CN103288755B - Midbody 4-chlorine-6-amino-7-hydroxy-quinazoline for synthesizing nilotinib type antineoplastic drug and preparation method for midbody 4-chlorine-6-amino-7-hydroxy-quinazoline - Google Patents

Abstract

The invention discloses a 4-chloro-6-amino-7-hydroxyquinazoline (I), an intermediate required for the synthesis of tinib-type antineoplastic drugs, and a preparation method thereof. The preparation method comprises the following steps: Acetanilide is used as raw material, and the 4-chloro-6-amino-7-hydroxyquinazoline (I) is prepared through nitration reaction, reduction reaction, ring-forming reaction, oxidation reaction, chlorination reaction and hydrolysis reaction. The preparation method is simple, fast, low in cost and suitable for industrialization.

Description

Intermediate 4-chloro-6-amino-7-hydroxyquinazoline required for the synthesis of tinib-type antineoplastic drugs and its preparation method

technical field

The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to an intermediate 4-chloro-6-amino-7-hydroxyquinazoline required for the synthesis of tinib-type antineoplastic drugs and its preparation method.

Background technique

Protein tyrosine kinase (PTK) is the most common growth factor receptor, by blocking the signal transmission of tyrosine kinase to destroy tumor cells, so as to achieve the purpose of anti-tumor. Receptor tyrosine kinase inhibitors include single-target tyrosine kinase inhibitors and multi-target tyrosine kinase inhibitors. At present, the active antineoplastic drug tinib is a multi-target tyrosine kinase inhibitor, which has anti-prostate cancer, lung cancer, gastric cancer, blood cancer, breast cancer, intestinal cancer, pancreatic cancer and gallbladder cancer.

Analyzing the molecular structure of tinib drugs, a large part of small molecular compounds with quinazoline as the core, such as gefitinib, erlotinib, icotinib and vandetanib, have been clinically used showed good biological activity. In particular, the newly marketed Afatinib (Afatinib) and Canertinib (Canertinib) and Dacomitinib (Dacomitinib) under clinical research all have quinine with 6-position hydroxyl and 7-position amino. The oxazoline structure.

World Patent No. WO0250043A1 and No. WO03094921A2 reported the preparation method of afatinib: the mother nucleus 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-fluoroquinazoline (VI) is used as a raw material, and afatinib is obtained through conversion reactions of functional groups such as substitution, reduction, amidation and amination in sequence.

"Chinese Journal of Pharmaceutical Industry" 2010, Volume 41, Issue 6, Page 404 and "Qilu Pharmaceutical Affairs" 2011, Volume 30, Issue 10, Page 559 respectively reported the synthesis method of Canertinib, using 7-fluoroquinazole Lin-4-ketone (VII) is used as raw material, respectively undergoes nitration, reduction and chlorination reactions in different orders to prepare 4-chloro-6-nitro-7-fluoroquinazoline (VII) or 4-chloro-6 -Amino-7-fluoroquinazoline (VIII), and then modifying the side chain to prepare canertinib.

It can be seen that the 7-fluoro-substituted quinazoline derivatives are important intermediates for the preparation of such drugs at present. Chinese Patent No. CN102311438 reported that 7-fluoroquinazolin-4-ketone (VI) was obtained by reacting o-amino-p-fluorobenzoic acid and formamidine acetate to form a ring. Like the above-mentioned documents, the intermediate (VI) was nitrated, Chlorination and reduction can prepare 4-chloro-6-nitro-7-fluoroquinazoline (VII) or 4-chloro-6-amino-7-fluoroquinazoline (VIII). At the same time, the patent also mentions a method for preparing methoxy derivative (IX) from fluorine-containing derivative (VIII).

It can be seen that the 7-position of the disclosed intermediates is halogen, and more is substituted by fluorine. Since the fluorine-containing compound raw materials are not easy to obtain, the cost is relatively high, and the alkoxyl substitution reaction requires severe reaction conditions such as high temperature reflux. Therefore, it is necessary to develop a new pharmaceutical intermediate for tinib-type antineoplastic drugs and a preparation method thereof which is simple, quick, low in cost and suitable for industrialization. In this way, it has very important practical significance for the production and preparation of antitumor drugs based on the quinazoline structure, such as Afatinib, Canertinib and Dacomitinib.

Contents of the invention

The object of the present invention is to provide a kind of pharmaceutical intermediate 4-chloro-6-amino-7-hydroxyquinazoline of new tinib class antitumor drug and preparation method thereof, and the preparation method is simple and fast, with low cost and suitable for industrialization.

In order to achieve the above object, the main technical scheme provided by the present invention is as follows: a kind of intermediate 4-chloro-6-amino-7-hydroxyquinazoline (I) and preparation method thereof required for the synthesis of tinib class antineoplastic drugs,

It is characterized in that the preparation method comprises the following steps: using o-acetoxyacetanilide as a raw material, undergoing nitration reaction, reduction reaction, ring formation reaction, oxidation reaction, chlorination reaction and hydrolysis reaction to prepare 4-chloro-6-amino -7-Hydroxyquinazoline (I).

In addition, the present invention also provides the following subsidiary technical solutions:

The nitrating agent for the nitration reaction is fuming nitric acid, and the molar ratio of the o-acetoxyacetanilide to the fuming nitric acid is 1:1-2, preferably 1:2.

The reducing agent for the reduction reaction can be sodium dithionite, hydrazine hydrate, iron powder, zinc powder or palladium carbon catalyzed hydrogenation, preferably sodium dithionite or palladium carbon catalyzed hydrogenation.

Described ring-forming reaction comprises the steps: first use alkyl chloroformate as protecting group to form N-protected transition state to the amino group of 2-acetoxy-4-aminoacetanilide (III), this transition state and hexamethylene Tetramine (HMTA) under the catalysis of trifluoroacetic acid (TFA) forms a ring, and removes the protecting group under the effect of potassium ferricyanide and alkali subsequently, obtains 6-acetamido-7-acetoxyquinazoline (IV ).

The alkyl group R in the protecting group alkyl chloroformate is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl, preferably ethyl.

The solvent for the cyclization reaction is toluene, xylene, methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane or tetrahydrofuran, preferably ethanol or methanol.

The oxidizing agent of the oxidation reaction is ceric ammonium nitrate, sodium tungstate, chromium trioxide, silver persulfate, peroxyalcohol, peroxyacid, oxygen or hydrogen peroxide, preferably ceric ammonium nitrate.

The solvent for the oxidation reaction is acetic acid, acetonitrile, benzonitrile or dioxane, preferably acetic acid.

Compared with the prior art, the pharmaceutical intermediate 4-chloro-6-amino-7-hydroxyquinazoline and the preparation method of the tinib class antitumor drug involved in the present invention have the advantages of stable process and easy raw materials. Its core advantage is the integration of classical reactions and novel modern synthesis techniques. The preparation method is suitable for industrial scale-up requirements, and provides another important and practical new intermediate for the preparation of quinazoline antineoplastic drugs.

Detailed ways

The technical solution of the present invention will be further described in a non-limiting manner in conjunction with several preferred embodiments below.

Among them, nitrification, reduction, chlorination and hydrolysis are well-known classical reactions. Specifically, the nitrification reaction can be found on page 237 of "Chemical World" 2003, Vol. 25, No. 4 or "Tetrahedron Letters" 2012, Vol. The reduction reaction can use palladium carbon hydrogenation system, iron powder acetic acid system, hydrazine hydrate ferric chloride system or sodium dithionite (sulfate) system. The chlorination reaction can use phosphorus oxychloride or thionyl chloride as the chlorination agent, and the hydrolysis reaction can use alkaline hydrolysis such as sodium hydroxide, potassium carbonate or ammonia water. The specific steps can be found in "West China Pharmaceutical Journal" 2012 Volume 27 No. Page 362, Issue 4, Page 401, Issue 6, Volume 39, 2008 of "Chinese Journal of Pharmaceutical Industry" or Page 92, Issue 1, Volume 36, 2005 of "Journal of China Pharmaceutical University".

Embodiment one:

At room temperature, 2-acetoxy-4-aminoacetanilide (III) (4.16g, 20mmol) and 50mL of dichloromethane were added to a 100mL three-neck flask, and ethyl chloroformate (2.4g, 22mmol) was added dropwise at 10°C and 1 mL of triethylamine, stirred at room temperature for 1 hour, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. To the residue were added hexamethylenetetramine (HMTA) (2.0 g, 14.3 mmol) and 20 mL of trifluoroacetic acid (TFA). The reaction system was placed in a microwave reactor, kept at 110°C, preheated by microwave for 1 minute, and reacted for 10 minutes. After cooling, 50 mL of 20% potassium hydroxide and 50 mL of ethanol were added, potassium ferricyanide (6.6 g, 2.2 g per batch, 20 mmol) was added in three batches, and the microwave reaction was repeated three times. The reaction conditions were to maintain 110°C, preheat with microwave for 1 minute, and react for 10 minutes. After cooling, add 50 mL of water, and extract 4 times with ethyl acetate (100 mL x 4), combine the organic phases, concentrate under reduced pressure and recover the solvent, and recrystallize the residue with ethanol to obtain a light yellow solid 6-acetamido-7-acetoxy Quinazoline (IV) 4.1g, the yield is 83.7%.

Embodiment two:

6-Acetamido-7-acetoxyquinazoline (IV) (2.5 g, 10 mmol) and 5 mL of acetic acid were added to a 100 mL three-necked flask, and a 50 mL aqueous solution of ceric ammonium nitrate (16.4 g, 30 mmol) was added dropwise at room temperature. Stir the reaction for 2 hours, and TLC detects that the reaction is complete. After filtering, the filter cake was washed with acetic acid to obtain 2.5 g of white solid 6-acetamido-7-acetoxyquinazolin-4-one (V), with a yield of 95.8%.

Embodiment three:

Add 6-acetamido-7-acetoxyquinazolin-4-one (V) (5.2g, 20mmol), phosphorus oxychloride (14mL, 80mmol) and dichloromethane 100mL in a 250mL three-necked flask, and reflux for 4 Hour. After cooling, it was washed with water, 5% sodium bicarbonate solution and water successively, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure to recover the solvent. The residue was recrystallized from isopropanol to give a white chloride solid. The solid was put into 30 mL of 10% potassium hydroxide solution, 100 mL of methanol was added, and the reaction was maintained at 50-60° C. for 6 hours. Cool, adjust the pH to 5-6 with 1M hydrochloric acid, solids are produced, filter, wash with a small amount of cold methanol, and dry in vacuo to give 2.8 g of light yellow solid 4-chloro-6-amino-7-hydroxyquinazoline (I) , the two-step total yield was 71.8%.

It should be pointed out that the above-mentioned embodiment is only to illustrate the technical concept and characteristics of the present invention, and its purpose is to enable those familiar with this technology to understand the content of the present invention and implement it accordingly, and cannot limit the protection scope of the present invention. . All equivalent changes or modifications made according to the spirit of the present invention shall fall within the protection scope of the present invention.

Claims (5)

1. a kind of preparation method of intermediate 4-chloro-6-amino-7-hydroxyquinazoline (I) required for the synthesis of Tini class antineoplastic drugs, its chemical formula is as formula (I): It is characterized in that the preparation method comprises the following steps: using an alkyl chloroformate as a protecting group to form an N-protected transition state on the amino group of 2-acetoxy-4-aminoacetanilide (III), and the transition state is the same as that of hexa Methylenetetramine carries out ring-forming reaction under the catalysis of trifluoroacetic acid, removes protecting group by the effect of potassium ferricyanide and alkali again, obtains 6-acetamido-7-acetoxyquinazoline (IV), Compound 6-acetamido-7-acetoxyquinazoline (IV) obtains 6-acetamido-7-acetoxyquinazolin-4-one (V) through the effect of oxidizing agent; Compound 6-acetamido-7 -Acetoxyquinazolin-4-ketone (V) is chlorinated and hydrolyzed to obtain the 4-chloro-6-amino-7-hydroxyquinazoline (I), 2. as claimed in claim 1, the preparation method of intermediate 4-chloro-6-amino-7-hydroxyquinazoline (I) required for the synthesis of Nib antineoplastic drugs is characterized in that: the chloroformic acid alkyl The alkyl group R in the ester is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl or benzyl. 3. as claimed in claim 1, the preparation method of intermediate 4-chloro-6-amino-7-hydroxyquinazoline (I) required for the synthesis of Nib antineoplastic drugs is characterized in that: the ring-forming reaction The solvents are toluene, xylene, methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane or tetrahydrofuran. 4. as claimed in claim 1, the preparation method of intermediate 4-chloro-6-amino-7-hydroxyquinazoline (I) required for the synthesis of Nib antineoplastic drugs is characterized in that: the oxidizing agent of the oxidation reaction It is ceric ammonium nitrate, sodium tungstate, chromium trioxide, silver persulfate, peroxyalcohol, peroxyacid, oxygen or hydrogen peroxide. 5. as claimed in claim 1, the preparation method of intermediate 4-chloro-6-amino-7-hydroxyquinazoline (I) required for the synthesis of Nib class antineoplastic drugs is characterized in that: the solvent of the oxidation reaction Is acetic acid, acetonitrile, benzonitrile or dioxane.