Diastereomer salt of optically active quinolinemevalonic acid

A diastereomer salt of optically active quinolinemevalonic acid of the formula ((-)I.(+)II): ##STR1##

The present invention relates to an important intermediate for the 
preparation of optically active quinolinemevalonic acid derivatives useful 
for the prevention or treatment of hyperlipemia, arteriosclerosis, etc. 
and a method for optically resolution thereof. 
A quinolinemevalonic acid compound of the formula (V) and a 
quinolinemevalonolactone compound of the formula (VI): 
##STR2## 
wherein R.sup.1 is a hydrogen atom, a C.sub.1-4 lower alkyl group such as 
a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a 
t-butyl group, a n-butyl group, an i-butyl group, a s-butyl group, or Na, 
K, 1/2Ca or HNR.sup.2 R.sup.3 R.sup.4 wherein each of R.sup.2, R.sup.3 and 
R.sup.4 is hydrogen, a C.sub.1-3 lower alkyl group or a 2-hydroxyethyl 
group, or when R.sup.2 hydrogen or methyl, R.sup.3 and R.sup.4 together 
form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.2 
--O--(CH.sub.2).sub.2 --or --(CH.sub.2).sub.2 --NH--(CH.sub.2).sub.2 --, 
are racemic mixtures or compounds having four optical isomers, as 
disclosed in Japanese and European Unexamined Patent Publication Nos. 
279866/1989 and 304063, and they are strong inhibitors against HMG-CoA 
reductase which is a rate limiting enzyme for the biosynthesis of 
cholesterol and thus expected to be useful as drugs for the prevention and 
treatment of hyperlipemia, arteriosclerosis, etc. 
Further, quinolinecarboxylic acid derivatives as HMG-CoA reductase 
inhibitors are disclosed, for example, in the following literatures: 
German Patent DE-3905908, U.S. Pat. No. 4,761,419, U.S. Pat. No. 4,923,861 
and European Patent Publication EP 356788A. 
As disclosed in Japanese and European Unexamined Patent Publication Nos. 
279866/1989 and 304063, the compounds of the formulas (V) and (VI) can be 
prepared as follows: 
##STR3## 
In the above formulas, each of R.sup.5, R.sup.6 and R.sup.7 is a C.sub.1-4 
lower alkyl group such as a methyl group, an ethyl group, a n-propyl 
group, an i-propyl group, a t-butyl group, a n-butyl group, an i-butyl 
group or a s-butyl group. 
Step A is a reduction reaction of an ester (VII) to a primary alcohol 
(VIII), and the reaction can be conducted in a solvent such as 
tetrahydrofuran or toluene at a temperature of from -20.degree. C. to 
20.degree. C., preferably from -10.degree. C. to 10.degree. C., using 
various metal hydrides, preferably diisobutylaluminum hydride. 
Step B is an oxidation reaction of the primary alcohol (VIII) to an 
aldehyde (IX), and the reaction can be conducted using various oxidizing 
agents. Preferred is a method wherein oxidation is conducted at a 
temperature of from 0.degree. C. to 25.degree. C. using pyridinium 
chlorochromate in methylene chloride, a method wherein oxidation is 
conducted using oxalyl chloride, dimethyl sulfoxide and a tertiary amine 
(such as triethylamine) (Swern oxidation), a method wherein oxidation is 
conducted using phosphorus pentoxide, dimethyl sulfoxide and a tertiary 
amine (such as triethylamine) or a method wherein oxidation is conducted 
using sulfur trioxidepyridine complex. 
Step C is a reaction for the preparation of an .alpha.,.beta.-unsaturated 
carboxylic acid ester (X), whereby a transform .alpha.,.beta.-unsaturated 
carboxylic acid ester (X) can be obtained by so-called Horner-Wittig 
reaction using an alkoxycarbonylmethyl phosphonate. As the base, sodium 
hydride, potassium-t-butoxide or the like is employed, and the reaction is 
conducted in dry tetrahydrofuran at a temperature of from -30.degree. C. 
to 0.degree. C., preferably from -20.degree. C. to -15.degree. C. 
Step D is a reduction reaction of the .alpha.,.beta.-unsaturated carboxylic 
acid ester (X) to an allyl alcohol (XI), and the reaction can be conducted 
in a solvent such as dry tetrahydrofuran or toluene at a temperature of 
from -10.degree. C. to 10.degree. C., preferably from -10.degree. C. to 
0.degree. C., using various metal hydrides, preferably diisobutylaluminum 
hydride. 
Step E is an oxidation reaction of the allyl alcohol (XI) to an enal (XII), 
and the reaction is conducted using various oxidizing agents. Preferred is 
a method wherein oxidation is conducted in a solvent such as 
tetrahydrofuran, acetone, ethyl ether or ethyl acetate at a temperature of 
from 0.degree. C. to 100.degree. C., preferably from 15.degree. C. to 
50.degree. C., using activated manganese dioxide, a method wherein 
oxidation is conducted using a sulfur trioxidepyridine complex, a method 
wherein oxidation is conducted using phosphorus pentoxide, 
dimethylsulfoxide and a tertiary amine (such as triethyl amine), or more 
preferably a method wherein oxidation is conducted using oxalyl chloride, 
dimethyl sulfoxide and a tertiary amine (such as triethylamine) (Swern 
oxidation). 
Step F is a condensation reaction of the enal (XII) and a double anion of 
an acetoacetate, and the reaction is preferably conducted in 
tetrahydrofuran at a temperature of from -80.degree. C. to 20.degree. C., 
preferably from -30.degree. C. to 0.degree. C., using sodium hydride as 
the base and n-butyl lithium. 
Step G is a reduction reaction of the carbonyl group of the compound 
(XIII). There is a method wherein the reduction is conducted in ethanol at 
a temperature of from -10.degree. C. to 5.degree. C. using a metal 
hydride, preferably sodium borohydride, a method wherein the reduction is 
conducted in dry ether or dry tetrahydrofuran at a temperature of from 
-100.degree. C. to 25.degree. C., preferably from -80.degree. C. to 
-50.degree. C. using zinc borohydride, and more preferably a method 
wherein the reduction is conducted in dry tetrahydrofuran-methanol at a 
temperature of from -80.degree. C. to -60.degree. C. using sodium 
borohydride and triethylborane or diethylmethoxyborane. (The compound 
(XIV) corresponds to the compound (V) wherein R.sup.1 is a C.sub.1-4 lower 
alkyl group.) 
Step H is a step for hydroryzing the ester (XIV), which can be conducted in 
a solvent mixture of methanol or ethanol with water at a temperature of 
from 10.degree. C. to 25.degree. C. using an equimolar amount of a base, 
preferably potassium hydroxide or sodium hydroxide. (The compound (XV) 
corresponds to the compound (V) wherein R.sup.1 is a hydrogen atom.) 
Step J is a step for forming mevalonolactone by a dehydration reaction of 
the free hydroxy acid (XV), and the reaction can be conducted using a 
suitable acid catalyst, preferably trifluoroacetic acid. Otherwise, the 
reaction can be conducted by removing the resulting water while refluxing 
in benzene or toluene under heating, or by adding a suitable 
water-removing agent such as molecular sieves. Further, the reaction can 
be conducted at a temperature of from 10.degree. C. to 35.degree. C., 
preferably from 20.degree. C. to 25.degree. C., using a lactone-modifying 
agent in dry methylene chloride, such as a carbodiimide, preferably a 
water-soluble carbodiimide such as 
N-cyclohexyl-N'-[2'-(methylmorpholinium)ethyl]carbodiimide 
p-toluenesulfonate. 
With respect to drugs, there are many cases in which the pharmacological 
activities and safety differ among optical isomers. In order to develop an 
excellent drug, it is desired to separate them by optical resolution. 
However, there has been no method for optical resolution known to be 
industrially useful for the separation of the racemic modification of the 
quinolinemevalonic acid ((.+-.)I). 
The present inventors have discovered that the racemic modification of 
quinolinemevalonic acid ((.+-.)I) forms a salt with D(+) 
phenethylamine((+)II) as an optically active amine, whereby the optically 
active 
lonic acid ((-)I) can be separated by optical resolution. The present 
invention has been accomplished on the basis of this discovery. 
Thus, the present invention provides a diastereomer salt of optically 
active quinolinemevalonic acid of the 
formula ((-)I.(+)II): 
##STR4## 
The present invention provides also a method for optical resolution of 
quinolinemevalonic acid ((+)I), which comprises reacting the 
quinolinemevalonic acid of the formula ((.+-.)I) with D(+) phenethylamine 
of the formula ((+)II), and separating the resulting diastereomer salt of 
optically active quinolinemevalonic acid of the formula ((-)I.(+)II): 
##STR5## 
Further, the present invention provides a process for producing optically 
active quinolinemevalonic acid of the formula ((-)I), which comprises 
treating the diastereomer salt of optically active quinolinemevalonic acid 
of the formula ((-)I.(+)II), with an acid: 
##STR6## 
Still further, the present invention provides a process for producing 
optically active quinolinemevalonolactone of the formula (III), which 
comprises dehydrating the optically active quinolinemevalonic acid of the 
formula ((-)I): 
##STR7## 
The present invention further provides a process for producing optically 
active quinolinemevalonic acid salt of the formula (IV), which comprises 
reacting the optically active quinolinemevalonic acid of the formula 
((-)I), with a base: 
##STR8## 
wherein R.sup.8 is Na, K, 1/2Ca or HNR.sup.2 R.sup.3 R.sup.4 wherein each 
of R.sup.2, R.sup.3, R.sup.4 is hydrogen, a C.sub.1-3 lower alkyl group or 
a 2-hydroxyethyl group, or when R.sup.2 is hydrogen or a methyl group, 
R.sup.3 and R.sup.4 together form --(CH.sub.2).sub.4 --, --(CH.sub.2)5--, 
--(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.2 
--NH--(CH.sub.2).sub.2 --. 
Furthermore, the present invention provides a process for producing 
optically active quinolinemevalonic acid salt of the formula (IV), which 
comprises reacting the diastereomer salt of optically active 
quinolinemevalonic acid of the formula ((-)I.(+)II), with a base. 
Now, the present invention will be described in detail with reference to 
the preferred embodiments. 
##STR9## 
In the above formulas, R.sup.8 is Na, K, 1/2Ca or HNR.sup.2 R.sup.3 R.sup.4 
wherein each of R.sup.2, R.sup.3 and R.sup.4 is hydrogen, a C.sub.1-3 
lower alkyl group or a 2-hydroxyethyl group, or when R.sup.2 is hydrogen 
or methyl, R.sup.3 and R.sup.4 together form --(CH.sub.2).sub.4 --, 
--(CH.sub.2).sub.5 --, --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 -- or 
--(CH.sub.2).sub.2 --NH--(CH.sub.2).sub.2 --, and R.sup.9 is a C.sub.1-4 
lower alkyl group. 
Step K is a step for hydroryzing a racemic ester (XVI), and the hydrolysis 
can be conducted in a solvent mixture of methanol or ethanol with water at 
a temperature of from 0.degree. C. to 25.degree. C. using an equimolar 
amount of a base, preferably potassium hydroxide or sodium hydroxide, 
followed by neutralization using an aqueous acid solution, preferably 
hydrochloric acid, to obtain a free quinoline mevalonic acid ((.+-.)I). 
Step L is a step for reacting D(+) phenethylamine (+)II) as an optical 
resolution agent to the quinolinemevalonic acid ((.+-.)I) for 
precipitation to obtain the diastereomer salt of optically active 
quinolinemevalonic acid ((-)I.(+)II) as crystals. Likewise, if 
L(-)phenethylamine((-)II) is used as an optical resolution agent, it is 
possible to obtain a diastereomer salt of optically active quinoline 
mevalonic acid ((+)I.(-)II). Thus, by selecting the optical resolution 
agent, a desired optical isomer of the quinolinemevalonic acid ((.+-.)I) 
can be obtained. As the solvent, a ketone-type solvent such as diethyl 
ketone or methyl isobutyl ketone, or a solvent such as toluene or xylene 
may be used alone, or a solvent mixture of such a solvent with an alcohol 
solvent such as methanol or ethanol, or a solvent such as 
dimethylformamide or dimethyl sulfoxide, may preferably be used. The 
reaction temperature is usually from 0.degree. C. to 100.degree. C., and 
the precipitation is conducted usually at a temperature of from 
-20.degree. C. to 100.degree. C., preferably from -10.degree. C. to 
80.degree. C. 
In step M, the optically active quinolinemevalonic acid ((-)I) can readily 
be obtained by treating the diastereomer salt of optically active 
quinolinemevalonic acid ((-)I.(+)II) with various aqueous acid solutions. 
As the acid, formic acid, trifluoroacetic acid or hydrochloric acid is 
preferred. Particularly preferred is hydrochloric acid. 
Step N is a step for forming an optically active quinolinemevalonolactone 
(III) by a dehydration reaction of the optically active quinolinemevalonic 
acid ((-)I), and the dehydration reaction can be conducted using an acid 
catalyst, preferably trifluoroacetic acid. Otherwise, the reaction can be 
conducted by removing the resulting water while refluxing in benzene or 
toluene under heating, or by adding a water-removal agent such as 
molecular sieves. Further, the dehydration can be conducted at a 
temperature of from 10.degree. C. to 35.degree. C., preferably from 
20.degree. C. to 25.degree. C., using a lactone-modification agent in dry 
methylene chloride, such as a carbodiimide, preferably a water-soluble 
carbodiimide such as 
N-cyclohexyl-N'-[2'-(methylmorpholinium)ethyl]carbodiimide 
p-toluenesulfonate. 
Step O is a step of reacting the optically active quinolinemevalonic acid 
((-)I) with a base to obtain an optically active quinolinemevalonic acid 
salt (IV). The base used here may be piperazine, morpholine, 
diethanolamine, triethanolamine, NaOH, KOH, Ca(OH).sub.2 or CaO. 
In step P, the optically active quinolinemevalonic acid salt (IV) can be 
obtained from the diastereomer salt of optically active quinolinemevalonic 
acid ((-)I.(+)II) without isolating the optically active 
quinolinemevalonic acid ((-)I). Namely, by adding an aqueous solution of 
alkali metal hydroxide (such as sodium hydroxide or potassium hydroxide) 
to the diastereomer salt of optically active quinolinemevalonic acid 
((-)I.(+)II), it is possible to directly obtain an alkali metal salt (such 
as a quinolinemevalonic acid salt (IV) wherein R.sup.8 is Na or K). 
Further, by adding an aqueous solution of an alkaline earth metal chloride 
(such as CaCl.sub.2) to such an aqueous alkali metal salt solution, it is 
possible to obtain an alkaline earth metal salt (such as a 
quinolinemevalonic acid salt (IV) wherein R.sup.8 is 1/2Ca). 
Now, the present invention will be described in detail with reference to 
Examples, but it should be understood that the present invention is by no 
means restricted by such specific Examples.

REFERENCE EXAMPLE 1 
(.+-.)-(E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'- 
yl ]hept-6-ene acid compound ((.+-.)I) 
60 g of 
(.+-.)-(E)-ethyl-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropylquino 
lin-3'-yl]hept-6-enoate (a compound (XVI) wherein R9 is Et) was suspended 
in 100 ml of ethanol, and 200 ml of a 1N sodium hydroxide aqueous solution 
was added thereto. As the reaction proceeded, the suspension became a 
uniform solution. After completion of the hydrolysis, 200 ml of 1N 
hydrochloric acid was added thereto. This reaction solution was extracted 
with 500 ml of dichloromethane to obtain the desired compound ((.+-.)I). 
H-NMR(CDCl.sub.3), .delta.ppm 1.0-1.1 (m, 2H), 1.3-1.4 (m, 3H), 1.5-1.6 (m, 
1H), 2.3-2.4 (m, 1H), 2.51 (d, 2H, J =6.1), 2.8-3.5 (b, 3H), 4.1-4.2 (m, 
1H), 4.4-4.5 (m, 1H), 5.59 (dd, 1H, J=6.1, J=16.1), 6.63 (d, 1H, J=6.1), 
7.1-7.4 (m, 6H), 7.5-7.7 (m, 1H), 7.9-8.0 (m, 1H). 
REFERENCE EXAMPLE 2 
Resolution of a Diastereomer Salt Using a Chiral Organic Amine 
To the dichloromethane solution of the compound ((.+-.)I) obtained in 
Reference Example 1, 1 equivalent of a chiral organic amine as identified 
in Table 1 was added, and then the solvent was distilled off to obtain a 
residue containing the corresponding diastereomer salt. Except for the 
case where the residue was oil, the residue was dissolved under heating in 
ten times by weight of methyl isobutyl ketone-dimethylformamide (20:1, 
v/v), followed by cooling to a temperature of from 10 to 25.degree. C. for 
crystallization. For the optical yield, the obtained diastereomer salt was 
treated with an acid and then converted to lactone, and the optical yield 
was measured by a high performance liquid chromatography using an optical 
resolution column (chiraSpher, tradename, manufactured by E. Merck 
Company). 
______________________________________ 
Resolution agent Chemical Optical 
(chiral organic amine) 
yield (%) 
yield (% ee) 
______________________________________ 
D(+)phenethylamine 44 73 
R(+).alpha.-(p-tolyl)ethylamine 
.sup. 30.sup.1) 
60 
R(-)2-amino-1-butanol 
80 0 
D(-).alpha.-phenylglycinol 
.sup. --.sup.2) 
-- 
(-)N-benzyl-.alpha.-phenylethylamine 
.sup. --.sup.2) 
-- 
(-)p-bromo-.alpha.-phenylethylamine 
.sup. --.sup.2) 
-- 
______________________________________ 
.sup.1) A gel substance precipitated. 
.sup.2) The diastereomer salt was an oily substance. 
EXAMPLE 1 
(E)-3(R)-5(S)-dihydroxy-7-[4'-(4"-fluorophenyl) 
-2'-clopropylquinolin-3'-yl]hept-6-ene acid.D(+) phenethylamine salt 
compound ((-)I.(+)II) 
To the dichloromethane solution of the compound ((.+-.)I) obtained in 
Reference Example 1, 16.2 g of D(+) phenethylamine ((+)II) was added, and 
the mixture was stirred. Then, dichloromethane was distilled off to obtain 
a residue. The residue was repeatedly crystallized from methyl isobutyl 
ketone and methyl isobutyl ketone-ethanol (10:1, v/v) to obtain 19.8 g of 
the desired compound ((-)I.(+)II) as white crystals. (Melting point: 
144.degree.-147.degree. C., optical purity: 97%ee.) 
EXAMPLE 2 
(E)-6(S)-[4'-(4"-flurophenyl)-2'-cyclopropylquinolin 
-3'-ylethenyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one compound 
(III) 
To 14.08 g of 
(E)-3(R)-5(S)-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'- 
yl]hept-6-ene acid.D(+) phenethylamine salt compound ((-)I.(+)II) obtained 
in Example 1, 25.9 ml of 1N hydrochrolic acid and 235 ml of water were 
added, and the compound was dissolved. To this solution, 250 ml of ethyl 
acetate was added to extract the compound ((-)I). The ethyl acetate 
solution was washed with a saturated sodium chloride aqueous solution, and 
the solvent was distilled off under reduced pressure. To the residue, 250 
ml of dry toluene was added and refluxed under heating for 3 hours by 
means of a Dean Stark apparatus. The solvent was distilled off under 
reduced pressure, and the residual solid thereby obtained was 
recrystallized from toluene-heptane to obtain 6.4 g of the desired 
compound (III). (Melting point: 136.degree.-139.degree. C.). 
EXAMPLE 3 
(E)-3(R)-5(S)-dihydroxy-7-[4'-(4"-fluorophenyl) 
-2'-cyclopropylquinolin-3'-yl]hept-6 -ene acid.1/2 calcium salt 
To 12.0 g of 
(E)-3(R)-5(S)-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-cyclopropylquinolin-3'- 
yl ]hept-6-ene acid.D(+) phenethylamine salt compound ((-)I.(+)II) obtained 
in Example 1, 24.3 ml of a 1N sodium hydroxide aqueous solution and 200 ml 
of water were added and stirred to dissolve the compound. To this 
solution, an aqueous calcium chloride solution obtained by dissolving 1.47 
g of dry calcium chloride to 200 ml of water, was dropwise added. This 
reaction solution was stirred overnight, and the resulting white 
precipitate was collected by filtration to obtain 9.0 g of white crystals 
(melting point: 190.degree.-192.degree. C. (decomposed)).