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Preparation method of cefiderocol side chain

A side chain, cephalosporin technology, applied in the field of drug synthesis, can solve the problems of large environmental pollution, high synthesis cost, difficult operation, etc., and achieves the effects of easy industrial production, safe industrial conditions, and simple reaction operation.

Pending Publication Date: 2021-11-26
CHENGDU UNIV
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AI Technical Summary

Problems solved by technology

The starting material of method 1 is relatively expensive, and the synthesis cost is high
Method 2 increases the synthesis steps, which is not environmentally friendly and difficult to operate, and both of the synthesis methods use methanesulfonyl chloride which is more toxic and pollutes the environment as a sulfonic anhydride reagent, which is not suitable for industrial production

Method used

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  • Preparation method of cefiderocol side chain
  • Preparation method of cefiderocol side chain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Step 1, the preparation of 2-chloro-3,4-dihydroxybenzaldehyde

[0035] Under nitrogen protection, add 10.0g (49.85mmol) 2-chloro-3,4-dimethoxybenzaldehyde and 50mL CH 2 Cl 2 , add 14.0g (104.99mmol) of anhydrous AlCl under stirring at room temperature 3 , and then dropwise added 33.8mL (419.98 mmol) of pyridine, after dropping, refluxed for 8.0h. Add 200 mL of dilute HCl solution, stir, and a solid precipitates out. Cool for 1.0 h, filter, wash with water 3 times, suck dry, and dry under reduced pressure at 50°C to obtain 7.8 g of off-white solid III with a yield of 90.6%.

[0036] 1 H NMR (600MHz, DMSO-d 6 )δ10.92(s, 1H, OH), 10.07(s, 1H, CHO), 9.66(s, 1H, OH), 7.33(d, J=51.0Hz, 1H, ArH), 6.83(d, J= 15.1Hz, 1H, ArH).

[0037] 13 C-NMR (150MHz, DMSO-d 6 )δ189.21, 153.25, 142.68, 125.19, 124.36, 122.28, 114.04.

[0038] Step 2, the preparation of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde

[0039] Under nitrogen protection, add 10.0g (57.95mmol) 2-chlo...

Embodiment 2

[0051] Step 1, the preparation of 2-chloro-3,4-dihydroxybenzaldehyde

[0052] Under nitrogen protection, 10.0g (49.85mmol) 2-chloro-3,4-dimethoxybenzaldehyde and 50mL N, N-dimethylacetamide were added dropwise to a 250mL three-necked flask, and 18.6g ( 139.57mmol) AlCl 3 anisole (56 mL). Then 11.2 mL (139.57 mmol) of pyridine was added dropwise, heated to 55° C., and reacted for 5.0 h. Add 100mL dilute HCl solution and 100mL tetrahydrofuran, concentrate under reduced pressure, a large amount of solid precipitates, cool and stir for 2.0h, filter and wash with water 3 times. After drying under reduced pressure at 50°C, 8.1 g of off-white solid III was obtained, with a yield of 94.2%.

[0053] 1 H NMR (600MHz, DMSO-d 6 )δ10.89(s, 1H, OH), 10.03(s, 1H, CHO), 9.62(s, 1H, OH), 7.30(d, J=51.1Hz, 1H, ArH), 6.83(d, J= 15.3Hz,1H,ArH).

[0054] 13 C NMR (150MHz, DMSO-d 6 )δ190.12, 153.65, 141.36, 125.40, 123.23, 122.19, 113.93.

[0055] Step 2, the preparation of 2-chloro-3,4-d...

Embodiment 3

[0068] Step 1, the preparation of 2-chloro-3,4-dihydroxybenzaldehyde

[0069] Under nitrogen protection, add 10.0g (49.85mmol) 2-chloro-3,4-dimethoxybenzaldehyde and 60mLCH 2 Cl 2 , cooled to 0 ° C, slowly dropwise added 50.0g (199.38mmol) BBr 3 , warming up to 25°C for 3.0h. Concentrate under reduced pressure until no liquid flows out, and then add 100 mL of dilute HCl solution, and an off-white solid precipitates out. Cool and stir for 1.0h, filter, wash with water 3 times, and drain. After drying under reduced pressure at 50°C, 7.3 g of white solid III was obtained, with a yield of 84.9%.

[0070] 1 H NMR (600MHz, DMSO-d 6 )δ10.90(s, 1H, OH), 10.05(s, 1H, CHO), 9.68(s, 1H, OH), 7.32(d, J=51.0Hz, 1H, ArH), 6.83(d, J= 15.3Hz, 1H, ArH).

[0071] 13 C-NMR (150MHz, DMSO-d 6 )δ189.65, 153.33, 142.41, 126.38, 123.39, 122.11, 113.89.

[0072] Step 2, the preparation of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde

[0073] Under nitrogen protection, 10.0g (57.95mmo...

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Abstract

The invention provides a preparation method of a cefiderocol side chain. The method comprises the following steps: carrying out demethylation on2-chloro-3,4-dimethoxybenzaldehyde serving as a raw material under the catalysis of a Lewis acid or base to obtain 2-chloro-3,4-dihydroxybenzaldehyde; then protecting the hydroxyl groups; oxidizing the aldehyde group, then performing sulfonic anhydride conversion, and finally, carrying out an amidation reaction with 1-(2-aminoethyl) pyrrolidine, so as to obtain the 3-position side chain of the cefiderocol. According to the invention, a new initial raw material is used, and four-step reaction of demethylation, hydroxyl protection, aldehyde group oxidation and amidation is carried out to obtain the product. The method is green and environment-friendly, the raw materials are easy to obtain, the operation is simple and convenient, the product yield and purity are high, the cost is low, and industrial production is easy.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of cefediril side chain. Background technique [0002] Cefiderocol (cefiderocol, see formula 1 for structure) is a new type of cephalosporin antibacterial drug developed by Shionogi in Japan. Approved by the US FDA, it is used for the treatment of complicated urinary tract infections (cUTI) caused by Gram-negative bacteria. Indicated for the treatment of cUTI and pyelonephritis caused by susceptible Gram-negative bacteria in patients 18 years of age and older with limited or no alternative treatment options. The successful marketing of cefdiril provides an effective solution to the problem of antibiotic resistance. [0003] [0004] Cefdiril is a new type of siderophore cephalosporin antibacterial drug. It has a unique mechanism of action to penetrate the cell membrane of Gram-negative bacteria. It complexes with ferric ions and is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/13
CPCC07D295/13
Inventor 石克金李江红陈林张斌唐美玲
Owner CHENGDU UNIV
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