Photoelectric synthesis method of cabozantinib intermediate

Abstract

The invention discloses a photoelectric synthesis method of a cabozantinib intermediate, which avoids using highly toxic chemicals and precious metals, and is low in cost and wide in application prospect. And the photoelectric condition is mild, the selectivity is high, and the photoelectric synergistic effect can accurately control the reaction process.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis, and more specifically to a method for synthesizing a cabozantinib intermediate. Background Technology

[0002] Cabozantinib, chemically known as N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, is a multi-target tyrosine kinase inhibitor (TKI) developed by Exelixis in the United States. It blocks tumor cell growth, proliferation, and angiogenesis by inhibiting nine targets, including MET, VEGFR, and RET. Its mechanism of action includes inhibiting tumor metastasis and angiogenesis, earning it the nickname "the panacea of ​​targeted therapies." Clinically, it is primarily used to treat medullary thyroid carcinoma.

[0003]

[0004] The earliest report on the synthesis method of cabozantinib free base was found in patent document WO2005030140A2. The synthetic route of this method is as follows:

[0005]

[0006] This method uses 1,1-cyclopropyl dicarboxylic acid and 6,7-dimethoxy-4-hydroxyquinoline as starting materials. The 6,7-dimethoxy-4-hydroxyquinoline is reacted with trifluoromethanesulfonyl chloride to obtain an esterification product. Subsequently, the two carboxyl groups of 1,1-cyclopropyl dicarboxylic acid are reacted sequentially with the amide products of 4-fluoroaniline and 4-hydroxyaniline. The esterification and amide products are then condensed at a high temperature of 165°C to obtain the free base of cabozantinib. This method requires a high temperature of 165°C, has harsh process conditions, produces many byproducts under high temperature conditions, is difficult to purify, and is unlikely to obtain a high-quality product. Furthermore, the reaction requires the use of corrosive SOCl2 as an acylation reagent twice, making it unsuitable for industrial production.

[0007] WO2012109510A1 discloses another method for synthesizing cabozantinib. This method uses 6,7-dimethoxy-4-hydroxyquinoline, p-fluoroaniline, and 1,3-cyclopropanedicarboxylic acid as raw materials, and synthesizes cabozantinib in five steps: chlorination, coupling, condensation, acylation, and amidation. The main drawback of this method is the large-scale use of highly toxic substances such as phosphorus oxychloride, sulfur dioxide, and oxalyl chloride, resulting in severe environmental pollution and equipment corrosion.

[0008] CN103664776A discloses another method for synthesizing cabozantinib, which uses ethyl cyclopropane-1,1-dicarboxylate as a raw material and prepares cabozantinib through hydrolysis, condensation, and other steps. This method also has disadvantages such as high reaction temperature, low yield, and complex operation.

[0009] In recent years, the field of photoelectrochemistry has made significant progress. Photoelectrochemistry generally has the advantages of mild conditions, high selectivity, and environmental friendliness, and is widely used. Most photoelectrochemical processes can be carried out at room temperature, without the need for high temperature and high pressure, thus causing less damage to electrodes and other equipment. At the same time, photoelectrochemical synergy can precisely control the reaction pathway, reduce the occurrence of side reactions, and is suitable for the synthesis of some drug molecules and their intermediates.

[0010] In existing technologies, the preparation of cabozantinib intermediates mostly requires high temperatures and the use of highly toxic substances such as phosphorus oxychloride and thionyl chloride, causing serious environmental pollution. Therefore, using photoelectrochemical methods to prepare cabozantinib intermediates is a good alternative. Summary of the Invention

[0011] To address the problems existing in the prior art, the present invention provides a method for preparing cabozantinib intermediates.

[0012] The present invention adopts the following technical solution:

[0013] Step 1: Add acetonitrile, (E)-2-(4-fluorobenzylhydrogen)-cyclohexyl-1-ol, electrolyte and photocatalyst to the bottle, use platinum electrodes as anode and cathode, irradiate with blue lamp, control the current at 3-8mA, and react for 8-12 hours; after the reaction is complete, add water, extract with ethyl acetate, concentrate, and obtain formula II by column chromatography.

[0014] Step 2: Add solvent to the reaction flask, add intermediate I to the flask, add oxidant, and react at room temperature; after the reaction is complete, add water, extract with ethyl acetate, concentrate, and obtain formula III by column chromatography;

[0015] Step 3: Add intermediate II to the reaction flask, add solvent, and add hydroxylamine hydrochloride. Heat to 70-90℃ and react for 10-12 hours. After the reaction is complete, add water, extract with ethyl acetate, concentrate, and obtain formula IV by column chromatography.

[0016] Furthermore, the electrolyte mentioned in step one is ammonium tetrabutylhexafluorophosphonate;

[0017] Furthermore, the photocatalyst mentioned in step one is 10-methyl-9-trimethylmethylacridinium perchlorate;

[0018] Furthermore, the blue light mentioned in step one is 40W;

[0019] Furthermore, the solvent mentioned in step two is DMF;

[0020] Furthermore, the oxidant mentioned in step two is potassium peroxymonosulfonate;

[0021] Furthermore, the solvent mentioned in step three is acetonitrile;

[0022] The beneficial effects of this invention are as follows:

[0023] 1) This invention significantly reduces the time and reaction temperature by synthesizing intermediate II via photoelectrochemical synthesis. It also avoids the use of irritating solvents such as thionyl chloride, thus reducing synthesis risks.

[0024] 2) The synthesis method of the present invention is simple to operate, convenient to post-process, and green and safe. Attached Figure Description

[0025] Figure 1 The reaction equation diagram is shown for the preparation method of cabozantinib intermediate according to the present invention.

[0026] Figure 2 The H-spectrum of cabozantinib intermediate II prepared for this invention

[0027] Figure 3 C-spectrum of cabozantinib intermediate II prepared for this invention

[0028] Figure 4 The F-spectrum of cabozantinib intermediate II prepared for this invention

[0029] Figure 5 The H-spectrum of cabozantinib intermediate IV prepared for this invention Detailed Implementation

[0030] Example 1 Preparation of 1-(4-fluorobenzoyl)cyclopropane-1-carboxaldehyde(II)

[0031] Formula 1, tetrabutylammonium hexafluorophosphonate, 10-methyl-9-trimethylmethylacrylidine perchlorate was added to a reaction flask, along with acetonitrile and water. Electrodes were inserted, and the mixture was irradiated with a 40W blue lamp. The current was controlled at 3-8 mA, and the reaction was carried out at room temperature for 8-12 hours. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The extract was then concentrated, and the intermediate of Formula II was obtained by column chromatography with a yield of 52%.

[0032] 1 H NMR (400MHz, CDCl3) δ9.64 (s, 1H), 7.85 (dd, J=8.6, 5.4Hz, 2H), 7.17 (t, J=8.5Hz, 2H), 1.80 (s, 2H), 1.74 (s, 2H).

[0033] 13 C NMR (101MHz, CDCl3) δ197.5, 195.2, 131.7 (d, J=9.4Hz), 116.3, 116.1, 41.2, 19.3.

[0034] 19 F NMR (377MHz, CDCl3) δ-104.25--104.40(m).

[0035] Example 21 - Preparation of (4-fluorobenzoyl)-cyclopropane-1-carboxylic acid (III)

[0036] Formula II was dissolved in DMF, and potassium peroxymonosulfonate was added as an oxidant. The mixture was reacted at room temperature for 16 hours. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The solution was then concentrated and subjected to column chromatography to obtain intermediate Formula III in 72% yield.

[0037] Example 31: Preparation of ((4-fluorophenyl)aminocarbonyl)cyclopropane-1-carboxylic acid (IV)

[0038] Formula III and hydroxylamine hydrochloride were added to a reaction flask, acetonitrile was added as solvent, and the mixture was refluxed overnight. After the reaction was completed, water was added, the mixture was extracted with ethyl acetate, concentrated, and then column chromatography was used to obtain intermediate of formula IV with a yield of 74%.

[0039] 1 H NMR (400 MHz, d6-DMSO) δ10.58 (s, 1H), 7.65-7.58 (m, 2H), 7.13 (t, J=8.5Hz, 2H), 1.41 (s, 4H).

[0040] The above description is merely a preferred embodiment of the present invention and does not constitute any limitation on the technical scope of the present invention.

Claims

1. A method of synthesis of cabozantinib, characterized in that, Comprising the following steps: Step one: methylenecyclobutanol compound (I) is synthesized into intermediate of formula II under photoelectrochemical conditions. Step two: the intermediate of formula II is oxidized into formula III under the action of an oxidant. Step three: the Beckmann rearrangement of formula III to obtain an important intermediate of formula IV for preparing cabozantinib.

2. The method of claim 1, wherein, The photoelectrochemical conditions described in step one, the anode is one of carbon electrode, foamed nickel electrode, platinum electrode, and the cathode is one of nickel electrode and platinum electrode.

3. The method of claim 1, wherein, The photoelectrochemical conditions described in step one, the solvent is one of acetonitrile, dichloromethane and diethyl ether.

4. The method of claim 1, wherein, The photoelectrochemical conditions described in step one, the photocatalyst is 10-methyl-9-mesityl acridine perchlorate.

5. The method of claim 1, wherein, The photoelectrochemical conditions described in step one, the light source uses a 35W or 40W blue lamp.

6. The method of claim 1, wherein, The current of the photoelectrochemical conditions described in step one is 2-8mA.

7. The method of claim 1, wherein, The method described in step two uses one of potassium peroxymonosulfate or selectflour and NaBr.

8. The method of claim 1, wherein, The method described in step three uses hydroxylamine hydrochloride as the source of nitrogen for Beckmann rearrangement.

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