ChemicalBook CAS DataBase List GS 441524

GS 441524 synthesis

7synthesis methods

Product Name:GS 441524
CAS Number:1191237-69-0
Molecular formula:C12H13N5O4
Molecular Weight:291.26

N-(7-lodopyrrolo[2,1-f][1,2,4]triazin-4-yl)-N,N-dimethylformimidamide (12) was prepared by heated 7-lodopyrrolo[2,1-f][1,2,4]triazin-4-amine (2) and N,N-dimethylformamide dimethyl acetal (DMF-DMA) in ethanol with >90% isolated yield. Compound 12 was firstly treated with tt-PrMgCl at ?20~?10 °C, then reacted with ribonolactone 3 to give the product 4 after quenched by ammonium chloride aqueous solution to remove the protecting group, in 60% yield by recrystallization from MTBE and heptane. The active amino group in compound 2 will block the Grignard reaction, so the protection methods of NH? has been widely examined. The reported protective groups included -TMS, 1,2-bis(dimethylsilyl)ethane, -Boc, and so on. The N-Si bond is unstable and it should be partly destroyed during the Grignard reaction and the residual NH will consume Grignard reagent, as well as gives side products. The N,N-dimethylformimidamide group used as the protective group has advantages. There is no NH group in compound 12 so the side product was lower, and the protective group can be deprotected easily during the work-up operation to give 4 directly. Compound 4 should be a mixture of 1’-isomers, while we had not established the method or identified the ratio by HPLC. It was taken into the subsequent 1’-cyanation reaction to give compound 5, by reacted with TFA, TMSOTf and TMSCN in CH?Cl? respectively at ?40~?30 °C in 81% yield and >99% anomeric ratio after purified from toluene. At the last step, compound 5 was added into BCl3 in CH2Cl2 solution at ?40~?30 °C to give the final GS-441524 in 83% yield and >99% purity (HPLC). ^[13]

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1191237-69-0
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Yield:1191237-69-0 95%

Reaction Conditions:

with boron trichloride in dichloromethane at 5;

Steps:

1

(1) Material preparation: Dissolve about 200g of raw materials in dichloromethane to prepare 0.5mmol/mL raw material liquid, and place it in the raw material liquid bottle;1.0mmol/mL boron trichloride dichloromethane solution (about 1200mL) is directly used as the auxiliary material liquid and placed in the auxiliary material liquid bottle;Connect the raw material liquid bottle to the metering pump A;Connect the auxiliary material liquid bottle to the metering pump B;(2) Reaction temperature parameter setting: start the circulating liquid cooling system, make the mixer and the main reaction pipeline at about 5 degrees of the set temperature;(3) Material flow rate parameter setting: the flow rate parameter of metering pump A is set to 25mL/min (12.5mmol/min); the flow rate parameter of metering pump B is set to 37.5mL/min (37.5mmol/min);(4) Continuous flow reaction system operation: start two pump systems at the same time, metering pump A and metering pump B respectively send the raw material liquid and auxiliary material liquid into the mixer at their respective set flow rates; the two feed liquids are mixed in the pre-cooling mixer (Holding liquid retention time is about 12 seconds), and then enters the pre-cooling main reaction pipeline (Holding liquid retention time is about 50 seconds);(5) Quenching process: the reaction liquid flows out into an aqueous sodium hydroxide solution (120g sodium hydroxide, dissolved in 1.8kg water) for quenching;(6) Post-treatment process: filtering, adding the obtained crude product to 150 g of methanol, beating and filtering to obtain 98.5 g of the target product, with a yield of 95%, a purity of the high performance liquid phase of 99.4%, and a single impurity of less than 0.15%.

References:

CN112745324,2021,A Location in patent:Paragraph 0040-0048