阅读说明：本技术 6-取代基呋喃基-4-取代氨基喹唑啉衍生物及其关键中间体的制备方法 (Preparation method of 6-substituent furyl-4-substituted amino quinazoline derivative and key intermediate thereof ) 是由 崔庆荣 王保林 徐欣 常仁义 于 2018-07-09 设计创作，主要内容包括：本发明涉及一种6-取代基呋喃基-4-取代氨基喹唑啉衍生物及其关键中间体的制备方法。用2-卤代-5-氰基苯甲酸酯和3-氯-4-(3-氟苄氧基)苯胺为原料,经酰胺化反应、甲脒盐取代反应、缩合反应得到6-氰基-4-[3-氯-4-(3-氟苄氧基)苯基]氨基喹唑啉,然后经格氏化反应、酸化反应得到6-(呋喃-2-基)-4-[3-氯-4-(3-氟苄氧基)苯基]氨基喹唑啉或6-(5-甲酰基呋喃-2-基)-4-[3-氯-4-(3-氟苄氧基)苯基]氨基喹唑啉,再经Mannich反应或亚胺化、还原胺化反应制备拉帕替尼或赛拉替尼。本发明原料价廉易得、稳定性好,反应选择性高,产品纯度高,利于工业化生产。(The invention relates to a preparation method of a 6-substituent furyl-4-substituted amino quinazoline derivative and a key intermediate thereof. Using 2-halogenated-5-cyanobenzoate and 3-chloro-4- (3-fluorobenzyloxy) aniline as raw materials, obtaining 6-cyano-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline through amidation reaction, formamidine salt substitution reaction and condensation reaction, then obtaining 6- (furan-2-yl) -4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline or 6- (5-formylfuran-2-yl) -4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline through Grignard reaction and acidification reaction, and then carrying out Mannich reaction or imidization, Preparing lapatinib or ceratinib by reductive amination reaction. The invention has the advantages of cheap and easily obtained raw materials, good stability, high reaction selectivity and high product purity, and is beneficial to industrial production.)

1. A preparation method of a 6-substituent furyl-4-substituted amino quinazoline intermediate shown in a formula IV comprises the following steps:

(1) carrying out amidation reaction on a compound shown in a formula II and 3-chloro-4- (3-fluorobenzyloxy) aniline in the presence of a solvent A and a Lewis acid catalyst to obtain a compound shown in a formula III;

(2) in the presence of a solvent B and an acid-binding agent, carrying out substitution and condensation reaction on a compound shown in a formula III and formamidine salt to obtain a compound shown in a formula IV: 6-cyano-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline;

wherein the content of the first and second substances,

x is chlorine or bromine, R is methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl or sec-butyl.

2. A process for the preparation of a 6-substituted furanyl-4-substituted aminoquinazoline intermediate of the formula iv as claimed in claim 1, wherein the amidation reaction in step (1) comprises any one or more of the following reaction conditions:

a. the solvent A is one or a combination of toluene, xylene, chlorobenzene or dichlorobenzene;

b. the mass ratio of the solvent A to the compound shown in the formula II is (2-15) to 1; preferably, the mass ratio of the solvent A to the compound of the formula II is (5-8): 1;

c. the Lewis acid catalyst is ammonium chloride, zinc chloride, ferric chloride or cuprous chloride;

d. the mass ratio of the Lewis acid catalyst to the compound shown in the formula II is 1.0-5.0%;

e. the molar ratio of the compound shown in the formula II to the 3-chloro-4- (3-fluorobenzyloxy) aniline is (0.9-1.5) to 1; preferably the molar ratio is (1.0-1.2): 1;

f. the amidation reaction temperature is 60-130 ℃; the reaction temperature is preferably from 90 to 110 ℃.

3. The process for preparing a 6-substituted furanyl-4-substituted aminoquinazoline intermediate of the formula iv according to claim 1, wherein in step (2) the solvent B is one or a combination of N, N-dimethylformamide, N-dimethylacetamide, chlorobenzene or dichlorobenzene; the mass ratio of the solvent B to the compound of the formula III is preferably (2-15): 1.

4. The method for preparing the 6-substituted furyl-4-substituted aminoquinazoline intermediate shown in the formula IV in claim 1, wherein in the step (2), the acid-binding agent is one or a combination of sodium methoxide solid, sodium methoxide methanol solution, sodium ethoxide ethanol solution, potassium carbonate, sodium carbonate and calcium carbonate.

5. The process for preparing a 6-substituted furanyl-4-substituted aminoquinazoline intermediate of the formula iv according to claim 1, wherein in step (2) the formamidine salt is formamidine hydrochloride or formamidine acetate; preferably, the molar ratio of the formamidine salt, the acid-binding agent and the compound of the formula III is (1.0-1.5): 1.0-2.0): 1.

6. The method for preparing a 6-substituted furyl-4-substituted aminoquinazoline intermediate represented by the formula iv according to claim 1, wherein the substitution and condensation reactions are sequentially performed in stages in the step (2); firstly, carrying out substitution reaction at the temperature of 30-70 ℃, and then carrying out condensation reaction at the temperature of 85-135 ℃; preferably, the substitution reaction temperature is 45-55 ℃; the condensation reaction temperature is 95-115 ℃.

7. A process for the preparation of a 6-substituted furanyl-4-substituted aminoquinazoline (i) comprising the step of preparing a compound of formula iv as claimed in any one of claims 1 to 8, further comprising the step of scheme a or scheme B below:

scheme A:

a1, in the presence of a solvent C, carrying out Grignard reaction on the compound shown in the formula IV and a Grignard reagent 1, 1-dialkoxypropyl-3-magnesium halide, and acidifying to obtain a compound shown in the formula V;

a2, in the presence of a solvent D, carrying out Mannich reaction on the compound of the formula V, 2-substituent ethylamine hydrochloride and formaldehyde to prepare lapatinib compound shown in the formula I2 or erlotinib compound shown in the formula I3;

scheme B:

b1, in the presence of a solvent C, carrying out Grignard reaction on the compound shown in the formula IV and Grignard reagent 1,1,2, 2-tetraalkoxybutyl-4-magnesium halide, and acidifying to obtain a compound shown in the formula I1; or, the compound of formula IV and Grignard reagent 1, 1-dialkoxy propyl-3-magnesium halide are subjected to Grignard reaction and acidification to obtain a compound of formula V, and the compound of formula V and formylation reagent are subjected to formylation reaction to prepare a compound of formula I1;

b2, carrying out imidization reaction on the compound of formula I1 and 2-substituent ethylamine hydrochloride organic base, and then adding a reducing agent to carry out reduction imine reaction to prepare the compound of formula I2 lapatinib or the compound of formula I3 selatinib;

8. the method of claim 7, wherein step a1 of scheme a comprises any one or more of the following reaction conditions:

a. the solvent C is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane or toluene;

b. the mass ratio of the solvent C to the compound shown in the formula IV is (5-25) to 1; preferably, the mass ratio of the solvent C to the compound shown in the formula IV is (7-15): 1;

c. the Grignard reagent 1, 1-dialkoxypropyl-3-magnesium halide is prepared from 1, 1-dialkoxy-3-halopropane and metal magnesium; wherein the molar ratio of the metal magnesium, the 1, 1-dialkoxy-3-halopropane and the compound shown in the formula IV is (1.0-1.5): 1.0-1.4): 1;

d. the Grignard reaction temperature is 10-80 ℃, and the preferred Grignard reaction temperature is 30-60 ℃;

e. the acidification reaction is 20-100 ℃, and the preferred acidification reaction temperature is 40-80 ℃.

9. The method of claim 7, wherein step a2 of scheme a comprises any one or more of the following reaction conditions:

a. the solvent D is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dichloromethane, chloroform, 1, 2-dichloroethane or toluene;

b. the mass ratio of the solvent D to the compound of the formula V is (5-20) to 1; preferably, the mass ratio of the solvent D to the compound of the formula V is (5-12): 1;

c. the 2-substituent ethylamine hydrochloride is 2-methylsulfonyl ethylamine hydrochloride or 2-methylsulfonyl ethylamine hydrochloride;

d. the molar ratio of the formaldehyde to the 2-substituent ethylamine hydrochloride to the compound of the formula V is (1.0-1.5): 1.0-1.4): 1;

e. the Mannich reaction temperature is 20-40 ℃.

10. The method of claim 7, wherein scheme B comprises any one or more of the following reaction conditions:

a. in step B1, the solvent C is one or a combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane or toluene;

b. in the step B1, the mass ratio of the solvent C to the compound shown in the formula IV is (5-25) to 1; preferably, the mass ratio of the solvent C to the compound shown in the formula IV is (7-15): 1;

c. in the step B1, the Grignard reaction temperature is 10-80 ℃, and preferably, the Grignard reaction temperature is 30-60 ℃;

d. in the step B1, the acidification reaction temperature is 20-100 ℃, preferably, the acidification reaction temperature is 40-80 ℃;

e. in step B2, the 2-substituent ethylamine hydrochloride is 2-methylsulfonylethylamine hydrochloride or 2-methylsulfonylethylamine hydrochloride; the organic base is diisopropylethylamine, triethylamine, tri-n-propylamine or tri-n-butylamine; the reducing agent is sodium triacetoxyborohydride;

f. in step B2, the molar ratio of the 2-substituted ethylamine hydrochloride, the organic base, the reducing agent and the compound of formula I1 is (1.0-2.0): 1.0-1.5): 1.5-2.5): 1.

Technical Field

The invention relates to a preparation method of a 4-substituted amino quinazoline derivative, in particular to a preparation method of a 6-substituent furyl-4-substituted amino quinazoline derivative and a key intermediate 6-cyano-4-substituted amino quinazoline thereof, belonging to the technical field of medical chemistry.

Background

Lapatinib is a dual inhibitor of epidermal growth factor receptor (ErbBl) and human epidermal factor receptor-2 (ErbB2) developed by glactin stackers, which were reviewed and approved by the united states Food and Drug Administration (FDA) and the European Medicines Administration (EMA) on 3, 13, and 12, 14 days 2007, for the treatment of advanced or metastatic breast cancer. Lapatinib is chemically known as 4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] amino-6- {5- [ (2- (methylsulfonyl) ethylamino) methyl ] furan-2-yl } quinazoline or as N- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] -6- {5- [ (2- (methylsulfonyl) ethylamino) methyl ] furan-2-yl } quinazolin-4-amine.

The erlotinib is a me-to drug of lapatinib, has stronger biological activity compared with lapatinib, and is expected to be used for treating breast cancer, gastric cancer and lung cancer. The chemical name of the salatinib is 4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] amino-6- {5- [ (2- (methylsulfonyloxy) ethylamino) methyl ] furan-2-yl } quinazoline or N- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] -6- {5- [ (2- (methylsulfonyloxy) ethylamino) methyl ] furan-2-yl } quinazolin-4-amine.

Lapatinib and Selatinib belong to 6-substituent furyl-4-substituted aminoquinazoline derivatives (I), and in the 6-substituent furyl-4-substituted aminoquinazoline derivatives (I), 6- (5-formylfuran-2-yl) -4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline (I1) is an important heterocyclic compound which can be used for preparing Lapatinib (Lapatinib, I2) or Selatinib (Selatinib, I3).

The related compound has the following structural formula:

wherein G is formyl or substituted aminomethyl

Lapatinib original research corporation in patents WO9935146, WO0202552 and CN1440403 proposes lapatinib and its salt preparation method, the preparation scheme is that iodo quinazoline derivative and furan derivative are coupled through carbon-carbon bond, and then the iodo quinazoline derivative and 2-methylsulfonylethylamine are subjected to reductive amination reaction to construct lapatinib. 4-hydroxy-6-iodoquinazoline is used as a raw material, halogenated reaction is carried out to obtain 4-chloro-6-iodoquinazoline, and then SN2 substitution reaction is carried out on the 4-chloro-6-iodoquinazoline and 4- (3-fluorobenzyloxy) -3-chloroaniline to prepare 4- [4- (3-fluorobenzyloxy) -3-chlorophenyl ] amino-6-iodoquinazoline; performing Stille coupling reaction on an organotin reagent [5- (1, 3-dioxolan-2-yl) furan-2-yl tri-tert-butyltin ] and a palladium catalyst to obtain 4- [4- (3-fluorobenzyloxy) -3-chloro ] phenylamino-6- [5- (1, 3-dioxolan-2-yl) furan-2-yl ] quinazoline; deprotection with hydrochloric acid to give 4- [4- (3-fluorobenzyloxy) -3-chloro ] phenylamino-6- (5-formylfuran-2-yl) quinazoline; then carrying out reductive amination reaction with 2-methylsulfonylethylamine and sodium triacetyl borohydride to obtain lapatinib, and salifying with hydrochloric acid or p-toluenesulfonic acid to prepare clinical medicinal salts of lapatinib. Or 4- [4- (3-fluorobenzyloxy) -3-chlorophenyl ] amino-6-iodoquinazoline, an organoboron reagent (such as 5-formylfuran-2-yl boric acid) and a palladium catalyst are subjected to Suzuki coupling reaction to obtain 4- [4- (3-fluorobenzyloxy) -3-chloro ] phenylamino-6- (5-formylfuran-2-yl) quinazoline hydrochloride, the 4- [4- (3-fluorobenzyloxy) -3-chloro ] phenylamino-6- (5-formylfuran-2-yl) quinazoline is obtained through neutralization, and then the 4- [4- (3-fluorobenzyloxy) -3-chloro ] phenylamino-6- (5-formylfuran-2-yl) quinazoline is subjected to reductive amination reaction with 2-methylsulfonylethylamine and sodium triacetyl borohydride to obtain lapatinib or 2-methylsulfonylethylamine, And (3) carrying out reductive amination reaction on sodium triacetyl borohydride and p-toluenesulfonic acid to form salt so as to obtain lapatinib di-p-methylbenzene sulfonate. The reaction sequence is depicted as scheme 1 below.

Synthesis scheme 1

The process of the route is complicated, the price of the used raw material 4-hydroxy-6-iodoquinazoline is high, the organic tin or organic boron reagent used in the coupling reaction is expensive and has poor stability, in addition, the organic tin has high toxicity, a plurality of related intermediates have poor stability, the reaction purity is low, the purification requirement is high, and the industrial production is not facilitated.

Chinese patents CN102702178 and US8853396 propose a preparation method of lapatinib hydrochloride, which uses 6-iodine-4-hydroxyquinazoline as a raw material, protects hydroxyl by 3, 4-dihydro-2H-pyran to generate 6-iodine-4- (tetrahydro-2H-pyran-2-yloxy) quinazoline, then carries out Suzuki coupling reaction with 2-formylfuran-5-boric acid to obtain 6- (5-formylfuran-2-yl) -4- (tetrahydro-2H-pyran-2-yloxy) quinazoline, and carries out reductive amination on 2- (methylsulfonyl) ethylamine to generate 6- [5- (2-methylsulfonylethylaminomethyl) furan-2-yl ] -4- (tetrahydro-2H-pyran-2-yloxy) The quinazoline and p-toluenesulfonic acid are deprotected to prepare 6- [5- (2-methylsulfonylethylaminomethyl) furan-2-yl ] -4-hydroxyquinazoline, the 6- [5- (2-methylsulfonylethylaminomethyl) furan-2-yl ] -4-chloroquinazoline is obtained through phosphorus oxychloride chlorination, and then the 6- [5- (2-methylsulfonylethylaminomethyl) furan-2-yl ] -4-chloroquinazoline and 4- (3-fluorobenzyloxy) -3-chloroaniline are subjected to SN2 substitution reaction to obtain lapatinib hydrochloride, wherein the reaction process is described as the following synthetic route 2.

Synthesis scheme 2

WO20150322050 and US9359333 optimize synthesis route 2, protect the side chain nitrogen atom, protect 6- [ N-trifluoroacetyl-N- (2-methanesulfonylethyl) -5-aminomethylfuran-2-yl ] -4- (tetrahydro-2H-pyran-2-yloxy) quinazoline with trifluoroacetic anhydride, deprotect to prepare 6- [ N-trifluoroacetyl-N- (2-methanesulfonylethyl) -5-aminomethylfuran-2-yl ] -4-hydroxyquinazoline, chloro-reacting to obtain 6- [ N-trifluoroacetyl-N- (2-methanesulfonylethyl) -5-aminomethylfuran-2-yl ] -4-chloroquinazoline, and performing SN2 substitution reaction, trifluoroacetyl removal and salification on p-toluenesulfonic acid with 4- (3-fluorobenzyloxy) -3-chloroaniline to obtain lapatinib di-p-methylbenzene sulfonate monohydrate, wherein the reaction process is described as the following synthetic route 3.

Synthesis scheme 3

Chinese patent CN102295638 proposes a one-pot method for preparing lapatinib di-p-methylbenzenesulfonate, aiming at the problem of poor stability of the used raw material 2-formylfuran-5-boric acid. The method comprises the steps of carrying out imidization reaction on 2-methylsulfonylethylamine and 2-formylfuran-5-boric acid to obtain 2- (N-2-methylsulfonylethyl) aminomethylidene furan-5-boric acid, carrying out Suzuki coupling reaction on the obtained product and 6-iodine-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline to obtain 6- [5- (2-methylsulfonylethylaminomethylidene) furan-2-yl ] -4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline, reducing the obtained product by using sodium triacetoxyborohydride, salifying p-toluenesulfonic acid to obtain lapatinib di-p-methylbenzenesulfonate, wherein the preparation yield of the one-pot method can reach 77.9 to 81.8 percent, the reaction sequence is depicted as scheme 4 below.

Synthesis scheme 4

The above routes all have the problems of high price of the raw material 6-iodoquinazoline derivative and the 2-formylfuran-5-boric acid, poor stability of the raw material and poor purity of the product, and are not beneficial to industrial production.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a preparation method of a 6-substituent furyl-4-substituted amino quinazoline derivative (I) and a key intermediate thereof.

One of the tasks of the invention is to provide a preparation method of a key intermediate 6-cyano-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline of a 6-substituent furyl-4-substituted aminoquinazoline derivative (I).

The invention also provides a preparation method of the 6-substituent furyl-4-substituted amino quinazoline derivative (I), which is safe, green, simple and convenient to operate and has cost advantage.

The method has the advantages of cheap and easily-obtained raw materials, simple preparation method, easy operation, less waste water and waste acid generation, safety, environmental protection and low cost; meanwhile, the method has high yield and selectivity and few side reactions.

Description of terms:

a compound of formula II: 2-halo-5-cyanobenzoate;

a compound of formula III: n- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] -2-halo-5-cyanobenzamide;

a compound of formula IV: 6-cyano-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline; intermediates for compounds of formula I;

a compound of formula V: 6- (furan-2-yl) -4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline;

a compound of formula I: 6-substituted furyl-4-substituted aminoquinazoline; the method specifically comprises the following steps: the compound 6- (5-formylfuran-2-yl) -4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline of formula I1, the compound lapatinib of formula I2, the compound selatinib of formula I3; the structural formula is as follows:

the compound of formula I1 is used for synthesizing formula I2 and formula I3.

In the specification, the compound number is completely consistent with the structural formula number, and the same reference relationship is provided for different fonts according to the structural formula of the compound.

The technical scheme of the invention is as follows:

a preparation method of a 6-substituent furyl-4-substituted amino quinazoline intermediate shown in a formula IV comprises the following steps:

(1) carrying out amidation reaction on a compound shown in a formula II and 3-chloro-4- (3-fluorobenzyloxy) aniline in the presence of a solvent A and a Lewis acid catalyst to obtain a compound shown in a formula III;

(2) in the presence of a solvent B and an acid-binding agent, carrying out substitution and condensation reaction on a compound shown in a formula III and formamidine salt to obtain a compound shown in a formula IV: 6-cyano-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline;

wherein the content of the first and second substances,

x is chlorine or bromine, R is methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl or sec-butyl.

According to the present invention, preferably, the solvent a in step (1) is one or a combination of two or more of toluene, xylene, chlorobenzene or dichlorobenzene; the mass ratio of the solvent A to the compound shown in the formula II is (2-15) to 1; preferably, the mass ratio of the solvent A to the compound of the formula II is (5-8): 1.

According to the present invention, it is preferred that the lewis acid catalyst in step (1) is ammonium chloride, zinc chloride, ferric chloride or cuprous chloride; the mass ratio of the Lewis acid catalyst to the compound shown in the formula II is 1.0-5.0%.

According to the invention, the molar ratio of the compound of formula II to 3-chloro-4- (3-fluorobenzyloxy) aniline in step (1) is preferably (0.9-1.5): 1; preferably, the molar ratio of the compound of formula II to 3-chloro-4- (3-fluorobenzyloxy) aniline is (1.0-1.2): 1.

According to the present invention, it is preferred that the amidation reaction temperature in step (1) is 60 to 130 ℃; preferably, the amidation reaction temperature is 90-110 ℃. The amidation reaction time is 2-10 hours; preferably, the amidation reaction time is 4 to 6 hours.

According to the present invention, preferably, in the step (2), the solvent B is one or a combination of two or more of N, N-dimethylformamide, N-dimethylacetamide, chlorobenzene or dichlorobenzene, and preferably, the solvent B is N, N-dimethylformamide; the mass ratio of the solvent B to the compound shown in the formula III is (2-15) to 1; preferably, the mass ratio of the solvent B to the compound of the formula III is (4-10): 1.

According to the invention, preferably, the acid-binding agent in the step (2) is one or a combination of more than two of sodium methoxide solid, sodium methoxide methanol solution, sodium ethoxide ethanol solution, potassium carbonate, sodium carbonate and calcium carbonate; the formamidine salt is formamidine hydrochloride or formamidine acetate; the molar ratio of the formamidine salt, the acid-binding agent and the compound shown in the formula III is (1.0-1.5): 1.0-2.0): 1. Wherein the mole number of the formamidine salt is slightly higher than that of the acid-binding agent, and the mole ratio of the formamidine salt to the acid-binding agent is preferably 1.05-1.15: 1; preferably, the molar ratio of the formamidine salt to the acid-binding agent is 1.09-1.1: 1. The residual small amount of formamidine hydrochloride in the system can play the role of a weak acid catalyst, and is beneficial to intramolecular dehydration of the subsequent condensation reaction.

According to the present invention, preferably, the substitution and condensation reactions in step (2) are performed in sequence by stages; firstly, carrying out substitution reaction at the temperature of 30-70 ℃, and then carrying out condensation reaction at the temperature of 85-135 ℃; further preferably, the substitution reaction temperature is 45-55 ℃; the condensation reaction temperature is 95-115 ℃. The substitution reaction time is 3-10 hours, and the preferable substitution reaction time is 4-6 hours; the condensation reaction time is 4-10 hours, and the preferable condensation reaction time is 6-8 hours.

The substitution and condensation reaction of the step (2) is carried out by a one-pot method.

A process for the preparation of a 6-substituted furanyl-4-substituted aminoquinazoline (i) comprising the steps of the preparation of a compound of formula iv as described above according to the invention, and further comprising the steps of scheme a or scheme B below:

scheme A:

a1, in the presence of a solvent C, carrying out Grignard reaction on the compound shown in the formula IV and a Grignard reagent 1, 1-dialkoxypropyl-3-magnesium halide, and acidifying to obtain a compound shown in the formula V;

a2, in the presence of a solvent D, the compound of the formula V, 2-substituent ethylamine hydrochloride and formaldehyde are subjected to Mannich reaction to prepare the compound Lapatinib of the formula I2 or the compound Seratinib of the formula I3.

Scheme B:

b1, in the presence of a solvent C, carrying out Grignard reaction on the compound shown in the formula IV and Grignard reagent 1,1,2, 2-tetraalkoxybutyl-4-magnesium halide, and acidifying to obtain a compound shown in the formula I1; or, the compound of formula IV and Grignard reagent 1, 1-dialkoxy propyl-3-magnesium halide are subjected to Grignard reaction and acidification to obtain a compound of formula V, and the compound of formula V and formylation reagent are subjected to formylation reaction to prepare a compound of formula I1;

b2, carrying out imidization reaction on the compound of formula I1 and 2-substituent ethylamine hydrochloride organic base, and then adding a reducing agent to carry out reduction imine reaction to prepare the compound of formula I2 lapatinib or the compound of formula I3 selatinib.

The structural formulas of the compounds II, III, IV, V, I1, I2 lapatinib and I3 selatinib are shown as follows:

preferably, in step a1, the solvent C is one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane or toluene; the mass ratio of the solvent C to the compound shown in the formula IV is (5-25) to 1; preferably, the mass ratio of the solvent C to the compound of the formula IV is (7-15): 1.

Preferably, in step A1, the Grignard reagent 1, 1-dialkoxypropyl-3-magnesium halide is prepared from 1, 1-dialkoxy-3-halopropane and magnesium metal; wherein the molar ratio of the metal magnesium, the 1, 1-dialkoxy-3-halopropane and the compound shown in the formula IV is (1.0-1.5): 1.0-1.4): 1.

Preferably, in step A1, the Grignard reaction temperature is 10 to 80 ℃, more preferably the Grignard reaction temperature is 30 to 60 ℃, and the Grignard reaction time is 2 to 8 hours, more preferably the Grignard reaction time is 3 to 5 hours; in the step A1, the acidification reaction is 20-100 ℃, and the acidification reaction temperature is further preferably 40-80 ℃; the acidification reaction time is 1-7 hours, and preferably, the acidification reaction time is 3-5 hours.

According to a preferred embodiment of the present invention, in step a2, the solvent D is one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dichloromethane, chloroform, 1, 2-dichloroethane, or toluene; the mass ratio of the solvent D to the compound of the formula V is (5-20) to 1; preferably, the mass ratio of the solvent D to the compound of the formula V is (5-12): 1.

Preferably, in step A2, the 2-substituent ethylamine hydrochloride is 2-methylsulfonylethylamine hydrochloride or 2-methylsulfonylethylamine hydrochloride; in step A2, the molar ratio of formaldehyde, 2-substituted ethylamine hydrochloride and the compound of formula V is (1.0-1.5): 1.0-1.4): 1.

According to the invention, in the step A2, the Mannich reaction temperature is preferably 0-80 ℃, and more preferably 20-40 ℃. The Mannich reaction time is 2-8 hours, and the preferred Mannich reaction time is 3-6 hours.

Preferably, in step B1, the solvent C is one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane or toluene; the mass ratio of the solvent C to the compound shown in the formula IV is (5-25) to 1; preferably, the mass ratio of the solvent C to the compound of the formula IV is (7-15): 1.

Preferably, in step B1, the Grignard reagent 1,1,2, 2-tetraalkoxybutyl-4-magnesium halide is prepared from 1,1,2, 2-tetraalkoxy-4-halobutane and magnesium metal, wherein the molar ratio of the magnesium metal, the 1,1,2, 2-tetraalkoxy-4-halobutane and the compound of formula IV is (1.0-1.5): 1.0-1.4): 1.

Preferably, according to the present invention, in the step B1, the Grignard reaction temperature is 10 to 80 ℃, and more preferably, the Grignard reaction temperature is 30 to 60 ℃. The Grignard reaction time is 2-8 hours; preferably the Grignard reaction is carried out for 3 to 5 hours; in the step B1, the acidification reaction temperature is 20-100 ℃, and more preferably, the acidification reaction temperature is 40-80 ℃; the time of the acidification reaction is 1-7 hours, and preferably, the acidification reaction is 3-5 hours.

Preferably, in step B2, the 2-substituent ethylamine hydrochloride is 2-methylsulfonylethylamine hydrochloride or 2-methylsulfonylethylamine hydrochloride; in step B2, the organic base is diisopropylethylamine, triethylamine, tri-n-propylamine or tri-n-butylamine; in step B2, the reducing agent is sodium triacetoxyborohydride.

According to a preferred embodiment of the invention, in step B2, the molar ratio of the 2-substituted ethylamine hydrochloride, the organic base, the reducing agent and the compound of the formula I1 is (1.0-2.0): (1.0-1.5): (1.5-2.5): 1.

Preferably, in step B2, the imidization temperature is 20-100 ℃, and more preferably, the imidization temperature is 40-70 ℃. The imidization reaction time is 0.5 to 3.0 hours; the preferred imidization time is 1-2 hours;

according to the invention, in the step B2, the reaction temperature of the reduction imine is preferably 0-60 ℃, and the reaction temperature of the reduction imine is further preferably 15-30 ℃; the reaction time of the reduction imine is 0.5-5 hours, and preferably, the reaction time of the reduction imine is 1-2 hours.

The present invention is depicted as the following synthetic scheme 5:

wherein: x is chlorine or bromine, R, R₁、R₂、R₃、R₄Each independently is one of methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl or sec-butyl.

Synthesis scheme 5

The invention has the technical characteristics and beneficial effects that:

1. the invention provides a preparation method of 6-substituent furyl-4-substituted amino quinazoline, which comprises the steps of carrying out amidation reaction on 2-halogeno-5-cyanobenzoate and 3-chloro-4- (3-fluorobenzyloxy) aniline to obtain N- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] -2-halogeno-5-cyanobenzamide, and carrying out substitution and condensation reaction on the N- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] -2-halogeno-5-cyanobenzamide and formamidine salt to obtain a key intermediate 6-cyano-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] amino quinazoline. The related quinazoline derivative can be prepared by the following two schemes, wherein the scheme A utilizes 6-cyano-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] amino quinazoline and Grignard reagent 1, 1-dialkoxypropyl-3-magnesium halide to carry out Grignard reaction and acidification reaction for furan cyclization to obtain 6- (furan-2-yl) -4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] amino quinazoline, and then the 6- (furan-2-yl) -4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] amino quinazoline and 2-methylsulfonylethylamine hydrochloride or 2-methylsulfonylethylamine hydrochloride and formaldehyde are subjected to Mannich reaction to prepare lapatinib or neritinib. Scheme B utilizes 6-cyano-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline and Grignard reagent 1,1,2, 2-tetraalkoxybutyl-4-magnesium halide to prepare 6- (5-formylfuran-2-yl) -4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline through Grignard reaction and acidification furan cyclization, and prepares lapatinib or talatinib through reductive amination reaction according to the prior art (such as synthetic scheme 1) and 2-methylsulfonylethylamine hydrochloride or 2-methylsulfonylethylamine hydrochloride and a reducing agent.

2. In the reaction route of the invention, the reaction activity and the reaction specificity of each step are high, for example, the amidation reaction of 2-halogeno-5-cyanobenzoate and 3-chloro-4- (3-fluorobenzyloxy) aniline has the advantages of specific selectivity, environment-friendly operation and high reaction controllability. And the substitution and condensation reaction of formamidine salt is benefited by the activation of para-cyano, so that the substitution reaction is easy to carry out, and the 6-cyano-4- [ 3-chloro-4- (3-fluorobenzyloxy) phenyl ] aminoquinazoline is further obtained by dehydration condensation, and the product stability is high. The Grignard reaction substrate is stable, the reaction of only cyano group and Grignard reagent exists, and furyl or 5-formyl furyl functional group can be introduced at the 6-position according to the used Grignard reagent. The lapatinib or ceratinib is prepared by utilizing the high electron cloud density Mannich reaction of the adjacent position of furan epoxy atoms, and the reaction activity and the reaction specificity are high.

3. The raw materials used in the invention are cheap and easily available, and the obtained intermediate has high stability, high safety and operability, high product purity and low cost, and is beneficial to industrialization.

Detailed Description

The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.