JP3481325B2 - Method for producing optically active 3-oxy-5-oxo-6-heptenoic acid derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to optically active 3-oxy-5-oxo-6-heptenoic acid derivatives, particularly (3R, 6
E) -3-[(tert-Butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-yl] -5-oxo-6-heptene The present invention relates to a method for producing acid methyl ester.
The methyl ester is a blood cholesterol lowering agent [4
-Hydroxy-3-methylglutaryl-5- (HMG)
Co-A reductase inhibitor] is useful as an intermediate in the synthesis.

The object compound of the present invention is (3R, 6E)
-3-[(tert-butyldimethylsilyl) oxy] -7-
[2′-Cyclopropyl-4 ′-(4 ″ -fluorophenyl) quinolin-3′-yl] -5-oxo-6-heptenoic acid methyl ester can be obtained by the method described in JP-A-5-178841. Deterioration of tert-butyldimethylsilylation using hydrogen fluoride according to the procedure in (3R, 6E) -7- [2'-cyclopropyl-4 '-(4''-fluorophenyl)quinoline-3'- Ill]
-3-Hydroxy-5-oxo-6-heptenoic acid methyl ester was derivatized and further subjected to syn reduction using diethylmethoxyborane and sodium borohydride (NaBH ₄ ) (3R, 5S, 6E) -7- (2'- cyclopropyl-4'-
It can be derivatized to (4 ''-fluorophenyl) quinolin-3'-yl] -3,5-dihydroxy-6-heptenoic acid methyl ester.

Produced as described above (3R, 5
S, 6E) -7- [2'-Cyclopropyl-4'-
(4 "-Fluorophenyl) quinolin-3'-yl]-
3,5-Dihydroxy-6-heptenoic acid methyl ester can be obtained, for example, from Journal of Medicinal Chemistry (Journal of Medicinal Chemistry).
Chemistry, 1985, Volume 28, No.
3, pp. 347-358), and then treated with sodium hydroxide and hydrochloric acid, 4 -hydroxy-3-
(E) -6- (S)-[2'-Cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-ylethenyl having methylglutaryl -5- (HMG) Co - A reductase inhibitory activity ] -3,4,5,6-Tetrahydro-4- (R) -hydroxy-2H-pyran-2-one (hereinafter referred to as the final compound) can be obtained.

[0004]

2. Description of the Related Art The racemate of the final compound and its production method are
It is disclosed in JP-A-1-279866. The production method is as follows: (E) -3- [4 '-(4 "-fluorophenyl) -2'-cyclopropylquinolin-3'-yl] propene aldehyde is reacted with ethyl acetoacetate to obtain ethyl (E) -7. -[4 '-(4 "-fluorophenyl)
-2'-cyclopropylquinolin-3'-yl] -5-
Hydroxy-3-oxohept-6-enoate (hereinafter referred to as 1-hydroxyl compound) is obtained. The resulting monohydroxyl compound is reduced to ethyl (E) -3,5-dihydroxy-7- [4 '-(4 "-fluorophenyl) -2'-cyclopropylquinolin-3'-yl] -hept. -6-Enoate (hereinafter referred to as a 2-hydroxyl compound) is obtained by hydrolyzing the ester of the obtained 2-hydroxyl compound to obtain (±).
-(E) -3,5-dihydroxy-7- [4 '-(4 "
-Fluorophenyl) -2'-cyclopropylquinolin-3'-yl] hept-6-enoic acid is obtained. The optical resolution method of the racemate of the final compound is described in JP-A-5-17884.
It is disclosed in Japanese Patent Publication No. The optical resolution method is (±)
-(E) -3,5-dihydroxy-7- [4 '-(4 "
-Fluorophenyl) -2'-cyclopropylquinolin-3'-yl] hept-6-enoic acid is reacted with D-(+)-phenethylamine to give (E) -3- (R)-
5- (S) -dihydroxy-7- [4 '-(4 "-fluorophenyl) -2'-cyclopropylquinoline-3'
-Yl] hept-6-enoic acid.D-(+)-phenethylamine salt is obtained. It was a method in which 1 mol / L-hydrochloric acid was allowed to act on the salt to lead to the final compound.

According to this method, the monohydroxyl compound is produced in a racemic form, and therefore the dihydroxyl compound obtained by carrying out syn-reduction is also obtained in a racemic form. for that reason,
Due to the presence of two asymmetric carbon atoms, selective racemization is difficult, and it is necessary to produce an unnecessary compound having an unrecoverable reverse optical configuration. The division yield due to optical resolution is poor. In that sense, it was not an industrially satisfactory method.

As a method for producing a 3-oxy-5-oxo-6-heptenoic acid derivative by reacting an aromatic aldehyde with an oxyglutarate derivative, there is the following method. Bio-organic & Medicinal Chemistry
letters, 1991, Vol. 1, No. 3, pp. 161-164), benzaldehyde as an aromatic aldehyde and (R) -3-[(tert-butyldimethylsilyl) oxy]-as an oxyglutarate derivative. Methyl 6- (dimethoxyphosphinyl) -5-oxohexanoate was used as a base in an acetonitrile solution in the presence of lithium chloride.
Reaction with 8-diazabicyclo [5,4,0] undecane-7-ene (hereinafter referred to as DBU) (3R, 6E)-
A method for obtaining methyl 3-[(tert-butyldimethylsilyl) oxy] -5-oxo-7-phenyl-6-heptenate is disclosed. However, the above method was not industrially satisfactory in that the yield was as low as 71%.

[0007] Journal of Medicinal Chemistry (1991,
34, No. 1, pages 367-373), 4- [6-fluoro-4- (4-fluorophenyl) as a heterocyclic aromatic aldehyde.
As 2- (1-methylethyl) -3-quinolinecarboxaldehyde and oxyglutarate derivative (3
R, 1 ′, S) -1- (1′-naphthyl) ethyl-3-[(tert
-Butyldimethylsilyl) oxy] -6- (dimethylphosphinyl) -5-oxo-hexanoate was reacted with DBU in the presence of lithium chloride in a dichloromethane solution to give [R- (R ^* , R ^* )]-1-phenylethyl-3-[(tert-butyldimethylsilyl) oxy]
-7- [6-Fluoro-4- (4-fluorophenyl) -2- (1-
A method for obtaining methylethyl) -3-quinolinyl] -5-oxo-6-heptenoate is disclosed. However, this method was not industrially satisfactory in that the yield was as low as 33%.

Journal of organic Chemistry, 1992, 57
Vol. 6, No. 6, pp. 1935-1937), as aliphatic aldehydes (1S, 2S, 4aR, 6S, 8S, 8aS) -1, 2, 4a,
5, 6, 7, 8, 8a-octahydro-2-methyl-8-[(2 ",
2 "-dimethyl-1" -oxo-butyl) oxy] -6-
[(E) -1-propenyl] naphthalene-1-carbaldehyde and (R) -as oxyglutarate derivative
3-[(tert-butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester was reacted in isopropanol solution using potassium carbonate or cesium carbonate as a base. Methyl (1S, 2S, 4aR, 6S, 8S, 8aS, 3'R) -7'-
[1,2,4a, 5,6,7,8, Sa-octahydro-2-methyl-8-[(2 ", 2" -dimethyl-1 "-oxo-butyl) oxy] -6-[(E ) -1-Propenyl] naphthalenyl] -3 ′
A method for obtaining-[(tert-butyldimethylsilyl) oxy] -5'-oxo-6'-heptenoate is disclosed.

However, this method is industrially satisfactory in that the reaction rate is very slow, it takes 2-3 days until the reaction is completed, the conversion rate is as low as 25%, and the yield is low. It wasn't the way to do it. In addition, a method is also disclosed in which cesium carbonate is used as a base and a similar reaction is carried out in a tert-butanol solution. However, this method also has a slow reaction rate, and the raw material conversion rate is 4 days after the start of the reaction. Was as low as 78% and the yield was 53%, which was not an industrially satisfactory method. Therefore, any of the known production methods-is unsatisfactory as an industrial method for obtaining an optically active 3-oxy-5-oxo-6-heptenoic acid derivative.

[0010]

DISCLOSURE OF THE INVENTION The inventors of the present invention have made diligent studies in order to improve the above-mentioned problems in the known production method. As a result, an aliphatic alcohol solvent was used as a solvent and potassium carbonate was used as a base. Using 2-cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde and (R) -3-tert-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid By reacting with a methyl ester, a novel optically active 3-oxy-5-oxo-6-heptenoic acid derivative (hereinafter also referred to as a target compound; (3R, 6E) -3-[(tert-
Butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-4- (4 ''-fluorophenyl) quinolin-3'-yl]
-5-oxo-6-heptenoic acid methyl ester)
The present invention has been completed by finding that by using the target compound, the final target product can be obtained without producing an unnecessary compound and without performing optical resolution.

Therefore, the present invention provides (3R, 6E) -3-
[(Tert-Butyldimethylsilyl) oxy] -7-
It is an object to provide a method for producing [2′-cyclopropyl-4 ′-(4 ″ -fluorophenyl) quinolin-3′-yl] -5-oxo-6-heptenoic acid methyl ester in good yield. .

[0012]

The present invention is based on the formula

[0013]

[Chemical 5]

(3R, 6E) -3-[(tert-
Butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-4 '-(4''-fluorophenyl)quinolin-3'-yl]
-5-oxo-6-heptenoic acid methyl ester,

A novel process for producing the above methyl ester, namely the formula

[0016]

[Chemical 6]

2-cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde represented by the formula

[0018]

[Chemical 7]

Reaction of (R) -3-tert-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid methyl ester represented by the following in the presence of potassium carbonate in an aliphatic alcohol. Let the formula

[0020]

[Chemical 8]

(3R, 6E) -3-[(tert-
Butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-4 '-(4''-fluorophenyl)quinolin-3'-yl]
(3R, 6E) -3-[(tert-Butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-, characterized by producing methyl 5-5-oxo-6-heptenoate
4 '-(4''-fluorophenyl)quinolin-3'-yl] -5-
It relates to a process for producing oxo-6-heptenoic acid methyl ester.

The aliphatic alcohol solvent used in the production method of the present invention mainly contains a secondary or tertiary alcohol (particularly preferably 80 to 100% by volume, more preferably 90 to 100% by volume). It is preferably a solvent.
Further, in the production method of the present invention, the aliphatic alcohol solvent (particularly the secondary or tertiary alcohol solvent) has a water content of 30.
It is preferable that the content is about 20,000 ppm.

The target compound of the production method of the present invention is (3R, 6
E) -3-[(tert-Butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-yl] -5-oxo-6-heptene Acid methyl ester.

From the compounds of the present invention, for example, the method and the journal of Medicinal Chemistry (Jou) described in the above-mentioned JP-A-5-178841.
rnal of Medicinal Chemist
ry, 1985, Volume 28, No. 3,347-35
4 -hydroxy-3 according to the method described in page 8).
-Methylglutaryl -5- (HMG) Co - A (E) -6- (S)-[2'-cyclopropyl-4 '-(4 "-fluorophenyl) quinoline-3'- having reductase inhibitory activity Ilethenyl] 3,4,5,6-tetrahydro-4- (R) -hydroxy-2H-pyran-2-one can be produced by a method such as the following. Formula (1),

[0025]

[Chemical 9]

It can be represented by

The 2-cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde used in the production method of the present invention is produced according to the method described in, for example, JP-A-1-279866. can do.

As a method for producing this aldehyde, for example,
2-Amino-4'-fluorobenzophenone was reacted with ethylcyclopropionyl acetate to give ethyl-4-
(4'-Fluorophenyl) -2-cyclopropylquinoline-
After obtaining 3-ylcarboxylate and then reacting with diisobutylaluminum hydride to give 4- (4'-fluorophenyl) -2-cyclopropyl-3-hydroxymethylquinoline, finally A preferable method is a method of producing 2-cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde by reacting pyridinium chlorochromate with anhydrous sodium acetate.

(R) -3-t used in the production method of the present invention
ert-Butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid methyl ester is a
Null of Medicinal Chemistry (Journal of M
edicinal Chemistry, 1987, Volume 30, No. 10, 1858
-Page 1873). For example, a method of producing by the following steps 1 to 7 can be preferably mentioned.

Step 1: To a solution of diethyl-3-hydroxyglutarate in methylene chloride was added imidazole and tert-.
Butylchlorodimethylsilyl is added and reacted to obtain diethyl 3-[(tert-butyldimethylsilyl) oxy] pentanedioate.

Step 2: Diethyl-3-obtained in Step 1
Sodium hydroxide is added to a methanol solution of [(tert-butyldimethylsilyl) oxy] pentanedioate and reacted to obtain a reaction mixture. Methanol was removed from the reaction mixture, and benzene and acetic anhydride were added to the residue for reaction to obtain 3-[(tert-butyldimethylsilyl) oxy] pentanedioic anhydride.

Step 3: 3-[(tert-butyldimethylsilyl) oxy] pentanedioic anhydride obtained in Step 2, trimethylamine, (N, N-dimethylamino) pyridine, methylene chloride and (R) -phenyl A reaction mixture is obtained by reacting with ethanol. The obtained reaction mixture was post-treated and then reacted with a solution of diazomethane in diethyl ether to react (3R, 1′R) -methyl-1′-phenylethyl-3-[(tert-butyldimethylsilyl) oxy. ] Pentandioate is obtained.

Step 4: Obtained in Step 3 (3R, 1 ')
R) -Methyl-1'-phenylethyl-3-[(tert-butyldimethylsilyl) oxy] pentanedioate was added to an acetonitrile solution of hydrogen fluoride to react, and (3
R, 1'R) -Methyl-1'-phenylethyl-3-hydroxypentanedioate can be obtained.

Step 5: The reaction solution of n-butyllithium and dimethylmethylphosphonate obtained in Step 4 (3)
R, 1'R) -Methyl-1'-phenylethyl-3-hydroxypentanedioate was added and reacted to give (R)-
Dimethyl [4-[(R) -phenylethoxycarbonyl]
-3-Hydroxybutyryl] methylphosphonate can be obtained.

Step 6: (R) -Dimethyl [4-[(R) -phenylethoxycarbonyl] -3-hydroxybutyryl] methylphosphonate obtained in Step 5, imidazole and tert-butylchlorodimethyl By reacting with silane, (R) -dimethyl [3- (tert-butyldimethylsilyloxy) -4-[(R) -phenylethoxycarbonyl] butyryl] methylphosphonate can be obtained.

Step 7: (R) -Dimethyl [3- (tert-butyldimethylsilyloxy) -4- obtained in Step 6
[(R) -Phenylethoxycarbonyl] butyryl] methylphosphonate is reacted with hydrogen in the presence of palladium supported on activated carbon to obtain a reaction mixture. The obtained reaction mixture was subjected to post-treatment, and then an ether solution of diazomethane was added and reacted to give (R) -dimethyl [3-
(tert-Butyldimethylsilyloxy) -4-methoxycarbonylbutyryl] methylphosphonate can be obtained.

(R) -3-tert-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5 in the production method of the present invention
-The amount of oxohexanoic acid methyl ester used is
The amount is usually 0.5 to 2.0 mol per 1 mol of 2-cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde used,
The amount is preferably 0.8 to 1.5 mol, and 1.0
More preferably, the amount is about 1.3 mol.

The potassium carbonate used in the production method of the present invention may be a commercially available product. The amount of potassium carbonate used in the production method of the present invention is usually 0.5 to 2 per 1 mol of 2-cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde used. The amount may be 0 mol, preferably 0.7 to 1.8 mol, and more preferably 0.8 to 1.5 mol.

The aliphatic alcohol solvent used in the production method of the present invention is a solvent mainly containing a secondary or tertiary aliphatic alcohol (particularly preferably 80 to 100% by volume, more preferably 90 to 100% by volume). Preferably there is. Further, in the production method of the present invention, it is preferable that the aliphatic alcohol solvent (particularly, the secondary or tertiary aliphatic alcohol solvent) contains about 30 to 20,000 ppm of water.

The aliphatic alcohol solvent used in the production method of the present invention has 1 to 10 carbon atoms (particularly 1 carbon atom).
To 6) a solvent mainly containing an aliphatic alcohol, for example, methyl alcohol (methanol), ethyl alcohol (ethanol), propyl alcohol, isopropyl alcohol, butanol, isobutanol at least 40% by volume, particularly 50% by volume. %, And more preferably 80 to 100% by volume can be suitably mentioned. In the present invention, the aliphatic alcohol is most preferably propyl alcohol or isopropyl alcohol.

In the present invention, when a secondary or tertiary aliphatic alcohol solvent is used, the reaction time is shortened by adding a small amount of water to the reaction. The water added in this case has a water content of 100 ppm or more with respect to the aliphatic alcohol solvent , and 2
It is 0000 ppm or less. Preferred water content range
Is 100 to 16000 ppm, more preferably
Is 100 to 15000 ppm .

In the present invention, the amount of the aliphatic alcohol solvent used is usually about 7.5 to 300 mol per 1 mol of 2-cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde. It is sufficient if the amount is 1
The amount is preferably about 0 to 100 mol, more preferably about 15 to 80 mol.

2-of the raw material compounds used in the production method of the present invention
Cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde has low solubility in aliphatic alcohol solvents and does not dissolve sufficiently in the progress of the reaction, so it is soluble in other organic solvents. Then, the reaction is carried out by adding it to the aliphatic alcohol solvent. The organic solvent is preferably an organic solvent that is soluble in the aliphatic alcohol solvent and does not hinder the progress of the reaction in the present invention. Examples of such other organic solvent include cyclic ether solvents such as tetrahydrofuran, ether solvents such as diethyl ether and diisopropyl ether, and nitrile solvents such as acetonitrile and propionitrile. , Halogenated hydrocarbon solvents such as dichloromethane, chloroform,
Aprotic solvents such as dimethylsulfoxide, dimethylformamide, 1,3-dimethyl-2-imidazolidone can be mentioned.

In the production method of the present invention, the aliphatic alcohol solvent may be a solvent consisting of only aliphatic alcohol (100% by volume), but when the starting compound is difficult to dissolve in the aliphatic alcohol as described above. In the aliphatic alcohol solvent used in the present invention, the above-mentioned aliphatic alcohol is at least 40% by volume, particularly 50% by volume.
In addition to containing the above, the balance of the solvent may be "a mixed solvent of an aliphatic alcohol and another organic solvent" which is the other organic solvent described above.

(3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-4'-
The ratio of isomers in (4 ''-fluorophenyl) quinolin-3'-yl] -5-oxo-6-heptenoic acid methyl ester is (R) -3-tert-butyldimethylsilyloxy-6 before the reaction. -Dimethoxyphosphinyl-5-oxohexanoic acid methyl ester is substantially the same as the isomer ratio, and the reaction in the present invention does not change the isomer ratio.

The reaction temperature in the production method of the present invention is usually −
It is 30 to 50 ° C, preferably -25 to 40 ° C, and more preferably -20 to 30 ° C.

In the production method of the present invention, the reaction time depends on the reaction temperature, the charged amount of raw materials, etc., but is usually 0.25.
~ 30 hours, preferably 0.3-24 hours, 0.
More preferably 5 to 20 hours.

In the production method of the present invention, the product (3R,
6E) -3-[(tert-butyldimethylsilyl) oxy]
-7- [2'-Cyclopropyl-4 '-(4''-fluorophenyl)quinolin-3'-yl] -5-oxo-6-Method for obtaining the target compound from a reaction mixture containing methyl heptenoate May be carried out by a combination of usual washing operations and separation operations.For example, an organic solvent is added to the reaction solution to dilute it, and inorganic base is removed by washing with water, followed by solvent extraction, vacuum concentration, and column chromatography. It is preferable to obtain the target compound by the method used.

Examples of the diluting organic solvent used for obtaining the target compound include aromatic hydrocarbon solvents such as benzene, toluene and xylene, ester solvents such as ethyl acetate and propyl acetate, methylene chloride and chloroform. Halogenated hydrocarbon solvents can be mentioned.
After washing the reaction solution with water, (3R, 6E) -3-[(tert
-Butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-4 '-(4''-fluorophenyl)quinolin-3'-yl] -5-oxo-6-heptenoic acid methyl ester is the same as described above. Deprotection can also be used in the following steps.

In the production method of the present invention, the starting compound (R) -3-tert-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid methyl ester and the target compound (3R, 6E) are used. -3-[(tert-butyldimethylsilyl) oxy] -7- [2'-cyclopropyl
-4 '-(4''-Fluorophenyl)quinolin-3'-yl] -5-
Optical isomers exist in oxo-6-heptenoic acid methyl ester. In such a case, the optical isomer of the corresponding target compound can be obtained by using the starting compound optically resolved or separated as desired.

It is also possible to treat each optical isomer by a conventional optical resolution method or separation method to obtain each isomer. The production method of the present invention can be applied to both racemic and optical isomers, and the ratio of isomers of (R) -3-tert-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid methyl ester Is substantially unaffected by the reaction, and has 3-[(tert-butyldimethylsilyl) oxy] -7 with each corresponding isomer.
-[2'-Cyclopropyl-4 '-(4''-fluorophenyl)
Quinoline-3'-yl] -5-oxo-6-heptenoic acid methyl ester is produced.

[0052]

The compound of the present invention (3R, 6E)-
3-[(tert-butyldimethylsilyl) oxy]-
7- [2'-cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-yl] -5-oxo-6-
If heptenoic acid methyl ester is used, there is no need to produce unnecessary compounds (compounds having the opposite optical configuration),
4 -hydroxy-3-methylglutaryl -5- (HM
G) (E) -6 having Co - A reductase inhibitory activity
-(S)-[2'-cyclopropyl-4 '-(4 "-fluorophenyl) quinolin-3'-ylethenyl] 3
4,5,6-Tetrahydro-4- (R) -hydroxy-
2H-pyran-2-one can be prepared. According to the production method of the present invention, the starting compound 2-cyclopropyl-4- (4′-fluorophenyl) -3-quinolinecarboxaldehyde and (R) -3-tert-
By reacting butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid methyl ester with an aliphatic alcohol solvent in the presence of potassium carbonate, the target compound (3R, 6E) -3 is obtained. −
[(Tert-Butyldimethylsilyl) oxy] -7-
[2′-Cyclopropyl-4 ′-(4 ″ -fluorophenyl) quinolin-3′-yl] -5-oxo-6-heptenoic acid methyl ester can be produced in a short time in a high yield. , Especially 3-tert-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid methyl ester, the optical purity obtained after completion of the reaction is (3R, 6E) -3-[(tert-
Butyldimethylsilyl) oxy] -7- [2′-cyclopropyl-4 ′-(4 ″ -fluorophenyl) quinolin-3′-yl] -5-oxo-6-heptenoic acid methyl ester Is the same as above, and the reaction does not change the optical purity.

[0053]

EXAMPLES Examples will be shown below. The yields in the examples are (3R, 6E) -3 based on 2-cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde (mol).
-[(Tert-Butyldimethylsilyl) oxy] -7- [2'-
Cyclopropyl-4 ′-(4 ″ -fluorophenyl) quinolin-3′-yl] -5-oxo-6-heptenoic acid methyl ester (mol) yield.

Example 1 2-Cyclopropyl-4- (4'-fluorophenyl) -3-quinolinecarboxaldehyde 200 mg (0.69 mmo
l) and (R) -3-[(tert-butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester 301 mg (0.75 mm
ol, 99% ee) and isopropanol + tetrahydrofuran mixed solvent 2.8 ml [mixing ratio (V / V) = 1:
1; water content: 0.63 wt%] to obtain a mixed solution. 104 mg of potassium carbonate in the obtained mixed solution
(0.75 mmol) was added, and the mixture was stirred at room temperature (20 ° C.) for 15 hours for reaction. 20 ml of ethyl acetate was added to the obtained reaction solution to dilute it, and then washed with 10 ml of water (twice). After washing, the organic layer obtained by performing a liquid separation operation was added anhydrous magnesium sulfate, dried, and filtered to obtain a filtrate. The residue obtained by concentrating the obtained filtrate under reduced pressure was separated and purified by silica gel chromatography [eluent: hexane: ethyl acetate (V / V) = 95: 5] to obtain (3R, 6E) -3. -[(Tert-Butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-4 '-(4''-fluorophenyl)quinolin-3'-yl] -5-oxo-6-heptenoic acid methyl ester 354 mg was obtained (yield: 94
%).

¹ H-NMR (CDCl ₃ , 400 MHz) δ = 0.00 (s, 3H) 0.05 (s, 3H) 0.82 (s, 9H) 1.08 (m, 2H) 1.40 (M, 2H) 2.35 (m, 1H) 2.44 (dd, 1H, J = 14.7 and 6.4
Hz) 2.50 (dd, 1H, J = 14.7 and 5.9)
Hz) 2.67 (dd, 1H, J = 15.6 and 5.9)
Hz) 2.73 (dd, 1H, J = 15.6 and 6.4)
Hz) 3.67 (s, 3H) 4.58 (dq, 1H, J = 6.4 and 5.9H)
z) 6.34 (d, 1H, J = 16.6 Hz) 7.18-7.25 (m, 4H) 7.33-7.39 (m, 2H) 7.64 (d, 1H, J = 16.6 Hz) 7.63-7.67 (m, 1H) 7.97 (d, 1H, J = 8.3 Hz)

Elemental analysis: Calculated value C ₃₂ H ₃₈ NO ₄ FSi; C: 70.30%, H: 7.01%, N: 2.56 measured value; C: 70.28%, H: 7.19 %, N: 2.55 IR (film); 778, 838, 1094, 148
9, 1514, 1606, 1740 cm ^-1 [α] _D ²⁵ : -10.1 ° (C = 1.02, CHCl
₃ )

The obtained (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -7- [2'-cyclopropyl-4 '-(4 "-fluorophenyl) quinoline-3'- Il] -5
The optical purity of -oxo-6-heptenoic acid methyl ester was measured under the following conditions. As a result, the optical purity is 99% ee.
Met.

Optical Purity Measuring Conditions: Column; CHIRALCEL OD Eluent; Hexane: Ethanol: Trifluoroacetic acid = 1
00: 0.3: 0.01 (volume ratio) Flow rate: 0.4 ml / min Detection: UV (wavelength: 260 nm) Temperature: 30 ° C. Sample concentration: 5 mg / 10 ml (eluent)

Example 2 Mixed solvent of isopropanol + tetrahydrofuran [mixing ratio (V / V) = 1: 1; water content: 0.63 wt%]
In the same manner as in Example 1 except that 2.8 ml of a mixed solvent of methanol + tetrahydrofuran [mixing ratio (V / V) = 1: 1] was used instead of (3R, 6E) -3- [ (Te
rt-Butyldimethylsilyl) oxy] -7- [2′-cyclopropyl-4 ′-(4 ″ -fluorophenyl) quinolin-3′-yl] -5-oxo-6-heptenoic acid methyl ester 309 m
g was obtained. (Yield: 82%)

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yasuhiro Kawauchi 5 1978, Kozagushi, Ube City, Yamaguchi Prefecture, Ube Institute of Industrial Research, Ube Laboratory (72) Inventor Hiroshi Sasaki 5 1978, Koushigushi, Ube, Yamaguchi Prefecture Ube Laboratory Ltd. (56) Reference JP-A-6-107673 (JP, A) JP-A-7-118233 (JP, A) JP-A-8-127557 (JP, A) JP-A-8- 127586 (JP, A) International Publication 94/06746 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07F 7/18 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. 2-Cyclopropyl-4- (4′-fluorophenyl) -3-quinolinecarboxaldehyde and (R) -3-tert-butyldimethylsilyloxy-
With 6-dimethoxyphosphinyl-5-oxohexanoic acid methyl ester in the presence of potassium carbonate, the water content was
100 ppm or more and 20000 ppm or less
And wherein the reaction is carried out in an aliphatic alcohol solvent, (3R, 6E) -3 - [(tert- butyldimethylsilyl) oxy] -7- [2'-cyclopropyl -
Process for producing 4 '-(4 "-fluorophenyl) quinolin-3'-yl] -5-oxo-6-heptenoic acid methyl ester. 2. The method according to claim 1, wherein the aliphatic alcohol is a solvent mainly containing a secondary or tertiary aliphatic alcohol.