JPH0383986A - New quinoline derivative and its production - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (A is >C=O or >CHOH; R<1> is H, aralkyl or lower alkyl). USE:A synthetic intermediate for camptothecin derivative useful as an anti-cancer drug. PREPARATION:p-Anisidine shown by formula II is reacted with propionitrile in the presence of boron chloride and aluminum chloride to give 2-amino-5- methoxypropiophenone. This compound is reacted with a pyrrolidine derivative to give a compound shown by formula III. The compound is heated in the presence of a base to give a compound shown by formula IV. This compound is heated in the presence of an acid, the reaction product is reduced and is heated in the presence of an acid to give a compound shown by formula V. This compound is reacted with a butyric acid derivative shown by formula VI (R<5> is aralkyl; R<6> is lower alkyl) to give a compound shown by formula I wherein group A is >C=O and R<1> is R<5>.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel quinoline derivative, and more particularly to a novel quinoline derivative useful as a synthetic intermediate for a camptothecin derivative useful as an anticancer agent, and a method for producing the same.

[Conventional technology]

Camptotheca acuminata
5i! ! It is a sexual alkaloid that is known to exhibit antitumor activity by inhibiting nucleic acid synthesis. Regarding the total synthesis of camptothecin, G. 5tork et al. (J. Am. Chem.
.

There have been many reports including the report of [Soc., 93.4074 (I971)].

On the other hand, various studies have been conducted in search of compounds with better antitumor activity, and it has been found that the compound represented by the following formula has excellent antitumor activity, is highly safe, and is useful as an anticancer agent. [Unexamined Japanese Patent Publication No. 58-39683]
No.; Jpn, J, Cancer Chemothe
r,, 14. Part-II, 850 (I985
)).

[Problem to be solved by the invention]

However, the conventional method for producing the above-mentioned camptothecin derivatives requires a long number of steps and cannot be said to be an industrially advantageous method. Therefore, it has been desired to provide an industrially advantageous production method and synthetic intermediate for the above camptothecin derivatives.

[Means for Solving the Problems] Under these circumstances, the present inventors have conducted intensive research to solve the above problems, and have found that a novel quinoline derivative synthesized in a short process using p-anisidine as a raw material has been found to be useful as an anticancer agent. The present invention was completed based on the discovery that the present invention is useful as an intermediate for the synthesis of excellent camptothecin derivatives.

That is, the present invention provides a novel quinoline derivative represented by the following general formula (I) (wherein ^ represents C=O or CHOH, and R1 represents a hydrogen atom, an aralkyl group, or a lower alkyl group) and its manufacturing method.

In the above general formula (I), the aralkyl group represented by R1 is preferably a benzyl group; the lower alkyl group is preferably a straight 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.

The following margin [In the reaction formula, R2, R3, R4, Ra and R7 each represent a lower alkyl group, R5 represents an aralkyl group,
X represents a halogen atom] Each step in the above reaction formula will be explained below.

(I) If p-anidine (ff) and propionitrile are reacted in the presence of boron chloride and aluminum chloride, 2-amino-5-methoxypropiophenone (III
) is obtained. This reaction was carried out using the method of Sugazawa et al.
Chem, 5oc1.100.4842 (I97B)
).

(2) 2-amino-5-methoxypropiophenone (I
Compound (V) is obtained by reacting II) with a pyrrolidine derivative (IV). This reaction is carried out, for example, in an aromatic hydrocarbon solvent such as toluene by heating to reflux.

(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 to reflux in a solvent such as ethanol or water.

(4) Compound (Vl) has an alkylmalonyl halide (■
) can be reacted to obtain compound (■).

This reaction involves sodium bicarbonate, sodium hydroxide,
Preferably, it is carried out in the presence of a base such as sodium carbonate.

(5) If compound (■) is reacted with a base, compound (I
X) is obtained. As the base, metal alcoholades such as sodium ethoxide are preferred.

(6) Compound (X) 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 (xl).

Preferably, the reduction is carried out using sodium borohydride.

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

(9) Next, intoxicate compound (XII)! ! 2 derivative (X
Compound (I a) is produced by reacting I[I].

This reaction is carried out in the presence of n-butyllithium etc.
It is carried out at a low temperature of ~0°C. Preferably, the reaction solvent is an ether such as tetrahydrofuran or a hydrocarbon such as n-hexane.

(L(I) Compound (I b) is produced by hydrolyzing compound (I a). The reaction is carried out by adding hydrogen in an alcoholic solvent such as methanol in the presence of a catalyst such as palladium on carbon. Implemented by

(2) Next, the ester derivative (I c) is produced by reacting the compound (I b) or its reactive derivative with a lower alcohol or an alkylating agent.

Compound (Id) can be produced by further reducing (Ic) of α using a reducing agent such as lithium aluminum hydride in an ether solvent such as tetrahydrofuran.

〔Effect of the invention〕

By utilizing the novel quinoline derivative (I) of the present invention, camptothecin derivatives useful as anticancer agents can be efficiently produced in a short process. Therefore, the compounds of the present invention are useful as intermediates for producing camptothecin derivatives.

〔Example〕

Next, the present invention will be explained in detail with reference to Examples.

Example 1 (I) 2-amino-5-methoxypropiophenone (I
Synthesis of II) Nianisidine 615■ (5 mmoA) was dissolved in benzene 5- and cooled with ice water to produce BCJ! 3 of 2.22mo j2
Benzene solution 2.47mj! (5.5 mmo 1)
added to. Anisidine-BCj! A white adduct of No. 3 precipitates out. Next, 500.8 mg of propionitrile (I0m
mof ) and AlC1, 733 mg (5,5 mmol
) and the 01J3-anisidine adduct and AI at room temperature.
Cj! ! After dissolving with stirring, the mixture was heated under reflux for 6 hours. After cooling, 2NHCj! 10rn1 was added and 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 sulfuric acid. After ethyl acetate was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride) to obtain yellow crystals (■) of 420
■ (47%) was obtained.

Yellow needles: mp58°C (methylene chloride-n-hexane)') I-NMR (CDC1s) δ: 1.2
1 (3H, t, J=7.3)1z), 2.96(
2t1. q, J=7Jtlz), 3.78(3)1.
s), 6.63(I)1. d.

J=9.0tlz), 6.96(III, dd,, J
=9.0.2.9Hz).

7, 23 (l)1. d, J=2.9Hz) IR(
CIICj! -): 3500.1650 am-
'MS m/z: 179 (M'') Elemental analysis (as CI881-NO2) Calculated value: C6
7,04; H7,26; N 7.82 Actual value: C
66,95; H7,54; N 7.83 (2) Compound (■> [In formula (V), R" = R' = Ca1
Synthesis of ls): 358 mg of 2-amino-5-methoxypropiophenone
(20 mmol) and 1-ethoxycarbonyl-3-year-old xopyrrolidine-2-acetic acid ethyl ester 486 mg
(20mmo1) to 20m1 of toluene! To the solution, 34 μm (2 mmof) of tosylic acid was added, and the mixture was heated under reflux for 8 hours using a Dean-Stark apparatus. 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 colorless crystals of the desired product (V).

Colorless needle crystals: mp85°C (ether-n-hexane)'H-NMR (CDCf,) δ: 1.09 (3
11,t, J=7.1llz), 1.33(3H
,t, J=7.6Hz), 1.35(311,t,
J=7,1llz), 2.95(2H,m), 3.
21 (2f1.m), 3.95 (3tl, s),
4.06 (211゜m), 4.27 (2ft, m
), 4.82 (2H, m), 5.32 (IH, m
).

7.26 (IH, d, J=2.7)1z), 7.34
(I)1. dd,, J=9.1.

2.71(z), 7.96(ill, d, J=9.
1tlz)IR(CHCl-): 1730. 16
90. 1620cmM5 m/z: 386(M”
) Elemental analysis (C2t) As ItsNJs〉Calculated value: C
65,28; H6,74; N 7,25 Actual value:
C65,09; II 6.91; N 7,24 (3
) Synthesis of compound (■) [in formula (VI), R'=C211S]: 2 g (5.2 mmoj!) of compound (V) was added to 20 liters of ethanol! Dissolve in 10% leaf solution 10-
was added and heated under reflux for 8 hours. After ethanol was distilled off under reduced pressure, a precipitate was deposited when neutralized with 10% HCI solution.
This was filtered. After drying the precipitate under vacuum, it was dissolved in 20 ml of ethanol, passed through II[J gas, and heated under reflux for 3 hours. After ethanol was distilled off under reduced pressure, the mixture was made alkaline to 10% with leaf solution to form a precipitate, which was collected by filtration. The precipitate was recrystallized to ether-n- from beef starch to obtain 1.1 g (67%) of the desired product (VI).

Colorless powder: mp86-87°C (ether-n-hexane) 'H-NMR (CDC1,) δ: 1.27 (3H, t
, J=7.311z), 1.30(3H,t, J
=7.3Hz), 2.64(LH, dd,, J=1
6.4°10.0)1z), 2.96(2)1. q,
J=7.3)1z), 3.29(IH, dd,.

J=16.4.2.9)1z), 3.95 (3H
,s), 4.20 (2f1.Q.

J=7.3Hz), 4.40 (2)1. s)
, 4.88 (211,ddo, J=10.0゜2
．． 9Hz), 7.26 (IH, d, J=2,511z
), 7.32 (IH, dd,.

J=9.0.2.5Hz), 7.96(IH, d, J
=9, O)lz)IR(CM(J-): 335
0.1720. 1630cm-'MS m7z:
314 (M”) Elemental analysis (as C+5H220sN*) Calculated value: C
68,79; II 7.01; N 8.92 Actual value: C68,56; H7,18; N 9.00 (4
) Compound (Vlll)C In the formula (■), R3=R'=C,
Synthesis of Compound (VI) 942■ (3 mmoj!) was dissolved in 5 rnl of benzene, and 10% NaH (I'0+ solution 3.3
ml was added.

Ethylmalonyl chloride 541 was added while stirring the reaction solution.
, 8 mg (3,6 mmol) of benzene solution 3 mj!
was dripped. 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 the desired product (■) 1
．． 1 g (86%) was obtained.

Colorless powder: mp105-106°C (methanol) 'H-NMR (CDC13) δ: 1.07 (31
1,t, J=7.311z), 1.30(6H,
t, J=7.3Hz), 2.98(2)1. m),
3.22 (IH, dd,.

J=1? , 1.3.4Hz), 3.53.3.61(
each 1f1. d.

J=15. IHz), 3.63(I)t,m), 3
．． 90 (2H, m), 3.95 (3t1.s), 4
．． 25 (21-1, q, J=t3Hz), 4.94.
5.04 (each IN, d, J=13JHz), 5
．． 48 (ltl, m), 7.25 (IM, d, J
=2.7)1z), 7.35 (IH, dd,,
J=9.3°2.7Hz), 7.98(IH, d,
J=9JHz)In<CllCls): 1730
．． 1650. 1620cm-'MS m/z:
428 (M”) Elemental analysis (as C23) 12106N2) Calculated value:
C64,49; H6,54; N 6.54 Actual value:
C64,22; 116.71; N 6.56 (5
) Base of compound (■) [R'=C2115 in formula (IX)]: 1% N in 428 mg (Immol) of compound (■)
10ml of a0Bt solution! was added and heated under reflux for 1 hour.

After the reaction, ethanol was distilled off under reduced pressure, water was added, and 10% H
Neutralization with C1 solution produced a precipitate. The precipitate was collected by filtration and recrystallized from chloroform-methanol to obtain the desired product (IX)2.
90■ (76%) was obtained.

Colorless powder: mp165°C (chloroform-methanol) 'H-NMR (CDC1,) δ: 1.34 (3H, t
, J=7.8Hz), 1.44(3)1. t, J=
7.3Hz), 2.84(It1.ddl, J=1
7.1゜3.4flz), 3.02(211,q,J
=7.8Hz), 3J2(IH, dd,.

J=17.1. 4.4)1z), 3.97(31
1,s), 4.43(2H,m).

4.76 (IH, d, J=16.1Hz), 5.1
3(ill, d, J=16,1)1z).

5.17 (IH, m), 7.213 (IH, d, J
=2.411z), 7J8 (IH.

dd6. J=9J, 2.4Hz), 7.98(ill,
d, J=9JHz)IR(C)ICl3,): 16
50. 1590cm-'MS aa/z: 382
(M”) (6) Base of compound (X): 10 g (2.6 mmol) of compound (IX)
% acetic acid solution 10mj! Add and heat for 30 minutes. The reaction solution was extracted with chloroform, washed with water, dried, and then chloroform was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) and recrystallized from n-hexane-chloroform to obtain 543 mg (67%) of the desired product (IX).
I got it.

Colorless powder: mp183-184°C (n-hexane-chloroform) 'H-NMR (CDfl! 3) δ: 1.35 (i
ll, t, J=7.811z), 2.57(H
l, dd,, J=17.6.12.01lz), 3.
02 (211,q.

J=7.8Hz), 3.42(IH,d, J=19.
01lz), 3.47(ltl.

dd,, J=17.6.3.9)tz), 3.60
(IH, d, J=19,0tlz).

3.97 (311,s), 4.83 (It1.
d, J=16.1)1z), 5.21(LH,d,
J=16.1Ilz), 5.32(LH, dd,,
J=12.0°3.9Hz), 7.28(I)1.
d, J=2.7Hz), 7.40(IH, dd,.

J=9J, 2.7Hz), 7.98(LH, d
, J=9.3flz)IR(CHCla): 173
0. 1660. 1620cm-'MS m/z:
310 (M”) (7) Synthesis of compound (XI): Dissolve 310 mg (Immol) of compound (X) in 10 ml of ethanol, and while stirring, make sure that NaBH<18
．． Add 9 mg (0.5 m+no 1) little by little.

After stirring at room temperature for 1 hour, ethanol was distilled off under reduced pressure, water was added, and the mixture was neutralized with 10% HCl solution to form a precipitate.

The entire precipitate was collected by filtration and recrystallized from chloroform-n-hexane to obtain 250 μm (80%) of the desired product (XI).

Colorless powder: mp105-108°C (chloroform-n-
H-NMR (CDC13) δ: 1.33
(3H, t, J=7.6Hz), 1.79 (IH
, m), 2.47 (IH, m), 3.02 (4H,
m), 3.97(3)1゜s), 4.45(IH,
m), 4.60 (I8, d, J = 16.1 H, z).

4.86 (if, m), 5.25 (IH, d, J
= 16.1Hz), 7.27 (E, d, J = 2.9f
lz), 7J7(I)1. ddl, J=9.0゜2
．． 9) 1z), 7.99 (IH, d, J=9.0H
z)IR(C)IC1a): 3400,1620c
m-'MS m/z: 312 (M") (8) Synthesis of compound (XI): 312 mg of compound (H) (82 mg of sodium acetate anhydride (ImmoJ!) and 1 rn1 of acetic anhydride)
and heat under a nitrogen stream for 1 hour. When the reaction solution is poured into ice water, a precipitate is deposited. After the precipitate was collected by filtration, it was recrystallized from chloroform-n-hexane to obtain the desired product as yellow crystals (
XII) 250 mg (85%) was obtained.

mp+73~75°C (n-hexane-ethyl acetate) 'H-NMR (C mouth tj!3) δ: 1.3
4 (3H, t, J=7.6Hz), 2.51(I)
1. m), 3.01 (2H, Q, J=7.6Hz),
3.15 (III, m).

3.97(3)1. s), 5.14 (lft, d, J
=16.11(z), 4.77(III.

d, J=16.1flz), 5.21(LH,m),
6.12 (LH, m).

6.74 (ltl, m), 7.28 (IB, d,
J=2.7Hz), 7.38(ill.

dd,, J=9.3.2.7Hz), 7.99(LH
, d, J=9JHz) IR (CHCls): 166
0.1620.1600cm-'MS m/z: 2
94 (M”) (9) Synthesis of compound Ha)C Formula (I a), R8 = benzyl]: Add 1.09 rnl (I5 mm0R) of diisopropylamine into 15 ml of tetrahydrofuran at 0°C under a nitrogen stream. Next, 1.62mo R/n-butyllithium
42 n-hexane solution 9.26mj! (I5mm
oj! ) under stirring. After 20 minutes, the temperature was raised to -78°C in a dry ice-acetone bath. A solution of 3.99 g (I5 mmof) of benzyl α-ethoxycarbonyloxyacetate in 20 ml of tetrahydrofuran. drip. After 1 hour, a solution of 882 mg (3 mmol) of compound (XI[) in 20 mj of tetrahydrofuran! drip. 2 at -78℃
After stirring for an hour, gradually warm 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 with water and drying, the solvent was distilled off and purified by silica gel column chromatography (chloroform), yielding 740 mg of the target product (Ia).
(48%).

Colorless powder 1np 197°C (ethyl acetate-n-hexane) 'H-NMR (CDCj' a) δ: 0.
99 (3H, t, J=7.31(z), 1.3
2(3)1. t, J=7. Hz), 1.62(ltl
, m), 1.97 (IH, +n).

2.16 (IH, m), 2.97 (3H, m), 3
．． 28 (I8, m), 3.60 (LH, d, J=7.
6) 1z), 3.96(311,s), 4.63(
ill, d.

J=16.1Hz), 4.84(LH, dd,, J=
11.5.2.9Hz).

5.28(2)1. s), 5.28(I)1. d, J
= 16.1 Hz), 7.26 (IH, d, J = 2.4
)1z), 7.39 (6H, br, s), 7.95
(III, d.

J:9.0Hz) IR (CHCl-): 1790.1740.166
0.1620cm-'MS m/z: 514(M"
) (Ll Synthesis of Compound (Ib): Compound (Ia) 514mg (Immoj) was dissolved in 50rnl of methanol and hydrogenated at normal pressure using 50mg of 10% palladium carbon as a catalyst. After the reaction, the catalyst was filtered off. The filtrate was dried under reduced pressure, and the residue was crystallized from chloroform to obtain the desired product (Ib) 402m.
g (95%) was obtained.

Colorless powder: mp231-232°C (chloroform)') l-NMR (CD, OD) δ: 1.07 (3f
l, t, J=7.311z), 1.33(3)1.
t, J=7.611z), 1.62(Iff, m)
, 1.96 (III, m).

2.20 (if, m), 2.93 (ill, m)
, 3.09 (2H, q.

J=7.6tlz), 3.47(LH,m),
3.97 (3H, s), 4.68 (IH, d, J=
16.1)lz), 4.98(IH,dd,,J=
11.5. 2.9Hz), 5.19(I8,d,
J=16.1Hz), 7.43 (2N, m).

7,94 (IJI, d, J=10.0Hz) [R
(KBr): 3500-3100 (br, OH),
1790. 1710°1640, 1620cm-
'MS mHz: 424 (M'') OD Compound (Ic)C In formula (Ic), R'=-C(
F&: 424 mg of compound (Ib) was mixed with 50 mj of methylene chloride! Suspend it in and add 0.5ml of concentrated sulfuric acid! , then 11
Isobutyne (gas) was introduced at 5°C for 30 minutes to react.
Further stir overnight at room temperature.

The reaction mixture was neutralized by pouring it into ice water, and then extracted with chloroform. The organic layer is taken, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column.
(Chloroform) to purify the target product (
Ic) 422 mg (88%) was obtained.

Colorless powder: mp225°C (ethyl acetate)'H-NMR
(CDC13) δ: 1.06 (3) 1. t, J=7
．． 311z), 1.33 (3tl, t, J=7.61
1z), 1.53(I0)I,br,s), 1.9
5 (IH.

m), 2.11 (LH, m), 2.95 (3H, m
), 3.30 (IN, m).

3.67 (IB, d, J = 7.IHz), 3.97 (
3tl,s), 4.66(If(.

d, J=16.1flz), 4.88(IN, dd,
, J=11.5.2,711z).

5, 30 (LH, d, J=16.ll-1z),
7.27 (LH, d, J=2.4Hz).

7J8 (LH, dd, J=9.3.2.4Hz),
7.96 (I8, d.

9.3tlz) IR (CtlCla): 1790.1730.16
50.1620cm-'MS mHz: 480(M
”) 0 Compound (Id) [In formula (Id), rl'=C([:
Synthesis of lithium boron hydride 22 to tetrahydrofuran 10-
mg of the compound (I c) obtained in Ql) under water cooling.
480mg (Immoi) Tetrahydrofuran solution 30ml! was dripped. The reaction was stopped with 0% II (J solution) in duplicate for 10 minutes.

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

Colorless powder: mp238°C (n-hexane-ethyl acetate) 'II-NMR (CDCj2,,) δ: 0.99 (3
)1. t, J=7.3tlz), 1.33(3H,t
, J=7.6)1z), 1.53(9N,br,s)
, 1.78 (ltl.

m), 1.93 (I8, m), 2.76 (IH, m
), 3.00 (211, Q.

J=7.6Hz), 3.12 (211, m), 3.
96 (311, s), 4.65 (Ill, d, J
=16.211z), 4.86(LH, dd, ,
J=11.5.2.9Hz), 5.29(II(,d
, J=16.2Hz), 5.55(I)1. m).

7.27 (I8, d, J = 2, 8) 1z), 7J7 (
Ift, dd,, J=9.0°2, 8f(z), 7.
97(IN, d, J=9.0)1z)IR(CHC
j! a): 3350 (Kano), 1720.164
0.1620cmMS mHz: 482(M+) or more

Claims (1)

[Claims] 1. The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, A is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲
There are mathematical formulas, chemical formulas, tables, etc. A new quinoline derivative represented by ▼, where R^1 represents a hydrogen atom, an aralkyl group, or a lower alkyl group. 2. A new quinoline derivative represented by the following formula (XII) ▲Mathematical formula, chemical formula, table, etc.▼(XII). 3. The following formula (XII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XII) The compound represented by the following general formula (XIII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XIII) [In the formula, R ^5 represents an aralkyl group, R^6 represents a lower alkyl group] The following general formula (Ia) is characterized by reacting a butyric acid derivative represented by ▲Mathematical formulas, chemical formulas, tables, etc.▼( I a) A method for producing a novel quinoline derivative represented by the formula: [wherein R^5 is the same as above].