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With thionyl chloride Heating; |
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With thionyl chloride |
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With thionyl chloride In chloroform Heating; |
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With thionyl chloride In N,N-dimethyl-formamide for 4h; Ambient temperature; |
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With thionyl chloride; N,N-dimethyl-formamide for 5h; |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide for 2h; Heating; |
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With thionyl chloride; triethylamine In tetrahydrofuran at 20℃; for 0.333333h; |
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With thionyl chloride |
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With oxalyl dichloride In dichloromethane |
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With oxalyl dichloride In dichloromethane at 20℃; for 2h; |
75.A
Step A:; To a solution of 2,6-dimethylbenzoic acid (192 mg, 1.28 mmol) in dichloromethane (8 mL) was added oxalyl chloride (0.33 mL, 3.85 mmol) slowly. The reaction was stirred at room temperature for 2 h. The solvent was evaporated and the solid was directly redissolved in dichloromethane (8 mL). 2-amino-3-hydroxybenzoic acid hydrobromide (314 mg, 1.34 mmol) was added, followed by triethylamine (0.75 mL, 5.4 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous 2 N HCl (25 mL) until the solution reached pH 1. The aqueous layer was extracted with dichloromethane. The organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The residue was directly re-dissolved in toluene (7 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (312 mg, 1.64 mmol). The reaction mixture was then heated to reflux for 1.5 h. The reaction was cooled down to room temperature and the toluene was evaporated. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, then washed with water, brine, dried over Na2SO4, filtered and concentrated to a yellow solid. The crude product was purified by column chromatography (silica gel, 9:1 to 2:1 ethyl acetate/methanol) to afford the desired product (101 mg, 35%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.95-7.86 (m, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.30-7.24 (m, 1H), 7.14-6.98 (m, 2H), 3.34 (s, 3H), 3.31 (s, 3H); MS (ESI+) m/z 268 (M+H). |
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With oxalyl dichloride In N,N-dimethyl-formamide; benzene |
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With thionyl chloride In toluene for 2h; Heating / reflux; |
5.a
To a mixture of 2,6-dimethylbenzoic acid (3 g; 0.02 mol) in toluene (50 ml) was added thionyl chloride (3.6 ml; 0.05 mol). The mixture thus obtained was refluxed for 2 hours. The solvent and the excess thionyl chloride were then evaporated off under reduced pressure. The residue thus obtained was taken up in toluene (50 ml) three times and evaporated under reduced pressure. The product thus obtained (3.6 g) was used without further purification. |
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With thionyl chloride In dichloromethane at 20℃; for 1h; Heating / reflux; |
A.29.a
2,6-Dimethylbenzoic acid (0.0666 mol) was dissolved in dry CH2Cl2 (150 ml). A drop of DMF was added. Thionyl chloride (0.33 mol) was added in drops under nitrogen atmosphere at room temperature. The reaction mixture was stirred and refluxed for one hour. The solvent was evaporated under reduced pressure. The residue was dried (under oil pump vacuum), to give the intermediate acid chloride, which was dissolved in dry CH2Cl2 (30 ml), to give solution (I). Solution (I) was added to a solution of 1,4-dioxa- 8-azaspiro[4.5]decane-8-ethanamine (0.0733 mol) and Et3N (0.0666 mol) in dry CH2Cl2 (150 ml). The reaction mixture was stirred and refluxed for 90 minutes. The reaction mixture was cooled, washed with a saturated aqueous NaHCO3 solution (30 ml), washed with water (30 ml), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure, yielding 23 g of intermediate (81). |
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With oxalyl dichloride In dichloromethane at 0 - 20℃; for 1.5h; Inert atmosphere; |
1.A
EXAMPLE 1: Synthesis of Compound DP; 4-(3-(2,6-Dimethylbenzoyloxy) phenyl)-4-oxobutanoic acid; Step A: Preparation of 2,6-Dimethylbenzoyl chloride:; 2,6-Dimethylbenzoic acid (15 g, 99.88 mmol) was added to anhydrous CH2Cl2 (20 ml) at O0C followed by drop wise addition of oxalyl chloride (2M in CH2Cl2, 14.14 g) under argon. The reaction mixture was stirred at the same temperature for 30 minutes and then warmed to the room temperature for 1 hour, concentrated and used without purification. |
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With thionyl chloride at 70 - 80℃; for 1h; |
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With thionyl chloride; N,N-dimethyl-formamide at 50℃; for 2h; |
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With oxalyl dichloride In dichloromethane for 2h; |
1.G
Step G. Preparation of (R*)-tert-butyl l-((2,6- dimethylbenzamido)(phenyl)methyl)-7-azabicyclo [2.2.1] heptane- 7-carboxylate from (R*)-tert-butyl l-(amino(phenyl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylateTo a solution of 2,6-dimethylbenzoic acid (0.114 g, 0.76 mmol) in dichloromethane (2 niL) was added oxalyl chloride (0.133 mL, 1.52 mmol) followed by 1 drop of DMF. After 2 h, the solution was concentrated to an oily semi-solid, redissolved in dichloromethane and reconcentrated to a light gold oil. This oil was then added via syringe as a solution in dichloromethane (1 mL) to a solution of (R*)-tert-butyl l-(amino(phenyl)methyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate (0.046 g, 0.15 mmol) and DIPEA (0.213 mL, 1.22 mmol) also in dichloromethane (1.18 mL). After 4.5 h, the reaction was concentrated to minimal volume and stored in a freezer for 16 h. The reaction was then purified by flash column chromatography (SiC^, 0-100% ethyl acetate in hexanes) to afford (R*)-tert-butyl 1-((2,6-dimethylbenzamido)(phenyl)methyl)-7-azabicyclo[2.2.1 ]heptane-7-carboxylate (0.052 g, 79 %) as a clear colorless residue. IH NMR (300 MHz, chloroform-J) δ ppm 1.24 - 1.36 (m, 2 H), 1.43 (s, 9 H), 1.47 - 1.56 (m, 1 H), 1.59 - 1.73 (m, 2 H), 1.73 - 1.89 (m, 2 H), 2.14 (td, /=8.2, 3.8 Hz, 1 H), 2.21 (s, 6 H), 4.30 (t, /=4.8 Hz, 1 H), 5.86 (d, /=8.6 Hz, 1 H), 6.96 (d, /=7.6 Hz, 2 H), 7.04 - 7.15 (m, 1 H), 7.20 - 7.35 (m, 3 H), 7.54 (dd, /=8.1, 1.4 Hz, 2 H), 8.15 (d, /=8.0 Hz, 1 H). m/z (ES+), (M+H)+ = 435.3. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 3h; |
1
EXAMPLE 1; Methyl 2,6-dimethyl-benzoate; To a cooled (0° C.) solution of 2,6-dimethylbenzoic acid (20.2 g, 134 mmol) in dichloromethane (200 mL) is added DMF (1 mL) followed by oxalyl chloride (14 mL, 162 mmol). On completion of addition, the cold bath is removed and stirring continued for 3 h. The resulting solution is concentrated under vacuum and the residue added slowly to a cooled (0° C.) solution comprising methanol (200 mL) and triethylamine (40 mL). On completion of addition, the reaction mixture is stirred for 30 min. then poured into hydrochloric acid solution (400 mL, 2N) which is then extracted with ether. The ether extract is washed with hydrochloric acid solution (1N), sodium bicarbonate solution and brine then dried over MgSO4 and concentrated to give the title compound which is used without further purification. MS (EI) 164 (M)+. |
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With thionyl chloride In N,N-dimethyl-formamide for 2h; Reflux; |
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With thionyl chloride In toluene for 2h; Heating / reflux; |
5.a
Example 5 ; EPO Preparation of Compound 5 (RI=CH3CH2, R2=R6=CH3, R3=R4=R5=X=Y=H); a) 2.6-Dimethylbenzoyl chloride; To a mixture of 2,6-dimethylbenzoic acid (3 g; 0.02 mol) in toluene (50 ml) was added thionyl chloride (3.6 ml; 0.05 mol). The mixture thus obtained was refluxed for 2 hours. The solvent and the excess thionyl chloride were then evaporated off under reduced pressure. The residue thus obtained was taken up in toluene (50 ml) three times and evaporated under reduced pressure. The product thus obtained (3.6 g) was used without further purification. |
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With thionyl chloride for 2h; |
166.A
Step A: Preparation of 2,6-dimethylbenzoyl chloride. DMF (2 drops) was added to 2,6-dimethylbenzoic acid (0.100 g, 0.666 mmol) in thionyl chloride (0.50 mL, 6.9 mmol). The reaction mixture was stirred for 2 h and concentrated to yield the titled compound, which was used in the next step without further purification. |
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With thionyl chloride In pyridine at 20℃; for 2.5h; Inert atmosphere; |
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With thionyl chloride In N,N-dimethyl-formamide for 2h; Reflux; |
Typical Procedure for Amidation of 2,6-Disubstituted Benzoic Acids Through Acid Chloride Formation
Typical Procedure for Amidation of 2,6-Disubstituted Benzoic Acids Through Acid Chloride Formation (Synthesis of N-[2-(3-chloro-benzylsulfanyl)-ethyl]-2,6-dimethyl-benzamide, 75 as representative example). One drop of DMF was added to a solution of 2,6-dimethylbenzoic acid (0.3 g, 2 mmol) in thionyl chloride (2 mL), and the mixture was refluxed for 2 h. It was then cooled to room temperature and the excess thionyl chloride was removed in vacuo. The solid residue was dissolved in dry DCM (5 mL) and cooled to 0° C. A mixture of β-(3-chlorobenzyl)mercaptoethylamine (0.404 g, 2 mmol) and triethylamine (1 mL, 7 mmol) in dry DCM (5 mL) was added in dropwise manner at 0° C. under nitrogen atmosphere, and the mixture was allowed to stir at room temperature for 1.5 h. After the completion of reaction (as judged by TLC) the solvent was removed in vacuo and the solid residue was dissolved in DCM (30 mL). The organic phase was washed with brine (15 mL) and water (15 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a mixture of hexane/ethyl acetate (gradient from 15% v/v ethyl acetate/hexane to 35% v/v ethyl acetate/hexane) as eluent to obtain the desired amidated product, 75 (0.507 g, 76%): mp=53-55° C. 1H NMR (CDCl3, 400 MHz): δ 2.27 (s, 6H), 2.65 (t, J=6.4 Hz, 2H), 3.57 (q, J=6.4 Hz, 2H), 3.69 (s, 2H), 6.06 (bs, 1H), 6.99 (d, J=7.6 Hz, 2H), 7.14 (t, J=7.6 Hz, 1H), 7.19-7.23 (m, 3H), 7.32 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 19.41, 31.42, 35.46, 38.11, 127.27, 127.65, 127.71, 128.96, 129.12, 130.07, 134.39, 134.65, 137.61, 140.32, 170.61. HRMS calculated for C18H21ClNOS (M+H)+ 334.10324, found 334.10221. |
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With thionyl chloride In toluene Reflux; |
2.1 Step 1) 2,6-dimethyl-N-phenylbenzamide
To a suspension of 2,6-dimethyl benzoic acid (5.0 g, 33.29 mmol) in toluene (100 was added SOCl12 (12.08 mL, 166.47 mmol) at rt. The reaction was stirred at reflux overnight, then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM (50 mL), and the solution was used for the next step directly. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; |
1.5
Oxalyl chloride (0.105 mL, 1.199 mmol) was added dropwise to a solution of 2,6-dimethylbenzoic acid (150 mg, 0.999 mmol) in DCM (6 mL) and the reaction was stirred at room temperature overnight. Solvents were evaporated giving 140 mg (83%) of crude acid chloride as a white solid (Intermediate 5a) and was used directly in the next step in the preparation of Example 2. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 4h; Inert atmosphere; |
20.1 Step 1) 2,6-dimethyl-N-phenylbenzamide
[379] To a mixture of 2,6-dimethylbenzoic acid (1.99 g, 13.3 mmol) and N,N- dimethylformamide (103 mg, 1.409 mmol) in dichloromethane (15 mL) was added oxalyl di chloride (2.25 mL) at rt. The reaction was stirred at rt for 4 hours, then concentrated in vacuo, and the residue was dissolved in 4 mL of 1,4-dioxane. The resulted solution was added to a mixture of aniline (1.28 g, 13.7 mmol) and sodium bicarbonate (2.80 g, 175 mmol) in 1,4- dioxane (11 mL) and water (7 mL) at 0 °C, then moved to rt, and stirred overnight. The mixture was poured into 0 (100 mL), and extracted with EtOAc (50 mL χ 2). The combined organic phase was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PE EtOAc (v/v) = 10/1) to give the title compound as an off-white solid (740 mg, 25%). MS (ESI, pos. ion) m/z: 226.0 [M+H]+; NMR (400 MHz, CDCb) δ (ppm): 7.63-7.61 (d, J = 8.0 Hz, 2H), 7.39-7.36 (dd, J = 8.0, 8.0 Hz, 2H), 7.36 (br s, 1 H), 7.23-7.13 (m, 2H), 7.08-7.06 (d, J= 7.6 Hz, 2H), 2.40 (s, 6H). |
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Stage #1: 2,6-dimethylbenzoic acid With N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.0833333h;
Stage #2: With thionyl chloride In dichloromethane at 0 - 20℃; |
Synthesis of 2,6-dimethylbenzoyl chloride
To a stirred CH2Cl2 (12 mL) solution of 2,6-dimethylbenzoic acid 0.3 g (2 mmol) was added DMF (0.016 mL) at 0 °C, and the resulting solution was stirred for 5 min. To the solution was added SOCl2 (0.4 mL) at 0 °C and the resulting solution was stirred at room temperature for 12 h, and concentrated in vacuo to give 2,6-dimethylbenzoyl chloride, which was used for the synthesis of 1-pyrenyl 2,6-dimethylbenzoate (1h) without purification. |
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With thionyl chloride at 60℃; for 2h; |
1.3 Experimental Procedure:
A mixture of 2,4,6-Trimethyl benzoic acid (50 g, 0.333 mol) and thionyl chloride (100 mL) was heated at 60° C. for 2 h. In-process check for acid chloride formation was confirmed by quenching an aliquot with methanol. (0174) After complete conversion, excess thionyl chloride was removed under vacuum. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1.5h; Inert atmosphere; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3.16667h; Inert atmosphere; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; Sealed tube; Inert atmosphere; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; |
12
To a stirred solution of 2,6-dimethylbenzoic acid (3 g, 20 mmol, 1.0 eq.) in anhydrous DCM (60 mL) was added DMF (10 drops, cat.) followed by dropwise addition of oxalyl chloride (3.43 mL, 40 mmol, 2.0 eq.) at 0° C. The solution was gradually brought to r.t. and stirred for 2 h. After such time, the volatiles were removed by concentration of the crude reaction mixture and the crude acid chloride was used directly in the following step without purification. |
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With thionyl chloride at 70℃; for 1h; |
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With thionyl chloride In toluene at 100℃; for 0.5h; |
2-(2,6-Dimethylphenyl)-6-nitro-1,3-benzoxazole (5)
To a solution of 2,6-dimethylbenzoic acid (3) (0.55g, 3.7 mmol) in toluene (4 mL) was added thionyl chloride (0.53 mL, 7.3 mmol). The mixture was stirredat 100 C for 30 min. After cooling to rt, the solvent was then distilled under reduced pressure to givecrude 2,6-dimethylbenzoyl chloride (0.62 g), which was used in the next reaction without furtherpurification |
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