|
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h; |
General procedure: To the various carboxylic acids (obtained from ASDI, Inc., 0.076 mmol, 1 equiv.) was added dry DCM (0.5 mL), oxalyl chloride (0.076 mmol, 1 equiv.), and then 2 drops of DMF. The reactions were placed in the shaker and reacted overnight at ambient temperature for 24 h. A solution of the hydrochloride salt of 3 (0.048 mmol, 1 equiv.) in 1.5 mL of DMF was added, followed by DIEA (0.240 mmol, 5 equiv.). The vials were agitated in the shaker for 24 h at ambient temperature. The solvent was removed in a Genevac HT24 centrifugal evaporator, and the crude intermediates were carried forward without purification. To each of the above crude products was added 10% TEA in MeOH (2 mL). The reaction vials were then placed in the shaker at 33 C overnight, and the solvent was evaporated. All the crude products were purified via preparative HPLC to >95% purity, and the desired products in the yields as described below. |
|
With oxalyl dichloride; N,N-dimethyl-formamide; In toluene; at 20℃; for 2h; |
2-(2,5-Dimethylphenyl)-8-methoxy-4-oxa-8-azaspiro[4.5]dec-1 -en-3-one 112-(2,5-Dimethylphenyl)-8-methoxy-4-oxa-8-azaspiro[4.5]dec-1 -en-3-one 11Oxalyl chloride (90 mu, 1.06 mmol) was added to a solution of <strong>[13612-34-5]2,5-dimethylphenylacetic acid</strong> (116 mg, 0.708 mmol) and A/,A/-dimethylformamide (2 drops) in toluene (1 mL) and the mixture was stirred at room temperature for 2 h after which time any volatiles were removed in vacuo and the crude residue was dissolved in THF (1 mL). A solution of 4-hydroxy-1-methoxy- piperidine-4-carbaldehyde (75 mg, 0.472 mmol)) 10 and triethylamine (130 mu, 0.944 mmol) in THF (1 mL) was added and the mixture was heated to 60 C for 16 h. Saturated aqueous sodium bicarbonate solution (5 mL) and EtOAc (10 mL) were added and the organics were extracted into EtOAc (2 x 10 mL). The combined organic phases were dried (MgSCU), filtered and concentrated. The crude residue was dissolved in A/,A/-dimethylformamide (0.6 mL) and potassium te/f-butoxide (106 mg, 0.944 mmol) was added. The mixture was heated at 80 C for 1 h, then was allowed to cool to room temperature and was stirred for 16 h. 1 M HCI (2 mL) and EtOAc (10 mL) were added and the organics were extracted into EtOAc (2 x 10 mL). The combined organic phases were dried (MgS04), filtered and concentrated to give the crude product. The resulting product was purified by flash chromatography on silica gel (solvent 50% EtOAc/hexane) to afford the title compound as a colourless solid (58 mg, 43%). |
|
With oxalyl dichloride; In dichloromethane; at 0 - 20℃; for 3h; |
Aside from analyses of NMR spectra, the structures of the meta-C-H alkylation products were also confirmed by the comparison with two authentic samples prepared from commercially available 2,5- dimethylphenylacetic acid and 3 , 5-dimethylphenyl- acetic acid. |
|
With thionyl chloride; In dichloromethane; at 40 - 50℃; for 8h; |
To the 2000 ml four bottle into the dichloromethane 630 g, under stirring from the hand hole is added acetic acid 2, 5 - 485 g, stirring 10 minutes; to the reaction in the cauldron adds by drops the chlorination sulfoxide 386 g, dropping processes of the transferred printing |
|
With thionyl chloride; In dichloromethane; at 40 - 50℃; for 8h; |
Dichloromethane (630 g) was added to a 2000 ml four-necked flask.Add 485 g of <strong>[13612-34-5]2,5-dimethylphenylacetic acid</strong> from the hand hole while stirring.Stir for 10 minutes;Thionyl chloride 386g was added dropwise to the reactor.The dropping process keeps the pot temperature less than 40C.A large amount of acid gas is produced during the reaction.Tail gas is absorbed by lye;After the end of the dropping, the temperature was raised to 50 C and the reaction was refluxed for 8 hours.Sampling and testing the percentage of raw material area is less than 0.5% after stopping the reaction;If the reaction is not complete, continue incubation for 1 hour before sampling.The reaction still does not completely need to add 10% of the total amount of thionyl chloride to continue the reaction.Until qualified.After the reaction is passed,Atmospheric pressure solvent dechlorination,Keep the kettle temperature no higher than 60C,Then vacuum -0.08Mpa,Steam until no liquid flows,The residue in the kettle is 2,5-dimethylphenylacetyl chloride,Bottling for use; closed storage. |
|
With thionyl chloride; In dichloromethane; at 40 - 50℃; for 8h; |
Dichloromethane (630 g) was added to a 2000 mL four-necked flask, and 485 g of <strong>[13612-34-5]2,5-dimethylphenylacetic acid</strong> was added to the mixture from a hand well and stirred for 10 minutes; thionyl chloride (386 g) was added dropwise to the reaction vessel. Keeping the kettle temperature less than 40C, a large amount of acid gas is generated during the reaction, and the tail gas is absorbed by the alkali liquor;After the end of dripping, the temperature was raised to 50C and the reaction was refluxed for 8 hours. The reaction was stopped after sampling the area percentage of the test raw material was less than 0.5%; if the reaction was not complete, the incubation was continued for another 1 h before sampling.The reaction still does not completely need to add 10% of the total amount of thionyl chloride to continue the reaction until it is qualified. After the reaction is qualified, remove the solvent dichloromethane at normal pressure, keep the pot temperature no higher than 60C, and then vacuum -0.08Mpa, and steam until no liquid flows. The residual liquid in the kettle is 2,5-dimethylphenylacetyl chloride, Bottling for use; closed storage. |
|
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; |
Step E: Preparation of 2-[4-[(2,5-dimethylphenyl)acetyl]-l-piperazinyl]-N-methyl-N-[(1R)-1-phenylethyl]-5-thiazolecarboxamide. 2,5-Dimethylphenylacetic acid (1.64 g, 10 mmol) in 40 mL of dry dichloromethane was treated with oxalyl chloride (1.0 mL, 11 mmol) and a catalytic amount of N,N-dimethylformamide (1 drop) and allowed to stir at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to give 2,5-dimethylphenylacetyl chloride as an oil. The acid chloride (97 mL, 0.6 mmol) was added to a mixture of N-methyl-N-[(1R)-1-phenylethyl]-2-(1-piperazinyl)-5-thiazolecarboxamide (i.e. the product of Example 4, Step D) (165 mg, 0.5 mmol) and polymer-bound 4-(dimethylamino)pyridine (PS-DMAP, 1.4 meq (milli-equivalent)/g, 1.0 g) in 15 mL of dichloromethane, which was then shaken for 3 h, filtered and concentrated under reduced pressure to give 140 mg of the title product, a compound of the present invention as a yellow solid.1H NMR (CDCl3) delta 1.6 (br d, 3H), 2.24 (s, 3H), 2.28 (s, 3H), 2.87 (s, 3H), 3.42 (m, 2H), 3.55 (m, 4H), 3.69 (s, 2H), 3.82 (m, 2H), 5.9 (m, IH), 6.9-7.1 (m, 3H) 7.25-7.45 (m, 5H), 7.46 (s, IH). |
|
With thionyl chloride; In toluene; at 25 - 110℃; for 1.5h; |
30 g of the raw material <strong>[13612-34-5]2,5-dimethylphenylacetic acid</strong> was added to 150 mL of solvent anhydrous toluene at 25 C.After heating to 70 C,Slowly add 26.08g of SOCl2.The temperature is raised to 90 C, and the reaction is carried out at 110 C for 1.5 h after the completion of the dropwise addition.Producing 2,5-dimethylphenylacetyl chloride,Evaporate excess SOCl2 at 80 C,After dropping to 25 C, 16.83 g of absolute ethanol was slowly added dropwise.After continuing the reaction for 0.5 h, 50 mL of water was added to the mixture three times for extraction.The origin impurity was removed, and the organic phase was steamed to obtain 36.39 g of a yellow liquid.The content is greater than 95.0%. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
