CN103254156B - Ah method is for the preparation method of Buddhist nun's intermediate - Google Patents

Abstract

Present invention is disclosed the preparation method of a kind of Ah method for Buddhist nun's intermediate, comprise the steps: with para hydroxybenzene nitrile as starting raw material, successively by the step such as nitrated, etherificate, reduction, amidation, nitrated and reduction, prepare 2-itrile group-4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-5-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] aniline (I).This preparation method's process stabilizing, raw material are easy to get, with low cost, institute responds and is classical reaction, is applicable to industrialization and amplifies requirement.

Description

The preparation method of Afatinib intermediate

The patent of this invention can refer to the other two invention patent applications submitted by the applicant on the same day, the titles of which are respectively "a preparation method of afatinib" and "afatinib 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 a preparation method of an afatinib intermediate.

Background technique

Afatinib (Afatinib, chemical name 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2 -buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline) was developed by Boehringer Ingelheim in Germany for the first time for epidermal growth factor Drugs for the treatment of lung cancer after failure of receptor inhibitor therapy. Clinically, it can be used for the treatment of advanced lung cancer, breast cancer and colon cancer. The drug passed the US Food and Drug Administration (FDA) fast-track approval channel on February 15, 2008, and its trade name is Tovok.

The original world patent No. WO0250043A1 and No. WO03094921A2 of Boehringer Ingelheim reported the preparation method of afatinib: the mother nucleus 4-[(3-chloro-4-fluorophenyl)amino]-6-nitrate Base-7-fluoroquinazoline (VII) is used as a raw material, and afatinib is obtained through conversion reactions of functional groups such as substitution, reduction, amidation and amination.

In order to overcome the defects of many steps, low yield and difficult purification in the existing preparation method of afatinib, the applicant of this patent and the other two Chinese invention patent applications submitted on the same day as the patent application of the present invention respectively disclosed new The preparation method of afatinib, whose patent names are respectively "a preparation method of afatinib" and "a preparation method of afatinib", can be referred to with this patent application. These two invention patent applications are all based on the intermediate 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-5-[ (S)-(tetrahydrofuran-3-yl)oxy]aniline (I) was used as a raw material to prepare afatinib by condensation and cyclization "one-pot" reaction. However, the preparation method of the intermediate (I) is not disclosed in the prior art, so it is necessary to provide a new preparation method of the intermediate (I).

Contents of the invention

The object of the present invention is to provide a kind of Afatinib intermediate 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino - a preparation method of 5-[(S)-(tetrahydrofuran-3-yl)oxy]aniline, the preparation method has stable process, easy-to-obtain raw materials, and low cost, all reactions are classical reactions, and are suitable for industrial scale-up requirements.

In order to achieve the above object, the main technical scheme provided by the present invention is as follows: a kind of afatinib intermediate 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2 -buten-1-yl]amino-5-[(S)-(tetrahydrofuran-3-yl)oxyl]aniline (I) preparation method,

It is characterized in that the preparation method comprises the following steps: taking p-hydroxybenzonitrile as the starting material, producing 3-nitro-4-hydroxybenzonitrile (II) through nitration reaction, and producing 3-nitro -4-[(S)-(tetrahydrofuran-3-yl)oxyl]benzonitrile (III), reduction reaction to obtain 3-amino-4-[(S)-(tetrahydrofuran-3-yl)oxyl] Benzonitrile (IV), amidation reaction to obtain 3-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-4-[(S)- (Tetrahydrofuran-3-yl)oxyl]benzonitrile (V), nitration reaction two to obtain 2-nitro-5-[4-(N,N-dimethylamino)-1-oxo-2-butane En-1-yl] amino-4-[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (VI) and reduction reaction two prepare 2-cyano-4-[4-(N,N -Dimethylamino)-1-oxo-2-buten-1-yl]amino-5-[(S)-(tetrahydrofuran-3-yl)oxy]aniline (I).

The raw materials for the etherification reaction are 3-nitro-4-hydroxybenzonitrile (II) and (S)-3-hydroxytetrahydrofuran, the molar ratio of which is 1:1-3, preferably 1:1.5-2.5.

The accelerator one of the etherification reaction is diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), dipropyl azodicarboxylate (DPAD), azobis Dimethyl carboxylate (DMAD), di-p-chlorobenzyl azodicarboxylate (DCAD), N, N, N', N'-tetramethyl azodicarboxamide (TMAD), N, N, N ', N'-tetraisopropylazodicarboxamide (TIPA) or azodicarboxyldipiperidine (ADDP), preferably diethyl azodicarboxylate (DEAD) or diisoazodicarboxylate Propyl ester (DIAD).

Accelerator two of the etherification reaction is triphenylphosphine (TPP), tributylphosphine (TBP), trimethylphosphine (TMA) or cyanomethylenetributylphosphorane (CMBP), preferably three Phenylphosphine (TPP) or Tributylphosphine (TBP).

The solvent of the etherification reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, dioxane, methylene chloride, chloroform, 1,2-dichloroethane, dimethyl sulfoxide , acetonitrile, N,N-dimethylformamide, acetone or tetrahydrofuran, preferably dichloromethane or tetrahydrofuran.

The raw materials for the amidation reaction are 3-amino-4-[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (IV) and 4-(N,N-dimethylamino)-2- Alkene-butyryl chloride, the feeding molar ratio is 1:1-2, preferably 1:1.1-1.3.

The acid-binding agent of the amidation reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, sodium hydroxide, sodium methylate, sodium hydroxide, potassium hydroxide, sodium carbonate, bicarbonate Sodium or potassium carbonate, preferably triethylamine or potassium carbonate.

The solvent for the amidation reaction is dichloromethane, chloroform, toluene, acetonitrile or dimethyl sulfoxide, preferably dichloromethane.

The temperature of the amidation reaction is 0-60°C, preferably 20-25°C.

Compared with the prior art, the afatinib intermediate 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-butene-1 involved in the present invention -base]amino-5-[(S)-(tetrahydrofuran-3-yl)oxy]aniline preparation method, its main advantages are stable process, easy to get raw materials, low cost, all reactions are classical reactions, suitable for industrialization Zoom request.

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, the first nitration reaction, the first reduction reaction, the second nitration reaction and the second reduction reaction are all 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.

For the side chain (S)-3-hydroxytetrahydrofuran and 4-(N,N-dimethylamino)-2-ene-butyryl chloride, please refer to the description of the preparation methods of similar compounds in World Patent Nos. WO0250043A1 and WO03094921A2.

Embodiment one:

At room temperature, add diisopropyl azodicarboxylate (3mL, 15mmol) and 5mL of tetrahydrofuran into a 100mL three-necked flask, add dropwise a solution of triphenylphosphine (4.0g, 15mmol) in 25mL of tetrahydrofuran at room temperature, and keep at room temperature for reaction 2 Hour. Under nitrogen protection, (S)-3-hydroxytetrahydrofuran (0.3g, 3.4mmol) in tetrahydrofuran 5mL solution was added dropwise to the above reaction system, after the addition was complete, 3-nitro-4-hydroxybenzonitrile was added (II) (0.5g, 3.0mmol), stirred at room temperature for 4 hours. A 5 mL solution of (S)-3-hydroxytetrahydrofuran (0.23 g, 2.6 mmol) in tetrahydrofuran was added dropwise, and the reaction was continued at room temperature for 2 hours, and the reaction was completed by TLC monitoring. The solvent was recovered by distillation under reduced pressure, the residue was adjusted to pH=5-6 with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was adjusted to pH=10-11 with saturated sodium carbonate. The aqueous phase was separated and freeze-dried in vacuo to obtain 5.9 g of off-white solid 3-nitro-4-[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (III), with a yield of 83.8%.

Embodiment two:

Add 3-amino-4-[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (IV) (0.51g, 2.5mmol) and triethylamine (0.25g, 2.5mmol) into a 100mL three-necked flask and dichloromethane 20mL, warm up to 40-45°C, and stir until the system is uniformly dissolved. Drop below 10°C, slowly add 4-(N,N-dimethylamino)-2-ene-butyryl chloride (0.42g, 2.8mmol) in dichloromethane 10mL solution dropwise, continue to react at room temperature for 6 hours , TLC detects that the reaction is complete. The reaction solution was washed with 10% sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain a white solid 3-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-4 -[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (V) 0.72 g, yield 91.4%.

Embodiment three:

Add 2-nitro-5-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-4-[(S)- (tetrahydrofuran-3-yl)oxy]benzonitrile (VI) (3.6 g, 10 mmol), 5% palladium on carbon (0.36 g, 10% w/w) and ethanol 50 mL. Keep a pressure of 3-4 kg at room temperature and react for about 12 hours. Suction filtration, recovery palladium carbon catalyst. Ethanol was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain a white solid 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-butene-1- 3.1 g of amino]amino-5-[(S)-(tetrahydrofuran-3-yl)oxy]aniline (I), the yield was 94.0%.

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 (7)

1. An afatinib intermediate 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-5-[ (S)-(tetrahydrofuran-3-yl)oxyl group] the preparation method of aniline (I), It is characterized in that the preparation method comprises the following steps: using p-hydroxybenzonitrile as a starting material, through nitration reaction to prepare 3-nitro-4-hydroxybenzonitrile (II), diethyl azodicarboxylate , Diisopropyl azodicarboxylate, dipropyl azodicarboxylate, dimethyl azodicarboxylate, di-p-chlorobenzyl azodicarboxylate, N,N,N',N'- Tetramethylazodicarboxamide, N,N,N',N'-tetraisopropylazodicarboxamide or azodicarbonyldipiperidine and triphenylphosphine, tributylphosphine, trimethyl 3-Nitro-4-[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (III) is produced by etherification under the condition of phosphine or cyanomethylenetributylphosphorane , reduction reaction one makes 3-amino-4-[(S)-(tetrahydrofuran-3-yl) oxygen group] benzonitrile (IV), under the condition that acid-binding agent exists, amidation reaction makes 3-[ 4-(N,N-Dimethylamino)-1-oxo-2-buten-1-yl]amino-4-[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (V ), nitration reaction two to obtain 2-nitro-5-[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino-4-[(S) -(tetrahydrofuran-3-yl)oxy]benzonitrile (VI) and reduction reaction two to obtain 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2- Buten-1-yl]amino-5-[(S)-(tetrahydrofuran-3-yl)oxy]aniline (I). 2. according to the preparation method of the described Afatinib intermediate of claim 1, it is characterized in that: the raw material of described etherification reaction is 3-nitro-4-hydroxybenzonitrile (II) and (S)-3- Hydroxytetrahydrofuran, its feeding molar ratio is 1:1-3. 3. according to the preparation method of the described afatinib intermediate of claim 2, it is characterized in that: the solvent of described etherification reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, dioxygen Hexacyclic, dichloromethane, chloroform, 1,2-dichloroethane, dimethylsulfoxide, acetonitrile, N,N-dimethylformamide, acetone or tetrahydrofuran. 4. according to the preparation method of the described afatinib intermediate of claim 1, it is characterized in that: the raw material of described amidation reaction is 3-amino-4-[(S)-(tetrahydrofuran-3-yl)oxyl group ]Benzonitrile (IV) and 4-(N,N-dimethylamino)-2-ene-butyryl chloride, the feeding molar ratio is 1:1-2. 5. according to the preparation method of the described Afatinib intermediate of claim 4, it is characterized in that: the acid-binding agent of described amidation reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine Amines, sodium hydroxide, sodium methoxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, or potassium carbonate. 6. according to the preparation method of the described afatinib intermediate of claim 4, it is characterized in that: the solvent of described amidation reaction is methylene chloride, chloroform, toluene, acetonitrile or dimethyl sulfoxide. 7. The preparation method of the afatinib intermediate according to claim 4, characterized in that: the amidation reaction temperature is 0-60°C.