2-Amino-5-chloro-N,3-dimethylbenzamide

Off-white powder

First, 15 g of toluene, 50 mL of dichloromethane was added successively to a 200 mL autoclave, 0.1 g of N-hydroxyphthalimide and 0.4 g of cobalt acetylacetonate were dissolved and stirred, Sealed autoclave, replaced with oxygen 3 times, pressurized to 3MPa, The temperature was raised to 30 ° C and the reaction was allowed to proceed for 1 h. After completion of the reaction, the mixture was cooled to room temperature, Filtering to obtain a solution containing benzoic acid;The above solution was placed in a 1000 mL four-necked flask equipped with a thermometer, And then to the flask by adding 100mL glacial acetic acid, stirring, access to nitrogen protection, The temperature was raised to 40 ° C, and then 30 mL of chlorine gas was introduced at a rate of 10 mL / min, Oil bath control solution temperature at 30 , reaction 3h, To obtain a solution containing 3, 5-dichlorobenzoic acid;To the above solution was added 3 g of a shielding reagent, stirred for 5 min, Then add 10gFormat reagent, For 1 h to give a solution containing 3-methyl-5-chlorobenzoic acid, Said shielding agent is dimethylmercury;Ice bath control solution temperature at 0 , To the above solution was added 5 mL of 98percent concentrated sulfuric acid at a rate of 5 mL / min, And 20 mL of 1 mol / L nitric acid was added thereto to control the reaction temperature at 40 ° C, For 1 h to give a solution containing 2-nitro-3-methyl-5-chlorobenzoic acid;Dissolve the aboveThe solution was placed in a 1000 mL four-necked flask equipped with a thermometer, A further 1 g of zinc sheet was added to the flask, 40 mL 0.1 mol / L NaOH, The oil bath control solution temperature was 70 ° C, Then stir the reaction for 2h, A solution containing 2-amino-3-methyl-5-chlorobenzoic acid was obtained at the end of the reaction;To the above solution was added 100 mL of dichloromethane, 40 mL of N, N'-diisopropylcarbodiimide, 5 mL of 1-hydroxybenzotriazole, stirred at room temperature for 2 h, And then control the temperature of ice water bath 0 , 40 mL of methylamine was added dropwise to the solution at 10 mL / min with stirring, After dripping, the insulation reaction 2h, A solution containing 2-amino-5-chloro-N, 3-dimethylbenzamide was obtained at the end of the reaction;The resulting solution was extracted with 100 mL of deionized water and 100 mL of methylene chloride. The resulting organic phase was obtained by using a mixed solution of petroleum ether: ethyl acetate = 1: 10 in a volume ratio to give a solution containing 2- Amino-5-chloro-N, 3-dimethylbenzamide, and the solution was distilled under reduced pressure to give a white solid, 2-amino-5-chloro-N, 3-dimethylbenzamide TheThe invention utilizes N-hydroxyphthalimide and cobalt acetylacetonate as the catalyst to oxidize toluene, which is favorable for oxidizing toluene to benzoic acid under mild conditions. The invention adopts N, N'-diisopropylcarbodiimide As the condensation agent, 1-hydroxybenzotriazole as the condensation activator, to avoid the use of phosgene; the invention simplifies the steps, and the yield has been significantly improved to 92.6percent.EXAMPLE 1Preparation of 2-amino-5-chloro-N, 3-dimethylbenzamide (Compound la)A 100 mL Hastelloy-C pressure-rated reactor (Reactor 1) fitted with an overhead stirrer, a thermocouple, a pressure transducer, a sample tube and a gas inlet tube was charged with 4.1 g of 2-bromo-4-chloro-6-methylbenzeneamine (Compound 2a) (97 wtpercent, 18.0 mmol), 0.0083 g of palladium(II) acetate (98 wtpercent, 0.0361 mmol, 0.002 eq.) and 0.0317 g of l, 4-bis(diphenylphosphino)butane (dppb) (98 wtpercent, 0.0721 mmol, 0.004 eq.). The reactor was twice sealed, pressurized (to 2.4 atm with nitrogen) and then vented. Following an acceptable leak test, Reactor 1 was vented to the atmosphere and then sealed. A separate but identical reactor (Reactor 2), was then charged with approximately 60 g of ethylene glycol. Reactor 2 was sealed and then, without agitation, nitrogen pressure was applied to discharge all of the ethylene glycol except that which lay below the bottom of the sample tube; the discharged ethylene glycol was discarded. Reactor 2 was opened and 55.5 g of fresh ethylene glycol was added. Reactor 2 was sealed again and pressurized with nitrogen to 3.4 atm and vented. After repeating this twice, agitation was started in Reactor 2 and with the vent open to an oil bubbler, nitrogen was sparged into the ethylene glycol through the sample tube for approximately 97 minutes. Nitrogen flow and agitation was stopped and Reactor 2 was sealed. The pressure in both reactors was approximately 1 atm. The sample tube of Reactor 2 was connected to the sample tube on Reactor 1 with pressure -rated, translucent, 1/8-inch Teflon.(R). tubing. Ethylene glycol was transferred from Reactor 2 to Reactor 1 by applying 3.4 atm nitrogen pressure to Reactor 2. After the transfer was complete, as determined by the absence of liquid seen in the Teflon.(R). transfer tube, Reactor 1 was sealed, Reactor 2 was vented and the tube connecting the two reactors was removed. Agitation in Reactor 1 was started. The temperature in Reactor 1 was maintained at approximately 25 °C by a combination of jacket fluid set at 20 °C and electrical resistance heating, both of which were controlled by computer. The nitrogen atmosphere in Reactor 1 was replaced with carbon monoxide by pressurizing Reactor 1 to 3.74 atm from a cylinder of compressed CO and then venting to atmosphere in three successive cycles.A lecture bottle of pressurized anhydrous methylamine was placed in a stand on top of a balance and the bottle was connected to Reactor 1 with stainless steel tubing. A total of 6.86 g of methylamine (98 wtpercent, 216 mmol, 12 eq.) was charged to Reactor 1 over approximately 18 minutes. The addition of methylamine was found to be exothermic and The contents of Reactor 1 briefly reached 37 °C. After the methylamine was added, Reactor 1 was sealed and heated to 110 °C by computer control. The methylamine cylinder was disconnected and the CO cylinder was reconnected to Reactor 1. After the Reactor 1 reached 110 °C, CO was fed to Reactor 1 to maintain 3.74 atm using a computer controlled flow meter; the amount of CO gas fed to the reactor was recorded. After 60 min, a sample was taken for HPLC analysis. The pressure and temperature were maintained for 25 h although after 3.8 h, 1.1 eq of CO had been fed to Reactor 1. At this point, the CO flow to the reactor substantially subsided. Reactor 1 was then cooled to 25 °C and made inert with nitrogen as described above. The contents of Reactor 1 were transferred to a glass bottle, sampled for HPLC analysis and then sealed.After four days stored at ambient temperature, 57.13 g of the reaction mixture were transferred to a 200 mL single-neck round bottom flask equipped with a magnetic stir bar. An additional funnel was attached to the round bottom flask and, with agitation, 50 mL de-ionized water was added to the flask over approximately 23 minutes. After approximatehy 11 mL of de-ionized water was added, the mixture turned from a clear solution to a thick slurry. The mixture was filtered and the solid product cake washed with 50 mL of de-ionized water. A total of 4.92 g of product was obtained, and this was dried in a vacuum oven at approximately 70 °C, under vacuum for six days to afford 2.36 g of the title compound with an assay of 99.1 wtpercent (corresponding to an approximate isolated yield of 70percent).REFERENCE Preparation of 2-amino-5-chloro-λf, 3-dimethylbenzamide (a compound of Formula 2). A 300-mL flask equipped with a thermometer and nitrogen bubbler was charged with ethyl acetate (100 mL) and acetic acid (12.6 g, 0.21 mol). Anhydrous methylamine (6.3 g, 0.20 mol) was added below the surface of the liquid mixture, which was cooled to maintain the temperature below 35 C, and then 6-chloro-8-methyl-2H-3, l-benzoxazine-2, 4(lH)- dione (21 g, 0.10 mol) (see Scheme 4 for a method of preparation) was added in portions while maintaining the reaction mixture at 35-40 C. After completion of the addition of the 6-chloro-8-methyl-2H-3, l-benzoxazine-2, 4(lH)-dione the temperature was maintained at 40-45 C, and the progress of the reaction was monitored by ηPLC analysis. When analysis of the reaction mixture indicated no more than 0.5percent of the 6-chloro-8-methyl-2H-3, l- benzoxazine-2, 4(lH)-dione remained (about 20 minutes), water (50 mL) was added to the reaction mixture. A distillation head was attached, moderate vacuum was applied, and ethyl acetate was distilled out at an internal temperature of about 46-60 C and pressure of about 30 to 50 kPa. To replace the ethyl acetate removed by distillation, water was added to maintain the original liquid volume in the reactor. When a significant amount of water began to distill, the aqueous slurry was cooled to 10 C. The solid was collected by filtration and dried at 60 C and 13.3 kPa to afford the title compound as a white crystalline solid (19 g, ca. 95percent yield, above 98percent purity by peak area in ηPLC analysis).A 300-mL flask equipped with a thermometer and nitrogen bubbler was charged with ethyl acetate (100 mL) and 12.6 g (0.21 mol) of acetic acid. Anhydrous methylamine (6.3 g, 0.20 mol) was added below the surface of the liquid mixture, which was cooled to maintain the temperature below 35 EXAMPLE 1Preparation of 2-amino-5-chloro-iV, 3-dimethylbenzamideTo a suspension of 6-chloro-8-methyl-2H-3, l-benzoxazine-2, 4(l//)-dione (211.6 g, 1000 mmol) in acetonitrile (700 mL) was added acetic acid (7.3 g, 122 mmol). Then 40percent aqueous methylamine (104 mL) was added dropwise over 30 minutes at 25-30 Step B: Preparation of 2-amino-5-chloro-iV, 3-dirnethylbenzarnideA mixture of 2-amino-Λ>, 3-dirnethylbenzarnide (i.e. the product of Step A) (16.6 g, 100 mmol) and ΛyV-dimethylformamide (15.0 g) was cooled to 10 The procedure of Example 3 was modified by using aqueous methylamine (40percent solution, 10.75 g, 0.138 mol) instead of anhydrous methylamine. Obtained after collection of solid and drying was 18.57 g of crude product, which ηPLC showed containing the title compound in only 92.4 wt. percent purity, thus corresponding to 87.3percent yield. ηPLC showed the crude product also containing about 3.4 wt. percent of 6-chJoro-3, 8-dimethyl-2, 4(lH, 3H)- quinazolinedione derived from cyclization of the 5-chloro-3-methyl-2-[[(methylamino)- carbonyl]amino]benzoic acid by-product, and about 1.7percent of the hydrolysis product 2-amino- 5-chloro-3-methylbenzoic acid. This Example demonstrates that water has a detrimental effect on the yield and purity of the product.EXAMPLE 3Preparation of 2-amino-5-chloro-iV, 3-dimethylbenzamideTo a suspension of methyl 2-amino-5-chloro-3-methylbenzoate (i.e. the product of Example 2) (4.03 g, 20.2 mmol) in acetonitrile (12.4 g) was added a solution of methylamine(3.1 g, 0.10 mol) in ethylene glycol (12.4 g). The mixture was heated at 60 °C for 23 h, and EPO

Molecular Weight:198.65
XLogP3:2.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:198.0559907
Monoisotopic Mass:198.0559907
Topological Polar Surface Area:55.1
Heavy Atom Count:13
Complexity:198
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes