JP5533654B2 - Method for producing 3,5-dihydroxy-6-heptenoic acid amine salt - Google Patents

Description

The present invention relates to high purity (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptene with low epimer content Novel production method of chiral amine salt of acid, and high purity (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline with low epimer content via the amine salt -3-yl] -3,5-dihydroxy-6-heptenoic acid.
The chiral amine of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid obtained in the present invention Some of the salts are novel compounds not yet described in the literature.

  Formula (1)

で表される（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸はコレステロール低下薬（ＨＭＧ−ＣｏＡ還元酵素阻害剤）などの医薬品として有用である（例えば特許文献１参照）。

(3R, 5S) -7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid is a cholesterol-lowering drug ( HMG- It is useful as a pharmaceutical such as a CoA reductase inhibitor (see Patent Document 1, for example).

Since the compound represented by the formula (1) is an optically active compound having two asymmetric centers, establishment of a stereoselective asymmetric synthesis method is desired as an industrial production method.
As a method for producing an intermediate (10) of the compound represented by formula (1) for asymmetric synthesis (wherein R represents an ethyl group),

で表される、微生物を用いた立体選択的還元反応を利用する方法が知られているが、ジアステレオ選択性について、９２乃至１００ｄ．ｅ．との記載がある（特許文献４参照）。

A method utilizing a stereoselective reduction reaction using a microorganism represented by the following formula is known. e. (See Patent Document 4).

  That is, the intermediate (10) obtained by this method has formula (11)

（式中、Ｒは前記と同義である。）
で表される（３Ｓ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸エステル及び／又は式（１２）

(In the formula, R is as defined above.)
(3S, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoate and / or the formula (12 )

（式中、Ｒは前記と同義である。）
で表される（３Ｒ，５Ｒ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸エステルなどの少量のエピマーが含有されている。そのため、その後のエステル基の加水分解反応においても、式（１０）、式（１１）及び式（１２）のエステル基は同程度の反応性を示すことから、最終的に得られる式（１）の化合物においてもエピマー体の混入が避けられず、高純度品が必要とされる特に医薬品の製造方法としては課題を残していた。

(In the formula, R is as defined above.)
A small amount of epimer such as (3R, 5R) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoate represented by Contained. Therefore, in the subsequent hydrolysis reaction of the ester group, the ester groups of the formula (10), the formula (11) and the formula (12) show the same degree of reactivity, so that the finally obtained formula (1) Even in this compound, the mixing of epimer bodies is unavoidable, and a problem remains as a method for producing a pharmaceutical product that requires a high-purity product.

  In addition, as an intermediate in another method for asymmetric synthesis, formula (13)

（式中、Ｒは炭素原子数１乃至４のアルキル基を表す。）
で表される（５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−５−ヒドロキシ−３−ケト−６−ヘプテン酸エステルの不斉合成法が知られている（例えば特許文献３参照）。

(In the formula, R represents an alkyl group having 1 to 4 carbon atoms.)
An asymmetric synthesis method of (5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -5-hydroxy-3-keto-6-heptenoate represented by the formula: It is known (see, for example, Patent Document 3).

  In this case, the resulting compound of formula (13) is reduced selectively with syn to give formula (14)

（式中、Ｒは前記と同義である。）
で表される（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸エステルとし、その後エステルを加水分解することにより式（１）で示される化合物が製造される。しかし、式（１３）の化合物のｓｙｎ選択的な還元反応が完全な選択性を示し難いため、やはり少量のエピマーの混入が避けられず、医薬品の製造方法としては課題を残していた（例えば特許文献４参照）。

(In the formula, R is as defined above.)
(3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoate represented by the formula: By decomposition, the compound represented by the formula (1) is produced. However, since the syn-selective reduction reaction of the compound of formula (13) is difficult to show complete selectivity, it is still unavoidable to mix a small amount of epimer, and there remains a problem as a pharmaceutical production method (for example, patents). Reference 4).

As a method for purifying the compound represented by the formula (14), a method using liquid chromatography in which the filler is silica gel is known (see, for example, Patent Document 6). However, this method requires a large amount of solvent, and requires a large-scale apparatus such as a simulated moving bed column system.
Under these circumstances, a novel production method for producing a high purity compound represented by the formula (1) having a low epimer content has been desired.

  In addition, as an amine salt of the compound represented by Formula (1), an achiral amine salt (refer patent document 5) and a chiral alpha-phenylethylamine salt (refer patent document 6) are known until now. . However, these conventional documents only describe the optical resolution of the racemate, and describe whether or not the epimer is contained in the amine salt of the compound represented by the formula (1). There is no.

JP-A-1-279866 International Publication No. 02/063028 Pamphlet International Publication No. 03/042180 Pamphlet International Publication No. 04/026838 Pamphlet WO 02/092570 pamphlet JP 05-148237 A

  The object of the present invention is (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6 with low epimer content and high purity. -A novel method for producing a chiral amine salt of heptenoic acid, and a high purity (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) with low epimer content via the amine salt ) Quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid.

  The present inventor has intensively studied to achieve the above object. As a result, the compound represented by the above formula (14) is obtained by a method of hydrolyzing a compound containing the epimer, and the like. (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by the formula (2)

で表される（式中のＲ^１、Ｒ^２、Ｒ^３は後記する）特定のキラルなアミン塩と反応させ、得られる式（３）で表されるキラルなアミン塩を結晶化させることにより、エピマー含有率の少ない高純度のアミン塩が製造できることを見出し本発明を完成させた。式（３）で表されるアミン塩からは、後記するように、定法により、純度を損なうことなく３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸が製造される。

(Wherein R ¹ , R ² and R ³ are described later) are reacted with a specific chiral amine salt, and the resulting chiral amine salt represented by the formula (3) is crystallized. The present invention was completed by finding that a highly pure amine salt with a low epimer content can be produced. From the amine salt represented by the formula (3), as will be described later, 3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline-3 is obtained by a conventional method without impairing the purity. -Yl] -3,5-dihydroxy-6-heptenoic acid is produced.

In addition, even in the chiral amine salt of the compound represented by the formula (1), when the amine is α-phenylethylamine described in Patent Document 6 , as shown in Comparative Example 1 described later, It was found that even a method for crystallizing an amine salt cannot provide a high purity amine salt with a low epimer content as in the present invention.

The present invention is based on the above novel findings and has the following gist.
(1) Formula (1)

で表される（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸に式（２）

(3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by the formula (2)

（式中、Ｒ^１、Ｒ^２及びＲ^３は、（i）その１つが水素原子であり、別の１つがヒドロキシメチル基であり、残りの１つがイソプロピル基若しくはベンジル基であるか、（ii）その１つが水素原子であり、別の１つがフェニル基であり、残りの１つがエチル基若しくはメトキシカルボニル基であるか、又は（iii）その１つが水素原子であり、別の１つが１−ナフチル基であり、残りの１つがメチル基のいずれかを意味する。）で表されるキラルなアミンを反応させ、生成した式（３）

(Wherein R ¹ , R ² and R ³ are either (i) one of which is a hydrogen atom, another is a hydroxymethyl group, and the other is an isopropyl group or a benzyl group, or (ii ) One of which is a hydrogen atom and the other is a phenyl group and the other is an ethyl group or a methoxycarbonyl group, or (iii) one of which is a hydrogen atom and the other is 1- A naphthyl group, and the remaining one means a methyl group .) Produced by reacting a chiral amine represented by formula (3)

（式中、Ｒ^１、Ｒ^２及びＲ^３は前記と同じ意味を示す。）で表される（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸のキラルなアミン塩を結晶化させることで含有するエピマーを減少させることを特徴とする（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸のキラルなアミン塩の製造方法。

(Wherein R ¹ , R ² and R ³ have the same meaning as described above) (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline-3 (3R, 5S) -7- [2-cyclopropyl-, characterized in that the epimer contained is reduced by crystallizing the chiral amine salt of -yl] -3,5-dihydroxy-6-heptenoic acid 4- (4-Fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid chiral amine salt production method.

(2) In formula (2) of the chiral amine, ^one of R ¹ , R ² and R ³ is a hydrogen atom, another is a hydroxymethyl group, and the other is an isopropyl group or a benzyl group The manufacturing method as described in ( 1 ) above.
( 3 ) (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by formula (3) The production method according to (1) or (2) , wherein the chiral amine salt is crystallized with a carboxylic acid ester, a ketone, an alcohol, or a mixed solvent containing the same.

( 4 ) (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by formula (3) The production method according to (1) or (2) , wherein the chiral amine salt is crystallized with ethyl acetate or a mixed solvent containing the same.
( 5 ) (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by formula (3) The production method according to (1) or (2) above, wherein the chiral amine salt is crystallized with methyl isobutyl ketone or a mixed solvent containing the same.

( 6 ) (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by formula (3) The production method according to the above (1) or (2) , wherein the chiral amine salt of is crystallized with ethanol or a mixed solvent containing the same.
( 7 ) (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline-3 obtained by the production method according to any one of (1) to ( 6 ) above - yl] -3,5, characterized by comprising treatment with an acid crystals chiral amine salts of dihydroxy-6-heptenoic acid, low content of epimers (3R, 5S) -7- [2 -Method for producing cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-hepteic acid.

( 8 ) Formula (3)

（式中、Ｒ^１、Ｒ^２及びＲ^３は、（i）その１つが水素原子であり、別の１つがヒドロキシメチル基であり、残りの１つがイソプロピル基若しくはベンジル基であるか、（ii）その１つが水素原子であり、別の１つがフェニル基であり、残りの１つがエチル基若しくはメトキシカルボニル基であるか、又は（iii）その１つが水素原子であり、別の１つが１−ナフチル基であり、残りの１つがメチル基のいずれかである）で表される（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸のキラルなアミン塩。

(Wherein R ¹ , R ² and R ³ are either (i) one of which is a hydrogen atom, another is a hydroxymethyl group, and the other is an isopropyl group or a benzyl group , or (ii ) One of which is a hydrogen atom and the other is a phenyl group and the other is an ethyl group or a methoxycarbonyl group, or (iii) one of which is a hydrogen atom and the other is 1- (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl]-, which is a naphthyl group and the remaining one is any methyl group) Chiral amine salt of 3,5-dihydroxy-6-heptenoic acid.

In (9) (3), ^R 1, ^{R 2} and ^{R 3} are the one of a hydrogen atom, another one is a hydroxymethyl group, the remaining one is an isopropyl group or a benzyl group ( 8 ) The chiral amine salt of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid described in 8 ).
( 10 ) The chiral amine is (R) -2-amino-3-methyl-1-butanol and has the formula (4)

で表される上記（９）に記載の（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸のキラルなアミン塩。

(3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid as described in ( 9 ) above Chiral amine salt.

( 11 ) The chiral amine is (S) -2-amino-3-phenyl-1-propanol and has the formula (5)

で表される上記（９）に記載の（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸のキラルなアミン塩。

(3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid as described in ( 9 ) above Chiral amine salt.

( 12 ) The chiral amine is (R) -2-amino-3-phenyl-1-propanol and has the formula (6)

で表される上記（９）に記載の（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸のキラルなアミン塩。

(3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid as described in ( 9 ) above Chiral amine salt.

( 13 ) The chiral amine is (R) -1- (phenyl) propylamine and has the formula (7)

で表される上記（８）に記載の（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸のキラルなアミン塩。

(3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid as described in ( 8 ) above Chiral amine salt.

( 14 ) The chiral amine is (R) -1- (1-naphthyl) ethylamine and has the formula (8)

で表される上記（８）に記載の（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸のキラルなアミン塩。

(3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid as described in ( 8 ) above Chiral amine salt.

( 15 ) The chiral amine is (S) -phenylglycine methyl ester and has the formula (9)

で表される上記（８）に記載の（３Ｒ，５Ｓ）−７−［２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸のキラルなアミン塩。

(3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid as described in ( 8 ) above Chiral amine salt.

According to the present invention, high purity (3R, 5S) -7- [2-cyclopropyl-4 having an epimer content of 1.6% or less, further 0.8% or less, particularly 0.2% or less. A process for the preparation of a chiral amine salt of-(4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid is provided.
Further, according to the present invention, from the above amine salt, (3R, 5S) -7- [2-cyclopropyl-4 represented by (1) having high purity with a low epimer content as much as the amine salt. -(4-Fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid is obtained.
The chiral amine of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid obtained by the present invention Some of the salts are novel compounds not yet described in the literature.

Hereinafter, the present invention will be described in more detail.
In the present invention, “n” is normal, “i” is iso, “s” or “sec” is secondary, “t” or “tert” is tertiary, “c” is cyclo, “O” means ortho, “m” means meta, “p” means para, “Me” means methyl group, “Bu” means butyl group, “t-Bu” means tertiary butyl group. .

The C _1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl group, ethyl group, n-propyl group, i-propyl group. Group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, 1-ethyl-2-methyl-n-propyl group and the like.
The C _1-3 alkyl group means a linear or branched alkyl group having 1 to 3 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, and an i-propyl group. Groups and the like.
The C _2-6 alkyl group means a linear or branched alkyl group having 2 to 6 carbon atoms, and specific examples thereof include ethyl group, n-propyl group, i-propyl group, n -Butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group or 1-ethyl-2-methyl-n-propyl group. More preferably, it is an ethyl group.

The C _3-6 alkyl group means a linear or branched alkyl group having 3 to 6 carbon atoms, and specific examples thereof include an n-propyl group, an i-propyl group, and an n-butyl group. I-butyl group, s-butyl group, t-butyl group, n-pentyl group, 1-ethyl-2-methyl-n-propyl group and the like. More preferably, it is an i-propyl group.
The C _1-6 hydroxyalkyl group means a C _1-6 alkyl group having one hydroxy group as a substituent, and specific examples thereof include a hydroxymethyl group, a hydroxyethyl group, a hydroxy-n-propyl group, Hydroxy-i-propyl group, hydroxy-n-butyl group, hydroxy-i-butyl group, hydroxy-s-butyl group, hydroxy-t-butyl group, hydroxy-n-pentyl group or hydroxy-1-ethyl-2- And methyl-n-propyl group.

The C _1-3 hydroxyalkyl group means a C _1-3 alkyl group having one hydroxy group as a substituent, and specific examples thereof include a hydroxymethyl group, a hydroxyethyl group, a hydroxy-n-propyl group, Examples include a hydroxy-i-propyl group. More preferably, it is a hydroxymethyl group.
The C _2-7 alkyl carboxyl group means a carboxyl group having one C _1-6 alkyl group as a substituent, and specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, i -Propoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group or 1-ethyl-2-methyl-n-propoxycarbonyl group Can be mentioned.

The C _6-14 aryl group means an aromatic hydrocarbon having 6 to 14 carbon atoms, and specific examples thereof include a phenyl group, a p-methylphenyl group, a 1-naphthyl group, a 2-naphthyl group, A biphenyl group or an anthranyl group is mentioned. A phenyl group or a naphthyl group is preferable, and a phenyl group is more preferable.
The C _7-14 aryl group means an aromatic hydrocarbon having 7 to 14 carbon atoms, and specific examples thereof include a 1-naphthyl group, a 2-naphthyl group, a biphenyl group, and an anthranyl group. A naphthyl group is preferable, and a 1-naphthyl group is more preferable.

The C _7-16 aralkyl group means an alkyl group having an aromatic hydrocarbon as a substituent and having 7 to 16 carbon atoms as a whole. Here, the aromatic hydrocarbon is preferably a phenyl group, the alkyl group is preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group, and still more preferably a methyl group. Specific examples of the C _7-16 aralkyl group include a phenylmethyl group (benzyl group), a phenylethyl group, a phenyl-i-propyl group, a naphthylmethyl group, a biphenyl group or an anthranyl group, and a preferred example is a benzyl group. Is mentioned.

The chiral amine used in the present invention is represented by the general formula (2). In the general formula (2), R ¹ , R ² and R ³ are not the same as each other, but are a hydrogen atom, C _1-6 alkyl group, C _1-6 hydroxyalkyl group, C _2-7 alkyl carboxyl group, C _6-14 aryl group (provided that ^one of R ¹ , R ² or R ³ is a methyl group, C ₆ An aryl group is excluded) or a C _7-16 aralkyl group.
More preferably, R ¹ , R ² and R ³ are (i) one is a hydrogen atom, another is a C _1-6 hydroxyalkyl group, and the other is a C _3-6 alkyl group or C 3 _7-16 aralkyl group, or (ii) one is a hydrogen atom, another is a C _6-14 aryl group, and the other is a C _2-6 alkyl group or a C _2-7 alkyl carboxyl group Or (iii) one is a hydrogen atom, another is a C _7-14 aryl group, and the other is a methyl group.

More preferably, ^one of R ¹ , R ² and R ³ is a hydrogen atom, the other is a C _1-6 hydroxyalkyl group, and the other is a C _3-6 alkyl group or C _7-16. Aralkyl group.
Particularly preferably, ^one of R ¹ , R ² and R ³ is a hydrogen atom, another is a C _1-3 hydroxyalkyl group, and the other is a C _3-6 alkyl group.
In addition, as a more preferable form as a specific combination of R ¹ , R ² and R ³ , R ¹ is a hydrogen atom, R ² is an isopropyl group, R ³ is a hydroxymethyl group, and the absolute configuration is R ( (R) -2-amino-3-methyl-1-butanol; R ¹ is a hydrogen atom, R ² is a benzyl group, R ³ is a hydroxymethyl group, and the absolute configuration is R (R) -2-amino -3-phenyl-1-propanol or (S) -2-amino-3-phenyl-1-propanol whose absolute configuration is S; R ¹ is a hydrogen atom, R ² is a propyl group, R ³ is a phenyl group, (R) -1- (phenyl) propylamine whose absolute configuration is R; or R ¹ is a hydrogen atom, R ² is a methyl group, R ³ is a 1-naphthyl group, and the absolute configuration is R (R) -1 -(1-Naphthyl) ethylamino Can be mentioned.

  In the present invention, when a chiral amine salt of the compound of formula (1) is produced, the amount of chiral amine used is (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline. -3-yl] -3,5-dihydroxy-6-heptenoic acid with respect to 1 mol, preferably 0.5 to 2.0 mol, more preferably 0.8 to 1.2 mol, particularly preferably 1.00 to 1. .04 mol.

  In the present invention, the chiral amine salt of the compound of formula (1) is represented by the following formula (3):

の如く、アミン（−ＮＨ_２）とカルボン酸（−ＣＯ_２Ｈ）の組み合わせとして記載するが、アンモニウム（−ＮＨ_３ ^＋）とカルボキシラート（−ＣＯ_２ ⁻）の組み合わせなどの通常表記されているアミンとカルボン酸の塩の形態を含むものである。

As described above, it is described as a combination of an amine (—NH ₂ ) and a carboxylic acid (—CO ₂ H), but is usually expressed as a combination of ammonium (—NH ₃ ⁺ ) and a carboxylate (—CO ₂ ⁻ ). Including the salt form of amine and carboxylic acid.

  In the present invention, crystallization in the production of a chiral amine salt of the compound of formula (1) is preferably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction between the compound of formula (1) and the chiral amine salt. For example, alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol; aromatic hydrocarbons such as benzene, toluene, xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether Ethers such as; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform and dichloroethane; carboxylic acid esters such as methyl acetate and ethyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; water; The mixed solvent to contain is mentioned.

Among them, it is preferably used in a mixed solvent containing carboxylic acid esters, ketones and alcohols, more preferably ethyl acetate, methyl isobutyl ketone and ethanol alone or containing them. More preferred is ethyl acetate, a mixed solvent of ethyl acetate and ethanol, or a mixed solvent of ethyl acetate and methyl isobutyl ketone.
The amount of the solvent used is appropriately adjusted according to the stirring ability of the reaction solution, but (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3 The amount is preferably 3 to 100 g, more preferably 5 to 30 g, and particularly preferably 8 to 15 g based on 1 g of 1,5-dihydroxy-6-heptenoic acid.
The temperature for crystallization of the chiral amine salt of the compound of formula (1) is preferably -20 to 100 ° C, more preferably -10 to 50 ° C, particularly preferably 0 to 30 ° C.

In the present invention, the procedure for crystallization of the chiral amine salt of the compound of formula (1) is as follows. First, a compound of formula (1) and a chiral amine are added to the solvent. Subsequently, it stirs as it is, or after distilling a solvent off, it adds to another solvent and stirs to make it precipitate as a crystal | crystallization. The order of adding the compound of formula (1) and the chiral amine to the solvent may be either, but it is desirable to add the compound of formula (1) first and then add the chiral amine. The chiral amine can be added after being dissolved in a solvent, and it is preferable. When adding a chiral amine or a solution of chiral amine, it is desirable to add dropwise in small portions. The dropping time is not particularly limited, but is usually 5 minutes to 1 hour, preferably 10 minutes to 30 minutes. Stirring may be continued for a certain time after the precipitation of crystals. The stirring time is not particularly limited, but is usually 30 minutes to 4 hours, preferably 1 hour to 1.5 hours.
This crystal can be obtained as a crystal by filtration. At that time, due to factors such as a difference in solubility, the epimer of the compound represented by formula (1) or the compound in which the epimer is converted to an amine salt is removed from the crystal of the chiral amine salt of the compound of formula (1). , The content of epimer will be significantly reduced.

The content of the epimer in the crystal of the chiral amine salt of the obtained compound of the formula (1) is usually reduced to 0.7 to 1.6%, but if it is still insufficient, or further In the case of reducing the content of the epimer, the same solvent as described above or a different solvent can be used for recrystallization or a purification operation such as suspension washing.
As the solvent used in this case, the solvents described in the case of the reaction of the compound of formula (1) with a chiral amine are used. For example, alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol; aromatic hydrocarbons such as benzene, toluene, xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether Ethers such as; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform and dichloroethane; carboxylic acid esters such as methyl acetate and ethyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; water; The mixed solvent to contain is mentioned. Preferably, a mixed solvent containing carboxylic acid esters, ketones and alcohols, more preferably ethyl acetate, methyl isobutyl ketone and ethanol alone or containing them is used. Particularly preferred is ethyl acetate, a mixed solvent of ethyl acetate and ethanol, or a mixed solvent of ethyl acetate and methyl isobutyl ketone.

Further, the amount of the solvent used is appropriately adjusted depending on the stirring property, etc., as in the case of the reaction of the compound of formula (1) with a chiral amine, but is preferably 3 with respect to 1 g of compound of formula (1). -100 g, more preferably 5-30 g, particularly preferably 8-15 g.
When the chiral amine salt of the compound of formula (1) is recrystallized or suspended in a solvent, it is dissolved and suspended and washed in a possible range from −20 ° C. to the boiling point of each solvent, then −10 to A method of cooling to 50 ° C., more preferably 0 to 30 ° C., to obtain crystals is used.
In the present invention, suspension washing refers to reducing impurities contained in a compound by bringing the solid compound into contact with the solvent by suspending and stirring in the solvent.

The above purification operation can be repeated as necessary. Further, the purified chiral amine salt of the compound of formula (1) can be obtained as a crystal by filtration. The content of epimers in a chiral amine salt of a compound of such to obtain formula (1) is 0.5% or less, and particularly may Mel Shi was reduced to 0.2% or less.
The chiral amine salt of the compound of the formula (1) obtained as described above is represented by the above formulas (4), (5), (6), (7), (8) and (9). New compounds are also included.

The chiral amine salt of the compound of the formula (1) obtained above is then treated with an acid to give a high purity (3R, 5S) -7 represented by the formula (1) with low epimer content. -[2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid can be prepared.
Examples of the acid used here include hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, and trifluoroacetic acid, and hydrochloric acid is particularly preferable.

  Treatment of the chiral amine salt of the compound of formula (1) with an acid can be carried out by a known method, for example, according to the method described in JP-A No. 05-148237. For example, by dissolving in methanol at 1-30 ° C., adding an equivalent 1 mol / liter hydrochloric acid, extracting with ethyl acetate, and distilling off the solvent under reduced pressure, the target product is obtained as a colorless oil. Can do.

The (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid produced is of high purity and is The content is 1.6% or less, further 0.8% or less, particularly 0.2% or less in terms of relative area percentage by HPLC.
In addition, (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid is not only in the form of free acid. , Calcium salt, and lactone form.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not construed as being limited thereto. In this example, HPLC means high performance liquid chromatography, and NMR means nuclear magnetic resonance spectrum analysis. The epimer content in the examples was expressed by calculating the relative percentage of the peak area derived from the epimer by analysis using high performance liquid chromatography under the following conditions.
Analytical condition column for high performance liquid chromatography: L-ColumnODS (manufactured by Chemicals Evaluation and Research Institute)
Column diameter 4.6mm, column length 250mm, particle size 5μm
Column temperature: 40 ° C
Eluent: acetonitrile-0.01M acetate buffer (pH 3.8), 40:60 (0-20 min.), 40: 60-90: 10 (20-40 min.), 90:10 (40-60 min.)
Flow rate: 1.0 ml / min.
Detection wavelength: 245 nm

  The retention time of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid or its amine salt is 21.7. Minutes. In contrast, (3S, 5S)-and (3R, 5R) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid Or the retention time of the amine salt was 23.7 minutes.

Reference example 1
Synthesis of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid Stirrer, thermometer, dropping funnel A 500 ml four-necked flask equipped with ethyl (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoate 10 0.01 g (22.3 mmol), 100 g of ethanol, and 100 g of water were added, and then 12.2 g (27.5 mmol) of a 9 mass% aqueous sodium hydroxide solution was added dropwise. After reacting at room temperature for 30 minutes, insoluble matters were filtered, and 164 g of the solvent was distilled off under reduced pressure. The residue was separated and washed with 50.5 g of ethyl acetate, 14.7 g (26.2 mmol) of 6.5 mass% hydrochloric acid aqueous solution was added, and the mixture was extracted with 100.7 g of ethyl acetate. The obtained organic layer was washed with 50.0 g of water, the solvent was distilled off to adjust the concentration, and (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline- An ethyl acetate solution of 3-yl] -3,5-dihydroxy-6-heptenoic acid was obtained. As a result of HPLC analysis, the epimer content was 2.63% in terms of relative area percentage.

Comparative Example 1
Of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid (R) -α-methylbenzylamine salt Synthesis 1.88 g of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid obtained in Reference Example 1 A solution of 553 mg (4.57 mmol) of (R) -α-methylbenzylamine and 2 ml of ethyl acetate was added dropwise to 19.66 g of the ethyl acetate solution containing (4.46 mmol) at 20 ° C. over 20 minutes. For 1.1 hours. The precipitated crystals were filtered, washed with 10 ml of ethyl acetate, dried under reduced pressure at 50 ° C., and (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] 1.95 g of -3,5-dihydroxy-6-heptenoic acid (R) -α-methylbenzylamine salt was obtained as a white solid (ethyl ester yield based on yield of 80.6%). The epimer content of this white solid was 2.69%.

Example 1
(3R, 5S) -7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid (R) -2-amino-3-methyl Synthesis of -1-butanol salt (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6 obtained in Reference Example 1 -To 102 g of ethyl acetate solution containing 9.35 g (22.2 mmol) of heptenoic acid, 10.0 g of ethanol was added, and 2.30 g (22.3 mmol) of (R) -2-amino-3-methyl-1-butanol was added. A solution of 9.97 g of ethyl acetate was added dropwise at 20 ° C. over 30 minutes and stirred for 30 minutes. The precipitated crystals were filtered, washed with 30.0 g of ethyl acetate, dried under reduced pressure at 50 ° C., and (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline-3- Yl] -3,5-dihydroxy-6-heptenoic acid (R) -2-amino-3-methyl-1-butanol salt as a white solid, 9.37 g (ethyl ester yield based on 80.3%) was obtained. . The epimer content of this white solid was 0.73%.

  This white solid was suspended and washed twice in 90.0 g of ethyl acetate and 9.00 g of ethanol, and (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline- 3.99 g of 3-yl] -3,5-dihydroxy-6-heptenoic acid (R) -2-amino-3-methyl-1-butanol salt as a white solid (ethyl ester yield based on yield 77.0%) Obtained. The epimer content of this white solid was 0.16%.

Melting point 147 ° C., ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.88 (6H, d, J = 6.9 Hz), 1.02-1.06 (2H, m), 1.11. -1.23 (3H, m), 1.37-1.47 (1H, m), 1.68-1.77 (1H, m), 1.99 (1H, dd, J = 7.9, 14.9 Hz), 2.12 (1H, dd, J = 4.3, 15.2 Hz), 2.61-2.67 (1H, m), 3.34 (1H, dd, J = 7.3) , 11.2 Hz), 3.51 (1H, dd, J = 4.3, 11.6 Hz), 3.61-3.65 (1H, m), 4.10-4.16 (1H, m) 5.62 (1H, dd, J = 5.9, 16.2 Hz), 6.49 (1H, d, J = 16.2 Hz), 7.24-7.41 (6H, m), 7. 63 (1H, dd, = 6.3,7.3Hz), 7.86 (1H, d, J = 8.3Hz)

Example 2
(3R, 5S) -7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid (S) -2-amino-3-phenyl Synthesis of -1-propanol salt (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6 obtained in Reference Example 1 -To 9.95 g of ethyl acetate solution of 0.940 g (corresponding to 2.23 mmol) of heptenoic acid, 337 mg (2.23 mmol) of (S) -2-amino-3-phenyl-1-propanol, 1 ml of ethanol and ethyl acetate 1 ml of the solution was added dropwise at 20 ° C. over 10 minutes and stirred at 20 ° C. for 1 hour. The precipitated crystals were filtered, dried under reduced pressure at 50 ° C., and (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy- As a white solid, 1.014 g of 6-heptenoic acid (S) -2-amino-3-phenyl-1-propanol salt was obtained as a white solid starting yield of 79.4%. The epimer content of this white solid was 1.38%.

Melting point: 146 ° C., ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.02-1.06 (2H, m), 1.15-1.23 (3H, m), 1.38-1 .48 (1H, m), 2.04 (1H, dd, J = 8.3, 15.2 Hz), 2.16 (1H, dd, J = 4.3, 14.9 Hz), 2.62 ( 1H, dd, J = 6.6, 13.2 Hz), 2.71 (1H, dd, J = 7.3, 13.5 Hz), 3.03-3.09 (1H, m), 3.25 (1H, dd, J = 6.3, 11.2 Hz), 3.37 (1H, dd, J = 4.3, 10.9 Hz), 3.65-3.68 (1H, m), 4. 12-4.14 (1H, m), 5.62 (1H, dd, J = 5.9, 16.2 Hz), 6.49 (1H, d, J = 16.2 Hz), 7.18-7 .41 (11 , M), 7.63 (1H, dd, J = 8.3,8.6Hz), 7.86 (1H, d, J = 7.9Hz)

Example 3
(3R, 5S) -7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid (R) -2-amino-3-phenyl Synthesis of -1-propanol salt (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6 obtained in Reference Example 1 -To 9.90 g of ethyl acetate solution of 0.940 g (corresponding to 2.23 mmol) of heptenoic acid, 336 mg (2.22 mmol) of (R) -2-amino-3-phenyl-1-propanol, 1 ml of ethanol, and ethyl acetate 1 ml of the solution was added dropwise at 20 ° C. over 10 minutes and stirred at 20 ° C. for 1 hour. The precipitated crystals were filtered, dried under reduced pressure at 50 ° C., and (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy- As a white solid, 0.977 g of 6-heptenoic acid (R) -2-amino-3-phenyl-1-propanol salt was obtained as a white solid (yield based on ethyl ester 76.5%). The epimer content of this white solid was 1.23%.

Melting point 143 ° C., ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.02-1.06 (2H, m), 1.13-1.23 (3H, m), 1.38-1 .48 (1H, m), 2.04 (1H, dd, J = 8.3, 15.2 Hz), 2.16 (1H, dd, J = 4.3, 14.9 Hz), 2.62 ( 1H, dd, J = 6.9, 13.2 Hz), 2.73 (1H, dd, J = 7.3, 13.5 Hz), 3.01-3.09 (1H, m), 3.25 (1H, dd, J = 6.3, 10.9 Hz), 3.38 (1H, dd, J = 4.3, 11.2 Hz), 3.64-3.69 (1H, m), 4. 10-4.17 (1H, m), 5.62 (1H, dd, J = 5.9, 16.2 Hz), 6.49 (1H, d, J = 16.2 Hz), 7.18-7 .41 (11 , M), 7.64 (1H, dd, J = 6.9,8.3Hz), 7.86 (1H, d, J = 8.6Hz)

Example 4
(3R, 5S) -7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid (R) -1- (phenyl) propylamine Synthesis of salt (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid 0 obtained in Reference Example 1 A solution of 314 mg (2.32 mmol) of (R) -1- (phenyl) propylamine and 1 ml of ethyl acetate over 19.94 g of an ethyl acetate solution of .940 g (corresponding to 2.23 mmol) at 19 ° C. over 15 minutes The solution was added dropwise and stirred for 1.5 hours. The solvent was distilled off, 9.14 g of methyl isobutyl ketone was added to the residue, and the mixture was stirred at 20 ° C. for 1.5 hours. The precipitated crystals were filtered, washed with 5 ml of methyl isobutyl ketone, dried under reduced pressure at 50 ° C. , 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid (R) -1- (phenyl) propylamine salt. As a yellow solid, 0.642 g (ethyl ester calculated yield: 51.7%) was obtained. The epimer content of this yellow solid was 1.40%.

Melting point 89 ° C., ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.84 (3H, t, J = 7.3 Hz), 1.01-1.04 (2H, m), 1.22-1 .46 (4H, m), 1.79-1.98 (2H, m), 2.13-2.24 (2H, m), 2.43-2.49 (1H, m), 3.90 (1H, dd, J = 5.9, 8.6 Hz), 3.98 (1H, m), 4.34 (1H, m), 4.74 (br), 5.60 (1H, dd, J = 5.9, 16.2 Hz), 6.60 (1 H, d, J = 16.2 Hz), 71.3-7.20 (4 H, m), 7.21-7.35 (7 H, m) 7.58 (1H, dd, J = 6.3, 6.6 Hz), 7.94 (1H, d, J = 8.6 Hz)

Example 5
(3R, 5S) -7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid (R) -1- (1-naphthyl) Synthesis of ethylamine salt (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid obtained in Reference Example 1 To 9.92 g of 0.940 g (corresponding to 2.23 mmol) of ethyl acetate solution, 392 mg (2.29 mmol) of (R) -1- (1-naphthyl) ethylamine and 1 ml of ethyl acetate were added at 20 ° C. over 20 minutes. It was dripped. After stirring for 1 hour, the solvent was distilled off, 8.88 g of methyl isobutyl ketone was added to the residue, and the mixture was stirred at 20 ° C. for 40 minutes. The precipitated crystals were filtered, washed with 5 ml of methyl isobutyl ketone, dried under reduced pressure at 50 ° C., and (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl ] -3,5-dihydroxy-6-heptenoic acid (R) -1- (1-naphthyl) ethylamine salt was obtained as a white solid, 0.874 g (ethyl ester calculated yield 66.1%). The white solid had an epimer content of 1.55%.

Melting point 116 ° C., ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.91-1.03 (3H, m), 1.13-1.25 (1H, m), 1.33 (2H, m ), 1.65 (3H, d, J = 6.6 Hz), 1.89 (2H, d, J = 6.3 Hz), 2.36-2.43 (1H, m), 3.71 (1H) M), 4.14 (1H, m), 4.95 (br), 5.08-5.13 (1H, m), 5.48 (1H, dd, J = 5.6, 16.2 Hz). ), 6.54 (1H, d, J = 16.2 Hz), 7.08-7.19 (4H, m), 7.30-7.34 (2H, m), 7.42-7.65. (5H, m), 7.75-7.82 (2H, m), 7.94-7.98 (2H, m)

Example 6
Synthesis of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid (S) -phenylglycine methyl ester salt To 452 mg (2.24 mmol) of (S) -phenylglycine methyl ester hydrochloride was added 10 ml of ethyl acetate, 10 ml of water, and 323 mg (3.05 mmol) of sodium carbonate, and then the organic layer was separated, and further washed twice with 10 ml of water. The solvent in the organic layer was distilled off.
With respect to the obtained residue, (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy- obtained in Reference Example 1 was used. 6.02 g of an ethyl acetate solution corresponding to 0.580 g (1.38 mmol) of 6-heptenoic acid was added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered, washed twice with 3 ml of ethyl acetate, dried under reduced pressure at 50 ° C., and (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline-3- Yl] -3,5-dihydroxy-6-heptenoic acid (S) -phenylglycine methyl ester salt was obtained as a white solid in an amount of 0.578 g (ethyl ester yield based on yield: 71.6%). The white solid had an epimer content of 1.05%.

Melting point: 122 ° C., ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.02-1.06 (2H, m), 1.22 (3H, m), 1.41-1.46 (1H, m ), 2.17 (1H, dd, J = 7.9, 14.9 Hz), 2.27 (1H, dd, J = 5.0, 15.2 Hz), 3.59 (3H, s), 3 .76 (1H, m), 4.12-4.14 (1H, m), 4.54 (1H, s), 5.63 (1H, dd, J = 5.9, 16.2 Hz), 6 .50 (1H, d, J = 15.9 Hz), 7.25-7.41 (1 H, m), 7.64 (1 H, dd, J = 6.9, 8.3 Hz), 7.86 ( 1H, d, J = 8.3Hz)

High purity (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6 with low epimer content obtained in the present invention -Heptenoic acid and its chiral amine salt are useful as raw materials for pharmaceuticals such as cholesterol-lowering drugs (HMG-CoA reductase inhibitors).

The entire contents of the specification, claims, and abstract of Japanese Patent Application No. 2008-228750 filed on September 5, 2008 are incorporated herein as the disclosure of the specification of the present invention. Is.

Claims (15)

Formula (1)

And (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by In contrast,
Formula (2)

(Wherein R ¹ , R ² and R ³ are either (i) one of which is a hydrogen atom, another is a hydroxymethyl group, and the other is an isopropyl group or a benzyl group, or (ii ) One of which is a hydrogen atom and the other is a phenyl group and the other is an ethyl group or a methoxycarbonyl group, or (iii) one of which is a hydrogen atom and the other is 1- A naphthyl group, and the remaining one means a methyl group .) Produced by reacting a chiral amine represented by formula (3)

(Wherein R ¹ , R ² and R ³ have the same meaning as described above) (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline-3 (3R, 5S) -7- [2-cyclopropyl-4-(-) having low epimer content, characterized by crystallizing a chiral amine salt of -yl] -3,5-dihydroxy-6-heptenoic acid 4-Fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid chiral amine salt production method. In the chiral amine formula (2), one of R ¹ , R ² and R ³ is a hydrogen atom, another is a hydroxymethyl group, and the other is an isopropyl group or a benzyl group. Item 2. The manufacturing method according to Item 1 . Chiral of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by the formula (3) The production method according to claim 1 or 2 , wherein the amine salt is crystallized with a solvent of carboxylic acid esters, ketones or alcohols, or a mixed solvent containing them. Chiral of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by the formula (3) The production method according to claim 1 or 2 , wherein the amine salt is crystallized with ethyl acetate or a mixed solvent containing the same. Chiral of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by the formula (3) The production method according to claim 1 or 2 , wherein the amine salt is crystallized with methyl isobutyl ketone or a mixed solvent containing the amine salt. Chiral of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid represented by the formula (3) The production method according to claim 1 or 2 , wherein the amine salt is crystallized with ethanol or a mixed solvent containing the amine salt. (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3, obtained by the production method according to any one of claims 1 to 6 . (3R, 5S) -7- [2-cyclopropyl-4- (4-cyclopropyl-4- (4-R)) having a low epimer content, characterized by treating a crystal of a chiral amine salt of 5-dihydroxy-6-heptenoic acid with an acid. Fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid. Formula (3)

(Wherein R ¹ , R ² and R ³ are either (i) one of which is a hydrogen atom, another is a hydroxymethyl group, and the other is an isopropyl group or a benzyl group, or (ii ) One of which is a hydrogen atom and the other is a phenyl group and the other is an ethyl group or a methoxycarbonyl group, or (iii) one of which is a hydrogen atom and the other is 1- (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl]-, which is a naphthyl group and the remaining one is any methyl group) Chiral amine salt of 3,5-dihydroxy-6-heptenoic acid. In the formula ^{(3), R 1, R} 2 and R ³ are the one of a hydrogen atom, another one is a hydroxymethyl group, according to claim 8 remaining one is an isopropyl group or a benzyl group A chiral amine salt of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid. The chiral amine is (R) -2-amino-3-methyl-1-butanol and has the formula (4)

Of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid according to claim 9 Chiral amine salt. The chiral amine is (S) -2-amino-3-phenyl-1-propanol and has the formula (5)

Of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid according to claim 9 Chiral amine salt. The chiral amine is (R) -2-amino-3-phenyl-1-propanol and has the formula (6)

Of (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid according to claim 9 Chiral amine salt. The chiral amine is (R) -1- (phenyl) propylamine and has the formula (7)

The (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid according to claim 8 represented by Chiral amine salt. The chiral amine is (R) -1- (1-naphthyl) ethylamine and has the formula (8)

The (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid according to claim 8 represented by Chiral amine salt. The chiral amine is (S) -phenylglycine methyl ester and has the formula (9)

The (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid according to claim 8 represented by Chiral amine salt.