Preparation method of 4-oximide-5'-(2-methylpropionyl) uridine

A technology of methyl propionyl and uridine is applied in the field of preparation of 4-oxime-5`-(2-methylpropionyl) uridine, and can solve the problems of low yield, high cost, difficult purification and the like, and achieves Simple preparation conditions, good crystallinity, good conversion and atom economy

Inactive Publication Date: 2021-03-26
NANJING CHEMPION BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In the compound reporting route, the multi-step intermediate is an oily substance, which requires column chromatography purification, which leads to difficulty in purification, and the yield is low and the cost is high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] In a 500 ml three-necked reaction flask, sequentially add 18.8 g of compound 1, 40.7 g of 2,2-dimethoxypropane, and 188.0 mL of acetone. The system is stirred at room temperature, and then 8.0 g of sulfuric acid is added dropwise, and the system is stirred at room temperature for 2 hours. TLC (thin-layer chromatography) showed that the conversion of the raw material was complete, filtered, and the filter cake was rinsed with 100.0 ml of acetone to obtain 28.1 g of the product 2`,3`-O-isopropylidene cytidine sulfate (compound 2). Yield: 95.25%, off-white solid.

Embodiment 2

[0041] Add 50.0 g of compound 2 into a 500 ml reaction flask, followed by adding 150 mL of anhydrous acetonitrile, 3.3 g of DMAP and 41.0 ml of DBU in sequence, stirring at room temperature, then adding 54.0 ml of isobutyric anhydride dropwise, and stirring the system at 60°C for 3 hours , TLC showed that the conversion of raw materials was complete, then the temperature was lowered, acetonitrile was removed by distillation under reduced pressure, 300.0 ml of dichloromethane and 200.0 ml of saturated sodium bicarbonate were added to the oil, and the layers were separated, and the dichloromethane layer was extracted with 200.0 ml of dilute hydrochloric acid (1M). Once, the dichloromethane phase was collected, dried, and concentrated to obtain the product 2`,3`-O-(1-methyl-1-oxopropyl)-N-(2-methyl-1-oxopropyl )-5`-(2-methylpropionyl)uridine (compound 3) 49.9 g, yield: 89.88%, off-white solid.

Embodiment 3

[0043] Add 50.0 g of compound 3 into a 500 ml reaction flask, add 200.0 mL of isopropanol, 100.0 ml of water, and 7.3 ml of 50% hydroxylamine aqueous solution in sequence, and stir the system at 80°C for 20 hours. TLC shows that the conversion of the raw materials is complete, and then cool down , distilled off isopropanol under reduced pressure, added 200.0 ml of ethyl acetate and 200.0 ml of saturated aqueous sodium chloride solution to the oily matter, separated layers, extracted the ethyl acetate layer twice with 200.0 ml of water, collected the ethyl acetate phase, dried, and concentrated , the yellow crude product was obtained, and the product 2`,3`-O-(1-methyl-1-oxopropyl)-4-oxime-5`-( 2-methylpropionyl)uridine (compound 4), 37.5 g, yield: 85.91%, white solid.

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PUM

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Abstract

The invention discloses a preparation method of 4-oximide-5'-(2-methylpropionyl) uridine, which comprises the following steps: S1, in the presence of acid, reacting a compound 1 with 2, 2-dimethoxypropane in an organic solvent to obtain a compound 2; S2, in the presence of an alkali, enabling the compound 2 to react in an organic solvent to obtain a compound 3; S3, reacting the compound 3 in an organic solvent in the presence of a hydroxylamine aqueous solution to obtain a compound 4; S4, reacting the compound 4 in an organic solvent in the presence of an acid to obtain a compound I; the solidwith good crystallization performance prepared by the method is simple in preparation condition and good in conversion rate and atom economy.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of 4-oxime-5'-(2-methylpropionyl)uridine. Background technique [0002] Molnupiravir (Formula I) (EIDD-2801, MK-4482) is an orally bioactive prodrug of the ribonucleoside analog β-d-N4-hydroxycytidine (NHC; EIDD-1931) with broad-spectrum antiviral activity Active against the pathogens of SARS-CoV-2, MERS-CoV, SARS-CoV and COVID-19. Molnupiravir may prove to be an effective antiviral drug on several occasions. Because oral medication is easy to use, it can be used both as a prophylaxis and as an outpatient and inpatient [0003] . [0004] At present, the main synthetic route of Molnupiravir is the compound synthetic route reported in patent WO2019113463 and WO2019173602 as follows: [0005] step one: [0006] ; [0007] Step two: [0008] ; [0009] Step three: [0010] ; [0011] Step four: [0012] ; [0013] S...

Claims

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Application Information

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IPC IPC(8): C07D405/04
CPCC07D405/04
Inventor 陈剑余长泉陈晨
Owner NANJING CHEMPION BIOTECHNOLOGY CO LTD
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