Synthetic Route of 39806-90-1,Some common heterocyclic compound, 39806-90-1, name is 4-Iodo-1-methyl-1H-pyrazole, molecular formula is C4H5IN2, traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.
Step 1: A clean and dry 500 L glass-lined reactor A was evacuated to -0.08–0.O5MPa and filled with nitrogen to normal pressure. It was repeated for 3 times. The reactors were sampled for oxygen content to ensure it was 3%.[001145j Diisopropylamine (106.0 kg) and 1-methyl-4-iodo-1H-pyrazole (24.3 kg, 23.6 kg corrected) were added to the reactor A at 15-25 C. Cuprous iodide (0.37 kg) was added to reactor A under the protection of nitrogen at 15-25 C. Bis(triphenylphosphine)palladium(II) chloride (1.09 kg) was added to the mixture under the protection of nitrogen at 15-25 C. The mixture was stirred for 20-30 mi Trimethylsilylacetylene (22.2 kg, 14.0 kg corrected) was added to the mixture in portions with 4-5 kg and an interval of 20-30 mm for each portion at 15-30 C. The mixture was allowed to react at 20-30 C. After 2h, the mixture was sampled every 1-2h for purity analysis by HPLC until area% of 1-methyl-4-iodo-1H-pyrazole was 0.5%.[001 146j After reaction completion, the mixture was filtered with a stainless steel centrifuge. The filter cake was rinsed twice with methyl tert-butyl ether (9.2 kg x2). The filtrate was transferred to reactor A and concentrated under reduced pressure (P -0.08 MPa) at T 45 C until 40-60 L was left. Methyl tert-butyl ether (92.5 kg) was added to the mixture and concentration was continued until 40-60 L was left. Methyl tert-butyl ether (92.2 kg) was added to concentrated mixture and the mixture was sampled for diisopropylamine residual analysis to ensure it was 1%. Active carbon (4.9 kg) was added to the mixture at 15-25 C and the mixture was maintained for 6-8 h under stirring. The mixture was filtered with stainless steel nutsche filter at 15-25 C. The filter cake was rinsed twice with methyl tert-butyl ether (9.2 kg x2). A solution of citric acid monohydrate (6.1 kg) in purified water (121.6 kg) was added to the filtrate at 15-25 C. The mixture was stirred for 20-30 mm and settled for 20-3 0 mm before separation. The emulsion layer was separated to aqueous phase. The aqueous phase was sampled for pH analysis and wt% analysis to ensure pH was < 7. Active carbon (4.9 kg) was added to the mixture at 15-25 C and the mixture was maintained for 6-8 h under stirring. The mixture was filtered with stainless steel nutsche filter at 15-25 C. The filter cake was rinsed twice with methyl tert-butyl ether (9.2 kg x2). The filtrate was checked to ensure it was yellow solution. The filtrate was transferred to reactor B and concentrated under reduced pressure (P -0.O8MPa) at T 35 C until 30-40 L was left. Anhydrous ethanol (96.3 kg) was added to the mixture and concentration was continued at T 45 C until 30-40 L was left. The mixture was sampled for methyl tert-butyl ether residual analysis to ensure it was 0.5%. The mixture was cooled to 15-25 C. Purified water (121.3 kg) was added to the mixture through peristaltic pump at 15-25 C at a reference rate of 25-50 kg/h. Brown yellow solid precipitated. The mixture was allowed to crystallize at 15-25 C. After 2h, the mixture was sampled every 1- 2h for mother liquor wt% analysis until it was 0.5% or the difference between the two samples was 0.3%. The mixture was filtered with a stainless steel nutsche filter. The filter cake was rinsed twice with purified water (12.1 kg x2). The filter cake was swept in the stainless steel nutsche filter. After 12h, the solid was sampled every 6-8h for ethanol residual until it was 1%. The product was packaged in one plastic bag. Product weight12.0 kg, Yield = 52.3%, Purity (HPLC) = 98.9%.
These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 4-Iodo-1-methyl-1H-pyrazole, its application will become more common.
Reference:
Patent; INFINITY PHARMACEUTICALS, INC.; CRENIER, Louis; LESCARBEAU, Andre; SHARMA, Praveen; GENOV, Daniel G.; (324 pag.)WO2017/48702; (2017); A1;,
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