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Preparation method of baloxavir intermediate

An intermediate and preparation process technology, which is applied in the field of preparation of baloxavir intermediates, can solve the problems of unfavorable industrial production, low three-step yield, long reaction route, etc., achieve stable industrial production and preparation, and avoid chiral disassembly points, the effect of reducing production costs

Active Publication Date: 2020-04-17
苏州楚凯药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patented process allows for easy manufacturing of an active ingredient that has improved properties compared with existing methods or processes used previously. It involves simplified reactions between different chemicals without compromising their desired effectiveness. Additionally, it offers higher yields than previous techniques while reducing costs. Overall, this technology makes possible commercialization of these drugs at large scales.

Problems solved by technology

Technological Problem addressed in this patents relates to improving the efficiency and effectiveness of treatments involving inflammatory diseases such as acne or respiratory tract illness caused by bacteria called Bacillus subtilis varistrellae. Current methods involve complicated processes like chemical vapor deposition techniques, crystal analysis, and solid phase separation. These technical problem highlights the challenge of developing efficient and safe agents for reducing infectious disease outbreak rates associated with current approaches including chemotherapy and biologically active substances.

Method used

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  • Preparation method of baloxavir intermediate
  • Preparation method of baloxavir intermediate
  • Preparation method of baloxavir intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0068]

[0069] 3-Morpholinone (10.1 g, 0.1 mol) and THF (100 mL) were added to the reaction flask, cooled to -78°C, and n-butyllithium solution (68 mL, 0.11 mol) was added dropwise under nitrogen. After the dropwise addition was completed, it was stirred at -78°C for 2h, and a THF (60mL) solution of allyl chloroformate (12g, 0.1mol) was added dropwise to the reaction solution, and after the dropwise addition was completed, it was stirred for 2h, then quenched by adding a saturated ammonium chloride solution. , after warming to room temperature, extracted with ethyl acetate, washed with brine, and concentrated under reduced pressure to obtain 14.8 g of compound I (yield 80%). 1 H-NMR (CDCl 3 )3.63(t,2H),3.72(t,2H),4.26(s,2H),4.58(d,2H),5.35(d,1H),5.45(d,1H),5.90-6.02(m,1H ).

Embodiment 2

[0071]

[0072] Under nitrogen, the [Ir(COD)Cl] 2 (0.2mmol) and phosphine ligand L3f (0.4mmol) were dissolved in DCM (10mL), stirred at room temperature for 20min to make it completely complexed, compound Ⅰ (14.8g, 0.08mol) and ammonium formate (6.1g, 0.096mol) Add DCM (100mL) solution into the reaction flask, then add TFA (4.5g, 0.04mol), tetraisopropyl titanate (4.5g, 0.0.16mol), 4A molecular sieve (10g) and metal complexes, pass into Hydrogen, reacted at 50°C for 24h, after the reaction was completed, neutralized with saturated aqueous sodium bicarbonate, extracted with DCM, passed through the column to remove the metal complex, and concentrated to obtain 14.1g of compound II (95% yield, enantiomer Selective S configuration:R configuration=99:1). 1 H-NMR (CDCl 3 ):δ2.80-3.03(m,2H),3.52(m,2H),3.79(m,4H),4.03(t,2H),4.87(m,1H),4.90-5.10(d,2H), 5.72(d,1H).

Embodiment 3

[0074]

[0075] 3-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (24.6g, 0.1mol) and methanol (100mL), water (100mL) were added to the reaction flask, and hydroxylamine hydrochloride ( 34.8g, 0.5mol), reflux reaction for 10h, the reaction was cooled and then concentrated in vacuo, and methanol / water was used as eluent to pass through the column to obtain 23.5g of compound III (yield 90%). 1 H-NMR(DMSO):δ2.52(s,1H),4.95(s,2H),6.30(d,1H),7.00(d,1H),7.38-7.47(m,5H),10.00(s, 1H).

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Abstract

The invention relates to a preparation method of a baloxavir intermediate (compound VI). The preparation method comprises the following steps: taking 3-morpholinone and 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid as initial raw materials; carrying out amino protection on 3-morpholinone to obtain a compound I, and carrying out selective reductive amination on the compound I and ammonium formatein the presence of a catalyst and a chiral ligand to obtain a chiral compound II; reacting the 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid with hydroxylamine hydrochloride to obtain a compound III,and carrying out an esterification reaction on the compound III and alcohol to obtain a compound IV; and carrying out an SN2 reaction on the compound IV and a chiral compound II to obtain a compoundV, removing a protecting group from the compound V under the action of a catalyst, and carrying out cyclization to obtain the compound VI. The method provides a simple and convenient industrial production route for the baloxavir intermediate, and has the advantages of simple reaction operation, avoidance of chiral resolution, few steps and low cost.

Description

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Claims

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Application Information

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Owner 苏州楚凯药业有限公司
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