in dichloromethane (20 ml)was added triethylamine (303 mg, 3.0 mmol). To the mixturewas added dropwisea solution of 3-methylbenzoyl chloride(170 mg, 1.1 mmol) in dichloromethane (5 ml)at15 0CThe mixturewas stirred for 1 hour before the reaction was quenched with ice-water (10 ml). The organic layer was collectedand the aqueous layer was extracted with ethyl acetate (3 x20 ml). The combined organiclayers were dried over anhydroussodium sulfate and the solventwas removed under reduced pressure.The residue was purified by silica gel column chromatography eluting with ethyl acetate: petroleum ether= 1:1 to afford methyl-2-(3-methylbenzamido)-2-(tetrahydro-2H-pyran-4-20 yl)acetate as a colorless oil (200- mg, 68%). LCMS (ESI): m/z = 292.1 (M+Ht1H-NMR (300 MHz, CDCI3): o = 1.45-1.71 (m, 4H), 2.10-2.25 (m, 1H), 2.41 (s, 3H), 3.31-3.46 (m, 2H),3.80 (s ,3H), 3.91-4.06 (m, 2H), 4.83-4.94(m, 1H), 6.61-6.75(m, 1H), 7.31-7.34(m, 2H), 7.51-7.68 (m, 2H).
N-(5-bromo-2-chloropyridin-3-yl)-3-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With pyridine; In pyridine; at 0 - 20℃; for 1h;
Step 1, Method 14: N-(5-Bromo-2-chloropyridin-3-yl)-3-methylbenzamide [0197] To a stirred solution of 5-bromo-2-chloropyridin-3 -amine (500 mg, 2.41 mmol) in pyridine (5 mL) at 0 C was added 3-methylbenzoyl chloride (410 mg, 2.65 mmol) and the mixture stirred at room temperature for 1 hour. Water (50 mL) was added to the mixture. The precipitate was filtered and washed with water to give the title compound 653 mg (83% yield) as an off-white solid. 5H NMR (250 MHz, DMSO) 10.28 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 7.85 - 7.70 (m, 2H), 7.45 (d, J = 5.2 Hz, 2H), 2.41 (s, 3H). Tr (METCR1278) = 2.25 min, (ES+) (M+H)+325/327.
83%
With pyridine; at 0 - 20℃; for 1h;
j0139j To a stirred solution of 5-bromo-2-chloropyriclin-3-amine (500 mg, 2.41 mmol) in pyridine (5 mL) at 0 C was added 3-methylbenzoyl chloride (410 mg, 2.65 mmol). The mixture was stirred at room temperature for 1 hour. Water (50 mL) was added to the mixture. The precipitate was filtered and washed with water to give the title compound 653 mg (83% yield) as an off-white solid. bu NMR (250 MHz, DMSO) 10.28 (s, 1H), 8.49 (d, I = 2.3 Hz, 1H), 8.39 (d, I = 2.3 Hz, IH), 7.85 -7.70 (m, 2H), 7.45 (d, I = 5.2 Hz, 2H), 2.41 (s, 3H). Tr (METCR1278) = 2.25 mi (ES) (M+H) 3251327.
General procedure: The synthesis of 1,2,4-oxadiazoles has been performed by theamidoxime route [35]. The appropriate amidoxime (0.3 g) wasdissolved in 50 mL of toluene in a 250 mL round bottomed flask.Then,1.2 eq. of the appropriate aroyl chloride and 1.2 eq. of pyridinewere added and the reaction mixture was refluxed for 6e8 hmonitoring the reaction by TLC until consumption of starting material. The solvent was removed under vacuum and water wasadded to the residue. Extraction with ethyl acetate and chromatographic separation on silica gel using mixtures of petroleum etherand ethyl acetate as eluent allowed to obtain the desired oxadiazole, further purified by crystallization.
General procedure: The synthesis of 1,2,4-oxadiazoles has been performed by theamidoxime route [35]. The appropriate amidoxime (0.3 g) wasdissolved in 50 mL of toluene in a 250 mL round bottomed flask.Then,1.2 eq. of the appropriate aroyl chloride and 1.2 eq. of pyridinewere added and the reaction mixture was refluxed for 6e8 hmonitoring the reaction by TLC until consumption of starting material. The solvent was removed under vacuum and water wasadded to the residue. Extraction with ethyl acetate and chromatographic separation on silica gel using mixtures of petroleum etherand ethyl acetate as eluent allowed to obtain the desired oxadiazole, further purified by crystallization.
With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 1h;Cooling with ice;
In a recovery flask having a volume of 100 (mL) were placed by 3 (g) (17.7 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 18 (mL) of tetrahydrofuran (Wako Pure Chemical Industries, Ltd.), and 18 (mL) of water, and the flask was then cooled in an ice bath. After sufficient cooling, 4.40 (g) (31.6 mmol) of potassium carbonate (Wako Pure Chemical Industries, Ltd.) and 2.19 (g) of m-toluyl, chloride (Tokyo Chemical Industry Co., Ltd.) were successively added while the solution temperature being prevented from rising. A reaction was performed under the ice bath for 1 hour, and 1.09 (g) of m-toluyl chloride (Tokyo Chemical Industry Co., Ltd.) were then added again. After the addition, the ice bath was removed and the mixture was stirred at room temperature. The progress of the reaction was checked by thin layer chromatography, and tetrahydrofuran was then removed by evaporation under reduced pressure. The resultant residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The filtrate was concentrated and supplemented with water (18 ml). The precipitated crystals were separated by filtration. The resultant crystals were washed by suspending them in acetone and collected by filtration. The crystals collected by filtration were dried at 60 C. to afford 1.65 (g) (5.74 mmol) of Compound 7 having the above-mentioned structure.
1.65 g
With potassium carbonate; In tetrahydrofuran; water; at 20℃;Cooling with ice;
L-cysteic acid 3 (g) (17.7 mmol) (Tokyo Chemical Industry Co., Ltd.), tetrahydroFuran 18 (mL) (Wako Pure Chemical Industries, Ltd.) and water 18 (mL) were placed in a 100 mL eggplant type flask and cooled in an ice bath. After sufficient cooling, potassium carbonate 4.40 (g) (31.6 mmol) (Wako Pure Chemical Industries, Ltd.), m-toluoyl chloride 2.19(G) (Tokyo Chemical Industry Co., Ltd.) were sequentially added so that the liquid temperature did not rise. 1 hour under ice bathAfter reacting, 1.09 g of m-toluoyl chloride (g) (Tokyo Chemical Industry Co., Ltd.)Was added. After the addition, the ice bath was removed and the mixture was stirred at room temperature. Progress of the reaction was confirmed by thin layer chromatography, and tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate (Wako Pure Chemical Industries, Ltd.), and the pH was adjusted to 2 or less with hydrochloric acid. The filtrate was concentrated, washed with water18 (mL) was added. After ripening at 4 C., the precipitated crystals were separated by filtration. The obtained crystals were washed with acetone (Wako Pure Chemical Industries, Ltd.) and filtered. The crystals collected by filtration were dried at 60 C. to obtain 1.65 (g (5.74 mmol) of the L isomer of the compound 2 having the above structure.
With tri-tert-butyl phosphine; palladium diacetate; cesium fluoride; In 5,5-dimethyl-1,3-cyclohexadiene; at 140℃; for 24h;Inert atmosphere; Sealed tube;
General procedure: To a screw-capped vial in a glovebox, Pd(OAc)2 (0.020 mmol, 4.5 mg), PtBu3 (0.0800 mmol, 16.2 mg), CsF (1.400 mmol, 212.7 mg), and xylene (0.4 mL) were added in that order. The vial was then sealed and removed from the glovebox, an acyl chloride (0.4 mmol) and an aryltrifluorosilane (1.2 mmol) were successively added to the vial. The mixture was heated at 140 C for 24 h. After the reaction, the resultant mixture was filtered through a pad of silica gel (2 g, eluent; EtOAc). After removal of the volatile materials by rotary evaporation, the filtrate was analyzed by GC (n-decane as a internal standard) or NMR (1,1,2,2-tetrachloroethane as a internal standard). The crude material was purified by silica gel column chromatography (eluent; hexane:EtOAc = 99:1).
3-(hydroxy(3-methylphenyl)methylene)benzofuran-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With sodium hydride; In tetrahydrofuran; toluene; mineral oil; at 20℃; for 6h;Cooling with ice;
59 g of 60% sodium hydrogen (1.47 mol) was placed in a 140 mL / 140 mL THF / toluene mixture,(0.7 mol) of benzofuranone, 108 g (0.7 mol) of benzofuranone was added dropwise at 10 to 20 C,3-methylbenzoyl chloride70 mL / 50 mL THF / toluene solution, add 10-20 C for 6 hours, add 1200mL A Reduction of THF by distillation under reduced pressure. 450 mL of 3M hydrochloric acid and 200 mL of water were added dropwise and the organic phase was washed with water Twice, saturated sodium chloride once, the organic phase concentrated, adding methanol to recrystallize, get 139g3- (hydroxy (3-methylphenyl) methylene) benzofuran-2 (3H) -one. Yield 79%, HPLC purity 99%.
300 mg (0.581 mmol) of <strong>[3482-49-3]fusidic acid</strong> and 142 mg (1.161 mmol) of 4-dimethylaminopyridine (DMAP) were first weighed in a 50 mL magnetron-containing round bottom flask,Under nitrogen protection, measure 10 mL of ultra-dried anhydrous methylene chloride in a flask, and stir at room temperature under nitrogen for about 15 minutes until it is completely dissolved.0.94 mL (1.161 mmol) of pyridine was added via syringe, and the mixture was stirred under nitrogen at room temperature for about 20 min. Finally, a triplicating amount of m-benzoyl chloride (0.23 mL, 1.743 mmol) was added. The reaction was stirred under nitrogen at room temperature. 2h.The end point of the reaction was checked by TLC (developer: dichloromethane:ethyl acetate=3:1, coloring agent: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio)=85:10:5:0.5), and the reaction was completed. The crude product of compound FA-E-03 was obtained by washing and extractive drying, etc., and purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate=6:1) to give Compound FA-E-03, which The molecular structural formula is shown in FIG. 3, white solid, Rf=0.42 (developer: dichloromethane:ethyl acetate=3:1), yield: 71%.
1-(3-methylbenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
General procedure: To a cooled (0 C) suspension of 1a-h20-26 (0.56 mmol) in anhydrousCH2Cl2 (2 mL), 0.72 mmol Et3N and 1.67 mmol of the appropriatechloride were added. The mixture was stirred at 0 C for 2 h and then atroom temperature for an additional 2 h. The solvent was evaporated,cold water was added, and the mixture was neutralized with 0.5 NNaOH. The reaction mixture was extracted with CH2Cl2 (3×15 mL),the solvent was dried over sodium sulfate, evaporated in vacuo, and thefinal compounds were purified by crystallization from ethanol (2a-i,3a,b,e, and 4b) or by column chromatography using cyclohexane/ethylacetate in different ratios: 1:1 (3d), 2:1 (3c and 4a), 3:1 (2l, 4b, 5a and5e), 5:1 (5c), or 6:1 (5b and 5d) as eluents
(3-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(m-tolyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
General procedure: To a cooled (0 C) suspension of 1a-h20-26 (0.56 mmol) in anhydrousCH2Cl2 (2 mL), 0.72 mmol Et3N and 1.67 mmol of the appropriatechloride were added. The mixture was stirred at 0 C for 2 h and then atroom temperature for an additional 2 h. The solvent was evaporated,cold water was added, and the mixture was neutralized with 0.5 NNaOH. The reaction mixture was extracted with CH2Cl2 (3×15 mL),the solvent was dried over sodium sulfate, evaporated in vacuo, and thefinal compounds were purified by crystallization from ethanol (2a-i,3a,b,e, and 4b) or by column chromatography using cyclohexane/ethylacetate in different ratios: 1:1 (3d), 2:1 (3c and 4a), 3:1 (2l, 4b, 5a and5e), 5:1 (5c), or 6:1 (5b and 5d) as eluents
(3-nitro-1H-pyrrolo[2,3-b]pyridin-1-yl)(m-tolyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With triethylamine; In dichloromethane; at 0 - 20℃; for 4.0h;
General procedure: To a cooled (0 C) suspension of 1a-h20-26 (0.56 mmol) in anhydrousCH2Cl2 (2 mL), 0.72 mmol Et3N and 1.67 mmol of the appropriatechloride were added. The mixture was stirred at 0 C for 2 h and then atroom temperature for an additional 2 h. The solvent was evaporated,cold water was added, and the mixture was neutralized with 0.5 NNaOH. The reaction mixture was extracted with CH2Cl2 (3×15 mL),the solvent was dried over sodium sulfate, evaporated in vacuo, and thefinal compounds were purified by crystallization from ethanol (2a-i,3a,b,e, and 4b) or by column chromatography using cyclohexane/ethylacetate in different ratios: 1:1 (3d), 2:1 (3c and 4a), 3:1 (2l, 4b, 5a and5e), 5:1 (5c), or 6:1 (5b and 5d) as eluents
(6-bromo-5-nitro-1H-indazol-1-yl)(m-tolyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With triethylamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; at 0 - 20℃;
General procedure: To 5-Nitroindazole derivative (0.2 g) in DCM (10 mL), mixture of triethylamine (1.1 equiv.) and benzoyl chloride or its derivative (1.1 equiv.) was slowly added and stirred at 0C 5-10 min and then stirred at room temperature for overnight. The reaction progress is monitored by the TLC. The reaction mass was extracted with dichloromethane (DCM) (3X10 mL) and organic layer was dried with MgSO4 and evaporated followed by the purification by column chromatography (EtOAc: Hexane = 1: 4 ~ 1: 6) to give corresponding N-benzoylindazole derivatives (6a-j).
With sodium carbonate; In dichloromethane; water; at 20℃;
General procedure: All materials, reagents and solvents were purchased fromSigma-Aldrich, Merck, and Tedia Brazil and were used as received.The classical Schotten-Baumann reaction was used for the synthesisof amides [23-25]. Typical procedure: A solution of the acylchloride (0.5 mmol) in dichloromethane (2 mL) was added dropwiseto a well-stirred mixture of the aniline (0.5 mmol) indichloromethane (2 mL) and 2 mL of aqueous sodium carbonate(10%) at room temperature. The reaction media was stirred for90 min and then the organic phase was separated and extractedwith brine (3 x 2 mL). The combined organic fractions were dried over MgSO4, filtered, and evaporated to dryness under reducedpressure to give the N-phenylbenzamides in 19-90% yields. Onehundred and seventeen compounds were synthesized followingthis procedure. Detailed physicochemical properties, 1H and 13CNMR data, FT-IR data, and yield are presented for each N-phenylbenzamidein the supplementary data.
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