WO2014183560A1 - Afatinib and preparation method of intermediate thereof - Google Patents

Abstract

Disclosed are a compound of 6-amino-7-hydroxy-3,4-dihydroquinazolin-4-one (I) which can be used in the preparation of Afatinib and the preparation method thereof, the method comprising the following steps: using 3-amino-4-hydroxy benzoic acid or 3-amino-4-hydroxy benzoate or 3-amino-4-hydroxy benzamide as raw materials to prepare the target compound (I) via nitration, reduction and cyclization reactions successively. At the same time, the present invention also reveals two synthesis routes which use compound (I) as a raw material to prepare Afatinib. The preparation and use of compound (I) make the synthesis of Afatinib more simple and environmental, and the yield and quality are improved, thus facilitating industrialization.

Description

 Method for preparing afatinib and its intermediate

The invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, in particular to an intermediate of afatinib 6-amino-7-hydroxy-3,4-dihydroquinazolin-4-one and Its preparation method and use in the preparation of afatinib.

Protein tyrosine kinase (PTK) is the most common growth factor receptor and is anti-tumor by blocking tyrosine kinases from disrupting the signaling of tumor cells. Receptor tyrosine kinase inhibitors include single-target tyrosine kinase inhibitors and multi-target tyrosine kinase inhibitors. The currently active Tini antitumor drugs are multi-target tyrosine kinase drugs with anti-prostate, lung, stomach, blood, breast, bowel, pancreatic and biliary cancers. Analysis of the molecular structure of the fentanyl drugs, a large part of the small molecule compounds with quinazoline as the core, such as gefitinib, erlotinib ectinib and vandetanib have been clinically expressed Very good biological activity. In particular, the newly marketed Afktinib and the clinically studied cantintinib and dexmitinib ib have a 6-position hydroxyl group and a 7-position amino group quinazoline. structure.

Aijnib隠 For the preparation of the above-mentioned fentanyl anti-splenotherapy drugs which have been disclosed by CansrtSnib, which can be disclosed in the above-mentioned two kinds of methods: World Patent No. WO0250043A1 and WO03094921A2 respectively report 4 chlorine- Preparation method of 6-amino-7-fluoroquinazoline (XI) and 4-chloro-6-amino-7 methoxy quinazoline (ΧΠ) as starting materials 4-bit condensation ^^::^

R ₂ . , ,,z ,! sT

 Target calving

 Xii

 In addition, a 6-position condensation of a chloroform intermediate (XIV) with an aniline derivative by chlorination using a 6,7-substituted 3,4-dihydroquinazolin-4-one (oxime) The target compound of the tritin antitumor drug can be conveniently prepared by the reaction.

 Xlll XIV H standard product

Thus, 6-amino 7-hydroxy-3,4-dihydroquinazolin-4-one (I) will be important for the preparation of the above-mentioned 6 amino-7 hydroxy oxazolidine derivatives. Intermediate. Existing ί "The synthesis of this intermediate must pass the steps of nitrification, reduction, ring formation, etc. The use of fuming nitric acid and concentrated sulfuric acid in the existing nitrification technology causes oxidation, elimination or substitution of the exposed amino and hydroxyl groups in the raw material. And other side reactions, so in the actual operation process, the amino and hydroxyl groups have to be protected as necessary, and after the completion of the nitration, reduction and other steps, the protective groups need to be removed, so that the reaction steps increase and the total yield decreases. At the same time, the selectivity of the current nitrification reaction is not strong, it is easy to produce pollution, and it is not suitable for industrialization. If a single tube can be developed, it is quick and inexpensive, and it is suitable for industrial preparation of 6-amino-7-hydroxy-3,4-dihydrogen. The preparation method of quinazoline-4-ketone (I) has very important practical significance for the preparation of anti-tumor drugs such as afatinib, carnitinib and dexmitinib based on quinazoline structure. Afatinib is a multi-target small molecule drug developed by Boehringer fogdheim, Germany. It belongs to epidermal growth factor receptor (EGFR) and human epidermal receptor (HE). R2) an irreversible inhibitor of tyrosine kinase, and the first drug for the treatment of lung cancer after treatment of epidermal growth factor with sputum inhibitors. Clinically, it can be used in advanced non-small cell lung cancer and advanced breast cancer and vine cancer. The drug passed the US on February 15, 2008: FDA's rapid approval channel, ^ Not on July 12, 2013, He Wei, on September 25, was approved by the US FDA and EU EMEA for the first-line treatment of non-small cell lung cancer (NSCLC) and HER2-positive patients with advanced breast cancer. The trade names are Gioiirif (United States) and Giotrif (EU).

The chemical name of afatinib (V) is 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4 N,N-dimethylamino)oxy-2-butene — 1 —yl]amino 7-[(S)-(tetrahydrofuran-3-yl)oxy] quinazoline.

 Tt

Boehringer Ingelheim's original patents No. WO0250043A1 and WO03094921A2 report the preparation of afatinib: a mother's core 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro- 7-Fluoroquine P _: starting material, substituted with S- 3-hydroxy-tetrahydrofuran under the catalysis of potassium tert-butoxide to form 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro

-7-[(8)-(tetrahydrofuran-3-yl)oxy]quinazoline (XVI); the intermediate (XVI) is reduced by 6-methyl group to give the corresponding amino compound (XVII); The amidation reaction with bromocrotonic acid chloride gives intermediate (XVIII), and the intermediate (XVIII) undergoes amination reaction with dimethylamine to obtain afatinib (V).

 A Lin

Obviously, the use of fluoride and the preparation of the route of the quinone and then the side chain functional group conversion, the raw materials More rare, cost increases,

为了实现上述目的, 提供的主要技术方案如下： 一种化合物， 其特征在于其化 学名为 6 -氨基 -7-羟基 -3,4-二氢喹唑淋 -4-酮， 分子式如式 (I)所示-

The object of the present invention is to provide a compound 6-amino-7-hydroxy-3,4-dihydroquinazolin-4-one which can be used for the synthesis of afatinib and the preparation thereof against the above defects in the prior art. The method, especially by the solid acid-catalyzed nitration reaction, enhances the activity and selectivity of the nitration reaction, avoids the protection and deprotection of the amino group and the hydroxyl group, and makes the atomic economy, process cleanliness and environmental friendliness of the entire preparation process Sexuality has been significantly improved. At the same time, 6-amino-7-hydroxy-3,4-porphyrin-4-one is used as a starting material to provide two preparation methods of afatinib, which makes the preparation of afatinib more convenient and economical.

In order to achieve the above object, the main technical solutions provided are as follows: A compound characterized by its chemical name 6-amino-7-hydroxy-3,4-dihydroquinazolin-4-one, molecular formula such as formula (I ) shown -

 0}

The preparation method of the compound 00 comprises the steps of: 3-amino~4-hydroxybenzoic acid or 3-amino-4-ylbenzoic acid ester or 3-oxa-4-hydroxybenzamide represented by the formula (II) The raw material is sequentially subjected to a nitration reaction, a reduction reaction, and a ring-forming reaction to obtain 6 amino-7-hydroxy~3,4dihydroquinazoline-4-one 0.

 iV ί

In addition, the present invention also includes the following subsidiary technical solutions: When R in the chemical formula (Π) is a hydroxyl group (ΟΗ), the starting material is 3-amino-4-hydroxybenzoic acid; when R is a hydrocarbyloxy group (OR') When the starting material is 3-amino-4-hydroxybenzoate, the hydrocarbon group R' is methyl, ethyl, propyl dry propyl isopropyl n-butyl, tert-butyl, cyclohexyl, benzyl or a benzyl group substituted on the phenyl ring, preferably a methyl group or an ethyl group; when R is an amine group NH: ₂ ) In the case, the starting material is 3-amino-4-hydroxybenzamide.

 The nitrating reaction agent is concentrated nitric acid, copper acidate, acid strontium or acid zinc, preferably concentrated nitric acid or bismuth zinc silicate. The catalyst for the 3⁄4 Xiaohua reaction is sulfuric acid/melamine formaldehyde resin, sulfuric acid/polyvinyl fluorenone (PVP), sulfuric acid/silica, hydrazine: chlorotriazine (TCT) or aluminum dihydrogen phosphate, preferably three Chlorotriazine or aluminum dihydrogen phosphate; the amount of the catalyst] is from 1 to 10%, preferably from 1 to 5%, based on the moles of the starting material (II).

 The solvent for the nitration reaction is methylene chloride, chlorobenzene, trichloromethane, 1,2-dichloromethane, acetonitrile or water, preferably acetonitrile or water.

 The temperature of the nitration reaction is 0 - 12 () ° C, preferably 20 - 30 ° C.

 In addition, the present invention also discloses that 6-amino-7-hydroxy-3,4-dihydroquinazoline-4one (I) is chlorinated to form 4-chloro-6-amino group.

所述制备方法包括如下歩骤： 6-氨基- 7-羟基- 3,4-二氢喹唑啉- 4-酮 (I)经氯化反应制得 4-氯 —6-氨基 -7-羟基喹唑啭 (VI), 所述化合物 (VI)和 (S 3-羟基四氢呋喃发生醚化反应生成 4 -氯 -6 氨基- 7- [(SX四氢呋喃- 3-基)氧基]喹唑淋 (VII), 所述化合物 (VII)与 4- (N，N-二甲基氨基) - 2-烯- 丁酰氯进行酰化反应生成 4氯- 6-{[4- (Ν,Ν-二甲基氨基 )小氧代- 2-丁烯- 1-基]氨基 7- [(SH四

, 所述化合物 C ffl)与 4 -氟 -3-氯苯胺发生取代反应制得所述阿 法替尼 (V)。

-7-hydroxy quinazoline (VI),

The preparation method comprises the following steps: 6-amino-7-hydroxy-3,4-dihydroquinazolin-4-one (I) by chlorination to obtain 4-chloro-6-amino-7-hydroxyl Quinazolium (VI), the compound (VI) and (S 3-hydroxytetrahydrofuran are etherified to form 4-chloro-6amino-7-[(SX tetrahydrofuran-3-yl)oxy]quinazoline ( VII), the compound (VII) is acylated with 4-(N,N-dimethylamino)-2-ene-butyryl chloride to form 4chloro-6-{[4-(Ν,Ν-dimethyl Amino group) small oxo-2-butene-1-yl]amino 7- [(SH four

, the compound C ffl) is substituted with 4-fluoro-3-chloroaniline to prepare the afatinib (V).

 Law # -V)

 The accelerator for the etherification reaction is diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), dipropyl azodicarboxylate (DM: D), azodi Dimethyl carboxylate (DM AD; di-dichlorobenzyl azodicarboxylate (DCAD),

Ν,Ν,Ν',Ν'-Tetramethylazodicarboxyamide (TMAD), Ν,Ν',Ν'-tetraisopropylazodicarboxyamide (TIPA) or azodicarboxylate Acridine (ADDP), preferably diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (D1: AD). The promoter of the etherification reaction may also be 'triphenyl S (TPP), tributyl S (TBP), trimethylphosphine (TMA) or cyanomethylenetributylphosphorane (CMBP). Preference is given to triphenylphosphine (TPP) or tributyl hydride (TBP). The solvent for the etherification reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, dimethylene. Sulfone, acetonitrile, hydrazine, hydrazine-dimethylformamide, acetone or tetrahydrofuran, preferably dichloromethane or tetrahydrofuran. The starting material of the acylation reaction is 4-chloro-6-amino 7-[(S)(tetrahydrofuran-3-yl)oxy]oxazolium ruthenium (VII) with 4-(Ν,Ν二Φ-amino 2 -ene - Butyryl chloride is charged in a molar ratio of 1: 2 -, preferably 1: 1.1 - 1.3. The acid binding agent of the acylation reaction is triethylamine, pyridine, methylmorphine, diisopropylethylamine, hydrogen Sodium oxide, uranium methoxide, sodium hydride, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate or potassium carbonate, preferably ethylamine or potassium carbonate. The starting material of the condensation reaction is 4-chloro-6- {[4-(Ν, Ν-Dimethylamino)-ί-oxo-2-buten-1-yl]amino 7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (VIII) and fluoro- The feed of 3-chloroaniline is 1:1-2, preferably 1:1.3. The acid binding agent of the condensation reaction is hydrazine: ethylamine pyridylmethylmorphine, diisopropylethylamine, sodium hydroxide methanol Sodium, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate or potassium carbonate, preferably triethylamine or pyridine. The solvent for the condensation reaction is methanol, ethanol, isopropanol, dichloromethane, chloroform, 2,-dichloroethane, acetonitrile, hydrazine, hydrazine-dimethylmethylamine, hydrazine, hydrazine Methylacetamide toluene, xylene, diethyl ether, diisopropyl ether, dihydrotetrahydrofuran or methyl tert-butyl ether, preferably isopropanol or toluene.

 Finally, the present invention also discloses that 6-amino-7-hydroxy-3,4-dihydroquinazoline 4-one is prepared without the chlorination reaction and directly with 4 fluoro-3-chloroaniline in the presence of a condensing agent. A method of afatinib, the preparation method thereof comprises the following steps; 6-amino-7-hydroxyl

Etherification of 3,4-dihydroquinazolin-4-one (I) and (S)-3-hydroxytetrahydrofuran to give 6-amino-7-[(S)-(tetrahydrofuran-3-yl)oxy -3,4-dihydroquinolin-4-one (IX), the compound (IX) is acylated with 4 (Ν, Ν-dimethylamino)-2-ene-butyryl chloride to form 6 - {[4-(Ν,Ν-dimethylamino)-1-oxo-2-buten-1-yl]amino)-7-[(S)-(tetrahydrofuran-3-yl)oxy] -3,4-Dihydroquinazolin-4-one PQ, the compound (X) is subjected to a condensation reaction with 4-fluoro-3-chloroaniline to obtain the afatinib (V;

 IX 隐弥 "V"

4—氟— 3-氯苯胺的投料摩尔比为】: 1-2, 优选 1丄】 -1. The starting material of the condensation reaction is 6-{[4-(Ν,Ν-dimethylamino)oxy-2-butenyl]aminotetrahydrofuran

The molar ratio of 4-fluoro-3-chloroaniline is: 1-2, preferably 1丄] -1.

The condensation agent for the condensation reaction is hydrazine, -dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), hydrazine, Ν'-diisopropylcarbodiimide (DIC;, 】-hydroxy- Benzotriazole (H: OBt), () - benzo: triazole - hydrazine, hydrazine, hydrazine, Ν'-tetramethyluronium tetrafluoroborate (TBTU), 0-(7-even Nitrobenzotriazine ⁵ sitting) - Ν, Ν, Ν ', Ν '-tetramethyl urea hexafluorophosphate (HATU), benzotriazole

, Ν'-tetramethylurea hexafluorophosphate (HBTU) or benzotriazol-1-yloxytris(dimethylamino)phosphorus hexafluorophosphate (ΒΟΡ), preferably benzotriazole - Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (HBTU) or benzopyrene: nitrogen 3⁄4- _-yloxy: (dimethylamino)phosphorus clock hexafluorophosphate (ΒΟΡ ).

The base accelerator of the condensation reaction is hydrazine: ethylamine (hydrazine), pyridine, 2,6-dimethylpyridinium, 4-dimethylaminopyridinium (DM/VP), N-methyl-Morraine (NMM), N-ethylmorphine (NEM), diisopropylethylamine (DffiA), 1,8-diazabicyclo[5.4.0] -11- 7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABC0), preferably 1,8-diazabicyclo[5.4.0]-^--7 - alkene (DBU) or 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or 1,4-diazabicyclo[2.2.2]octane

(DABCO).

 The solvent for the condensation reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile, preferably acetonitrile.

 The temperature of the condensation reaction is from 0 to 120 ° C, preferably 50 60 ° C.

 Compared with the prior art, the pharmaceutical intermediate 6-amino-7-hydroxy-3,4-dihydroquinazolin-4-one disclosed in the present invention and its preparation method enhance the nitrification reaction by using a novel catalyst. The selectivity, omitting functional group protection and deprotection, makes the entire preparation process simple and efficient. The use of the intermediate 6-amino-7-hydroxy-3,4-dihydroquinazoline 4 ketone to prepare afatinib, the advantages are mainly easy to obtain raw materials, less reaction steps, economical and environmentally friendly, which is conducive to the industrial production of the drug, promote The economic and technological development of the drug substance. The technical solution of the present invention will be further described in detail below with reference to a few preferred embodiments. The side chain (S) hydroxytetrahydrofuran and 4-(anthracene, fluorenyl-dimethylamino)-2-ene-butyryl chloride can be described in the preparation methods of the same compounds as described in the patents WO0250043 and WO03094921.

Embodiment 1:

3-Amino-4-hydroxy-benzoic acid methyl ester (II) (3.4 g, 20 mmd), zinc octothrate (4.2 g, 22 mmol), trichloro-s-triazine (O. llg) were added to the reaction flask at room temperature. , 3% eq) and 25 mL of acetonitrile. The stirring reaction was 3 small. The residue was dried over anhydrous sodium sulfate (MgSO4). 82.5%. Embodiment 2:

 Add 3-amino-4-hydroxy-benzoic acid methyl ester (II) (3.4g, 20mmoi), nitric acid (703⁄4, 2.7mL, 30mmo!), aluminum dihydrogen phosphate (0.07g, l) to the reaction flask at room temperature. % eq) and acetonitrile 20 mL. The reaction was stirred for 2 hours. The sodium hydrogencarbonate solution was added to adjust the pH: to neutrality, extracted with ethyl acetate, and the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallised from ethyl acetate. Example:

 At room temperature T, 3-amino-4-hydroxy-benzoic acid (II) (3.1 g, 20 mmol), zinc nitrate (4.2 g, 22 mmol), trichloro-s-triazine (O.l lg, 33⁄4 eq) were added to the reaction flask. And 25 mL of acetonitrile. The reaction was stirred for 4 hours. The organic solvent was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl ether to give pale-yellow succinium 2-nitro-4-hydroxy-5-aminobenzoic acid (III) 3.2 g, yield 80.8%. . Implement steel four:

 3-Amino-4-hydroxy-benzamide (3.1 g, 20 mmol), zinc nitrate (4.2 g, 22 mmo!), trichloro-triazine (0.11 g, 3%) were added to the reaction flask at room temperature. Eq) and acetonitrile 25 mL. Stirring reaction 2 small. The solvent was recrystallized with anhydrous sodium sulfate, and the residue was purified by methanol to give crystals crystals crystals crystals of crystal The rate is 78.3%.

Embodiment 5:

 Methyl 2-nitro-4-hydroxy-5-aminobenzene decanoate (2.1) (2.12 g, 10 mmol), ferric chloride (O.Ug, 5% w/w), activated carbon (0.22) were added to the reaction flask. g, 10% w/w) and 50 ml of ethanol were heated to 45-50 ° C, 80% hydrazine hydrate (1.25 g, 20 mmol) was added dropwise, and the reaction was kept under reflux for 5 hours, and the reaction was completed by TLC. The mixture was cooled, filtered, and concentrated to give a crude material. The crude material was recrystallized from acetonitrile to give a white solid solid of methyl 2,5-diamino-4-methyl benzoic acid i. Example 6:

To the hydrogenation reactor was added 2-nitro-4-hydroxy-5aminobenzamide (III) (1.97 g, l Onmiol), 5% palladium on carbon (0.2 g, 10% w/w) and 50 mL of ethanol, hydrogen is introduced according to the hydrogenation reaction procedure, maintaining 2-5 metric tons; The pressure was reacted at 40-45 ° C for 4 hours, and the reaction was completed by TLC. The temperature was lowered, and the palladium carbon was collected by filtration, and concentrated. The obtained crude product was recrystallized from acetonitrile to give a white solid, 2,5-diamino-4-hydroxybenzamide [V] 1.5 g, yield 89.8%.

Example 7:

 Methyl 2,5-diamino-4-hydroxybenzoate (IV) (3.64 g, 20 mmol), ammonium formate (L5g, 24 mmol) and N,N-dimethylformamide 20 mL were added to the reaction flask at room temperature. The temperature was raised to 165 ° C, and the reaction was stirred for 3 hours. Cool, pour into ice water, and solids appear. Filtration, the filter cake was washed with water and dried in vacuo to give a white solid 6-amino-7-hydroxy-3,4-dihydroquinazoline-4-one 0) 3.2 g, yield 90, 43⁄4.

Implementation ^8:

2,5-diamino-4-hydroxybenzoic acid amine (1_¥) (3.34 ₈ , 20 mmol), formamide 20 mL and formic acid 20 mL were added to the reaction flask at room temperature, and the temperature was adjusted to 170 ° C. The reaction was stirred for 6 hours. . Cool, pour into ice water, and there are carcasses. Filtration, the filter cake was washed with water and dried in vacuo to give a white solid, 6-amino-7-hydroxy-3,4-dihydroquinazolin-4-one (I) 3.0 g, yield 84.7%. Example 9:

6-Amino-7-hydroxy-3,4-dihydroquinazolin-4-one (I) (3.54 g, 20 mmol), phosphorus oxychloride (14 mL, 8 () _m mol) and Dichloromethane OOmL, reflux for 4 hours. After cooling, the organic phase was washed with water and dried over anhydrous sodium sulfate and evaporated. Residue) 3⁄4 isopropyl alcohol / n-hexane 0/3) was recrystallized to give pale yellow solid 4-chloro-6-amino-7-hydroxy quinazoline (VI) 3.2 g.

Example 10 - Add isopropyl azodicarboxylate (3 mL, 15 mmol) and 4 mL of tetrahydrofuran to a OOmL three-necked flask at room temperature, and add a solution of triphenyl (4.0 g, 15 mmd) in tetrahydrofuran in 25 mL at room temperature. The reaction was carried out for 2 hours at room temperature. Under a nitrogen atmosphere, a solution of (S)-3-hydroxytetrahydrofuran (0.3 g, 3.4 mmol) in tetrahydrofuran (5 mL) was added dropwise to the above reaction system. After completion of dropwise addition, 4-chloro-6-amino-7-hydroxyquinazoline (VI) (0.59 g, 3.0 mmol) was added, and the mixture was stirred at room temperature for 4 hours. A 5 mL solution of (S)-3-hydroxytetrahydrofuran P (0.23 g, 2.6 mm oi) in tetrahydrofuran was added dropwise, and the mixture was allowed to react at room temperature for 2 hours, and the reaction was terminated by TLC. The solvent was distilled off under reduced pressure, and the residue was adjusted to pH = 5 - 6 with dilute hydrochloric acid, and ethyl acetate was applied, and the organic phase was adjusted to pH==10-11 with saturated sodium carbonate. The aqueous phase was separated and dried in vacuo to give a white solid, 4-chloro-6-amino- 7-[(SM tetrahydrofuran 3-yl)oxy] quinazoline (VII) 0.69 g, yield 86.8%.

Example 11:

To a 100 mL three-necked flask was added 4-chloro-6-amino-7-[(S)-(tetrahydrofuran-3-yl)oxy] quinazoline (VII) (0.66 g, 2.5 mmol), triethylamine (0, 25g, 2.5mrao]) and 20raL of methylene chloride, the temperature is raised to 40-45 ° C, and stirred until the system dissolves uniformly. Decrease to below 10 °C, slowly add 4 mL solution of 4-(^, Ν-dimethylamino)-2-ene-butyryl chloride (0.42 _& 2.8 mmol) in dichloromethane, and continue to react at room temperature after the dropwise addition. Hours, TLC detects the end of the reaction. The reaction solution was washed with a 10% sodium hydrogencarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure and the residue was crystallised from ethyl acetate toiel Amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy] quinazoline (Vffl) 0.84 g, yield 89.4%.

Implementation ^12:

 In !OOraL: 3-Bottle is added 4-chloro-6-{[4-,N-dimethylamino)-]-oxo-2-butene-]-yl]amino 7-[(SH tetrahydrofuran 3- Alkyloxyquinazoline (VIII) (i. i3g, 3.0 mmol), triethylamine (0.45 g, 4.5 mmol) and isopropanol 30 laL were stirred until the system was homogeneous. 4-Fluoro-3-chloroaniline (0.48 g, 3.3 mmol) in isopropanol 20raL solution was slowly added dropwise, and the reaction was continued at room temperature after the completion of the dropwise addition for 2 hours, and the reaction was terminated by TLC. The reaction solution was poured into OO mL of i* water and filtered. After the filter cake was dried, it was recrystallized from anhydrous ethanol to give a white solid solid of afatinib (V), 15 g, yield 79.0%.

Example 10 - 3:

Add diisopropyl azodicarboxylate (3 mL, 15 mmol) and 4 mL of tetrahydrofuran to a three-necked flask at room temperature. A 25 mL solution of triphenylphosphine (4.0 g, 5 mmol) in tetrahydrofuran was added dropwise, and the reaction was kept at room temperature for 2 hours. Under a nitrogen atmosphere, a 5 mL solution of (S)-3-hydroxytetrahydrofuran (0.3 g, 3.4 mmd) in tetrahydrofuran was added dropwise to the above reaction system, and after completion of dropwise addition, 6-amino-7-hydroxy-3 was added. 4-Dihydroquinazoline 4-ketone (I) (0.53 g, 3.0 mmol) was stirred at room temperature for 4 hr. A solution of (S)-3-hydroxytetrahydrofuran (0.23 g, 2.6 mmol) in tetrahydrofuran (5 mL) was added dropwise and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was evaporated to ethylamine. The aqueous phase was separated and dried in vacuo to give a white solid 6-amino- 7- s-tetrahydrofuran-3-yl)oxy] - 3,4-dihydroquinazoline t# 4- ketone (IX) 0.64 g, The yield was 86.8%.

Example 14 - Addition of 6-amino-7-H tetrahydrofuran-3-yloxy]-3,4-dihydroquinium to a three-necked vial - 4-ketone (IX) (0.62 g, 2.5 mm) !), triethylamine (0.25 g, 2.5 mmol) and dichloromethane 20 mL, warmed to 40-45 ° C, stirred until the system dissolved uniformly. Decrease to below 10 °C, slowly add dropwise 4-(N,N-dimethylamino)-2-ene-butyryl chloride (0.42g, 2.8mmoi) in 10mL solution of dichloromethane, continue to react at room temperature after the dropwise addition. After 6 hours, the TLC assay ended. The reaction solution was washed with a 10% sodium hydrogen carbonate solution and water, respectively, and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure, and the residue was crystallised from ethyl acetate to afford white crystals of 6-{[4-(N,N-dimethylamino)-1-oxo-2-butenyl]amino}-7 -[(SH tetrahydrofuran-3-yl)oxy]-3,4-dihydroanthracene 15 linone-4-one (X) 0,80 g, yield 89.4%.

Implementation of two fifteen:

Under the protection of nitrogen, 6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}- 7- [(S)- (tetrahydrofuran-3-yl)oxy]-3,4-quinoline- 4- l (:X) (3.58 g, 10 mmol), benzotriazole-1-yloxytri(II) Methylamino)phosphorus octafluorophosphate (BOP) (6.63 g, 15 mmol) and acetonitrile 50 mL. 1,8-diazabicyclo[5.4.0]-unda-7-dry (DBU) (2.28 g, IS mmol) was added dropwise with stirring, and the mixture was reacted at room temperature for 2 hours. The temperature was raised to 60 ° C and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, dissolved in ethyl acetate (100 mL), and washed with 2M sodium hydroxide 20 mL Polyester. The organic phase was separated, dried, and concentrated under reduced pressure. The residue was dissolved in 100 mL of tetrahydrofuran, 4-chloro-trifluoroaniline (.89 g, 13 mmol) and sodium hydride (0.32 g, Bmmol). The reaction was quenched by a saturated aqueous solution of sodium chloride, and then the organic phase was separated, dried, and the solvent was evaporated under reduced pressure to give a white solid. Recrystallization from ethanol gave 3.88 g of a white solid alfatinib (V) with a yield of 79.4%.

Example 16:

 6-{[4-(N-Dimethylamino)-]-oxo-2-buten-1-yl]amino 7-[(S)-(tetrahydrofuran 3-) was added to a three-necked flask under nitrogen. -oxy) - 3,4-quinazolin-4-one (X) (3.58g, lOramol), benzotriazole-1-yloxytris(dimethylamino)phosphoric hexafluoroantimonic acid Salt (BO:P) (6.63 g, 15τηηηο!) and acetonitrile 50 m: L. Under stirring, 5-diazabicyclo [4.3.0]-indole-5-ene (DBN) (1.86 g, 15 mmol) was added dropwise, and the mixture was reacted at room temperature for 12 hours. Warm up to 60 ° C and continue to react for 12 hours. The solvent was distilled off under reduced pressure, and then ethyl acetate (100 mL) was added and dissolved, and washed with 2M sodium hydroxide 20mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 100 mL of tetrahydrofuran, and 4-chloro-3-fluoroaniline ( _.89 g, 13mm?) and sodium hydride (0.32 g, 13 mmol) were added, and the mixture was warmed to 50 ° C, and the reaction was stirred for 5 hours, and the reaction was monitored by TLC. The reaction mixture was quenched with saturated brine, and the organic phase was separated, dried, and evaporated to vacuo to give a white solid. Recrystallization from ethanol gave a white solid, afatinib (V) 3.65 g, yield 75.3%.

Example 17:

Under a nitrogen atmosphere, (Ν,Ν-dimethylamino)-1-oxo-2-buten-1-yl]amino}- 7- [(S)- (tetrahydrofuran- 3-yl)oxy]-3,4-quinovalin-4-one (X) (3.58 g, lOnimol), benzo: triazol-1-yloxytris(dimethylamino)phosphor Hexafluoroantimonate (BOP) (6.63 g, IS mmol), 4-chloro-3-fluoroaniline (1.89 g, 13 mm oi) and N,N-dimethylformamide 50 mL. 1,8-diaza 3⁄4cyclo[5.4.0]-undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise with stirring, and the mixture was reacted at room temperature for 12 hours. Dan Wen to 60 ° C, continue to react for 12 hours. The solvent was evaporated under reduced pressure, dissolved in ethyl acetate (100 mL), and washed with 2M: The organic phase was separated, dried and concentrated under reduced pressure. Residue with B The alcohol was recrystallized to give a white solid, afatinib (V) 2.12 g, yield 43.7%.

 It should be noted that the above-mentioned embodiments are only for explaining the technical idea and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the contents of the present invention and implement them, and the scope of the present invention cannot be limited thereby. . Equivalent changes or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims

1. A compound, characterized in that its chemical name is 6-amino-7-hydroxy-3,4-dihydroquinazolin-4-one, and its molecular formula is as follows:

2. The preparation method according to claim 1, characterized in that it includes the following steps: represented by formula (II) 3-Amino-4-hydroxybenzoic acid or 3-amino-4-hydroxybenzoate or 3-amino-4-hydroxybenzamide is used as raw material, and the compound is obtained through nitration reaction, reduction reaction and cyclization reaction in sequence. 6-amino-7-hydroxy-3,4-dihydroxazole-4-one (I);

3. The preparation method of the compound according to claim 2, characterized in that: when R in the chemical formula (II) is a hydroxyl group, the raw material is 3-amino-4-hydroxybenzoic acid; when R is a hydrocarbyloxy group , the raw material is 3-amino-4-hydroxybenzoate; when: R is an amine group, the raw material is 3-1-yl-4-hydroxybenzoic acid amide. 4. The method for preparing the compound according to claim 2, characterized in that: the nitrating agent of the nitration reaction includes concentrated nitric acid, copper nitrate, bismuth nitrate or zinc nitrate. 5. The preparation method of the compound according to claim 2, characterized in that: the catalyst for the nitration reaction is sulfuric acid/tris. Polycyanamine formaldehyde resin, sulfuric acid/polyvinylpyrrolidinone, sulfuric acid/polyethylene dioxide, tris . Chloro-s-triazine or aluminum dihydrogen phosphate, the catalyst dosage is 0% of the moles of the raw material (Π). 6. The preparation method of the compound according to claim 2, characterized in that: the solvent of the chemical reaction is dichloroane, chlorobenzene, chloroform, 1,2 dichloromethane, acetonitrile or water, 7. The preparation method of the compound according to claim 2, characterized in that: the temperature of the nitration reaction is 0-120° 8. A method for preparing afatinib (V) using the compound described in any one of claims 1 to 7 as raw material,

Dharma good β iV)

Compound 4-chloro-6-amino-7-hydroxyquinoalkyl R should be prepared. The compound (VI) and (S 3-hydroxytetrahydrofuran) undergo an etherification reaction to generate compound 4-chloro-6-amino-7-[(8 (tetrahydrofuran-3-yl)oxy]quinoline (11), the compound (VII) and 4-(N,N-Dimethylamino)-2-ene-butanoyl chloride undergoes acylation reaction to generate compound 4-chloro-6-{[4-(N,N-dimethylamino)-1-oxo Butenyl]amino}"[(S)-(tetrahydrofuran" ₃ -yl)oxy]quino p 1}, the compound (VIII) and 4-fluoro-3-

9. The preparation method of afatinib (V) according to claim 8, characterized in that: the accelerator of the etherification reaction is diethyl azodicarboxylate, diisopropyl azodicarboxylate , dipropyl azodicarboxylate, dimethyl azodicarboxylate, di-p-chlorobenzyl azodicarboxylate, N, N, N', N'-tetramethylazodicarboxamide, N , N, N', N'-tetraisopropyl azodicarboxamide or azodicarboxyl dipipridine. 10. The preparation method of afatinib (V) according to claim 8, characterized in that: the accelerator of the etherification reaction is triphenylphosphine, tributylphosphine, trimethylphosphine or cyanophosphine Φ-tributylphosphine. 11. The preparation method of afatinib (V) according to claim 8, characterized in that: the raw material for the acylation reaction is 4-chloro-6-amino-7-[(SM tetrahydrofurazoline-3 -The feeding molar ratio of quinazoline (VII) and 4-(N,N-diylamino)-2-ene-butanoyl chloride is 1:12. 12. The preparation method of afatinib (V) according to claim 8, which is characterized in that: the acid binding agent for the acylation reaction For triethylamine, pyridine, V-methylmorpholine, diisopropylethylamine, sodium hydroxide, sodium methoxide, sodium hydroxide, potassium hydroxide, carbonic acid, sodium bicarbonate or potassium carbonate. 13. The preparation method of afatinib (V) according to claim 8, characterized in that: the raw material of the condensation reaction is 4-chloro-6-{[4-(N,N-dimethylamino)- ί-Oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (Vin) and 4-fluoro-3- The molar ratio of chloroaniline is 2. 14. The preparation method of afatinib (V) according to claim 8, characterized in that: the acid binding agent of the condensation reaction is triethylamine, pyridine, V methylmorpholine, diisopropylethylamine , sodium hydroxide, sodium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate. 15. The preparation method of afatinib (V) according to claim 8, characterized in that: the solvent of the condensation reaction is methanol, ethanol, isopropyl alcohol, dichloromethane, chloroform, 1,2, -Dichloroethane, acetonitrile, N,N-dimethylformamide, ,N-dimethylacetamide, benzene, diphenyl, diethyl ether, isopropyl ether, dioxane, tetrahydrofuranthene or ethyl ether Butyl ether. 16. A method for preparing afatinib C using the compound of any one of claims 1 to 7 as raw material, characterized in that the preparation method includes the following steps: 6-amino-7-hydroxy-3,4- The etherification reaction between dihydroquinazoline-4-one (:) and (S 3-hydroxytetrahydrofuran) produces compound 6-amino-7-[(S (tetrahydrofuran-3-yl)oxy]-3, 4-Dihydroquinazoline 4-one (IX), the compound (IX) is acylated with 4-(N,N-dimethylamino)-2-ene-butanoyl chloride to generate compound 6-{[4 - (N, N-dimethylamino)4-oxo-2buten-1-yl]amino7-[(S (tetrahydrofuran-3yl)oxy]3,4-dihydroquinolin- 4-ketone (X), the compound (X) and 4-fluoro-3-chloroaniline are subjected to a condensation reaction to prepare the afatinib (V). 17. The preparation method of afatinib (V) according to claim 16, characterized in that: the raw material of the condensation reaction is 6-{[4-(N,N-dimethylamino)-1-oxo -2-Buten-1-yl]amino}-7-[(SHtetrahydrofuran 3-yl)oxy]-3,4-dihydroquinazolin-4-one (X) and 4-fluoro-3- The molar ratio of chloroaniline is 2. 18. The preparation method of afatinib (CV) according to claim 16, characterized in that: the condensation agent of the condensation reaction is N,N-dicyclohexylcarbodiimide, carbonyldiimidazole, N,N'-diisopropylcarbodiimide, hydroxy-benzotriazole, 0 benzotriazole-N,N ,N',N'-tetramethylurea tetrafluoroborate, 0-(7-azobenzotri:nitrogen)-N,N,N',N'-tetramethylphenanthrene hexafluorophosphate , benzotriazole N, N, N', N' tetramethylphosphonium hexafluorophosphate or benzotriazole-yloxytris(dimethylamino)phosphonium hexafluorophosphate. 19. The preparation method of afatinib (V) according to claim, characterized in that: the alkali accelerator of the condensation reaction is: triethylamine, aridine, 2,6-dimethylpyridine, 4- Dimethylaminobicyclo[4.3.0]-nonane, 1,8 -Diazabicyclo[5.4.0] † ------ -7-ene or 1,4-diazabicyclo[2.2.2] octane. 20. The preparation method of afatinib (V) according to claim, characterized in that: the solvent of the condensation reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, dimethylbenzene Methyl sulfoxide, N,N dimethylformamide or B'" 21. The preparation method of afatinib (V) according to claim 16, characterized in that the temperature of the condensation reaction is 0-120 ^° C.