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Seven-membered heterocyclic compound or salt thereof, and preparation method and application thereof

A technology for seven-membered heterocycles and compounds, which is applied in the field of seven-membered heterocycles or their salts, their preparation and application, can solve problems such as uncertain structures and lack of preparation methods, and achieve the effect of improving safety and effectiveness

Pending Publication Date: 2021-10-12
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The problem to be solved by the present invention is to overcome the defects of impurity source, uncertain structure and lack of preparation method in the prior art irapulin products, and provide a seven-membered heterocyclic compound or its salt, its preparation Method and application; the synthetic method step of the seven-membered heterocyclic compound provided by the present invention is simple, and reaction condition is gentle, operability is strong, can obtain the product of higher purity through simple purification; It can be used as Iclaprim related substance, is beneficial to Iclaprim Process research and formulation of quality standards have effectively reduced R&D costs and are of great significance to drug development

Method used

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  • Seven-membered heterocyclic compound or salt thereof, and preparation method and application thereof
  • Seven-membered heterocyclic compound or salt thereof, and preparation method and application thereof
  • Seven-membered heterocyclic compound or salt thereof, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 (5-[(2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl)methyl]-2,4-pyrimidine-diamine) preparation

[0038] Step (1) Preparation of (N,N'-(5-(2-acetyl-3,4,5-trimethoxybenzyl)pyrimidine-2,4-diyl)diacetamide)

[0039]

[0040] Add compound 1 (trimethoprim) (10.02g, 34.52mmol), acetic anhydride (17.06g, 167.11mmol) and 100ml chloroform in the 250ml reaction flask, add tin tetrachloride (8.00ml, 68.36mmol) under stirring, Reflux reaction for 1 hour, TLC detected that the raw materials basically disappeared, cooled to room temperature, poured the reaction solution into 50ml of ice water, stirred for 6mins, separated liquids, washed the organic phase with 5ml of water for 3 times, combined the aqueous phase, extracted the aqueous phase with 5ml of chloroform for 3 times, combined the organic phase, adjust the pH to 7-8 with saturated aqueous sodium carbonate solution, separate the liquid, wash the organic phase once with 5ml of water, dry it with anhydrous sodium...

Embodiment 2

[0078] Add compound 6 (1.69g, 4.54mmol) and 20ml tetrahydrofuran to the reaction flask, add trifluoroacetic acid (1.56g, 13.68mmol) under stirring, heat and reflux for 15h, TLC detects that there is basically no raw material remaining, and adjust the pH to 7 or so, tetrahydrofuran was distilled off, the organic phase was adjusted to pH 10 with saturated sodium carbonate solution, stirred for 1 h, filtered with suction, and dried to obtain 1.59 g of compound 7, with a crude yield of 98.87%. HPLC detection (same as Example 1) compound 7 had a purity of 97.01%, wherein HPLC showed that the impurity content was 2.10%, and we obtained 0.021 g by preparative chromatographic column enrichment and separation.

[0079] Its structural identification data are as follows:

[0080] mp.202-204℃; 1 H-NMR (600MHz, DMSO-d 6 ).δ(ppm):7.50(s,1H),6.91(s,1H),6.53(s,1H),5.56(s,2H),5.05-5.04(d,1H),4.41-4.39(d, 1H),3.73(s,3H),3.64(s,3H),3.33-3.30(m,1H),3.17-3.13(d,2H),2.26-2.23(d,1H),1.86-1.82(m, ...

Embodiment 3

[0086] Add compound 6 (2.00g, 5.38mmol) and 20ml tetrahydrofuran to the reaction flask, add p-toluenesulfonic acid monohydrate (1.54g, 8.10mmol) under stirring, and heat to reflux for 1h. TLC detects that there is basically no raw material remaining, and it drops to At room temperature, adjust the pH to about 7 with saturated sodium carbonate, evaporate THF, adjust the pH to 10 with saturated sodium carbonate solution, stir for 1 h, filter with suction, and dry to obtain 1.81 g of crude compound 7 with a total yield of 95.10%. HPLC detection (HPLC method 2) showed that the purity of compound 7 was 98.25%, and the content of impurity 7a was 1.02%.

[0087] The analysis and identification data (including the peak time of HPLC) are all the same as the above-mentioned Example 1.

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Abstract

The invention discloses a seven-membered heterocyclic compound or salt thereof, and a preparation method and application thereof. The invention provides a seven-membered heterocyclic compound as shown in a formula 7a or a salt thereof. The invention also provides application of the seven-membered heterocyclic compound shown in the formula 7a or the salt thereof as an impurity standard substance of Iclaprim. The seven-membered heterocyclic compound as shown in the formula 7a is used as a reference substance to establish an analysis method for quality control of Iclaprim, so that the safety and the effectiveness of clinical application of Iclaprim can be improved.

Description

technical field [0001] The invention relates to a seven-membered heterocyclic compound or its salt, its preparation method and application. Background technique [0002] 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) indications . 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. In terms of regulation, Iclaprim has been granted Qualified Infectious Disease Product Qualification (QIDP) and Fast Track status by the US FDA. In addition, the FDA granted Orphan Drug status to Iclaprim for the treatment of Staphylococcus aureus lung infection in patients with cystic fibrosis. Its chemical nam...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/16G01N30/02
CPCC07D491/16G01N30/02G01N2030/047
Inventor 刘潍源周伟澄林快乐周亭吕训磊臧金鹏王成成
Owner SHANGHAI INST OF PHARMA IND CO LTD
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