阅读说明：本技术 一种合成来那替尼中间体的方法 (Method for synthesizing neratinib intermediate ) 是由 许志伟 胡林 邹平 吴伟 左昂禾 邱小龙 左智伟 刘文博 储玲玲 王平 张大永 于 2019-12-06 设计创作，主要内容包括：本发明在于提供一条制备来那替尼关键中间体3-氰基-4-氧代-6-硝基-7-乙氧基-1,4-二氢喹啉的新路线,该路线以2-卤代-4-氟-5-硝基苯甲酸为起始物料,经过4步反应方便实现目标中间体的合成。(The invention provides a new route for preparing a key intermediate 3-cyano-4-oxo-6-nitro-7-ethoxy-1, 4-dihydroquinoline of neratinib, which takes 2-halogeno-4-fluoro-5-nitrobenzoic acid as a starting material and conveniently realizes the synthesis of a target intermediate through 4 steps of reaction.)

1. A method for synthesizing a neratinib intermediate 3-cyano-4-oxo-6-nitro-7-ethoxy-1, 4-dihydroquinoline comprises the following reaction formula:

comprises the following steps:

in the reaction 1, fluorine on a benzene ring is replaced by ethoxy to generate a compound in a formula II under the action of sodium ethoxide.

The reaction 2 is that the compound in the formula II is firstly activated into acyl chloride or active acid anhydride, and then the acyl chloride or the active acid anhydride and 3-dimethylamino acrylonitrile are subjected to condensation reaction to generate the compound in the formula III.

And in the reaction 3, under the action of ammonia, the dimethylamino group of the compound in the formula III is replaced by amino to generate a compound in the formula IV.

And the reaction 4 is that the compound shown in the formula V is generated by the cyclization reaction of the formula IV under the action of a copper reagent and an acid-binding agent.

2. The reaction scheme of claim 1, wherein X in the compounds of formula I to IV represents bromine or iodine.

3. The reagent of claim 1 used in the synthesis of the compound of formula ii is an alkali metal salt of ethanol, including sodium ethoxide, potassium ethoxide, and the like, and mixtures thereof.

4. The process of claim 1, wherein the activating reagent used in the synthesis of the compound of formula III comprises thionyl chloride, oxalyl chloride, carbonyldiimidazole, trifluoroacetic anhydride.

5. The process of claim 1, wherein the ammonia source used in the synthesis of the compound of formula iv comprises ammonia in free form, ammonia monohydrate, and amine salts, such as ammonium chloride and amine carbonate.

6. The process of claim 1, wherein the copper reagent used in the synthesis of the compound of formula V comprises cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, copper powder.

Technical Field

The invention belongs to the technical field of preparation methods of bulk drug intermediates, and particularly relates to preparation of a neratinib intermediate 3-cyano-4-oxo-6-nitro-7-ethoxy-1, 4-dihydroquinoline.

Background

Neratinib is an oral, irreversible pan-human Epidermal Growth Factor Receptor (EGFR) inhibitor that inhibits the HER1, HER2, and HER4 receptors and related tyrosine kinases. The composition is used for adjuvant treatment of early-stage HER2 overexpression and amplification breast cancer adult patients, and plays an anticancer role by preventing HER1, HER2 and HER4 signal pathway transduction. The medicine is approved by the FDA to be taken as a strengthening adjuvant therapy medicine for breast cancer patients who have completed trastuzumab injection treatment, have not improved diseases and still have high-risk factors. It can prolong the disease-progression-free survival of HER2+ breast cancer patients and reduce the risk of cancer recurrence.

Neratinib, the english name Neratinib, the alias names Neratinib and noratinib, and the chinese chemical name (E) -N- {4- [ [ 3-chloro-4- [ (pyridin-2-yl) methoxy ] phenyl ] amino ] -3-cyano-7-ethoxy-6-quinolinyl } -4- (dimethylamino) but-2-enamide. The product was originally developed by Hewlett-packard company and after being purchased by Cerebrolein, it was licensed to the U.S. PUMA Biotech company for subsequent development, production and sale. 7 months and 17 days 2017 were approved by the FDA for marketing. The chemical structural formula is as follows:

the 3-cyano-4-oxo-6-nitro-7-ethoxy-1, 4-dihydroquinoline is a key intermediate for synthesizing the neratinib, can be used as a raw material to conveniently synthesize the neratinib, and has the following structural formula:

patent US7399865 reports a synthesis process of 3-cyano-4-oxo-6-acetamido-7-ethoxy-1, 4-dihydroquinoline. The process comprises the steps of taking 2-amino-5-nitrophenol as a raw material, reacting acetic anhydride with a substrate to protect amino with acetyl, alkylating phenolic hydroxyl with bromoethane under an alkaline condition, reducing nitro, condensing with 2-cyano-3-ethoxy propylene ethyl acetate to introduce a basic structure of a quinoline ring, closing the ring at a high temperature of 250 ℃ to obtain the quinoline ring structure, and finally obtaining the 3-cyano-4-oxo-6-acetamido-7-ethoxy-1, 4-dihydroquinoline. The synthetic route is as follows:

in the fifth step of the cyclization process, Dowtherm A is used as a heat carrier, has certain irritation to skin, mucous membrane and respiratory tract, can generate certain influence on central nerve, has a high boiling point, is difficult to recover, and is easy to cause great pollution to the environment. The reaction needs high temperature of 250 ℃, the conditions are harsh, and the raw materials are easy to generate side reactions, so that the yield is low and the operation is inconvenient. The price of the raw material 2-cyano-3-ethoxy ethyl acrylate is higher.

Chenfeng et al (journal of Chinese medical industry, 2014,45(8),701-705) nitrify methyl 4-hydroxybenzoate in acetic anhydride by using aluminum nitrate, reduce nitro group to amino group by using sodium hydrosulfite, and protect amino group by using acetic anhydride. Reacting with bromoethane under alkaline condition to complete ethylation of phenolic hydroxyl, nitrifying with nitric acid, reducing nitro by sodium hydrosulfite, condensing the reduced intermediate with trans-3- (dimethylamino) acrylonitrile, and finally cyclizing to obtain the 3-cyano-4-oxo-6-acetamido-7-ethoxy-1, 4-dihydroquinoline. The process is optimized aiming at the reduction and cyclization steps of the original process, but the process route is longer, the total yield is lower, two-step nitration reaction is needed after the route, and the reaction risk is higher. The reaction synthetic route is shown as follows:

the Chenqing and the like (CN106905234A) are improved on the basis, 4-ethoxy-2-chloro-5-nitrobenzoic acid methyl ester is taken as a raw material, condensed with amino acrylonitrile by a catalyst, and cyclized to form a quinoline ring structure under the catalysis of alkali, so that the 3-cyano-4-oxo-6-nitro-7-ethoxy-1, 4-dihydroquinoline is obtained. The synthetic route is as follows:

the process for synthesizing the neratinib intermediate has a short route and mild reaction conditions, but almost equivalent ZrO needs to be used in the condensation process of the raw materials and the aminoacrylonitrile₂-Cr₂O₃. Not only consumes a large amount of raw material cost, but also generates more waste solids and wastewater containing heavy metal chromium, and increases the treatment cost. And the raw material of the aminoacrylonitrile has few suppliers and inconvenient sources, and is not suitable for industrial production.

Disclosure of Invention

The invention aims to provide a new route for preparing a key intermediate 3-cyano-4-oxo-6-nitro-7-ethoxy-1, 4-dihydroquinoline of neratinib, and overcomes the defects of difficult obtainment of raw materials, low yield, more steps, complex operation, poor operation safety, generation of more waste solid and waste water and the like in the reported route.

The synthetic route of the invention is as follows:

x in formulae I to IV represents bromine or iodine.

In the reaction 1, under the action of sodium ethoxide, fluorine on a benzene ring is replaced by ethoxy to generate 2-bromo (iodo) -4-ethoxy-5-nitrobenzoic acid (formula II).

The solvent used in reaction 1 was ethanol.

The base used in reaction 1 is sodium ethoxide or potassium ethoxide. The ratio of the amount of the raw material to the amount of the raw material is 1.8-2.5: 1.

The reaction 2 is that the formula II is firstly activated into acyl chloride or active acid anhydride, and then the acyl chloride or the active acid anhydride and 3-dimethylamino acrylonitrile are subjected to condensation reaction to generate 2- (2-bromine (iodine) -4-ethyoxyl-5-nitrobenzoyl) -3- (dimethylamino) -acrylonitrile (formula III).

The solvent used in reaction 2 is dichloromethane or toluene.

Reaction 3 is that in the formula III, under the action of ammonia water, dimethylamino is replaced by amino to generate 3-amino-2- (2-bromo (iodo) -4-ethoxy-5-nitrobenzoyl) -acrylonitrile (formula IV).

The ammonia source used in reaction 3 includes ammonia gas and various ammonium salts including, but not limited to, ammonium chloride, ammonium carbonate, ammonium bicarbonate, and the like.

The reaction 4 is that the formula IV generates a cyclization reaction under the action of a copper reagent and an acid-binding agent to generate 3-cyano-4-oxo-6-nitro-7-ethoxy-1, 4-dihydroquinoline (formula V).

The copper reagent used in reaction 4 includes cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, copper powder, etc.

The reagent used in the process is easy to be purchased commercially in large quantities, the process operation is simple, and the method is more suitable for industrial scale-up production of the neratinib intermediate 3-cyano-4-oxo-6-nitro-7-ethoxy-1, 4-dihydroquinoline. And the production process generates less waste solids and waste water, is easy to treat and is environment-friendly.

Detailed Description

The following exemplary embodiments are provided to illustrate the present invention, and simple substitutions, modifications and the like of the present invention by those skilled in the art are within the technical scope of the present invention.