JP2711728B2 - Novel quinoline derivative and method for producing the same - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel quinoline derivative, and more particularly to a novel quinoline derivative useful as a synthetic intermediate of a camptothecin derivative useful as an anticancer agent, and a method for producing the same.

[Conventional technology]

Camptotheca acuminat
Camptothecin isolated from bark, roots, fruits, leaves and the like in a) is a pentacyclic alkaloid and is known to exhibit antitumor activity by inhibiting nucleic acid synthesis.
And for the total synthesis of the camptothecin, see G. Stork
[J. Am. Chem. Soc., 93 , 4074 (1971)].

On the other hand, various studies have been made in search of compounds having better antitumor activity, and the following formula The compound represented by has excellent antitumor activity, and is known to be highly safe and useful as an anticancer agent (JP-A-58-39683; Jpn.J. Cancer Chemother., 14 , Part
-II, 850 (1985)].

[Problems to be solved by the invention]

However, the conventional method for producing the camptothecin derivative has a long number of steps, and is not industrially advantageous. Therefore, it has been desired to provide an industrially advantageous production method of the camptothecin derivative and a synthetic intermediate.

[Means for solving the problem]

Under such circumstances, the present inventors have intensively studied to solve the above-mentioned problems, and as a result, a novel quinoline derivative synthesized in a short process using p-anisidine as a raw material has been proposed as a synthetic intermediate of a camptothecin derivative excellent as the anticancer agent. The present invention was found to be useful, and the present invention was completed.

That is, the present invention provides the following general formula (I) [Wherein A represents C = O or CHOH, and R ¹ represents a hydrogen atom, an aralkyl group or a lower alkyl group] and a method for producing the same.

In the above general formula (I), the aralkyl group represented by R ¹ is preferably a benzene group; the lower alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, particularly preferably a t-butyl group. .

The novel quinoline derivative (I) of the present invention is produced, for example, according to the following reaction formula.

[In the reaction formula, R ² , R ³ , R ⁴ , R ⁶ and R ⁷ each represent a lower alkyl group, R ⁵ represents an aralkyl group, and X represents a halogen atom.] Will be described.

(1) By reacting p-anisidine (II) with propionitrile in the presence of boron chloride and aluminum chloride, 2-amino-5-methoxypropiophenone (II)
I) is obtained. This reaction is performed according to the method of Sugasawa et al. [J. Am. Chem. S.
oc., 100 , 4842 (1978)].

(2) The compound (V) is obtained by reacting 2-amino-5-methoxypropiophenone (III) with a pyrrolidine derivative (IV). This reaction is carried out by heating and refluxing in an aromatic hydrocarbon solvent such as toluene.

(3) Compound (VI) is obtained by heating compound (V) in the presence of a base such as potassium hydroxide. This reaction is
It is preferable to heat and reflux in a solvent such as ethanol or water.

(4) Compound (VI) is substituted with alkylmalonyl halide (VI
By reacting I), compound (VIII) is obtained. This reaction is preferably carried out in the presence of a base such as sodium hydrogen carbonate, sodium hydroxide, sodium carbonate and the like.

(5) Compound (IX) is obtained by reacting compound (VIII) with a base. As the base, a metal alcoholate such as sodium ethoxide is preferable.

(6) Compound (IX) is obtained by heating compound (IX) in the presence of an acid. Examples of the acid used include acetic acid.

(7) Compound (X) is reduced to obtain compound (XI).
The reduction is preferably carried out using sodium borohydride.

(8) If compound (XI) is heated in the presence of an acid,
Compound (XII) is obtained. As the acid used, a mixture of sodium acetate and acetic anhydride is preferred.

(9) Then, butyric acid derivative (XIII) is added to compound (XII).
Is reacted to produce compound (Ia). This reaction is carried out at a low temperature of -80 to 0 ° C in the presence of n-butyllithium or the like. The reaction solvent is preferably an ether such as tetrahydrofuran or a hydrocarbon such as n-hexane.

(10) By subjecting compound (Ia) to hydrogenolysis, compound (Ia)
b) is manufactured. The reaction is carried out by adding hydrogen in an alcohol solvent such as methanol in the presence of a catalyst such as palladium carbon.

(11) Next, an ester derivative (Ic) is produced by reacting a lower alcohol or an alkylating agent on the compound (Ib) or its reactive derivative.

(12) Further, compound (Id) can be produced by reducing (Ic) in an ether solvent such as tetrahydrofuran using a reducing agent such as lithium aluminum hydride.

〔The invention's effect〕

By using the novel quinoline derivative (I) of the present invention, a camptothecin derivative useful as an anticancer agent can be efficiently produced in a short process. Therefore, the compound of the present invention is useful as an intermediate for producing a camptothecin derivative.

〔Example〕

 Next, the present invention will be described in detail with reference to examples.

Example 1 (1) Synthesis of 2-amino-5-methoxypropiophenone (III): 615 mg (5 mmol) of anisidine was dissolved in 5 ml of benzene,
2.47 ml of a 2.22 mol benzene solution of BCl ₃ cooled on ice
(5.5 mmol). A white adduct of anisidine-BCl ₃ precipitates. Next, 500.8 mg (10 mmol) of propionitrile
And AlCl ₃ 733 mg of (5.5 mmol) was added, at room temperature BCl ₃ - After stirring dissolved anisidine adduct and AlCl _3, was heated under reflux for 6 hours. After cooling, 10 ml of 2N HCl was added, and the mixture was heated at 70 to 80 ° C. for 20 minutes to hydrolyze the reaction product. The reaction solution was neutralized with 10% NaOH, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (methylene chloride).
Then, 420 mg (47%) of yellow crystals of (III) were obtained.

Yellow needles: mp 58 ° C. (methylene chloride-n-hexane ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.3 Hz), 2.96 (2
H, q, J = 7.3Hz), 3.78 (3H, s), 6.63 (1H, d, J = 9.0Hz),
6,96 (1H, dd., J = 9.0,2.9Hz), 7.23 (1H, d, J = 2.9Hz) IR (CHCl ₃ ): 3500,1650cm ^-1 MS m / z: 179 (M ⁺ ) Element Analysis (as C ₁₆ H ₁₃ NO ₂ ) Calculated: C 67.04; H 7.26; N 7.82 Found: C 66.95; H 7.54; N 7.83 (2) Compound (V) [in formula (V), R ² = R ³ = C ₂ H _5]
Synthesis of 2-amino-5-methoxypropiophenone 358 mg (2
0 mmol) and 486 mg (20 mmol) of 1-ethoxycarbonyl-3-oxoprolidine-2-acetic acid ethyl ester are dissolved in 20 ml of toluene, 34 mg (2 mmol) of tosylic acid is added, and the mixture is added using a Dean-Stark apparatus. The mixture was heated under reflux for 8 hours. After the reaction, toluene was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride) to obtain 726 mg (94%) of the target compound (V) as colorless crystals.

Colorless needles: mp 85 ° C. (ether-n-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.09 (3H, t, J = 7.1 Hz), 1.33 (3
H, t, J = 7.6Hz), 1.35 (3H, t, J = 7.1Hz), 2.95 (2H, m),
3.21 (2H, m), 3.95 (3H, s), 4.06 (2H, m), 4.27 (2H,
m), 4.82 (2H, m), 5.32 (1H, m), 7.26 (1H, d, J = 2.7H
z), 7.34 (1H, dd., J = 9.1,2.7Hz), 7.96 (1H, d, J = 9.1H)
z) IR (CHCl ₃ ): 1730, 1690, 1620 cm ⁻¹ MS m / z: 386 (M ⁺ ) Elemental analysis (as C ₂₁ H ₂₆ N ₂ O ₅ ) Calculated: C 65.28; H 6.74; N 7.25 Value: C 65.09; H 6.91; N 7.24 (3) Synthesis of compound (VI [R ³ = C ₂ H _{5 in} formula (VI)]: 2 g (5.2 mmol) of compound (V) was dissolved in 20 ml of ethanol, and The ethanol was distilled off under reduced pressure and neutralized with a 10% HCl solution to precipitate a precipitate, which was collected by filtration and dried under vacuum. Dissolve in ethanol (20 ml) and pass HCl gas through.
Heated to reflux for an hour. After distilling off ethanol under reduced pressure, 10
When the solution was made alkaline with a% KOH solution, a precipitate was deposited and collected by filtration. The precipitate was recrystallized from ether-n-hexane to obtain 1.1 g (67%) of the desired product (VI).

Colorless powder: mp 86-87 ° C. (ether-n-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 1.30 (3
H, t, J = 7.3Hz), 2.64 (1H, dd., J = 16.4,10.0Hz), 2.96
(2H, q, J = 7.3Hz), 3.29 (1H, dd., J = 16.4, 2.9HZ), 3.9
5 (3H, s), 4.20 (2H, q, J = 7.3Hz), 4.40 (2H, s), 4.88
(2H, dd., J = 10.0,2.9Hz), 7.26 (1H, d, J = 2.5HZ), 7.3
2 (1H, dd., J = 9.0, 2.5 Hz), 7.96 (1H, d, J = 9.0 Hz) IR (CHCl ₃ ): 3350, 1720, 1630 cm ⁻¹ MS m / z: 314 (M ⁺ ) Element analysis (C ₁₈ H ₂₂ 0 ₃ as N ₂₎ calculated: C 68.79; H 7.01; N 8.92 Found: C 68.56; H 7.18; N 9.00 (4) in the compound (VIII) [formula (VIII), R ³ = R ⁴ = C ₂
Synthesis of H ₅ ]: 942 mg (3 mmol) of the compound (VI) was dissolved in 5 ml of benzene, and 3.3 ml of a 10% NaHCO ₃ solution was added. While stirring the reaction solution, 3 ml of a benzene solution of 541.8 mg (3.6 mmol) of ethylmalonyl chloride was added dropwise. After stirring the reaction solution for 1 hour at room temperature, the benzene layer was separated, washed with water and dried. Benzene was distilled off under reduced pressure, and the residue was recrystallized from methanol to obtain 1.1 g (86%) of the target compound (VIII).

Colorless powder: mp 105-106 ° C. (methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7.3 Hz), 1.30 (6
H, t, J = 7.3Hz), 2.98 (2H, m), 3.22 (1H, dd., J = 17.1,
3.4Hz), 3.53, 3.61 (each 1H, d, J = 15.1Hz), 3.63 (1H,
m), 3.90 (2H, m), 3.95 (3H, s), 4.25 (2H, q, J = 7.3H
z), 4.94,5.04 (each 1H, d, J = 13.3Hz), 5.48 (1H, m),
7.25 (1H, d, J = 2.7Hz), 7.35 (1H, dd., J = 9.3,2.7Hz),
7.98 (1H, d, J = 9.3Hz) IR (CHCl 3): 1730,1650,1632cm -1 MS m / z: 428 (M +) Elemental analysis (C ₂₃ H ₂₈ 0 as ₆ N ₂₎ Calculated: C 64.49; H 6.54; N 6.54 Found: C 64.22; H 6.71; N 6.56 (5) Synthesis of compound (IX) [in the formula (IX), R ⁴ = C ₂ H ₅ ]: Compound (VIII) 428 mg ( 1mmol) 10% 1% NaOEt solution
Was added and heated under reflux for 1 hour. After the reaction, ethanol was distilled off under reduced pressure, water was added, and the mixture was neutralized with a 10% HCl solution to produce a precipitate. The precipitate was collected by filtration and recrystallized from chloroform-methanol to obtain 290 mg (76%) of the desired product (IX).

Colorless powder: mp 165 ° C. (chloroform-methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.8 Hz), 1.44 (3
H, t, J = 7.3Hz), 2.84 (1H, dd., J = 17.1,3.4Hz), 3.02
(2H, q, J = 7.8Hz), 3.32 (1H, dd., J = 17.1,4.4Hz), 3.9
7 (3H, s), 4.43 (2H, m), 4.76 (1H, dJ = 16.1Hz), 5.13
(1H, d, J = 16.1Hz), 5.17 (1H, m), 7.28 (1H, d, J = 2.4H
z), 7.38 (1H, dd., J = 9.3,2.4Hz), 7.98 (1H, d, J = 9.3H)
z) IR (CHCl ₃ ): 1650, 1590 cm ⁻¹ MS m / z: 382 (M ⁺ ) (6) Synthesis of compound (X): 10 g of a 10% acetic acid solution was added to 1 g (2.6 mmol) of compound (IX). Heat for 30 minutes. The reaction solution was extracted with chloroform,
After washing with water and drying, chloroform was distilled off under reduced pressure. The residue is purified by silica gel cam chromatography (chloroform).
-Recrystallized from hexane-chloroform to give the desired product (IX)
543 mg (67%) were obtained.

Colorless powder mp 183-184 ° C (n-hexane-chloroform) ¹ H-NMR (CDCl ₃ ) δ: 1.35 (1H, t, J = 7.8 Hz), 2.57 (1
H, dd., J = 17.6,12.0Hz), 3.02 (2H, q, J = 7.8Hz), 3.42
(1H, d, J = 19.0Hz), 3.47 (1H, dd., J = 17.6,3.9Hz), 3.
60 (1H, d, J = 19.0Hz), 3.97 (3H, s), 4.83 (1H, d, J = 1
6.1Hz), 5.21 (1H, d, J = 16.1Hz), 5.32 (1H, d, J = 12.0,
3.9Hz), 7.28 (1H, dJ = 2.7Hz), 7.40 (1H, dd., J = 9.3,
2.7 Hz), 7.98 (1H, d, J = 9.3 Hz) IR (CHCl ₃ ): 1730, 1660, 1620 cm ⁻¹ MS m / z: 310 (M ⁺ ) (7) Synthesis of compound (XI): compound (XI) X) 310 mg (1 mmol) are dissolved in 10 ml of ethanol and, while stirring, 18.9 mg (0.5 mmol) of NaBH ₄ are added in small portions. After stirring for 1 hour at room temperature, ethanol is distilled off under reduced pressure, water is added, and neutralization with a 10% HCl solution causes precipitation. The precipitate was collected by filtration and recrystallized from chloroform-n-hexane to obtain 250 mg (80%) of the desired product (XI).

Colorless powder: mp 105-108 ° C (chloroform-n-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.6 Hz), 1.79 (1
H, m), 2.47 (1H, m), 3.02 (4H, m), 3.97 (3H, s), 4.45
(1H, m), 4.60 (1H, d, J = 16.1Hz), 4.86 (1H, m), 5,25
(1H, d, J = 16.1Hz), 7.27 (1H, d, J = 2.9Hz), 7.37 (1H,
dd., J = 9.0, 2.9 Hz), 7.99 (1H, d, J = 9.0 Hz) IR (CHCl ₃ ): 3400, 1620 cm ⁻¹ MS m / z: 312 (M ⁺ ) (8) Compound (XII) Synthesis of Compound (XI) 312 mg (1 mmol) to anhydrous sodium acetate 82
mg (1 mmol) and 1 ml of acetic anhydride are added, and the mixture is heated under a nitrogen stream for 1 hour. When the reaction solution is poured into ice water, a precipitate is formed. The precipitate was collected by filtration and recrystallized from chloroform-n-hexane to obtain 250 mg (85%) of the target compound (XII) as yellow crystals.

mp: 73-75 ° C. (n-hexane-ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.6 Hz), 2.51 (1
H, m), 3.01 (2H, q, J = 7.6Hz), 3.15 (1H, m), 3.97 (3H,
s), 5.14 (1H, d, J = 16.1Hz), 4.77 (1H, d, J = 16.1Hz),
5.21 (1H, m), 6.12 (1H, m), 6.74 (1H, m), 7.28 (1H, d,
J = 2.7Hz), 7.38 (1H, dd., J = 9.3,2.7Hz), 7.99 (1H, d,
J = 9.3 Hz) IR (CHCl ₃ ): 1660,1620,1600 cm ⁻¹ MS m / z: 294 (M ⁺ ) (9) Compound (Ia) [in the formula (Ia), R ⁵ = benzyl]
Synthesis of 1.09 ml (15 mmol) of diisopropylamine in 15 ml of tetrahydrofuran at 0 ° C. under a stream of nitrogen. Next, 9.26 ml of a 1.62 mol / l n-hexane solution of n-butyllithium (1
5 mmol) are added dropwise with stirring. 20 minutes later, the solution was cooled to −78 ° C. in a dry ice-acetone bath and a solution of 3.99 g (15 mmol) of benzyl α-ethoxycarbonyloxybutyrate in tetrahydrofuran 2 was added.
0 ml is added dropwise. One hour later, 882 mg (3 mmol) of compound (XII)
20 ml of a tetrahydrofuran solution is added dropwise. 2 at -78 ° C
After stirring for an hour, the temperature is gradually raised to room temperature.

After the reaction, the reaction solution is poured into ice water, made weakly acidic with a 10% HCl solution, and extracted with chloroform. After washing and drying,
The solvent was distilled off, the residue was subjected to silica gel column chromatography (chloroform), and purification yielded 740 mg (48%) of the desired product (Ia).

Colorless powder: mp 197 ° C. (ethyl acetate-n-hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, t, J = 7.3 Hz), 1.32 (3
H, t, J = 7.6Hz), 1.62 (1H, m), 1.97 (1H, m), 2.16 (1H, m
m), 2.97 (3H, m), 3.28 (1H, m), 3.60 (1H, d, J = 7.6H)
z), 3.96 (3H, s), 4.63 (1H, dJ = 16.1HZ), 4.84 (1H, d
d., J = 11.5,2.9Hz), 5.28 (2H, s), 5.28 (1H, d, J = 16.1)
Hz), 7.26 (1H, d, J = 2.4 Hz), 7.39 (6H, br.s), 7.95 (1
H, d, J = 9.0 Hz) IR (CHCl ₃ ): 1790,1740,1660,1620 cm ⁻¹ MS m / z: 514 (M ⁺ ) (10) Synthesis of compound (Ib): 514 mg of compound (Ia) ( 1 mmol) was dissolved in 50 ml of methanol, and hydrogenated at normal pressure using 50 mg of 10% palladium carbon as a catalyst. After the reaction, the catalyst was removed by filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was crystallized from chloroform to obtain 402 mg (95%) of the desired product (Ib).

Colorless powder: mp 231 to 232 ° C. (chloroform) ¹ H-NMR (CD ₃ OD) δ: 1.07 (3H, t, J = 7.3 Hz), 1.33 (3
H, t, J = 7.6Hz), 1.62 (1H, m), 1.96 (1H, m), 2.20 (1H, m
m), 2.93 (1H, m), 3.09 (2H, q, J = 7.6Hz), 3.47 (1H,
m), 3.97 (3H, s), 4.68 (1H, d, J = 16.1Hz), 4.98 (1H, d
d., J = 11.5,2.9Hz), 5.19 (1H, d, J = 16.1Hz), 7.43 (2
H, m), 7.94 (1H, d, J = 10.0Hz) IR (KBr): 3500-3100 (br, OH), 1790,1710,1640,1620cm
^{-1 MS m / z: 424 (} M +) (11) Compound (Ic) wherein ^{(Ic), R 7 = -C} (CH 3) 3 ]
The compound (Ib) (424 mg) is suspended in methylene chloride (50 ml), concentrated sulfuric acid (0.5 ml) is added thereto, and isobutene (gas) is passed through the mixture at -15 ° C for 30 minutes, and the mixture is further stirred at room temperature overnight.

The reaction mixture is poured into ice water, neutralized and extracted with chloroform. After removing the organic layer and drying over anhydrous magnesium sulfate,
Concentrate under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 422 mg (88%) of the desired product (Ic).

Colorless powder: mp 225 ° C. (ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, t, J = 7.3 Hz), 1.33 (3
H, t, J = 7.6Hz), 1.53 (10H, br.s), 1.95 (1H, m), 2.11
(1H, m), 2.95 (3H, m), 3.30 (1H, m), 3.67 (1H, d, J =
7.1Hz), 3.97 (3H, s), 4.66 (1H, d, J = 16.1Hz), 4.88
(1H, dd., J = 11.5,2.7Hz), 5.30 (1H, d, J = 16.1Hz), 7.
27 (1H, d, J = 2.4 Hz), 7.38 (1H, dd., J = 9.3, 2.4 Hz), 7.
96 (1H, d, J = 9.3 HZ) IR (CHCl ₃ ): 1790, 1730, 1650, 1620 cm ^-1 MS m / z: 480 (M ⁺ ) (12) Compound (Id) [in the formula (Id) Synthesis of R ⁷ CC (CH ₃ ) ₃ ]: 22 ml of lithium boron hydride in 10 ml of tetrahydrofuran
And 480 mg (1%) of the compound (Ic) obtained in (11) under ice cooling.
30 mmol) of a tetrahydrofuran solution was added dropwise. 10 minutes later
The reaction was stopped with a 10% HCl solution.

After distilling off tetrahydrofuran, the mixture was extracted with chloroform, washed with water and dried, and then chloroform was distilled off. The residue was subjected to silica gel column chromatography (ethyl acetate) and purified to obtain 290 mg (60%) of the desired product (Id).

Colorless powder: mp 238 ° C. (n-hexane-ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, t, J = 7.3 Hz), 1.33 (3
H, t, J = 7.6Hz), 1.53 (9H, br.s), 1.78 (1H, m), 1.93
(1H, m), 2.76 (1H, m), 3.00 (2H, q, J = 7.6Hz), 3.12
(2H, m), 3.96 (3H, s), 4.65 (1H, d, J = 16.2Hz), 4.86
(1H, dd., J = 11.5,2.9Hz), 5.29 (1H, d, J = 16.2Hz), 5.
55 (1H, m), 7.27 (1H, d, J = 2.8Hz), 7.37 (1H, dd., J =
9.0, 2.8 Hz), 7.97 (1 H, d, J = 9.0 Hz) IR (CHCl ₃ ): 3350 (OH), 1720, 1640, 1620 cm ⁻¹ MS m / z: 482 (M ⁺ )

Claims (3)

(57) [Claims] 1. The following general formula (I) [Wherein, A represents C = O or CHOH, and R ¹ represents a hydrogen atom, an aralkyl group or a lower alkyl group]. 2. The following formula (XII) A novel quinoline derivative represented by the formula: 3. The following formula (XII) The compound represented by the following general formula (XIII) Wherein R ⁵ represents an aralkyl group and R ⁶ represents a lower alkyl group. A butyric acid derivative represented by the following general formula (Ia): [Wherein R ⁵ is the same as defined above].