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Sulfa compounds, intermediates, preparation and application targeting carbonic anhydrase ⅸ

A technology of carbonic anhydrase and compounds, applied in the preparation of sulfonamides, organic chemistry, radioactive carriers, etc.

Active Publication Date: 2017-10-17
SHANGHAI ATOM KEXING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, regarding the sulfonamides targeting CA IX 18 There are few reports on the related research of F-labeled PET probes at home and abroad, which makes this invention have good innovation and good application value

Method used

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  • Sulfa compounds, intermediates, preparation and application targeting carbonic anhydrase ⅸ
  • Sulfa compounds, intermediates, preparation and application targeting carbonic anhydrase ⅸ
  • Sulfa compounds, intermediates, preparation and application targeting carbonic anhydrase ⅸ

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Synthesis of 5-nitro-2,3,6-trifluorobenzoic acid (C0)

[0077] Under ice bath, dissolve 4.0g of 2,3,6 trifluorobenzoic acid (E) in 30mL of concentrated sulfuric acid, slowly add the mixed acid solution of concentrated nitric acid (5.1mL) and concentrated sulfuric acid (5.1mL) dropwise below 0°C, add dropwise After completion, react at room temperature for 5 h. The above reaction solution was cooled in an ice bath, and 60 mL of ice water was slowly added dropwise with stirring. Extract twice with 100 mL of ethyl acetate, combine the ethyl acetate layers, wash twice with saturated sodium chloride solution, dry the organic layer over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 4.4 g of a light yellow solid. Yield 87.6%, purity >98% (HPLC).

[0078] The identification data of C0 are as follows: TOF-ESI-MS: M(C7H2F3NO4)=221.09(m / z), 244.0[M+Na]+, 276[M+Na+CH3OH]+.

[0079] 1 H-NMR (300MHz, CDCl 3 )δ8.18(m,1H,H)

Embodiment 2

[0081] Synthesis of 5-nitro-2,3,6-trifluorophenylacetic acid (C1)

[0082] 1. At room temperature, 235.7mg (1.07mmol) of CO was dissolved in 5mL of SOCl2, refluxed at 80°C for 5h, and the reaction solution was concentrated under reduced pressure to obtain light yellow liquid F, which was directly used in the next reaction.

[0083] 2. Dissolve F prepared in 1 above in 5 mL of ether, add 120 mg (2.14 mmol) of CaO, and slowly add CH2N2 (2.14 mmol) in ether solution dropwise under ice-cooling to react. After the reaction, the product was purified by silica gel column chromatography (developing solvent: n-hexane, ethyl acetate). 233.7 mg of product G was obtained with a yield of 89.1% and a purity of 99% (HPLC).

[0084] 3. 123.0mg (501.8umol) of compound G was dissolved in 5mL of dioxane solution, and 9mL ( 500mmol) of the silver oxide catalyst solution, heated at 50°C for reaction. After the reaction, the product was purified by silica gel column chromatography (developing so...

Embodiment 3

[0088] Preparation of labeled precursor compound B0

[0089] 68.9 mg (0.4 mmol) of sulfanilamide, 88.5 mg (0.4 mmol) of CO were dissolved in 6 mL of acetonitrile, 76.7 mg (0.4 mmol) of EDC.HCl and 56 uL (0.4 mmol) of triethylamine were added and the reaction was stirred at room temperature. After the reaction, the product was purified by silica gel column chromatography (developing solvent: n-hexane, ethyl acetate). The product B0125.2 mg was obtained with a yield of 83.4% and a purity of 99% (HPLC).

[0090] The identification data of B0 are as follows: TOF-ESI-MS: M(C13H8F3N3O5S)=375.28(m / z), 398.0[M+Na]+, 430.0[M+Na+CH3OH]+.

[0091] 1H-NMR (300MHz, CDCl3): δ11.36(s, 1H, NH), 8.67(m, 1H, CH), 8.23(s, 1H, CH), 7.75(m, 1H, CH), 7.59(m ,2H,CH),7.43(s,2H,NH2).

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Abstract

The invention relates to a sulfonamides compound of target carbonic anhydrase IX and an intermediate as well as preparation and application thereof. The sulfonamides compound of the target carbonic anhydrase IX has a structural formula shown as the description, wherein n is equal to 0 to 6, R1 is H, C1 to C4 linear alkyl, C3 to C4 branched alkyl, C3 to C6 naphthenic base or phenyl-C1 to C4 alkyl. Compared with the prior art, a precursor for radiolabelling is simple in synthesis step and high in yield and large-scale preparation is easy to realize. A preparation method of the sulfonamides compound of the target carbonic anhydrase IX is simple and reaction time is short; the sulfonamides compound is more suitable for radiopharmaceutical clinical application; the radiochemical purity of a <18>F labeled compound prepared by the sulfonamides compound is more than 99 percent. Reagents used in the invention are commercial reagents and raw materials are convenient and easy to obtain.

Description

technical field [0001] The invention relates to sulfonamide compounds, in particular to a sulfonamide compound targeting carbonic anhydrase IX, an intermediate and a preparation method thereof. Background technique [0002] Carbonic anhydrase Ⅸ (carbonic anhydrase Ⅸ, referred to as CA Ⅸ) is one of the isomers of the carbonic anhydrase family (CAs). It is a transmembrane glycoprotein composed of acidic amino acids, distributed in the cell membrane and nucleus, with relative molecular masses of 58kD and 54kD, respectively (Opavsky R., Pastorekova S, Zelnik V, et al.Human MN / CA9gene, novel member of the carbonic anhydrase family: Structure and exon to proteindomain relationships[J].Genomics,1996,(3),480-487.Supuran C T,ScozzafavaA.Carbonic anhydrase inhibitors and their therapeutic potential[J].Expert Opinion on Therapeutic Patents,2000,10( 5), 575-600.). The main function of CA IX is to participate in the regulation of transmembrane ion and gas transport, and may also partic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C311/16C07C303/40A61K31/18A61K51/04A61K101/02
Inventor 贾丽娜曹本红
Owner SHANGHAI ATOM KEXING PHARMA
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