KR101950942B1 - Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one - Google Patents

Abstract

The present invention relates to a process for the preparation of the desired 1- (4- (4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one is much simpler than the conventional method.

Description

6-yloxy) piperidin-l-yl) prop-2-en-1 -yl) -pyridin- 1-YL) PROP-2-EN-1-YLP METHOD FOR PREPARING 1- (4- (3,4- DICHLORO-2-FLUOROPHENYLAMINO) -7- METHOXYQUINAZOLIN-6-YLOXY) PIPERIDIN- 1-ONE}

The present invention relates to a pharmaceutical composition comprising 1- (4- (4- (3,4-dichloro-4-fluoropyrimidin-4-yl) 2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1-yl) prop-2-en-1-one in a much simpler manner than the conventional method .

(4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin- 1 -yl) Prop-2-en-1-one hydrochloride has an antiproliferative activity such as anticancer activity and is an important drug that can selectively and effectively treat the resistance of a drug induced by tyrosine kinase mutation. 1- (4- (4-Dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidin-1- Yl) prop-2-en-1-one was prepared according to CAS Registry no. It is known as 1092364-38-9.

The compound of Formula 1 may be prepared according to the method described in Korean Patent Registration No. 1013319, and the specific preparation process is shown in Reaction Scheme 1 below. The hydrochloride of Formula 4 can be prepared by reacting the compound of Formula 1 (Compound I) prepared according to Reaction Scheme 1 with hydrochloric acid:

[Reaction Scheme 1]

Wherein R is halogen.

According to the preparation method as shown in Reaction Scheme 1, Compound X is condensed with formamidine hydrochloride at a high temperature, for example, 210 ° C. to obtain Compound IX, which is then reacted with L-methionine To remove the methyl group at the C-6 position of the compound IX to give the compound of the formula VIII.

Then, compound VIII is protected by a base such as pyridine and acetic anhydride to obtain compound VII, which is then reacted with an inorganic acid such as thionyl chloride and phosphorus oxychloride in the presence of a catalytic amount of N, N -dimethylformamide Lt; RTI ID = 0.0 > VI < / RTI >

The obtained compound VI was stirred in an ammonia-containing alcohol solution (for example, a methanol solution containing 7 N ammonia) to deprotect the acetyl group to obtain a compound V, which was treated with tert -butyl 4-hydroxypiperidine-1-carboxylate (Compound IV), followed by substitution reaction with aniline in an organic solvent such as 2-propanol or acetonitrile to prepare compound III, which is reacted with trifluoroacetic acid in an organic solvent such as dichloromethane The t-butoxycarbonyl group is deprotected by reacting with an inorganic acid such as an organic acid or concentrated hydrochloric acid to obtain Compound II. In the Mizunobu reaction, diisopropyl azodicarboxylate, diethyl azodicarboxylate or di-t-butyl azodicarboxylate, and triphenylphosphine may be used.

Compound II thus obtained is acylated with acryloyl chloride in the presence of an inorganic base such as sodium hydrogencarbonate or an organic base such as pyridine or triethylamine in a mixed solvent of an organic solvent such as tetrahydrofuran and water or dichloromethane, (EDC) or 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl-europium hexa Fluorophosphate Compound (I) (compound of formula (1) of the present invention) can be prepared by condensation reaction with acrylic acid using a coupling agent such as methanaminium (HATU).

However, according to the above method, there is a problem that the process of preparing Compound IX is dangerous because the process is performed at a high temperature without a solvent, and the reaction does not proceed uniformly. Further, since the thionyl chloride is excessively used in the process of preparing the compound V, there is a disadvantage in that it is difficult to perform a post-treatment process and it is not suitable for application on an industrial scale.

The biggest problem in preparing the compound I according to the above method is that the yield of the acrylation reaction is as low as 13% and the side reaction occurs much, so that the purification by the column chromatography must be performed. In addition, when the compound III is produced through the Mizunobu reaction, many by-products are produced, and it is difficult to apply it on an industrial scale because a column chromatography purification process requiring the use of expensive silica gel and a large amount of developing solvent is required.

Accordingly, the present inventors have completed the present invention by finding a novel production method capable of producing a compound of the formula (1) at a high purity and a high yield as well as being suitable for economic and industrial scale applications.

Korean Patent Registration No. 1013319

Accordingly, an object of the present invention is to provide a process for the preparation of 1- (4- (4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6- yloxy) piperidin- Prop-2-en-1-one.

In order to achieve the above object,

Claims 1. A process for preparing a compound of formula (1), which comprises reacting a compound of formula (2): EMI2.1 in the presence of a base in an inert polar aprotic solvent with a compound of formula

[Chemical Formula 1]

In this formula,

X is tosyloxy (OTs), mesyloxy (OMs), trifluoromethanesulfonate, fluorosulfonate or halogen;

Y is ethenyl or halogenoethyl.

According to the preparation method of the present invention, the desired (1- (4- (4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yloxy) piperidine- 1-yl) prop-2-en-1-one can be very easily produced with high yield and high purity.

According to the process of the present invention, the compound of formula (2) [4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-ol] is reacted in an inert polar aprotic solvent with a base To obtain the desired compound of formula (1) [(1- (4- (4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin- Yl) prop-2-en-1-one], which can be represented by the following reaction formula 2:

[Reaction Scheme 2]

In this formula,

X and Y are as defined above.

Specific examples of the inactive polar aprotic solvent used in the present invention include N, N -dimethylformamide, N, N -dimethylacetamide, N -methylpyrrolidin-2-one, dimethylsulfoxide, .

Specific examples of the base used in the present invention include sodium hydrogencarbonate, potassium carbonate, cesium carbonate and mixtures thereof, and the base is used in an amount of 1 to 5 molar equivalents based on 1 molar equivalent of the compound of the formula (2) desirable.

The reaction may be carried out at a temperature of 60 ° C to 100 ° C, preferably 70 ° C to 90 ° C, more preferably 70 ° C to 80 ° C.

The compound of formula (2) used as a starting material in the present invention can be prepared by reacting a compound of formula (7) with a halogenating agent in the presence of an organic base to produce a compound of formula (6) To give a compound of formula (5) [4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yl acetate]; And (ii) reacting the resulting compound of formula (5) with ammonia water in a polar protic solvent (see Scheme 3 below): < EMI ID =

[Reaction Scheme 3]

Specific examples of the organic base used in the step (i) include diisopropylamine, triethylamine, diisopropylethylamine, diethylamine, pyridine, 4-dimethylpyridine, morpholine, and mixtures thereof . Specific examples of the halogenating agent include thionyl chloride, phosphorus oxychloride, and mixtures thereof. The reaction may be carried out at a temperature of from 50 ° C to 150 ° C, preferably from 60 ° C to 90 ° C, most preferably at a temperature of about 75 ° C, in which the compound of formula (6) is prepared in an organic solvent It does not separate itself. The compound of formula 6 in the form of an organic solvent is then reacted with a compound of formula 8 to form 4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6- Diacetate can be produced.

The compound of formula (7) used as a starting material in the above can be prepared according to the method described in Korean Patent Registration No. 1013319.

Then, in step (ii), the compound of formula 5 prepared in step (i) is reacted with ammonia water or ammonia gas in a polar protic solvent (e.g., methanol, ethanol, propanol, (4-chloro-2-fluorophenylamino) -7-methoxyquinazoline of formula (II) is reacted at a temperature of from -40 to 40 캜, 6-ol can be prepared.

The compound of formula (3) used as a starting material in the present invention can also be prepared by reacting a compound of formula (9) or a salt thereof with a compound of formula (10) in the presence of a base or amide coupling agent (see Scheme 4 below) :

[Reaction Scheme 4]

In this formula,

X and Y are as defined above;

Z is halogen or hydroxy.

The reaction may be carried out in an organic solvent such as tetrahydrofuran, ethyl acetate, acetone, 1,4-dioxane, acetonitrile, dichloromethane, carbon tetrachloride, chloroform, N, N -dimethylformamide or dimethylsulfoxide, Can be carried out in a mixed solvent.

Specific examples of the base include inorganic bases such as sodium carbonate, sodium hydrogencarbonate, calcium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and cesium carbonate, and organic bases such as diisopropylamine, triethylamine, diisopropylethylamine and diethylamine And specific examples of the amide coupling agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, hydroxybenzotriazole, O- (7- Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphite, N, N'-dicyclohexylcarbodiimide, 1 -hydroxy- Triazole, N, N'-diisopropylcarbodiimide, (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphite, and mixtures thereof. The base or amide coupling agent is preferably used in an amount of 3 to 5 molar equivalents based on 1 molar equivalent of the compound of the formula (9) or a salt thereof.

The salt of the compound of Formula 9 is preferably a hydrochloride salt (2HCl salt) or a hydrobromic acid salt (2HBr salt), and the reaction is carried out by stirring at an appropriate temperature at -30 ° C to 30 ° C, preferably at about 0 ° C to room temperature .

According to the method of the present invention as described above, the desired compound [1 - (4- (4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin- Yl) piperidin-1-yl) prop-2-en-1-one] can be prepared very easily with high yield and high purity.

Further, the compound of formula (I) thus prepared is dissolved in an organic solvent (for example, methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, acetone, tetrahydrofuran, acetonitrile, Which is capable of selectively and effectively inhibiting the resistance of a drug caused by mutation of tyrosine kinase and growth of cancer cells by reacting with hydrochloric acid at a temperature of from 60 to 60 DEG C, preferably from 10 to 40 DEG C, most preferably at about 25 DEG C. 6-yloxy) piperidin-l-yl) prop-2-en-1 -yl) -pyridin- 1-one hydrochloride can be obtained.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Manufacturing example 1: 4 - (3,4- Dichloro -2- Fluorophenylamino ) -7- Methoxyquinazoline 6-ol (compound of formula 2)

Step (i) Preparation of 4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yl acetate (compound of formula 5)

100 g of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate was added to 850 ml of toluene and 82.5 ml of N, N -diisopropylethylamine, 100 ml of chloride were added for 20 minutes and then stirred for 3 hours. 450 ml of toluene was further added to the resulting reaction solution, 84.6 g of 3,4-dichloro-2-fluoroaniline was added, and the mixture was stirred for 2 hours. When the reaction was completed, the temperature of the reaction solution was cooled to 25 ° C, and the resulting solid was filtered under reduced pressure and washed with 400 ml of toluene. 1000 ml of isopropanol was added to the obtained solid, and the mixture was stirred for 2 hours. The solid was filtered and washed with 400 ml of isopropanol. The obtained solid was dried in a drying oven at 40 占 폚 to obtain the title compound (143 g, yield 83%).

^{1 H-NMR (DMSO-d} 6, 300 MHz, ppm) δ 8.92 (s, 1H), 8.76 (s, 1H), 7.69-7.57 (m, 3H), 4.01 (s, 3H), 2.38 (s, 3H).

Step (ii) Preparation of 4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-ol (compound of formula 2)

100 g of the 4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6-yl acetate prepared in the above step (i) and 1,000 ml of methanol were mixed, Was lowered to 10 to 15 DEG C, 460 g of ammonia water was added, and the mixture was stirred at 25 DEG C for 3 hours. The resulting solid was filtered and washed with a mixed solution of 200 ml of methanol and 200 ml of water. The obtained solid was dried in a drying oven at 40 占 폚 to obtain 74 g (yield 83%) of the title compound.

^{1 H-NMR (DMSO-d} 6, 300 MHz, ppm) δ 9.57 (br, 2H), 8.35 (s, 1H), 7.68 (s, 1H), 7.61-7.52 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H).

Example  1: (1- (4- (4- (3,4- Dichloro -2- Fluorophenylamino ) -7- Methoxyquinazoline -6-yloxy) piperidin-1-yl) prop-2-en-1-one

Step (1-1) Preparation of 1-acryloylpiperidin-4-yl 4-methylbenzenesulfonate (compound of formula 3a)

(200 g, 685 mmol), tetrahydrofuran (THF, 1.6 L) and NaHCO ₃ (172 g, 2047 mmol) were mixed with water (2 L) , And the temperature of the mixed solution was lowered to 0 캜. To this solution was slowly added acryloyl chloride (56 ml, 519 mmol) diluted in THF (0.4 L) for 30 minutes and stirred for 1 hour. After completion of the reaction, MeOH (0.4 L) was added to quench the reaction, extracted with ethyl ester (2 L), and washed with water (2 L). The organic layer was separated, vacuum distilled, and the obtained residue was recrystallized from dichloromethane and hexane to obtain 174 g (yield 82%) of the title compound.

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 7.82 (d, 2H), 7.48 (d, 2H), 6.80-6.71 (m, 1H), 6.10-6.03 (m, 1H), 5.67-5.62 ( 2H), 2.42 (s, 3H), 1.73 (m, 2H), 1.52 (m, 2H), 3.73-3. 2H).

Step (1-2) Synthesis of (1- (4- (4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6- yloxy) piperidin- Prop-2-en-1-one (compound of formula 1)

(12 g, 34 mmol) synthesized in Production Example 1 and 4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin- (16 g, 51 mmol), K ₂ CO ₃ (9.4 g, 68 mmol) and dimethylacetamide (DMAc, 300 ml) were mixed with the prepared 1-acryloylpiperidin-4-yl 4-methylbenzenesulfonate , The temperature of the mixed solution was raised to 70 캜 and stirred for 24 hours. After completion of the reaction, the temperature of the reaction mixture was cooled to room temperature, extracted with ethyl ester (300 ml), and washed with water (300 ml). The organic layer was separated and distilled under reduced pressure. Ethyl ester was added to the residue to solidify it, followed by filtration and drying to obtain the title compound (12.8 g, yield 77%).

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.65 (bs, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.64-7.56 (m, 2H), 7.24 (s, 1H) , 3.89 (s, 3H), 3.87 (m, 2H), 3.48 (m, IH) (m, 2 H), 2.03 (m, 2 H), 1.70 (m, 1 H).

Example  2: (1- (4- (4- (3,4- Dichloro -2- Fluorophenylamino ) -7- Methoxyquinazoline -6-yloxy) piperidin-1-yl) prop-2-en-1-one

Step (2-1) Preparation of 1- (3-chloropropanoyl) piperidin-4-yl 4-methylbenzenesulfonate (compound of Formula 3b)

4-yl 4-methylbenzenesulfonate hydrochloride (20 g, 68 mmol) and dichloromethane (200 ml) were mixed and the temperature of the mixture was lowered to 0 占 폚. To this solution was added triethylamine (29 ml, 205 mmol) and 3-chloropropionyl chloride (7.9 ml, 82 mmol), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl ester (200 ml) and washed with water (200 ml). The organic layer was separated, vacuum distilled, and the obtained residue was purified to obtain the title compound (18 g, yield 76%).

^{1 H-NMR (300 MHz,} CDCl 3) δ 7.80 (d, 2H), 4.76-4.72 (m, 1H), 3.80 (t, 2H), 3.64-3.57 (m, 3H), 3.40 (m, 1H) , 2.77 (t, 2H), 2.46 (s, 3H), 1.85 - 1.70 (m, 4H).

Step 2-2 Synthesis of (1- (4- (4- (3,4-dichloro-2-fluorophenylamino) -7-methoxyquinazolin-6- yloxy) piperidin- Prop-2-en-1-one (compound of formula 1)

The same procedure as described in the above step (2-1) was repeated but using 1- (3-methoxybenzenesulfonate) prepared in the step (2-1) instead of the 1-acryloylpiperidin- The title compound was prepared according to the procedure described in step (1-2) of Example 1, except that 4-methylbenzenesulfonate (13 g, 35 mmol) was used in place of 4-chlorophenoxy) g (yield: 58%).

^{1 H-NMR (300 MHz,} DMSO-d 6) δ 9.65 (bs, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.64-7.56 (m, 2H), 7.24 (s, 1H) , 3.89 (s, 3H), 3.87 (m, 2H), 3.48 (m, IH) (m, 2 H), 2.03 (m, 2 H), 1.70 (m, 1 H).

Claims (13)

Claims 1. A process for preparing a compound of formula (1), comprising reacting a compound of formula (2) in the presence of a base in an inert polar aprotic solvent with a compound of formula
[Chemical Formula 1]

(2)

(3)

In this formula,
X is tosyloxy (OTs), mesyloxy (OMs), trifluoromethanesulfonate, fluorosulfonate or halogen;
Y is ethenyl or halogenoethyl. The method according to claim 1,
Wherein is selected from dimethylacetamide, N- methylpyrrolidin-2-one, dimethyl sulfoxide and mixtures thereof - wherein the inert polar aprotic solvent, N, N-dimethylformamide, N, N Lt; RTI ID = 0.0 > (I) < / RTI > The method according to claim 1,
Wherein the base is an alkali metal carbonate selected from the group consisting of sodium hydrogencarbonate, potassium carbonate, cesium carbonate, and mixtures thereof. The method according to claim 1,
Wherein the base is used in an amount of 1 to 5 molar equivalents based on 1 molar equivalent of the compound of formula (2). The method according to claim 1,
(I) reacting a compound of the following formula (7) with a halogenating agent in the presence of an organic base to prepare a compound of the formula (6) and subsequently reacting it with a compound of the formula (8) Lt; / RTI > And (ii) reacting the compound of formula (5) thus prepared with ammonia water in a polar protic solvent to prepare a compound of formula (1): < EMI ID =
[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

6. The method of claim 5,
Wherein the organic base is selected from the group consisting of diisopropylamine, triethylamine, diisopropylethylamine, diethylamine, pyridine, 4-dimethylpyridine, morpholine and mixtures thereof. ≪ / RTI > 6. The method of claim 5,
Wherein the halogenating agent is selected from the group consisting of thionyl chloride, phosphorus oxychloride, and mixtures thereof. 6. The method of claim 5,
Wherein the polar protic solvent is selected from the group consisting of methanol, ethanol, propanol, and mixtures thereof. The method according to claim 1,
Wherein the compound of formula (3) is prepared by reacting a compound of formula (9) or a salt thereof with a compound of formula (10) in the presence of a base or amide coupling agent.
[Chemical Formula 9]

[Chemical formula 10]

In this formula,
X and Y are as defined in claim 1;
Z is halogen or hydroxy. 10. The method of claim 9,
The reaction is carried out in an organic solvent or an organic solvent and water mixed solvent, the organic solvent is tetrahydrofuran, ethyl acetate, acetone, 1,4-dioxane, acetonitrile, dichloromethane, carbon tetrachloride, chloroform, N, N - Lt; RTI ID = 0.0 > (I) < / RTI > is dimethylformamide or dimethylsulfoxide. 10. The method of claim 9,
Wherein the base is selected from the group consisting of sodium carbonate, sodium bicarbonate, calcium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, diisopropylamine, triethylamine, diisopropylethylamine, diethylamine and mixtures thereof ≪ RTI ID = 0.0 > 1. ≪ / RTI > 10. The method of claim 9,
The amide coupling agent may be selected from the group consisting of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, hydroxybenzotriazole, O- (7-azabenzotriazol- N'-tetramethyluronium hexafluorophosphite, N, N'-dicyclohexylcarbodiimide, 1-hydroxy-7-azabenzotriazole, N, N'-diisopropylcarbodiimide, 1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphite, and mixtures thereof. The method of claim 1, 10. The method of claim 9,
Wherein the salt of the compound of Formula 9 is a hydrochloride or hydrobromide.