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Iclaprim intermediate, and preparation method for iclaprim

A scheme and compound technology, applied in the field of alaprime intermediates and their preparation, can solve the problems of low yield, long route, expensive reagents, etc.

Active Publication Date: 2020-01-24
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The technical problem to be solved by the present invention is to overcome the defects such as the need to use expensive reagents, high cost, complicated post-treatment, long route, low yield and unsuitability for industrialized production in the existing synthetic method of irapulin, And provide a kind of Elaprime intermediate, and preparation method thereof

Method used

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  • Iclaprim intermediate, and preparation method for iclaprim
  • Iclaprim intermediate, and preparation method for iclaprim
  • Iclaprim intermediate, and preparation method for iclaprim

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Preparation of Compound 1a (N,N'-(5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diyl)diacetamide)

[0116]

[0117] Add compound 1 (100.0g, 344.5mmol), acetic anhydride (176g, 1710.4mmol) and 900ml toluene to the reaction flask, heat to reflux for 1.5h, let it stand for crystallization after cooling down to room temperature, suction filter, and dry to obtain 109.0g White solid 1a, the yield is 84.5%, mp.201-203°C, the purity is 98.72% by HPLC, 1 H-NMR (400MHz, CDCl 3 ).δ(ppm):10.41(s,1H),10.09(s,1H),8.36(s,1H),6.48(s,1H),6.34(s,2H),3.84(s,2H),3.71 (s,6H), 3.61(s,3H), 2.16(s,6H).

Embodiment 2

[0119] Preparation of Compound 1a (N, N'-(5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diyl)diacetamide)

[0120] Add compound 1 (100.1g, 344.8mmol), acetyl chloride (98.1ml, 1379.6mmol) and 900ml toluene to the reaction flask, heat and reflux and stir for 1.5h, after cooling down to room temperature, stand for crystallization, filter with suction, and dry to obtain 104.0 g white solid 1a, yield 80.6%, mp.201-203 ° C, HPLC detection of its purity is 98.70%, 1 H-NMR (400MHz, CDCl 3 ).δ(ppm):10.41(s,1H),10.09(s,1H),8.36(s,1H),6.48(s,1H),6.34(s,2H),3.84(s,2H),3.71 (s,6H), 3.61(s,3H), 2.16(s,6H).

Embodiment 3

[0122] Preparation of Compound 1a (N,N'-(5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diyl)diacetamide)

[0123] Add compound 1 (100.0g, 344.5mmol), acetic anhydride (70.3g, 688.5mmol) and 900ml toluene to the reaction flask, heat to reflux for 1.5h, let it stand for crystallization after cooling down to room temperature, suction filter, and dry to obtain 102.8 g white solid 1a, yield 71.7%, mp.201-203°C, HPLC detected its purity as 98.62%, 1 H-NMR (400MHz, CDCl 3 ).δ(ppm):10.41(s,1H),10.09(s,1H),8.36(s,1H),6.48(s,1H),6.34(s,2H),3.84(s,2H),3.71 (s,6H), 3.61(s,3H), 2.16(s,6H).

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Abstract

The invention discloses an iclaprim intermediate, and a preparation method for iclaprim, and provides a preparation method of a phenol compound represented by formula 8. An acetyl compound representedby formula 2 undergoes a selective demethylation reaction in an organic solvent in the presence of a Lewis acid to obtain the phenol compound of the formula 8. The invention also provides the acetylcompound of the formula 2, and a preparation method and an application thereof. The method for preparing iclaprim from the iclaprim intermediate has the advantages of economical reagents, short route,high yield, low preparation cost, simplicity in post-treatment, and suitableness for industrial production.

Description

technical field [0001] The present invention relates to a kind of Elapulene intermediate and preparation method thereof. Background technique [0002] Iclaprim (English name: Iclaprim) chemical name: 5-[(2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl)methyl]- 2,4-pyrimidine-diamine, the structural formula is as follows: [0003] [0004] Iclaprim is a dihydrofolate reductase inhibitor developed by Motif Bio. In 2018, it submitted a marketing application to the US FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Iclaprim is currently in Phase II clinical trials for the treatment of hospital-acquired bacterial pneumonia (HABP). In addition, it is currently in preclinical development as a drug for the treatment of Staphylococcus aureus lung infection in patients with cystic fibrosis. [0005] In terms of regulation, Iclaprim has been granted Qualified Infectious Disease Product Qualification (QIDP) and Fast Track status by the US FDA...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/49
CPCC07D239/49
Inventor 刘潍源周伟澄林快乐吕训磊李超超臧金鹏王成成孟雪
Owner SHANGHAI INST OF PHARMA IND
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