* 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.
Under an argon atmosphere, 40 mL of dry ortho-xylene was quickly added to a 250 mL PTFE-lined autoclave.2.5 g of anhydrous AlCl3, 1.16 g of dry N-butylimidazole, the reaction vessel was sealed after the addition was complete. Then connect the CO2 cylinder to the autoclave through the pipe, open the valve to control the CO2 pressure to 6MPa,At the same time stirring was turned on, the stirring rate was 1000 rpm, and finally heating was started and 48 hours at 40°C. After the reaction was completed, 150 mL of water was added to the reaction system, and the mixture was reacted for 30 min while stirring. After that, it was extracted 3 times with 50 mL of ether. The combined extracts were concentrated and dried to give 2.76 g of an off-white solid.The off-white solid was 2,3-dimethylbenzoic acid. The above-mentioned off-white solid was dissolved in 20 mL of a 10percent wt sodium hydroxide solution, insolubles were filtered off, and a filtrate was obtained. Then, the filtrate was adjusted to pH 1 with 1 mol/L HCl and allowed to stand at room temperature for 60 min. Then it was transferred to -10°C and further crystallized and filtered to obtain crystals. The crystals were dried to give 2.29 g of 2,3-dimethylbenzoic acid as a white solid.The yield of 2,3-dimethylbenzoic acid was 81.3percent.
Reference:
[1] Patent: CN107827742, 2018, A, . Location in patent: Paragraph 0059; 0060
2
[ 5724-56-1 ]
[ 603-79-2 ]
Reference:
[1] Tetrahedron Letters, 1981, vol. 22, p. 161 - 162
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 3087 - 3091
[3] Monatshefte fuer Chemie, 1933, vol. 63, p. 79,95
[4] Journal of the American Chemical Society, 1960, vol. 82, p. 1349 - 1352
[5] Pesticide Science, 1994, vol. 41, # 2, p. 139 - 148
3
[ 124-38-9 ]
[ 576-23-8 ]
[ 603-79-2 ]
Reference:
[1] Organic Letters, 2009, vol. 11, # 4, p. 963 - 966
[2] Recueil des Travaux Chimiques des Pays-Bas, 1960, vol. 79, p. 1211 - 1222
Reference:
[1] Journal of the American Chemical Society, 2002, vol. 124, # 38, p. 11379 - 11391
[2] Chemical Communications, 2014, vol. 50, # 92, p. 14360 - 14363
Reference:
[1] Chemistry Letters, 2006, vol. 35, # 7, p. 820 - 821
[2] Journal of Organic Chemistry, 2010, vol. 75, # 22, p. 7855 - 7862
11
[ 56812-61-4 ]
[ 603-79-2 ]
Reference:
[1] Journal of the American Chemical Society, 1960, vol. 82, p. 1349 - 1352
12
[ 87-59-2 ]
[ 603-79-2 ]
Reference:
[1] Pesticide Science, 1994, vol. 41, # 2, p. 139 - 148
[2] Monatshefte fuer Chemie, 1933, vol. 63, p. 79,95
[3] Recueil des Travaux Chimiques des Pays-Bas, 1960, vol. 79, p. 1211 - 1222
13
[ 526-73-8 ]
[ 603-79-2 ]
Reference:
[1] Chemische Berichte, 1886, vol. 19, p. 2518
14
[ 5724-56-1 ]
[ 5580-34-7 ]
[ 603-79-2 ]
Reference:
[1] Yakugaku Zasshi, 1954, vol. 74, p. 312,314[2] Chem.Abstr., 1955, p. 3078
15
[ 15012-36-9 ]
[ 603-79-2 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2339 - 2342
16
[ 603-79-2 ]
[ 5724-56-1 ]
Reference:
[1] Russian Journal of Organic Chemistry, 1996, vol. 32, # 10, p. 1447 - 1470
17
[ 64-19-7 ]
[ 603-79-2 ]
[ 2142-71-4 ]
Reference:
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 1362,1366
18
[ 67-56-1 ]
[ 603-79-2 ]
[ 15012-36-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
Heating / reflux
Step 1. To a solution of 2,3-dimethylbenzoic acid (50.2 g; 0.33 mol) in MeOH (1L) was added dropwise thionyl chloride (62 mL; 0.83 mol, exothermic). The reaction mixture was stirred at reflux overnight and allowed to cool to room temperature. Evaporation of the solvent in vacuo yielded compound 5 (53.3 g; 98percent) as a yellow liquid.1H-NMR (300 MHz, CDCI3): δ 2.34 (s, 3H), 3.45 (s, 3H), 3.90 (s, 3H), 7.15 (t, 1H), 7.28 (d, 1H), 7.62 (d, 1H).
98%
for 3 h; Reflux
[0505] Preparation of compound 2 (Scheme 13): To a solution of 1; 2,3- dimethylbenzoic acid (2.0 g, 13.3 mmol, 1.0 eq) in MeOH (30 mL) was added thionyl chloride (1.5 mL) and stirred at reflux for 3h. The mixture was concentrated, extracted with EA (30 mL). The organic layers were washed with water (2 x 30 mL),dried over Na2504, concentrated to give the desired product 2 without further purification (2.1 g, 98percent).
With thionyl chloride; for 8h;Inert atmosphere; Reflux;
In a two-neck round-bottom flask, under stirring and nitrogen, 3.0 g (20 mmol) of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> were added and the mixture was refluxed with 3.62 mL (50 mmol) of SOCl2. After 8 h the excess of SOCl2 was removed at the rotavapor and under vacuum to give the 3,3-dimethyl benzoyl chloride as a yellow oil in quantitative yield that was used further without purification.
92%
With thionyl chloride; In benzene;
Preparation of 2,3-dimethylbenzoyl chloride (D5) STR31 <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (35.0 g, 233 mmol) was heated to reflux temperature, in dry benzene (80 ml) containing thionyl chloride (45.0 g, 378 mmol) for five hours. The mixture was cooled, filtered and evaporated under reduced pressure to give 2,3-dimethylbenzoyl chloride (36.0 g, 92%) as an oil. NMR: delta (CDCl3) 2.26 (s,3H), 2.36 (s,3H), 6.90-7.96 (m,3H). IR: (film)(cm-1) 1766.
With thionyl chloride;
REFERENCE EXAMPLE 25 2,3-Dimethylbenzoyl chloride As described for Reference Example 21, 3.0 g of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> is reacted with 40 ml of thionyl chloride to give 3.2 g of the product as a colorless oil.
With thionyl chloride;
REFERENCE EXAMPLE 30 2,3-Dimethylbenzoyl chloride As described for Reference Example 26, 3.0 g of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> is reacted with 40 ml of thionyl chloride to give 3.2 g of the product as a colorless oil.
With thionyl chloride;
Reference Example 25 2,3-Dimethylbenzoyl chloride As described for Reference Example 21, 3.0 g of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> is reacted with 40 ml of thionyl chloride to give 3.2 g of the product as a colorless oil.
With thionyl chloride; at 80℃; for 1h;Product distribution / selectivity;
A solution of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (100 g, 666 mmol) in thionyl chloride (350 ml) was heated at 80 C. for 1 h, before cooling to room temperature and concentrating in vacuo. To the residue was added toluene (100 ml) and the solution was again concentrated in vacuo. The intermediate acid chloride was added to a mixture of 1-benzylimidazole (100 g, 632 mmol) and triethylamine (100 ml) in acetonitrile (1 l) and the reaction mixture was heated at reflux for 18 h. The reaction mixture was concentrated in vacuo and to the residue was added diethyl ether (500 ml) and ethyl acetate (50 ml). This solution was washed with water (500 ml) and saturated aqueous sodium hydrogen carbonate solution (500 ml), filtered through silica gel (100 g) and concentrated in vacuo to give the title compound (182 g).Experimental MH+ 291.4; expected 291.1
With oxalyl dichloride;N,N-dimethyl-formamide; In toluene; at 20℃; for 4h;Product distribution / selectivity;
To a solution of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (2.0 kg, 13.2 mol) in toluene (20 L) was added N,N-dimethylformamide (20 ml), followed by oxalyl chloride (2.0 kg, 15.6 mol) at room temperature. The reaction mixture was stirred at room temperature for 4 h and monitored by thin layer chromatography. If necessary, excess oxalyl chloride (25 g) was added until no starting material was observed. Excess toluene and oxalyl chloride were removed by distillation under vacuum at temperatures below 70 C. To the residue was added toluene (150 ml) and the mixture was again concentrated in vacuo to give 2,3-dimethylbenzoyl chloride (2.0 kg).To a solution of 1-benzyl-1H-imidazole (1.69 Kg, 10.56 mol) in dichloromethane (14.0 L), at -7 C., was added triethylamine (1.61 kg, 10.56 mol). A solution of 2,3-dimethylbenzoyl chloride (2.0 kg, 11.99 mol) in dichloromethane (6.0 L) was then added dropwise and the reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by Thin layer Chromatography. After completion of the reaction, the reaction mixture was diluted with water (5.0 L) and the mixture was stirred for a further 15 min. The two layers were separated and the organic phase was concentrated in vacuo. To the residue was added toluene (8.0 L) and the solution was cooled to -5 C., before addition of hydrochloric acid (5N, 8.0 L). The two layers were separated and the aqueous layer was adjusted to pH 9-12, by addition of aqueous sodium hydroxide solution (50%), and extracted with toluene (4.0 L and then 8.0 L). The combined organic phases were concentrated in vacuo to give the title compound (2.8 kg).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 15 - 25℃; for 2h;Product distribution / selectivity;
Step-lb: Preparation of (2,3-dimethylphenyl)-imidazol-l-yl-methanone.To the compound 1 (250 g, 1.66 mol) in dry dichloromethane (1.8 L) was added N- dimethylformamide (15 ml) and oxalyl chloride (222 g, 1.75 mol) at about 15 C for about 1 h and continued stirring for about 1 h at about 25 C. A solution of imidazole (225.7 g, 3.32 mol) in dichloromethane (1.8 L) was added dropwise at about 0 C and stirred for about 1 h. The reaction mixture was quenched with ice-cold water (1.5 L) and extracted with dichloromethane. The organic layer was washed with sat. NaHC03 solution (1.25 L), dried over anhydrous sodium sulphate and concentrated under reduced pressure to get 2b as a yellowish syrupy mass. Yield 291 g (87 %)..H NMR (300 MHz, CDC13): delta 7.84 (s, 1H), 7.46- 7.35 (m, 2H), 7.23 (d, J = 4.8 Hz, 2H), 7.1 1 (m, 1H), 2.36 (s, 3H), 2.22 (s, 3H)LCMS (m z): 200.6 (M+l)
With thionyl chloride; at 0℃; for 16h;Reflux;
SOCl2 (3.0 g, 25 mmol) was added to <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> 40 (1.00 g, 6.7 mmol) at 0 C. The mixture was heated at reflux for 16 h. The evaporation residue, in CH2Cl2 (1.0 mL), was added dropwise to Me2NH in water (40%, 3.7 mL) at 0-20 C. The mixture was stirred at 20 C for 1 h, diluted with CH2Cl2, washed (water, 3*) and dried. Evaporation gave 41 (990 mg, 84%) as a pale yellow oil: 1H NMR (CDCl3) (COSY/NOESY) delta 2.16 (3H, s, 2-Me), 2.27 (3H, s, 3-Me), 2.81 (3H, s, N-Me), 3.12 (3H, s, N-Me'), 6.99 (1H, dd, J = 7.2, 1.8 Hz, 4-H), 7.10 (1H, t, J = 7.5 Hz, 5-H), 7.13 (1H, dd, J = 7.6, 1.8 Hz, 6-H); 13C NMR (CDCl3) (HSQC/HMBC) delta 16.00 (2-Me), 20.03 (3-Me), 34.48 (N-Me'), 38.37 (N-Me), 123.40 (4-C), 125.82 (5-C), 130.01 (6-C), 132.25 (2-C), 137.02 (1-C), 137.42 (3-C), 171.99 (C=O); MS m/z 178.1226 (M+H)+ (C11H16NO requires 178.1232).
To a refluxing THF solution (0.5 M) of 2,3-dimethylbenzoic acid (1 eq.) was added dropwise neat borane-methyl sulfide complex (1.25 eq.) over a period of 10 min. After the completion of addition, the resulting mixture was heated at reflux for another 2 h. The reaction mixture was then cooled to RT, diluted with ether and carefully quenched with 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Further purification of the crude product thus obtained by way of column chromatography (SiO2, CH2Cl2) afforded the title compound as a white solid.
Step 1. To a solution of 2,3-dimethylbenzoic acid (50.2 g; 0.33 mol) in MeOH (1L) was added dropwise thionyl chloride (62 mL; 0.83 mol, exothermic). The reaction mixture was stirred at reflux overnight and allowed to cool to room temperature. Evaporation of the solvent in vacuo yielded compound 5 (53.3 g; 98%) as a yellow liquid.1H-NMR (300 MHz, CDCI3): delta 2.34 (s, 3H), 3.45 (s, 3H), 3.90 (s, 3H), 7.15 (t, 1H), 7.28 (d, 1H), 7.62 (d, 1H).
98%
With thionyl chloride; for 3h;Reflux;
[0505] Preparation of compound 2 (Scheme 13): To a solution of 1; 2,3- dimethylbenzoic acid (2.0 g, 13.3 mmol, 1.0 eq) in MeOH (30 mL) was added thionyl chloride (1.5 mL) and stirred at reflux for 3h. The mixture was concentrated, extracted with EA (30 mL). The organic layers were washed with water (2 x 30 mL),dried over Na2504, concentrated to give the desired product 2 without further purification (2.1 g, 98%).
[2, N-DIMETHYL-BENZAMIDES] General procedure for the preparation of [2, N-DIMETHYL-BENZAMIDES] [0133] The benzoic acid was dissolved in THF (75 mL/g) and triethylamine (5 eqv) was added. Under vigorous stirring [SOC12] (1.3 eq. ) was added drop wise and the mixture was stirred at rt for 20 minutes. Methylamine (2M in THF) (2 eqv) was added slowly and the reaction was stirred for another 2 h. The mixture was poured into water and extracted twice with EtOAc. After concentration of the combined organic phases the crude oil was dissolved in CH2C12 and filtered through a plug of [SILICA/MGSO4] (5: 1) Evaporation of the solvent yielded the pure amides. 2, 3, N-Trimethyl benzamide [[0134]] 2, 3- Dimethylbenzoic acid (3 g; 20 mmol) yielded 2g (63%) of the title compound as light yellow crystals. Mp 99.0-99. [1 C. IH] NMR (400 MHz) 8 2.20 (s, 3H), 2.22 (s, 3H), 2.90 (d, 3H, [J=] 4.8 Hz), 5.70 (bs, 1H), 7.00-7. 11 (m, 2H), 7.18 (d, 1H, J= 3.6 Hz). [13C] NMR (100 MHz) 8 16.1, 20.1, 26.4, 124.1, 125.2, 130.8, 133.8, 137.2, 137.5, 171.5. Anal. Calcd for [CLOH13NO] : C, 73.6 ; H, 8.0 ; N, 8.6. Found: C, 73.4 ; H, 8.0 ; N, 8.4.
PREPARATION 4 To a mixture of nitric acid (d=1.42:20 ml) and sulfuric acid (d=1.84:20 ml) was added <strong>[603-79-2]2,3-dimethyl benzoic acid</strong> (6.0 g) at 0 C. After stirring for 3 hours, the mixture was poured into ice water (300 ml). The organic layer was extracted with ethyl acetate (100 ml) and washed with water (100 ml*3). The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by a column of silica gel to give a yellow solid of 2,3-dimethyl-5-nitrobenzoic acid (1.80 g). NMR (CDCl3 +CD3 OD, delta): 2.43 (3H, s), 2.58 (3H, s), 8.14 (1H, d, J=2 Hz), 8.56 (1H, d, J=2 Hz).
With sulfuric acid; potassium nitrate; at 0℃; for 5h;
Intermediate 32.6; To a solution of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (3 g, 20 mmol) in cone. H2SO4 (40 ml_) is added KNO3 (2.02 g, 22 mmol) at 0 0C. After stirring for 5 h at 0 0C, the reaction mixture is poured into ice, then the white precipitate is collected by filtration. The collected precipitate is triturated with CH3CN (10 ml_) and H2O (20 ml_) and the solids are collected by filtration to give Intermediate 32.6 as a white solid material; ES-MS: [M+H]+= 195; HPLC: ctRe, =2.73 min.
(RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dimethylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In N-methyl-acetamide; dichloromethane; toluene;
Method A (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dimethylbenzamide The following is the preparation of a compound of Formula II via Scheme I, Step 1 in which the optional bond is present; X is methyl in the 3-position; Y is hydrogen; R1 is hydrogen; and R2 is (RS)-1-azabicyclo[2.2.2]oct-3-yl. 2,3-dimethylbenzoic acid (5.0 g; 33.3 mmol), oxalyl chloride (40.0 mmol, 3.5 mL) and dimethylformamide (0.1 mL) were dissolved in methylene chloride (100 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. A solution of the concentrate in toluene (100 mL) was added dropwise to a stirred solution of <strong>[6530-09-2](RS)-3-amino-1-azabicyclo[2.2.2]octane dihydrochloride</strong> (7.0 g; 35 mmol)in toluene (50 mL) and NaOH (2.0N, 50 mL) at 0 C. The reaction mixture was maintained at 0 C. and stirred for 30 minutes. The aqueous layer was extracted with of toluene (2*50 mL) and the combined organic layers dried over magnesium sulfate. Removal of the solvent under reduced pressure gave (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dimethylbenzamide as a white solid (5.5 g, 25.4 mmol), m.p. 160-161 C.
(1) To 160 ml of methanol cooled to -10 C. was dropwise added 46.4 ml of thionyl chloride while stirring. To the solution was added a mixture of 24 g of 2,3-dimethyl benzoic acid and 1 ml of DMF, and the mixture was stirred at room temperature for 4 days. After concentration, the residue was dissolved in ether. The solution was washed with water, 5% sodium carbonate, and water in this order. The solvent was evaporated and the residue was purified by vacuum distillation to obtain 25.1 g of methyl 2,3-dimethylbenzoate.
With N-ethyl-N,N-diisopropylamine; HATU; In ISOPROPYLAMIDE; at 20℃;
Example 75 (2Z)-2-(3-butyl-5-methyl-1.3.4-thiadiazol-2(3H)-ylidene)-l-(2.3- dimethylphenyPethanoneIn a 20 mL vial <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-l,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) delta ppm theta.85 - 0.91 (m, 3 H) 1.25 - 1.34 (m, 2 H) 1.65 - 1.75 (m, 2 H) 2.23 (s, 3 H) 2.27 (s, 3 H) 2.48 (s, 3 H) 4.12 (t, 2 H) 6.09 - 6.13 (m, 1 H) 7.07 - 7.14 (m, 1 H) 7.16 - 7.23 (m, 2 H); MS (ESI) m/z 303 (M+H)+.
Example 235; f2,3-Dimethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (235) :2-Amino-indane-2-carboxylic acid ethyl ester (250mg, 1.2 mmol), <strong>[603-79-2]2,3-dimethyl-benzoic acid</strong> (183mg, 1.2 mmol) and HATU (555mg, 1.46 mmol) are taken in a vial, evacuated and refilled with nitrogen. Anhydrous DMF (2mL) is added and stirring is initiated. After a few min, DIPEA (0.302mL, 1.82 mmol) is added and stirred at RT overnight. Analysis by tic of the reaction mixture (silica, 50% EtO Ac/heptanes) indicates complete consumption of the starting amine. Water (1OmL) is added, extracted with EtOAc (3 x 5mL), dried over Na2SO4, concentrated and the crude product is chromatographed on a 25 g silica gel column using 20- 50% EtOAc in heptane as a gradient to afford 2-(2,3-dimethyl-benzoylamino)-indan-2- carboxylic acid ethyl ester (350mg, 87%).1H NMR (CDCl3, 300 MHz,): delta 1.3 (t, 3 H), 2.26 (s, 3 H), 2.29 (s, 3 H), 3.55 (dd, 4H), 4.28 (q, 2H), 6.19 (s, IH), 7.04 - 7.22 (m, 7H). LC/MS m/z = 338.17.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
3-Aminomethyl-2-methyl-benzoic acid methyl ester: 2,3-Dimethylbenzoic acid (1.0 g, 6.66 mmol) was dissolved in DMF (15 mL) and then Cs2CO3 (1.5 equiv.) and MeI (1.2 equiv.) were added. The mixture was stirred for 2 h at room temperature then diluted with EtOAc and H2O. The organic layer was washed with H2O and a saturated LiCl solution, and then dried over MgSO4 and concentrated under reduced pressure to give sticky oil. The oil was dissolved in CCl4 (20 mL) and NBS (1.1 equiv.) and AIBN (0.1 equiv.) were added. The mixture was heated at reflux for 4 h then cooled to room temperature to give a white precipitate which was filtered off. The yellow solution was concentrated, the oil was dissolved in DMF (15 mL) and then NaN3 (1.2 equiv.) was added. The mixture was stirred for 2 h at room temperature then diluted with ethyl acetate and H2O. The organic layer was washed with H2O and a saturated lithium chloride solution, dried over MgSO4, and concentrated under reduced pressure to give sticky oil. The crude oil was dissolved in of CHCl3 (20 mL) and MeOH (20 mL), and then 10% Pd/C (0.20 g) and conc. HCl (1.5 mL) were added. The mixture was shaken under H2 gas (50 psi) for 16 h. The Pd/C was filtered through a pad of Celite and the pad was washed with a solution of 20% MeOH in CH2Cl2. The pale yellow solution was concentrated under reduced pressure, and the residual was dissolved in MeOH (10 mL) and diluted with Et2O (100 mL) to give a white precipitate. The precipitate was collected by filteration and dried to give the title compound (0.79 g, 55%).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
I-144: N2-(3,4-dimethyl-5-methoxycarbonyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine 2,3-Dimethylbenzoic acid (1 g) and K2CO3 (1.1 g, 1.2 eq.) were suspended in DMF (10 mL). To the reaction mixture, was added iodomethane (0.5 mL, 1.2 eq.). The reaction was stirred at rt overnight, then diluted with water (80 mL). The solution was extracted with ethyl acetate (80 mL) and evaporated to give the methyl ester. 1H NMR (300 MHz, DMSO) delta 7.49 (d, J=7.8 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 3.79 (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H).
With bromine; nitric acid; In water; acetic acid; at 20℃; for 1.5h;
To a solution of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (5 g, 33.3 mmol, 1.0 eq) in acetic acid (167 mL) at room temperature was added a solution of cone, nitric acid (25.2 g, 399 mmol, 12 eq), water (15 g, 0.83 mmol, 25 eq) and bromine (5.85 g, 36.6 mmol, 1.1 eq). A solution of silver nitrate (7.35 g, 43 mmol, 1.3 eq) in water (43 mL) was then added dropwise over 30 min. Once addition was completed, the reaction was stirred at room temperature for 1 h, then quenched by addition of water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried ( a2S04), filtered and evaporated in vacuo to give the title compound as a yellow solid (6.4 g, 83 %).LC-MS: m/z 228.4 [M+H]+
With bromine; nitric acid; silver nitrate; acetic acid; In water; at 20℃;
To an acetic acid solution (0.2 M) of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (1 eq.), nitric acid (12 eq.) and bromine (1.1 eq.) was added dropwise silver nitrate (2.5 M aq. solution, 1.3 eq.) over a period of 30 min. After 1 h of stirring at RT, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed further with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Concentration of the filtrate in vacuo and trituration of the crude product thus obtained in hexanes afforded the title compound as an off-white solid.
With bromine; nitric acid; silver nitrate; In water; acetic acid; at 20℃;
To a stirred acetic acid solution (0.2 M) of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (1 eq.) was added25 sequentially nitric acid (12 eq.), water (25 eq.) and bromine (1.1 eq.). Finally, silver nitrate (1 M aqueous solution, 1.3 eq.) was added dropwise over a period of 30 min. After another hour of stirring at RT, the crude reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were then washed with brine, dried over nua2Stheta4, filtered and the filtrate concentrated in vacuo. Trituration of the crude product thus obtained in hexanes afforded the title compound as a yellow solid.
With bromine; nitric acid; silver nitrate; acetic acid; In water; at 20℃; for 1.5h;Inert atmosphere;
To a stirred acetic acid solution (0.2 M) of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (1 eq.) was added sequentially nitric acid (12 eq.), water (25 eq.) and bromine (1.1 eq.). Finally, silver nitrate (I M aqueous solution, 1.3 eq.) was added dropwise over a period of 30 min. After another hour of stirring at RT, the crude reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were then washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Trituration of the crude product thus obtained in hexanes afforded the title compound as a yellow solid.
EXAMPLE 22 2,3-Bis[(2-Chlorophenoxy)Methyl]-alpha-Hydroxybenzeneacetic Acid To a stirred solution of <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> (1.50 g, 10 mmol) in CH2Cl2 (10 ML) under argon at room temperature was added oxalyl chloride solution (8.0 ML, 2 M in CH2Cl2, 16 mmol) and then DMF (0.2 ML).After 2 h, the solution was evaporated and re-evaporated twice from CH2Cl2 and then dissolved in CH2Cl2 (10 ML).This solution was added, over 30 min, to a stirred slurry of N-methoxy-N-methylammonium chloride (1.10 g, 11 mmol), DMAP (5 mg, 0.04 mmol) and triethylamine (3.0 ML, 21.4 mmol) in CH2Cl2 (15 ML) at 10 C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 16 h.The reaction mixture was then diluted with CH2Cl2, washed once with 10% citric acid, once with water and once with brine.The organic extract was dried (MgSO4) and evaporated.Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 1.38 g (71% yield). LC/MS gave the correct molecular ion [(M+H)+=194] for the desired compound.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere;
To a solution of <strong>[603-79-2]2,3-dimethyl benzoic acid</strong> (1 eq) in DMF (5 v), was added HOBT (1. 5 eq). To this reaction mixture, was added EDAC.HCl (1.2 eq), cyclopropylamine (1.2 eq) and DIEA (1.5 eq) under N2 at 0-5 C. The resulting reaction mixture was stirred at RT for 16 h. Mixture was quenched in water, solid obtained was filtered, dried in vacuo to afford title compound as off white solid.
2,3,N,N-Tetramethylbenzamide (16). Thionyl chloride (3.0 g, 25 mmol) was added to <strong>[603-79-2]2,3-<strong>[603-79-2]dimethylbenzoic acid</strong></strong> 15 (1.00 g, 6.7 mmol) at 0C. The mixture was then heated at reflux for 16 h, then the excess thionyl chloride was evaporated. The residue, in dichloromethane (1.0 mL), was added dropwise to a stirred solution of dimethylamine in water (40 %, 3.7 mL) at 0-20 C. The mixture was then stirred at room temperature for 1 h. The mixture was diluted with dichloromethane, then washed thrice with water and dried (magnesium sulfate). The solvent was evaporated to give 2,3,N,N- tetramethylbenzamide 16 (990 mg, 84%) as a pale yellow oil: 1H NMR (CDCI3) (COSY / NOESY) delta 2.16 (3 H, s, 2-Me), 2.27 (3 H, s, 3-Me), 2.81 (3 H, s, N-Me), 3.12 (3 H, s, N- Me'), 6.99 (1 H, dd, J = 7.2, 1.8 Hz, 4-H), 7.10 (1 H, t, J = 7.5 Hz, 5-H), 7.13 (1 H, dd, J = 7.6, 1.8 Hz, 6-H); 13C NMR (CDCI3) (HSQC / HMBC) delta 16.00 (2-Me), 20.03 (3-Me), 34.48 (N-Me'), 38.37 (M-Me), 123.40 (4-C), 125.82 (5-C), 130.01 (6-C), 132.25 (2-C), 137.02 (1-C), 137.42 (3-C), 171.99 (C=0); MS m/z 178.1226 (M + H) (CnH16NO requires 178.1232).
N,N-Diethyl-2,3-dimethyl-benzamide To a stirred solution of <strong>[603-79-2]2,3-dimethyl-benzoic acid</strong> (1.52 g, 10.1 mmol) in CH2Cl2/DMF (118 mL/12 mL) was added N,N-diisopropylethylamine (1.76 mL, 10.1 mmol) and TBTU (3.25 g, 10.1 mmol) and the reaction mixture stirred at RT for 50 min. N,N-diethylamine (1.58 mL, 15.2 mmol) was added and the reaction mixture stirred for 18 h. The reaction mixture was washed with 10% Na2CO3 solution (2*100 mL) and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 30% EtOAc/isohexane to obtain N,N-diethyl-2,3-dimethyl-benzamide as a colourless liquid (1.48 g, 72%). 1H NMR (400 MHz, DMSO-d6): delta 7.20-7.10 (m, 2H), 6.90 (d, J=8 Hz, 1H), 3.70-3.55 (m, 1H), 3.35-3.20 (m, 1H), 3.15-2.90 (m, 2H), 2.25 (s, 3H), 2.07 (s, 3H), 1.17 (t, J=7 Hz, 3H), 0.95 (t, J=7 Hz, 3H). AnalpH2_MeOH-4 min: Rt 2.75 min; m/z 206 [M+1]+.
With dipotassium hydrogenphosphate; potassium dihydrogenphosphate; [ruthenium(II)(eta6-1-methyl-4-isopropyl-benzene)(chloride)(mu-chloride)]2; In 1,4-dioxane; at 130℃; for 24h;Inert atmosphere;
General procedure: An oven-dried reaction vessel was charged with [RuCl2(pcymene)]2 (Ru*, 6.1 mg, 0.01 mmol, 5 mol%), acids (0.2mmol), isocyanates (0.5 mmol), K2HPO4 (17.4 mg, 0.1 mmol), and KH2PO4 (13.6 mg, 0.1 mmol). After the vessel was evacuated and purged with argon three times, 1,4-dioxane (0.5 mL) was added to the system by syringe. The mixture was stirred at 130 C for 24 h. When the reaction was complete, the resulting mixture was cooled to room temperature and filtered through a short silica-gel pad. The mixture was then concentrated in vacuo to give a residue, which was purified by preparative thin layer chromatography (TLC) to afford the corresponding product.
To 2,5-<strong>[603-79-2]dimethylbenzoic acid</strong> 30g(0.2mol) was added toluene 100ml, dimethylformamide 1.46 area (0.02m0l), and stirred at room temperature. To the solution was added thionyl chloride dropwise 23.8 g (0.2 mol), and stirred at 50 C for 1 hour, whereby reaction liquid C was obtained.Then,To a 25% aqueous sodium hydroxide solution216 g of toluene was added, and the intermediate F obtained in example 112. 23.2 g (0.025 mol),And stirred at room temperature. To the solution, the previously prepared reaction liquid C was dropwise added,And stirred at room temperature for 10 hours.After completion of the reaction,The aqueous layer was removed,The reaction solution was washed three times with 200 ml of a 10% aqueous solution of sodium hydroxide, followed by washing once with 200 ml of 5% acetic acid water. Then, 200 ml of methanol was added to the solution, and the mixture was stirred for 2 hours. Then, the precipitated solid was filtered and dried. Thus, 15.9 g (yield: 58%) of the intermediate of the following structural formula was obtained.
With 1-Butylimidazole; aluminum (III) chloride; at 40℃; under 45004.5 Torr; for 48h;Autoclave; Inert atmosphere;
Under an argon atmosphere, 40 mL of dry ortho-xylene was quickly added to a 250 mL PTFE-lined autoclave.2.5 g of anhydrous AlCl3, 1.16 g of dry N-butylimidazole, the reaction vessel was sealed after the addition was complete. Then connect the CO2 cylinder to the autoclave through the pipe, open the valve to control the CO2 pressure to 6MPa,At the same time stirring was turned on, the stirring rate was 1000 rpm, and finally heating was started and 48 hours at 40C. After the reaction was completed, 150 mL of water was added to the reaction system, and the mixture was reacted for 30 min while stirring. After that, it was extracted 3 times with 50 mL of ether. The combined extracts were concentrated and dried to give 2.76 g of an off-white solid.The off-white solid was 2,3-dimethylbenzoic acid. The above-mentioned off-white solid was dissolved in 20 mL of a 10% wt sodium hydroxide solution, insolubles were filtered off, and a filtrate was obtained. Then, the filtrate was adjusted to pH 1 with 1 mol/L HCl and allowed to stand at room temperature for 60 min. Then it was transferred to -10C and further crystallized and filtered to obtain crystals. The crystals were dried to give 2.29 g of 2,3-dimethylbenzoic acid as a white solid.The yield of 2,3-dimethylbenzoic acid was 81.3%.
4-bromo-N-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-pyrrole-2-carboxamide[ No CAS ]
[ 603-79-2 ]
4-(3-fluorophenoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-pyrrole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
4-Bromo-N-(3-methyl-1,2,4-thiadiazolyl-5)-1H-pyrrole-2-carboxamide (10 mmol) was dissolved in 30 ml of toluene.Copper sulfide (1 mmol) and cesium carbonate (12 mmol) were added thereto, and the mixture was stirred for half an hour, and p-ethylbenzoic acid (12 mmol) was added thereto, and the mixture was heated to 100 C for 10 hours. Then, the temperature is lowered to normal temperature, filtered, and the solvent is evaporated to dryness. and then purified by flash column chromatography to give 2.7 g of yt-y-(3-methyl-1,2,4-thiadiazolyl-5)-4-(2,3 Methylphenoxy)-lH-pyrrolyl-2-carboxamide solid, yield 82%
N-hydroxy-2-[4-(7-pyridin-4-ylquinolin-4-yl)piperazin-1-yl]acetamidine[ No CAS ]
[ 603-79-2 ]
N-{1-[(Z)-hydroxyimino]-2-[4-(7-pyridin-4-ylquinolin-4-yl)piperazin-1-yl]ethyl}-2,3-dimethylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;
General procedure: To a solution of acid derivative (a-f) (1.2 eq) in DMF (20 mL, 20 vol) was added EDC.HCl (1.054 g, 5.518 mol), HOBt (0.557 g, 4.125 mmol) and DIPEA (1.4 mL, 8.277 mmol) at 0 oC. To the above mixture N-Hydroxy-2-[4-(7-pyridin-4-yl-quinolin-4-yl)-piperazin-1-yl]-acetamidine (8a) (1 g, 2.759 mmol) was added at 0 C. The reaction mixture was gradually warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with ice cold water. The aqueous layer was extracted with dichloromethane (20 mL X 2). The combined organic layer was washed with saturated brine solution, dried over sodium sulphate, filtered and concentrated under vacuum to get a crude compound. It was purified by column chromatography over silica gel using 1 to 3 % methanol in dichloromethane.
2-{4-[7-(2,5-difluoro-phenyl)-quinolin-4-yl]-piperazin-1-yl}-N-hydroxy-acetamidine[ No CAS ]
[ 603-79-2 ]
N-[2-{4-[7-(2,5-difluoro-phenyl)-quinolin-4-yl]-piperazin-1-yl}-1-hydroxyamino-ethylidene]-2,3-dimethyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;
General procedure: To a solution of acid derivative (a-f) in DMF (20 mL, 20 vol) was added EDC.HCl (0.962 g, 5.023 mol), HOBt (0.509 g, 3.774 mmol) and DIPEA (1.3 mL, 7.548 mmol) at 0 C. To the above mixture 2-{4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin-1-yl}-N-hydroxy-acetamidine (8b) (1 g, 2.516 mmol) was added at 0 C. The reaction mixture was gradually warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with ice cold water. The aqueous layer was extracted with dichloromethane (20 mL X 2). The combined organic layer was washed with saturated brine solution, dried over sodium sulphate, filtered and concentrated under vacuum to get crude compound. It was purified by column chromatography over silica gel using 1 to 3 % methanol in dichloromethane.
2-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-N-hydroxy-acetamidine[ No CAS ]
[ 603-79-2 ]
N-[2-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-1-hydroxyamino-eth-(Z)-ylidene]- 2,3-dimethyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;
General procedure: To a solution of acid derivative (a-f) in DMF (20 mL, 20 vol) was added EDC.HCl (1.2 g, 6.32 mol), HOBt (0.633 g, 4.690 mmol) and DIPEA (1.6 mL, 9.360 mmol) at 0 C. To the above mixture 2-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-N-hydroxy-acetamidine (8c) (1 g, 3.126 mmol) was added at 0 C. The reaction mixture was gradually warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with ice cold water and the phases were separated. The aqueous layer was extracted with dichloromethane (20 mL X 2). The combined organic layer was washed with saturated brine solution and dried over sodium sulphate, filtered and concentrated under vacuum to get a crude compound. It was purified by column chromatography over silica gel using 1 to 3 % methanol in dichloromethane.
N-hydroxy-2-[4-(7-pyridin-3-yl-quinolin-4-yl)-piperazin-1-yl]-acetamidine[ No CAS ]
[ 603-79-2 ]
N-{1-[(Z)-hydroxyimino]-2-[4-(7-pyridin-3-ylquinolin-4-yl)piperazin-1-yl]ethyl}-2,3-dimethylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.3%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;
General procedure: To a solution of acid derivative (a-f) in DMF (20 mL, 20 vol) was added EDC.HCl (1.2 g, 6.32 mol), HOBt (0.633 g, 4.690 mmol) and DIPEA (1.6 mL, 9.360 mmol) at 0 C. To the above mixture 2-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-yl]-N-hydroxy-acetamidine (8c) (1 g, 3.126 mmol) was added at 0 C. The reaction mixture was gradually warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with ice cold water and the phases were separated. The aqueous layer was extracted with dichloromethane (20 mL X 2). The combined organic layer was washed with saturated brine solution and dried over sodium sulphate, filtered and concentrated under vacuum to get a crude compound. It was purified by column chromatography over silica gel using 1 to 3 % methanol in dichloromethane.
62.3%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; at 20℃;
3-(2-hydroxypropan-2-yl)-7,8-dimethyl-4-phenyl-1H-isochromen-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; potassium acetate; copper diacetate In 1,2-dichloro-ethane at 60℃; for 24h; regioselective reaction;
3. General procedure for the cyclization reactions
General procedure: A mixture of 2-methylbenzoic acid (1a) (0.2 mmol, 27 mg), propargyl alcohol (2a) (0.4 mmol, 64 mg), [Cp*RhCl2]2 (5 mol%, 6.2 mg), Cu(OAc)2 (0.4 mmol, 72.6 mg), and KOAc (0.4 mmol, 39.3 mg) was stirred in DCE (1.0 mL) at 60 °C for 24 h. After cooling, the reaction mixture was extracted with dichloromethane (40 mL). The organic layer was washed by water (40 mL, three times), and dried over Na2SO4. After evaporation of the solvent under vacuum, the crude product was purified with column chromatography (petroleum/EtOAc) and the fraction was collected and concentrated to provide 49.2 mg, 83% yield of 3a as a pale gray solid.
5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.37%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 17h;
3.1; 8.1 Step 1: 5-(2,3-Dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester
Add hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (500mg, 2.36mmol), 2,3-dimethylbenzoic acid (530mg, 3.5mmol) into a 25mL single-mouth bottle ,), add DCM to dissolve, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903mg, 4.71mmol), 4-dimethylaminopyridine (580mg, 4.75mmol), react at room temperature for 17h. Add 10 mL of water to the reaction solution, extract the aqueous phase with DCM (30 mL), combine the organic phases and wash with water (10 mL×2), dry with anhydrous sodium sulfate and concentrate, and perform silica gel column chromatography. The eluent is PE-PE/EA (v/ v=1/1), 660 mg of colorless viscous liquid is obtained as the product, and the yield is 81.37%.