Synthesis of HIV-1 inhibitor etravirin

The synthesis of 1.2.1,4-bis (2,6-dichloropyridine-4-oxo) - 3,5-dimethylbenzonitrile (IV) was studied. 12.46 g (67.95 mmo1) 2,4,6-trimethylpyrimidine (II), 10.00 (67.95 mmo1) 3,5-dimethyl-4-hydroxybenzonitrile (III), 10.54 g (81.54 mmo1) n, n-diisopropylacetylamine and 4 ml 1,4-dioxane were put into the reaction flask The reaction was carried out at 65 ℃ for 1.5 h and 70 ℃ for 1 h. After the reaction solution was cooled to about 10 ℃, the filter cake was washed with 10 ml cold 1,4-dioxane, then the filter cake was added into 40 ml water at 25 ℃, stirred for 30 min and filtered. After drying, 16.44 g of intermediate Ⅳ was obtained in the yield of 82.3 m.p.2o7.8-209.6 ℃ (literature value) [16] Synthesis of 16.00g (54.40mmo1) intermediate IV and 6.43g (54.40mmo1) p-aminobenzonitrile (V) in 70ml N-methylpyrrolidone (N-methylpyrrolidone); H NMR (dmso-d, 400 MHz): 82.12 (s, 6h), 7.61 (s, 1H), 7.74 (s, 2h), 1.2.24-6-chloro-2-bis (4-cyanophenyl) amino) pyridine-4-oxo-3,5-dimethylbenzonitrile (V) Add 12.21g (108.80mmo1) potassium TERT butanol in batches at 0-5 ℃, add it for 30min, continue to stir for 2h, then slowly add 300ml water, filter, suspend the filter cake in 180ml water, adjust it to pH 6-7 with concentrated hydrochloric acid. After filtration, the filter cake still contains more impurities (isomer of V) after drying. Add the filter cake Then, the filter cake was washed with 2 ml cold ethyl acetate and dried in vacuum at 55-60 ℃ to obtain 12.61 g intermediate V with a yield of 61.7.mp.278.1-279.6 ℃ (reference value [16]: 278.5-280.5 ℃); MS (ESI)+ )Synthesis of 1.2.3 4 - (6-amino-2-one ((4-cyanophenyl) amino) pyridine-4-oxy) - 3,5-dimethylbenzonitrile (VI). 10.00g (26.60mmo1) intermediate V, 5 () ml of 25 mass fraction ammonia and 80ml 1,4-dioxane were added to the autoclave and stirred at 120 ℃ for 12h. The reaction solution was cooled to 5O ℃ After that, add 2 ml water, cool to 5 ℃, stir for 1 h, filter, wash the filter cake twice with 8 ml cold 1,4-dioxane, and then vacuum dry at 55 ~ 60 ℃ to obtain 8.01 g intermediate VI in 84.59/6.mp.283.6 ~ 285.9 ℃ (reference value [16]: 284.5 ~ 287 ℃); MS (ESI bucket) m / z357 (M + H). 1.2.4 etravirin (1) Methods: 7.00 g (19.64 retoo1) of intermediate VI was dissolved in 70 ml dichloromethane, bromine (3.55 g, 22.19 mmo1) dichloromethane (15 mi) solution was dropwise added at 0 ~ 5 ℃, stirring for 4 h at this temperature, adding 70 ml water, adjusting to pH 9 ~ 10 with 4 mol / l dilute sodium hydroxide solution, and then adding 0.35 g sodium pyrosulfite to dissolve in 1 ml water The precipitated solid was filtered, washed, and dried in vacuum at 55-6o ℃ to obtain crude etravirin. The crude etravirin was dissolved in 125ml acetone at 50-55 ℃, decolorized by adding activated carbon, filtered, and most of the acetone was removed under reduced pressure. The volume of the remaining product was about 10% 35ml, cooled to 5-10 ℃, filtered, washed with 15ml cold acetone, dried in vacuum at 55-60 ℃, 6.95g etravirin was obtained in 81.3% yield, O4.mp.254.5 ~ 256.2oc (reference value [16]: 255 ~ 257 ℃); MS (esi4 -) m / z435 (M + H); H NMR (400MHz, DMSO-d6) (chemical shift) 2.11 (s, 6h, me), 7.10 (brs, 2h, NH2), 7.41 (D, j-8.8 Hz, 2h, arh2.6), 7.54 (D, j-8.4 Hz, 2h, arh3, 5), 7.74 (s, 2h, ar'h ·), 9.55 (s, 1H, N, H)

2. Results and discussion: the synthetic routes of etravirin can be divided into the following two categories: a. the synthetic routes using p-cyanophenylguanidine as raw material or intermediate: p-cyanophenylguanidine cyclized with ethyl malonate to form pyrimidine ring segment, then chlorinated with phosphorus oxychloride, brominated with bromine, reacted with sodium 2,6-dimethyl-4-cyanophenol Itravirin was obtained by nucleophilic substitution and finally amino substitution of the chlorine atom in pyrimidine ring. This method has higher price and lower yields of nucleophilic substitution and ammoniation_ ]It is reported that p-cyanophenylguanidine is cyclized with ethyl cyanoacetate to form a pyrimidine ring segment. This route reduces the ammoniation reaction, but there are still some problems, such as the high price of p-cyanophenylguanidine and the poor selectivity of the last nucleophilic substitution reaction. Patent I reports that p-cyanophenylguanidine is obtained by the reaction of p-cyanoaniline with cyanamide However, the yield of p-cyanophenylguanidine is only 24, and the yields of the last three steps are 48, 44 and 43 respectively. The total yield is very low, which is not suitable for industrial production.. B. the synthetic route using halopyrimidine as raw material: patent wo0027825 [1] first disclosed that 2,4,6-trichloro-5-bromo-pyrimidine was synthesized by two steps of nucleophilic substitution reaction and ammoniation reaction using 2,4,6-trichloro-5-bromo-pyrimidine as raw material The synthetic route of trowelin is not suitable for industrial production because of the disadvantages of difficult to obtain raw materials, long ammoniation time and low conversion

Etravirin was synthesized from 2,6-dichloro-4-aminopyridine by amino acetylation protection, two-step nucleophilic substitution, deacetylation protection and bromination reaction. The raw materials of this route are not suitable for industrial production because of the problems of difficult to obtain raw materials and long route. The synthetic route reported in reference [16] Etravirin was synthesized from 2,4,6-trichloropyrimidine by two steps of nucleophilic substitution, ammoniation and bromination (Fig. 1). This route is not only cheap and easy to obtain, but also avoids the common problems of other routes, such as redundant route, long ammoniation time, low conversion and low reaction yield Therefore, a synthetic route using 2,4,6-trichloropyrimidine as raw material was selected in this study (as shown in Fig. 1). The melting points, MS and NMR data of Intermediates IV, V, VI and target product I were consistent with those reported in reference [16]. In the synthesis process of intermediate IV, the time reported in reference [16] was 0 In this study, it was improved to react at 65 ℃ for 1.5 h, and then react at 70 ℃ for 1 h. because the initial reaction temperature was reduced, the side reaction was reduced, the reaction yield was increased to 82.3, and the purity of Ⅳ was higher, which showed that the melting range of the intermediate was narrower. The preparation yield of intermediate V was reported by literature The yield of target product I increased from 80 to 81.3. The total yield of four step reaction increased from 30.4 to 34.9, which significantly improved the synthesis efficiency and reduced the synthesis cost. Pyrimidine compounds have a wide range of biological activities, such as antiviral and antiviral In conclusion, intermediate VI was obtained from 2,4,6-trichloropyrimidine (Ⅱ) by three steps of nucleophilic substitution reaction, which substituted three chlorine atoms in pyrimidine ring in turn The intermediate [1 /] was prepared by nucleophilic substitution of 3,5-dimethyl-4-hydroxybenzonitrile (Ⅲ) in 82.39/6 yield; the intermediate V was prepared by nucleophilic substitution of 4-aminobenzonitrile with Ⅳ in 61.7 yield; the intermediate VI was prepared by ammoniation of V in 84.59/6 yield The target product etravirin was prepared by bromination in 81.3% yield. The melting point, MS and NMR data were in good agreement with those reported in the literature. The total yield of the four step reaction was increased from 3o.4 reported in the literature to 34.9. The improved synthesis method in this study improved the synthesis efficiency, reduced the cost and was suitable for pyrimidine compounds It is of great reference significance for the synthesis of.