KR101345471B1 - Process for Preparing 3,4-Dihydroquinazoline Derivative and Intermediate therefor - Google Patents

Abstract

The present invention relates to a process for producing 3,4-dihydroquinazolin derivatives economically and efficiently and to novel intermediates therefor.

Description

Process for preparing 3,4-dihydroquinazoline derivatives and intermediates therefor {Process for Preparing 3,4-Dihydroquinazoline Derivative and Intermediate therefor}

The present invention relates to a process for the preparation of 3,4-dihydroquinazoline derivatives and intermediates therefor. More specifically, the present invention relates to a process for producing 3,4-dihydroquinazoline derivatives economically and efficiently and to novel intermediates therefor.

3,4-dihydroquinazoline derivative of the general formula (1) is a compound developed by the present inventors has been reported to exhibit an excellent anti-cancer effect through T-type calcium channel blocking [Reference: Korean Patent No. 10- 0902145].

[Formula 1]

It is known that the compound can be prepared by the method disclosed in Scheme 1 below.

[Reaction Scheme 1]

However, this method is very unstable for long time storage of the intermediate azaphosphoran (iii) completely separated, 4-biphenylyl isocyanate used for the reaction with azaphosphoran is a very expensive reagent and the purification method of the reaction mixture is also a large amount There was a problem using column chromatography to be avoided in the production process. In addition, there is a problem that takes a long time for the final step of removing the benzyl group and the reduction amination reaction (reductive amination).

The present inventors have studied diligently to solve the above problems in the synthesis of 3,4-dihydroquinazoline derivatives, a new method that can be produced more efficiently and economically to 3,4-dihydroquinazoline derivatives Developed.

Accordingly, it is an object of the present invention to provide a method for economically and efficiently preparing 3,4-dihydroquinazolin derivatives.

Another object of the present invention is to provide novel intermediates for the preparation of 3,4-dihydroquinazoline derivatives.

The present invention relates to a method for preparing a 3,4-dihydroquinazoline derivative of the following formula (1),

(i) esterifying the 2-nitrocinnamic acid of Formula 2 with methanol and then reducing the nitro group to obtain methyl 2-aminocinnamate of Formula 3;

(ii) reacting methyl 2-aminocinnamate of Formula 3 with biphenyl-4-carboxylic acid and diphenylphosphoryl azide to obtain a urea compound of Formula 4;

(iii) dehydrating the urea compound of formula 4 to obtain a carbodiimide compound of formula 5;

(iv) reacting a carbodiimide compound of formula 5 with a diamine of formula 6 to obtain a dihydroquinazolin ester compound of formula 7; And

(v) reacting the dihydroquinazolin ester compound of formula (7) with benzylamine.

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

[Formula 7]

[Formula 1]

Hereinafter, the production method of the present invention will be described in more detail with reference to Scheme 2 below.

[Reaction Scheme 2]

First Step: Synthesis of Methyl 2-aminocinnamate of Formula 3

Methyl 2-aminocinnamate of Formula 3 is prepared by esterifying 2-nitrocinnamic acid of Formula 2 with methanol and then reducing the nitro group.

The esterification reaction is preferably carried out in the presence of an acid catalyst. As the acid catalyst, sulfuric acid, hydrochloric acid, nitric acid, etc. may be used, but is not limited thereto. The reaction temperature is most preferably the reflux condition of methanol.

In addition, in order to avoid the reduction of the double bond, the reduction reaction of the nitro group is particularly preferable to use SnCl _{2 ˙} 2H ₂ O. Ethyl acetate may be used as the reaction solvent.

Second Step: Synthesis of Urea Compound of Formula 4

When methyl 2-aminocinnamate of formula 3 is reacted with biphenyl-4-carboxylic acid and diphenylphosphoryl azide (DPPA), the urea compound of formula 4 is obtained by Curtius rearrangement. Is generated.

The reaction is preferably carried out in the presence of a base. Triethylamine, diisopropylethylamine, etc. may be used as the base, but is not limited thereto. Toluene, xylene, benzene and the like may be used as the reaction solvent, and the reaction temperature is preferably from room temperature to 100 ° C.

Third Step: Synthesis of Carbodiimide Compound of Formula 5

The carbodiimide compound of Formula 5 is prepared by dehydrating the urea compound of Formula 4.

The dehydration reaction is carried out in the presence of PPh ₃ · Br ₂ or CBr ₄ / Ph ₃ P and Et ₃ N.

Methylene chloride, chloroform and the like may be used as the reaction solvent, and the reaction temperature is preferably 0 ° C.

Fourth Step: Synthesis of Dihydroquinazoline Ester Compound of Formula 7

Reaction of the carbodiimide compound of formula 5 with the diamine of formula 6 produces a dihydroquinazolin ester compound of formula 7 through a continuous nucleophilic reaction and intramolecular conjugate addition reaction.

Toluene, benzene and the like may be used as the reaction solvent, and the reaction temperature is preferably room temperature.

Step 5: Synthesis of Dihydroquinazoline Derivative of Formula 1

Dihydroquinazoline derivatives of Formula 1 are prepared by reacting the dihydroquinazoline ester compound of Formula 7 with benzylamine.

The reaction is carried out in the presence of 1,5,7-triazabicyclo [4.4.0] dec-5-ene (1,5,7-triazabicyclo [4.4.0] dec-5-ene: TBD). desirable.

As for reaction temperature, normal temperature-60 degreeC is preferable.

On the other hand, the present invention relates to a diamine of formula (6) which is a novel intermediate for the preparation of 3,4-dihydroquinazoline derivative of formula (1).

[Chemical Formula 6]

 The diamine of Chemical Formula 6 may be prepared as shown in Scheme 3 below.

Scheme 3

The 1,5-diaminopentane of Chemical Formula 8 is reacted with 2 equivalents of di-t-butyl dicarbonate and then reduced to obtain a compound of Chemical Formula 9 having methyl groups introduced into two terminal groups, respectively, The compound of Formula 1 may be reacted with 1.5 equivalents of di-t-butyl dicarbonate to obtain a compound of Formula 10, and then the compound of Formula 10 may be reduced to prepare a diamine of Formula 6.

Preferably, the reduction reaction uses LiAlH _4, and the reaction of the compound of Formula 9 with di-t-butyl dicarbonate is preferably performed in the presence of HCl.

According to the preparation method of the present invention, the 3,4-dihydroquinazoline derivative of the formula (1) can be prepared in a high yield by a shorter process than a known method. In addition, the manufacturing method of the present invention is drastically shortened the process time without using expensive reagents, it is economical and suitable for mass production.

Hereinafter, the present invention will be described in more detail with reference to Examples. It should be apparent to those skilled in the art that these embodiments are for illustrative purpose only and that the scope of the present invention is not limited to these embodiments.

Example 1 Synthesis of Methyl 2-aminocinnamate (3)

To a solution of 2-nitrocinnamic acid (2) (3.00 g, 15.53 mmol) dissolved in CH ₃ OH (100 mL) was added dropwise 95% H ₂ SO ₄ (0.25 mL, 4.66 mmol) at room temperature, and over 12 hours (overnight). The reaction was refluxed and then cooled to room temperature. After adding saturated aqueous NaHCO ₃ solution and extracting with dichloromethane, the organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure to obtain 3.21 g (99%) of methyl 2-nitrocinnamate as a yellow solid.

The resulting methyl 2-nitrocinnamate (3.21 g, 15.53 mmol) was dissolved in EtOAc (100 mL) and SnCl ₂ .2H ₂ O (17.52 g, 77.65 mmol) was added at room temperature, and then the reaction mixture was refluxed for 1 hour. . After cooling to room temperature, NaHCO ₃ was added to the reaction mixture, and the mixture was filtered through celite. The water layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO _4, and the solvent was removed under reduced pressure to yield 2.70 g (98%) of the title compound as a yellow solid.

Mp 67 ^o C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, J = 15.9 Hz, 1H, -CC H = CH-), 7.44-6.76 (m, 4H, aromatic), 6.39 (d, J = 15.8 Hz, 1H, -C-CH = C H- ), 3.83 (s, 3H, -OC H ₃ );

¹³ CNMR (100 MHz, CDCl ₃ ) δ 167.7, 145.6, 140.3, 131.3, 128.1, 119.8, 118.9, 117.7, 116.8, 51.7.

Example 2: Synthesis of Methyl 3- [2- (3-biphenylureido) phenyl] acrylate (4)

In a solution of biphenyl-4-carboxylic acid (5.00 g, 23.96 mmol) dissolved in anhydrous toluene (100 mL), Et ₃ N (6.66 mL, 47.93 mmol) and diphenylphosphoryl azide (DPPA, 10.36 ml, 47.93 mmol) ) Was placed under argon gas. The mixture was stirred at room temperature for 3 hours and again at 100 ^° C. for 3 hours. After cooling to room temperature, compound (3) (4.25 g, 23.96 mmol) obtained in Example 1 was added thereto, and the mixture was stirred at room temperature for 12 hours. The solvent of the reaction mixture was removed and the solid residue was washed with CH ₃ OH to give 7.14 g (80%) of the title compound as a white solid.

Mp 189 ^o C;

¹ H NMR (400 MHz, acetone- d ₆ ) δ 8.54 (s, 1H, -N H -CO-), 8.08 (s, 1H, -N H -CO-), 7.95-7.17 (m, 13H, aromatic ), 7.96 (d, 1H, J = 16 Hz, -CC H = CH-), 6.52 (d, 1H, J = 16 Hz, -CH = C H -CO-), 3.77 (s, 3H, -OC H ₃ );

^{13 C NMR (100 MHz, DMSO-} d 6) δ 169.9, 152.1, 140.4, 139.5, 137.9, 137.0, 128.9, 128.5, 127.8, 127.4, 127.0, 126.6, 125.6, 121.4, 120.9, 113.8, 59.0, 51.4.

Example 3: Synthesis of Methyl 3- [2- (3-biphenyliminomethyleneamino) phenyl] acrylate (5)

Dibromotriphenylphosphorane (8.50) was dissolved in a solution of compound (4) (5.00 g, 13.43 mmol) and Et ₃ N (5.62 mL, 40.28 mmol) obtained in Example 2 in CH ₂ Cl ₂ (100 mL). g, 20.14 mmol) was added at 0 ° C. and stirred at the same temperature for 12 hours. Water (50 mL) was added, extracted with CH ₂ Cl ₂ , and dried over anhydrous MgSO ₄ . The solid obtained by removing the solvent under reduced pressure was washed with CH ₃ OH to give 3.65 g (77%) of the title compound.

Mp 105-106 ^o C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, 1H, J = 16 Hz, -CC H = CH-), 7.61-7.17 (m, 1 3H, aromatic), 6.53 (d, 1H, J = 16 Hz, -CH = C H -CO-), 3.82 (s, 3H-OC H ₃ );

¹³ C NMR (100 MHz, CDCl ₃ ) δ 167.4, 140.3, 140.2, 138.8, 138.1, 136.9, 131.1, 128.9, 128.7, 128.2, 127.8, 127.5, 127.4, 126.9, 12.8, 125.8, 124.7, 119.3, 51.8.

Example 4: Synthesis of N, N-dimethyl-N'-methylpentane-1,5-diamine (6)

1,5-diaminopetane (8) (3.0 g, 29.4 mmol) was dissolved in dry THF (100 mL), and then di-t-butyl dicarbonate (12.8 g, 58.7 mmol) was added dropwise in dry THF. The reaction was carried out at room temperature for 24 hours. Then LiA1H ₄ (8.9 g, 0.23 mol) was slowly added in the presence of an ice container. After the LiA1H ₄ both into, and the mixture was refluxed for 12 hours. After 12 hours, excess LiA1H ₄ was slowly destroyed with 10 mL of water in the presence of an ice container. Then, 10 mL of 15% NaOH aqueous solution was added thereto, and 30 mL of water was added thereto, followed by stirring. After filtration through celite, the filtrate was reduced under reduced pressure to give compound (9) (2.0 g, 60%).

The crude compound (9) (2.0 g, 15.4 mmol) was dissolved in methanol (50 mL), and then 3N hydrochloric acid (5.2 mL) was slowly added dropwise and stirred for 30 minutes. Then 1.5 equivalents of di-t-butyl dicarbonate (5.0 g, 23.1 mmol) was slowly added dropwise. After the reaction for 1 hour, the solvent was removed under reduced pressure when the reaction is complete. The product was extracted into the water layer using ether / water in the reaction mixture. The obtained water layer was basified with NaOH and extracted with CH ₂ Cl ₂ . The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound (10) (1.88 g, 53%).

After dissolving compound (10) (1.88 g, 8.12 mmol) in dry THF, 4 equivalents of LiA1H ₄ (1.24 g, 32.7 mmol) was slowly added in the presence of an ice container. After adding all LiA1H ₄ it was refluxed for 12 hours. After 12 hours, excess LiA1H ₄ was slowly destroyed with 1 mL of water in the presence of an ice container. Then, 1 mL of 15% NaOH aqueous solution was added, 5 mL of water was added thereto, followed by stirring. After filtration through celite, the filtrate was reduced under reduced pressure to give 351 mg (30%) of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 2.93 (t, J = 7.2 Hz, 2H, -CH₂-C H ₂-NH-CH₃), 2.74 (t, J = 7.2 Hz, 2H, (CH₃) ₂-NC H ₂-CH₂-), 2.65 (s, 3H, -NH-C H ₃), 2.55 (s, 6H, (C H ₃) ₂-N-), 1.41-1.32 (m, 6H, -CH₂- CH ₂ -CH ₂- CH ₂-CH₂-).

Example 5: 3-biphenyl-4-yl-2-[(5-N, N-dimethylaminopentyl) -N'-methylamino] -4-methoxycarbonylmethyl-3,4-dihydroquina Synthesis of sleepy 7

N, N-dimethyl-N'-methylpentane-1,5 obtained in Example 4 in a solution of compound (5) (0.53 g, 1.48 mmol) obtained in Example 3 in toluene (20 mL) at room temperature. -Diamine (6) (0.88 g, 2.97 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, then basified with 1N NaOH and extracted with CH ₂ Cl ₂ . The organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. Flash column chromatography (EtOAc / n -hexane / CH ₂ Cl ₂ = 1: 2: 1) afforded 0.74 g (99%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.50-6.88 (13H, m, Ph), 5.11 (1H, dd, J = 10.4 and 4.8 Hz, COCH ₂ C H ), 3.76 (1H, s, C H ₃ -O), 3.50-3.20 (2H, m, CH ₃ NC H ₂ ), 2.88-2.81 (4H, C H ₃ -N and COC H ), 2.52 (1H, dd, J = 15.6 and 4.8 Hz, COC H ), 2.30-2.29 (2H, m, -NC H ₂ ), 2.26 (6H, s, 2 × NC H ₃ ), 1.65-1.35 (4H, m, 2 × C H _2- ), 1.25-1.10 ( 2H, m, C H _2- ).

Example 6: 4- (N-benzylacetamino) -3- (biphenyl-4-yl) -2-N '-(5-N ", N" -dimethylaminopentyl) -N-methyl-amino- Synthesis of 3,4-dihydroquinazoline (1)

Compound (7) obtained in Example 5 (0.5 g, 0.77 mmol) and benzylamine (0.2 mL, 1.84 mmol) and 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD, 0.03 g, 0.23 mmol) was stirred at 40 ° C. for 12 h and then the solvents were removed under reduced pressure. Flash column chromatography (CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH = 100: 9: 1) afforded 0.38 g (89%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72-6.98 (18H, m, Ph), 5.32 (1H, dd, J = 9.1 and 4.6 Hz, COCH ₂ C H ), 4.50 (2H, d, J = 5.8 Hz, PhC H _2- ), 3.50-3.20 (2H, m, CH ₃ NC H ₂ ), 2.71-2.33 (4H, C H ₃ -N and COC H ), 2.44 (1H, dd, J = 14.5 and 5.2 Hz, COC H ), 2.30-2.29 (2H, m, -NC H ₂ ), 2.21 (6H, s, 2C NC H ₃ ), 1.65-1.35 (4H, m, 2xC H ₂ ), 1.25-1.10 (2H , m, C H ₂ );

¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.1, 153.9, 145.3, 143.8, 140.4, 138.4, 136.7, 128.8, 128.6, 128.1, 128.0, 127.8, 127.4, 127.1, 127.0, 126.2, 125.1, 122.8, 122.4, 122.2 , 61.2, 59.7, 49.5, 45.2, 43.8, 41.8, 35.3, 27.1, 27.0, 24.7;

MS (FAB +), m / z (relative intensity,%) 596.7 ([M + Na] ⁺ , 100), 574.7 ([M + H] ⁺ , 30);

MS (FAB-), m / z (relative intensity,%) 572.7 ([M−H] ⁺ , 100);

HRMS (FAB +) calcd for C ₃₇ H ₄₄ N ₅ O: [M + H] ⁺ = 574.3546, found = 574.3516.

Claims (10)

(i) esterifying the 2-nitrocinnamic acid of Formula 2 with methanol and then reducing the nitro group to obtain methyl 2-aminocinnamate of Formula 3;
(ii) reacting methyl 2-aminocinnamate of Formula 3 with biphenyl-4-carboxylic acid and diphenylphosphoryl azide to obtain a urea compound of Formula 4;
(iii) dehydrating the urea compound of formula 4 to obtain a carbodiimide compound of formula 5;
(iv) reacting a carbodiimide compound of formula 5 with a diamine of formula 6 to obtain a dihydroquinazolin ester compound of formula 7; And
(v) A process for preparing a 3,4-dihydroquinazolin derivative of formula 1 comprising reacting a dihydroquinazolin ester compound of formula 7 with benzylamine:
(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 1]

The process according to claim 1, wherein the esterification reaction in step (i) is carried out in the presence of an acid catalyst. The process according to claim 2, wherein the acid catalyst is sulfuric acid, hydrochloric acid or nitric acid. The process according to claim 1, wherein in step (i) the reduction reaction is carried out using SnCl _2˙ 2H ₂ O. The process according to claim 1, wherein the reaction of step (ii) is carried out in the presence of a base. A process according to claim 5, wherein the base is triethylamine or diisopropylethylamine. The process according to claim 1, wherein the dehydration reaction of step (iii) is carried out in the presence of PPh ₃ · Br ₂ or CBr ₄ / Ph ₃ P and Et ₃ N. The process according to claim 1, wherein the reaction of step (iv) is carried out in the presence of 1,5,7-triazabicyclo [4.4.0] dec-5-ene. delete delete