| Methyl 3-(2-amino-2-thioxoethyl)benzoate is the key intermediate of novel phosphate transport inhibitor benzoic acid,2-[[3-[[4-(2-hydroxyethyl)-2-thiazolyl]methyl]benzoyl]amino]-5-(1-piperidinyl)-,(2E)-2-[[4-chloro-3-(trifluoromethyl)phenyl]methylene]hydrazide(BAH),with large domestic and external demand.The reported synthetic routes were mainly using 3-methylbenzoic acid as the starting material to afford methyl 3-(2-amino-2-thioxoethyl)benzoate via esterification,bromination,cyanation and thionation.There are some disadvantages in this process.The total yield of final product was 16.4%.The starting materials 3-methylbenzoic acid and cyanide reagent trimethylsilyl cyanide are expensive.The atom economy of Bromide NBS used in the bromination reaction is poor.The products of cyanation need to be purified by silica gel chromatography.A great deal of organic solvent using in the thionation reaction is hard to recycle and the waste water is difficult to deal with.Moreover,the total yield of final product is low and the cost of production is high.In this paper,the available benzoic acid was used as initial raw material to synthesize methyl 3-(2-amino-2-thioxoethyl)benzoate via esterification,chloromethylation,cyanation and thionation.And the target product was got in 73.2%overall isolated yield.A new process that jointed two kettles in the production of methyl benzoate from benzoic acid with methyl chloride in the presence of phase transfer catalyst(PTC)was developed.Using benzoic acid instead of 3-methylbenzoic acid as starting material solved the problem of expensive raw material.The recovery of the excess methyl chloride in 50%was achieved through the operation of jointing the two kettles,reduced the emission and consumption of the raw material.The optimized conditions were shown as below.The molar ratio of benzoic acid,sodium hydroxide and methyl chloride was 1:1.15:2.The dosage of the PTC,tetrabutylammonium bromide(TBAB),was 2 wt%of benzoic acid.The amount of the solvent,water,was 300 ml/mol(benzoic acid)and the reaction temperature was 80℃.The product yield was 96.2%.The process of selective chloromethylation of methyl benzoate catalyzed by Lewis acid was studied.The formation of by-products was inhibited by the room temperature catalytic process and the recycling of the by-products from multichloromethylation.Crystallization-mother liquor circulation process used in the post-processing can avoid the emission of the waste water containing aluminum,recycled the solid of AICl3.6H2O in 83.7%,siginificant for saving water resources and environmental protection.The optimized conditions were shown as below.The optimization of Lewis acid catalyst was AICl3.The molar ratio of methyl benzoate,AICl3 and paraformaldehyde was 1:1.3:1.8.The amount of the solvent,dichloroethane,was 500 ml/mol(methyl benzoate)and the reaction temperature was 20-30℃.The flow of hydrogen chloride was 60 ml/min and the reaction time was 8 h.The conversion of raw material was 99.1%and the product yield was 78.8%.The yield of product from the recycling of the by-products from multichloromethylation was 85.5%,6.7%higher than that not.The synthesis of methyl 3-(cyanomethyl)benzoate from methyl 3-(chloromethyl)benzoate with sodium cyanide under the existence of PTC was studied.Using water as the solvent avoided the use of organic solvent,reduced the energy consumption and the cost.The optimized conditions were shown as below.The molar ratio of methyl 3-(chloromethyl)benzoate and sodium cyanide was 1:1.2.The amount of the solvent,water,was 140 ml/mol(methyl 3-(chloromethyl)benzoate).The amount of the PTC,TBAB,was 3 wt%of methyl 3-(chloromethyl)benzoate.The reaction temperature was 55-60℃ and the reaction time was 6 h.The conversion of raw material was 99.5%and the product yield was 90.2%.The thionation of methyl 3-(cyanomethyl)benzoate catalyzed by the amidine hydrochlorides was investigated,which had many advantages,such as fast reaction rate,little consumption of catalyst and low cost.Recycling the filtrate achieved the recovery of catalyst,reduced the amount of the waste water.The optimized conditions were shown as below.The amount of the solvent,water,was 260 ml/mol(methyl 3-(cyanomethyl)benzoate).The amount of the amidine hydrochlorides was 5wt%of methyl 3-(cyanomethyl)benzoate and the pH value of the system was 9-11.The pressure of H2S was 0.5-0.7 MPa.The reaction temperature was 70-80℃ and the reaction time was 4 h.The conversion of raw material was 99.5%and the product yield was 98.6%.The products of the reactions are confirmed by mass spectroscopy(MS),1HNMR and 13CNMR.The innovations of research are on the following two aspects:the process of selective chloromethylation of methyl benzoate catalyzed by Lewis acid and the thionation of methyl 3-(cyanomethyl)benzoate catalyzed by the amidine hydrochlorides... |
