JP3243979B2 - Optically active 3-oxy-5-oxo-6-heptenoic acid derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to (3R, 6E) -3
-[(Tert-butyldimethylsilyl) oxy] -7-
[2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl)
-5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo
-6-Heptenoic acid methyl ester is a new optically active
The present invention relates to a 3-oxy-5-oxo-6-heptenoic acid derivative and a method for producing the same. Optically active 3-[(tert-butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-4'-
(4 ''-Fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo-6-heptenoic acid methyl ester is a blood cholesterol lowering agent [3-hydroxy-3- Methylglutaryl coenzyme A (HMG-CoA) reducer
Inhibitor] is useful as an intermediate in the synthesis.

In the target compound of the present invention, (3R, 6
E) -3-[(tert-Butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridine-3' -Il) -5
-Oxo-6-heptenoic acid methyl ester is disclosed in
According to the method described in Japanese Patent No. 178841, tert-butyldimethylsilylation is carried out using hydrogen fluoride to give (3R, 6E) -7- [2 ', 6'-diisopropyl-4'-.
(4 ''-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -3-hydroxy-5-oxo-6-heptenoic acid methyl ester, and then diethylmethoxyborane, borohydride Synth reduction was carried out using sodium (NaBH ₄ ) to give (3R, 5S, 6E) -7- [2 ′, 6′-diisopropyl-4 ′-(4 ″ -fluorophenyl) -5 ′-(methoxymethyl ) Pyridin-3'-yl] -3,5-dihydroxy-6-
Heptenoic acid methyl ester can be derived.

It is manufactured as described above (3R, 5
S, 6E) -7- [2 ', 6'-Diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -3,5-dihydroxy-6 -Methyl heptenoate can be treated with sodium hydroxide and hydrochloric acid, for example, according to the method described in JP-A-3-501613.
3-hydroxy-3-methylglutaryl coenzyme A (HMG-
(3R, 5) having CoA) reductase inhibitor activity
S, 6E)-(+)-Erythro-7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -3 Sodium 5-, 5-dihydroxy-6-heptenoate (hereinafter also referred to as final compound).

[0004]

BACKGROUND OF THE INVENTION The final compound is disclosed, for example, in JP-A-1-2169.
74 and JP-A-4-30.
It can be produced by the optical resolution method described in JP-A-8573. The production method can be shown by the following steps 1 and 2. Step 1; (E) -3- [2 ′, 6′-diisopropyl-4 ′-(4 ′
-Fluorophenyl) -5 '-(methoxymethyl) pyrido-
3′-yl] prop-2-enal is reacted with methyl acetoacetate to give methyl (E) -7- [2 ′, 6′-diisopropyl
-4 '-(4'-fluorophenyl) -5'-(methoxymethyl)
(Pyrid-3'-yl) -5-hydroxy-3-oxohept-6-
An enoate (hereinafter referred to as a monohydric compound) is obtained. Step 2: The monohydric compound obtained in Step 1 is subjected to syn reduction using tetraethylborane and sodium borohydride to give methyl erythro- (E) -7- [2 ′, 6′-diisopropyl-4 ′-( 4 ''-fluorophenyl) -5 '-(methoxymethyl) pyrid-3'-yl] -3,5-dihydroxyhept-6
-An enoate (hereinafter referred to as a dihydroxy compound) is obtained.

The optical division method can be shown in the following steps 3 and 4. Step 3: reacting the racemic dihydroxy compound obtained in Step 2 with R-(+)-phenethylamine,
(1 '''R) -N- (1'''-phenylethyl)-
Erythro- (E) -7- [2 ', 6'-diisopropyl-4'-
Two diastereomers of (4 ″ -fluorophenyl) -5 ′-(methoxymethyl) pyrid-3′-yl] -3,5-dihydroxyhept-6-enamide are obtained. Step 4: The diastereomer obtained in Step 3 was subjected to optical resolution by column chromatography, and (6E, 3R, 5S,
1 '"R) -N- (1'"-phenylethyl)-
(+)-Erythro-7- [2 ', 6'-diisopropyl-4'-
(4 ″ -Fluorophenyl) -5 ′-(methoxymethyl) pyrid-3′-yl] -3,5-dihydroxyhept-6-enamide (hereinafter referred to as optically active amide). Step 5: The optically active amide obtained in Step 4 is reacted with hydrochloric acid or sodium hydroxide to obtain a final compound.

In this method, since an acetoacetic ester having no asymmetric carbon atom is used as a starting compound, the monohydroxy compound is racemic, and the dihydroxy compound derived therefrom is also obtained in racemic form. When an unnecessary compound is recovered and reused after optical resolution, it is difficult to selectively racemize the dihydroxy compound because there are two asymmetric carbon atoms (there are four different optically active substances). It is. Therefore,
This method is not industrially satisfactory in that it is necessary to produce an unnecessary compound (a compound having the opposite optical configuration).

A method for producing a 3-oxy-5-oxo-6-heptenoic acid derivative by reacting an aromatic aldehyde with an oxyglutarate derivative includes the following methods. Bio-Organic and Medicinal Chemistry
letters, 1991, Vol. 1, No. 3, pp. 161-164), there are benzaldehyde as an aromatic aldehyde and (R) -3-[(tert-butyldimethylsilyl) oxy]-as an oxyglutarate derivative. 6- (Dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester is converted into 1,8-diazabicyclo [5,4, O] undecane-7- as a base in an acetonitrile solution in the presence of lithium chloride.
Reaction using ene (hereinafter referred to as DBU) (3R,
6E) -3-[(tert-butyldimethylsilyl) oxy]
A method for obtaining methyl-5-oxo-7-phenyl-6-heptenoate is disclosed. However, the above method was not industrially satisfactory in that the yield was as low as 71%.

[0008] Journal of Medicinal Chemistry, 1991,
34, No. 1, pp. 367-373) describes 6-fluoro-4- (4-fluorophenyl) -2- as a heterocyclic aromatic aldehyde.
(1-Methylethyl) -3-quinolinecarboxaldehyde and oxyglutarate derivative (3R,
1 ′, S) -1- (1′-naphthyl) ethyl-3-[(tert-butyldimethylsilyl) oxy] -6- (dimethylphosphinyl) -5-oxo-hexanoate in dichloromethane solution In the presence of lithium chloride, the reaction was carried out using DBU to obtain [R- (R ^* , R ^* )]-1-phenylethyl-3-[(tert-butyldimethylsilyl) oxy] -7-
A method for obtaining [6-fluoro-4- (4-fluorophenyl) -2- (1-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%.

[0009] Journal of organic Chemistry, 1992, 57
Volume, No. 6, pp. 1935-1937), (1S, 2S, 4aR, 6S, 8S, 8aS) -1, 2, 4a, as an aliphatic aldehyde.
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 an oxyglutarate derivative
3-[(tert-butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester is reacted in an isopropanol solution using potassium carbonate or cesium carbonate as a base. And 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 process 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 two to three days for the reaction to be completed, and the conversion is as low as 25% and the yield is low. There was no way to do that. Further, a method in which cesium carbonate is used as a base and a similar reaction is carried out in a tert-butanol solution is also disclosed. However, this method also has a low 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.

[0011]

SUMMARY OF THE INVENTION The present inventors have conducted intensive studies in order to improve the above-mentioned problems in the known production method. As a result, they have used an aliphatic alcohol solvent as a solvent and potassium carbonate as a base. Using 2,6-diisopropyl-4- (4′-fluorophenyl) -5-methoxymethylpyridine-3-carbaldehyde and (R) -3-tert-butyldimethylsilyloxy-6-dimethoxyphosphini When reacted with methyl 5-oxohexanoate, the novel (3R, 6E) -3-[(tert
-Butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo- According to the present invention, it has been found that by obtaining 6-heptenoic acid methyl ester (hereinafter referred to as a target compound) and using the target compound, unnecessary compounds are not produced and the final target product can be obtained without performing optical resolution. Was completed.

Accordingly, the present invention provides a novel (3R, 6E)
-3- [(tert-butyldimethylsilyl) oxy] -7
-[2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo-6-heptenoic acid methyl ester and 2, 6-diisopropyl-4- (4'-fluorophenyl) -5-methoxymethyl
-3-Pyridinecarboxaldehyde and (R) -3-tert-
[(Butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester is reacted in the presence of potassium carbonate to give a new (3R, 6E) -3- [ (Tert-butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridine-3'-
Yl] -5-oxo-6-heptenoic acid methyl ester.

[0013]

[0014]

[0015]

[0016]

SUMMARY OF THE INVENTION The present invention provides an

[0017]

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2,6-diisopropyl-4- (4'-
Fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde and a compound of the formula

[0019]

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[0020] represented by (R) -3 - [(tert-butyldimethylsilyl) oxy] -6- and (dimethoxyphosphinyl) -5-oxo-hexanoic acid methyl ester in the presence of potassium carbonate, water From 100 to 20,000
Reaction in an aliphatic alcohol solvent containing 0 ppm

[0021]

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(3R, 6E) -3-[(ter
t-butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo -6-Heptenoic acid methyl ester (3
R, 6E) -3-[(tert-butyldimethylsilyl)
Oxy] -7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo-6-methyl heptenoate It relates to a method for producing an 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). Preferably it is a solvent.
In the production method of the present invention, the aliphatic alcohol solvent (particularly, a secondary or tertiary alcohol solvent) has a water content of 30%.
It is preferable to contain about 20,000 ppm.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION

The compound of the present invention is (3R, 6E) -3-
[(Tert-butyldimethylsilyl) oxy] -7-
[2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl)
-5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo
-6-Heptenoic acid methyl ester.

From the compound of the present invention, the method described in JP-A-5-178841 and the method disclosed in
According to the method described in JP-A-501613, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co
A) It has a reductase inhibitory activity (3R, 5S, 6
E)-(+)-Erythro-7- [2 ', 6'-diisopropyl-
4 '-(4''-fluorophenyl)-5'-(methoxymethyl)
Pyridin-3'-yl] -3,5-hydroxy-5-oxo-6-heptenoic acid. The production method of such a compound is, for example, the following reaction formula (1):

[0027]

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Can be represented by

The 2,6-diisopropyl-4- (4'-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde used in the production method of the present invention is disclosed in
It can be manufactured according to the method described in US Pat.

As a method for producing this aldehyde, for example,
In a solution of isopropanol, 4-fluorobenzaldehyde is reacted with ethyl isobutyryl acetate in the presence of piperidine and acetic acid to give (E / Z) -4-carboxyethyl-5- (4'-fluorophenyl). ) -2-Methyl-pent
-4-en-3-one was obtained. (E / Z) -4-carboxyethyl-5- (4'-fluorophenyl) -2-methyl obtained
-Pent-4-en-3-one and ethyl 3-amino-4-methyl-pent-2-enoate in an ethanol solvent to give diethyl 1,4-dihydro-2,6- Diisopropyl
-4- (4'-Fluorophenyl) -pyridine-3,5-dicarboxylate is obtained. Diethyl 1,4-dihydro-2,6-diisopropyl-4- (4'-fluorophenyl) -pyridine-
3,5-Dicarboxylate and 2,3-dichloro-5,6-dicyano-p-benzoquinone are reacted in methylene chloride to give diethyl 2,6-diisopropyl-4- (4'-fluorophenyl). -Obtaining pyridine-3,5-dicarboxylate.
The obtained diethyl 2,6-diisopropyl-4- (4'-fluorophenyl) -pyridine-3,5-dicarboxylate and sodium bis- (2-methoxyethoxy) -dihydroaluminate are mixed in a dry tetrahydrofuran solution. And reacted with ethyl 2,6-diisopropyl-4- (4'-fluorophenyl) -5-hydroxymethylpyridine-3-carboxyle-
Get

The obtained ethyl 2,6-diisopropyl-4
-(4'-Fluorophenyl) -5-hydroxymethylpyridine-3-carboxylate is reacted with methyl iodide and sodium hydride in a dry tetrahydrofuran solution to give ethyl 2,6-diisopropyl-4-carboxylate. (4'-Fluorophenyl) -5-methoxymethyl-pyridine-3-carboxylate is obtained. The obtained ethyl 2,6-diisopropyl-4
-(4'-fluorophenyl) -5-methoxymethyl-pyridine-3-carboxylate, water and potassium hydroxide are reacted in anhydrous tetrahydrofuran solution in the presence of lithium aluminum hydride to give 2,2 6-diisopropyl-4- (4 '
-Fluorophenyl) -3-hydroxymethyl-5-methoxymethyl-pyridine is obtained. 2,6-Diisopropyl-4- (4'-fluorophenyl) -3-hydroxymethyl obtained
Neutral alumina and pyridinium chlorochromate are allowed to act on -5-methoxymethyl-pyridine in methylene chloride solution to give 2,6-diisopropyl-4- (4'-fluorophenyl) -5-methoxymethylpyridine-3 -Obtain carbaldehyde. To produce 2,6-diisopropyl-4- (4'-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde.

(R) -3-t used in the production method of the present invention
ert-[(Butyldimethylsilyl) oxy] -6-dimethoxyphosphinyl-5-oxohexanoic acid methyl ester was prepared from Journal of Medicinal Chemistry.
(Journal of Medicinal Chemistry, 1987, Volume 30,
No. 10, pp. 1858-1873). For example, a method of producing by the following steps 1 to 7 can be suitably mentioned.

Step 1: In a methylene chloride solution of diethyl-3-hydroxyglutarate, 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 is removed from the reaction mixture, and benzene and acetic anhydride are added to the residue and reacted 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 It is reacted with ethanol to obtain a reaction mixture. The obtained reaction mixture was subjected to post-treatment, and then reacted with a diethyl ether solution of diazomethane to react with (3R, 1′R) -methyl-1′-phenylethyl-3-[(tert-butyldimethylsilyl) oxy. To obtain pentanedioate.

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

Step 5: The reaction solution of n-butyllithium and dimethylmethylphosphonate was added to the reaction solution obtained in step 4 (3
R, 1′R) -Methyl-1′-phenylethyl-3-hydroxypentanedioate is 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, imidazole obtained in step 5 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. After post-treatment was performed on the obtained reaction mixture, an ether solution of diazomethane was added to react the (R) -dimethyl [3-
(tert-butyldimethylsilyloxy) -4-methoxycarbonylbutyryl] methylphosphonate can be obtained.

In the production method of the present invention, (R) -3-tert-
[(Butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester is used in an amount of 2,6-diisopropyl-4- (4′-fluorophenyl). -5-methoxymethyl-3-pyridinecarboxaldehyde is usually 0.5 to 2.0 mol per mol.
The amount may be a molar ratio, preferably from 0.8 to 1.5 mol, more preferably from 1.0 to 1.3 mol.

As the potassium carbonate used in the production method of the present invention, a commercially available product may be used. The amount of potassium carbonate used in the production method of the present invention is 2,6-diisopropyl-4- (4-fluorophenyl) -5-methoxymethyl
-3- The amount may be usually 0.5 to 2.0 mol per 1 mol of pyridinecarboxaldehyde, and 0.7 to 0.7 mol.
The amount to be 1.8 mol is preferable, and 0.8 to 1.5
More preferred is a molar ratio.

The aliphatic alcohol solvent represented by the general formula (1) used in the production method of the present invention mainly comprises a secondary or tertiary aliphatic alcohol (particularly preferably 8).
The solvent preferably contains 0 to 100% by volume (more preferably 90 to 100% by volume). In the production method of the present invention, the aliphatic alcohol solvent (particularly, a secondary or tertiary aliphatic alcohol solvent) has a water content of 30 to 20,000.
It is preferable to contain about ppm.

The aliphatic alcohol solvent used in the production method of the present invention may have 1 to 10 carbon atoms (particularly 1 to 10 carbon atoms).
Solvents mainly containing aliphatic alcohols of (6) to (6) are preferred, for example, at least 40% by volume, especially 50% by volume of methyl alcohol (methanol), ethyl alcohol (ethanol), propyl alcohol, isopropyl alcohol, butanol and isobutanol. %, More preferably 80 to 100% by volume. In the present invention, the aliphatic alcohol is most preferably propyl alcohol or isopropyl alcohol.

As the aliphatic alcohol solvent used in the present invention, a commercially available aliphatic alcohol solvent may be used as it is in the reaction, or a small amount of water may be added to use in the reaction in the present invention. Good. In the present invention, especially 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 and using it for the reaction. The water added in this case has a water content of, for example, 30 to 20,000 p with respect to the aliphatic alcohol solvent.
pm, preferably 50 to 16,000.
0 ppm, more preferably 100-15,000.
It is preferable that the ratio is ppm.

In the present invention, the amount of the aliphatic alcohol solvent used is usually 7 to 1 mol of 2,6-diisopropyl-4- (4'-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde. The amount may be about 0.5 to 300 mol, particularly preferably about 10 to 100 mol, and more preferably 15 to 80 mol.

The starting compounds used in the production method of the present invention
6-diisopropyl-4- (4'-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde, (R)
-3-tert-[(Butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester is dissolved in an aliphatic alcohol solvent to an extent sufficient for the reaction to proceed. In addition, although other organic solvents are not necessarily required for the reaction, the starting compound may be dissolved in another organic solvent and added to the aliphatic alcohol solvent to carry out the reaction. The organic solvent is preferably an organic solvent that dissolves in the aliphatic alcohol solvent and does not hinder the progress of the reaction in the present invention. Examples of such other organic solvents include cyclic ether solvents such as tetrahydrofuran, ethers such as diethyl ether and diisopropyl ether.
Tertiary solvents, nitrile solvents such as acetonitrile and propionitrile, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aprotic systems such as dimethyl sulfoxide, dimethylformamide, and 1,3-dimethyl-2-imidazolidone Solvents can be mentioned.

In the production method of the present invention, the aliphatic alcohol solvent may be a solvent consisting only of the aliphatic alcohol (100% by volume), but if the starting compound is hardly soluble in the aliphatic alcohol as described above. The aliphatic alcohol solvent used in the present invention contains at least 40% by volume or more, particularly 50% by volume of the above-mentioned aliphatic alcohol.
In addition to the above, the remainder of the solvent may be the above-mentioned other organic solvent “mixed solvent of aliphatic alcohol and other organic solvent”.

(3R, 6E) -3-[(tert-butyldimethylsilyl) 'oxy] -7- [2', 6'-diisopropyl-4 '-(4 "
-Fluorophenyl) -5 '-(methoxymethyl) pyridine-
The ratio of the isomers in 3′-yl] -5-oxo-6-heptenoic acid methyl ester is as follows: (R) -3-tert-[(butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) before the reaction. ) -5-oxohexanoic acid methyl ester and the ratio of isomers thereof are substantially the same, and there is no change in the ratio of isomers due to the reaction in the present invention.

The reaction temperature in the production method of the present invention is usually-
It is 30-50 degreeC, Preferably it is -25-40 degreeC, More preferably, it is -20-30 degreeC.

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

In the production method of the present invention, (3R,
6E) -3-[(tert-butyldimethylsilyl) oxy]
-7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo-6-heptenoic acid methyl ester A method for obtaining the target compound from the reaction mixture containing the same may be performed by a combination of ordinary washing operation and separation operation.For example, an organic solvent is added to the reaction solution to dilute it, and after removing the inorganic base by washing with water or the like, Solvent extraction, vacuum concentration, column chromatography
It is preferable to obtain the target compound by a method using

Examples of the organic solvent for dilution used in obtaining the target compound include aromatic hydrocarbon solvents such as benzene, toluene and xylene, ester solvents such as ethyl acetate and propyl acetate, and 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 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo- 6-Heptenoic acid methyl ester can be directly subjected to the steps following the above deprotection.

In the production method of the present invention, the starting compound (R) -3-[(tert-butyldimethylsilyl) oxy]
-6- (Dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester and (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-4' -(4 "-Fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo-6-heptenoic acid methyl ester has optical isomers. In such a case, the corresponding optical isomer of the target compound can be obtained by using the starting compound which has been optically resolved or separated as required.

Further, the optical isomers can be treated according to a usual optical resolution method or separation method to obtain respective isomers. The production method of the present invention can be applied to both racemic and optical isomers, and isomers of methyl 3-[(tert-butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoate Is substantially unaffected by the reaction, and has the corresponding isomer in 3-[(tert-butyldimethylsilyl) oxy] -7- [2 ′, 6′-diisopropyl-4 ′-( 4 ''-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5
-Oxo-6-heptenoic acid methyl ester is produced.

[0055]

The compound of the present invention (3R, 6E) -3
-[(Tert-butyldimethylsilyl) oxy] -7-
[2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl)
-5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo
By using -6-heptenic acid methyl ester, there is no need to produce an unnecessary compound (a compound having the opposite optical configuration), and 3-hydroxy-3-methylglutaryl coenzyme A (HM
(3R, 5) having G-CoA) reductase inhibitory activity.
S, 6E)-(+)-Erythro-7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -3 , 5-dihydroxy-5-oxo
-6- Sodium heptenoate can be produced. According to the production method of the present invention, the raw material compounds 2,6-diisopropyl-4- (4-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde and (R) -3-t
By reacting ert-[(butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester in an aliphatic alcohol solvent in the presence of potassium carbonate, 3R, 6E) -3- [(te
rt-butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo -6- Heptenoic acid methyl ester can be produced in a short time and with high yield. In particular, the optical purity of 3-tert-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid methyl ester is determined by 3-[(tert-butyldimethylsilyl) oxy] -7 obtained after completion of the reaction. -
[2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl)
-5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo
-6-Heptenoic acid methyl ester 3-oxy-5-oxo-6-
It is substantially the same as the optical purity of heptenoic acid, and the reaction does not change the optical purity.

[0056]

Examples are shown below. The yield in the examples was 2,6-
Diisopropyl-4- (4'-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde (mole)
Reference (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-4'-(4 "-
Fluorophenyl) -5 '-(methoxymethyl) pyridine-
3′-yl] -5-oxo-6-heptenoic acid methyl ester (mol).

Example 1 2,6-diisopropyl-4- (4'-fluorophenyl) -5-
Methoxymethyl-3-pyridinecarboxaldehyde 42
7 mg (1.3 mmol) and 550 mg of (R) -3-tert-[(butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester
(1.43 mmol, 99% ee) was dissolved in 5 ml of ethanol (water content: 1.18 Wt%) to obtain an ethanol solution. 199 mg (1.43 mmol) of potassium carbonate was added to the obtained ethanol solution, and the mixture was added at room temperature (20%).
C.) for 8 hours to obtain a reaction solution. 20 ml of ethyl acetate was added to the obtained reaction solution to obtain a diluted solution.
The resulting diluent was washed with 10 milliliters of water (x2). From the diluted solution after washing, perform a liquid separation operation,
An organic layer was obtained. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered to obtain a filtrate. The obtained filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was separated and purified by silica gel column chromatography (separation liquid; hexane: ethyl acetate = 95: 5, V / V) to give (3.
R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridine- 3'-Ill) -5
639 mg of -oxo-6-heptenoic acid methyl ester was obtained (yield 84%).

¹ H-NMR (CDCl ₃ , 400 MHz) δ = −0.02 (S, 3H) 0.03 (S, 3H) 0.81 (S, 9H) 1.26 (d, 3H, J = 6.8 Hz) 1.27 (d, 3H, J = 6.8 Hz) 1.33 (d, 6H, J = 5.9 Hz) 2.39 (dd, 1H, J = 14.7 and 6.4 Hz) 2.45 (dd, 1H, J = 14.7 and 5.4 Hz) 2.57 (dd, 1H, J = 15.6 and 5.9 Hz) 2.62 (dd, 1H, J = 6.8 and) 6.4 Hz) 3.20 (s, 3H) 2.28 (qq, 1H, J = 6.8 and 6.4 Hz) 3.38 (qq, 1H, J = 6.8 and 6.4 Hz) 66 (s, 3H) 4.60 (s, 2H) 4.52 (tt, 1H, J = 6.4 and 5.9 Hz) 9 (d, 1H, J = 16.6Hz) 7.06-7.18 (m, 4H) 7.34 (d, 1H, J = 16.6Hz)

Elemental analysis: Calculated value C ₃₃ H ₄₈ NO ₅ FSi; C: 67.66%, H: 8.25%, N: 2.39% Measurement value C: 67.71%, H: 8.27 %, N: 2.45% IR (KBr); 777, 842, 1100, 1509, 1667, 1740 cm ^-1 [α] _D ²⁵ : -11.4 ° (C = 1.00, CHCl ₃ ) m. p. : 61.5-63.5 ° C

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

Optical purity measurement conditions: Column; CHIRALCEL OD eluent; Hexane: Ethanol: Trifluoroacetic acid = 100: 0.3: 0.01 (volume ratio) Flow rate: 0.4 ml / min Detection; UV (wavelength : 260nm) Temperature; 30 ° C Sample concentration; 5mg / 10ml (eluent)

Example 2 2,6-diisopropyl-4- (4'-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde 427
mg (1.3 mmol) and (R) -3-tert-[(butyldimethylsilyl) oxy] -6-dimethoxyphosphinyl-5
-Oxohexanoic acid methyl ester 550 mg (1.4
3 mmol, 99% ee) was dissolved in 5 ml of isopropanol (water content: 0.6 Wt%) to obtain an isopropanol solution. 199 mg (1.43 mmol) of potassium carbonate was added to the obtained isopropanol solution, and the mixture was stirred at room temperature (22 ° C.) for 8 hours to obtain a reaction solution. 20 ml of ethyl acetate was added to the obtained reaction solution to obtain a diluted solution. The resulting diluent was washed with 10 milliliters of water (x2). A liquid separation operation was performed from the diluted solution after washing to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered to obtain a filtrate. The obtained filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue is subjected to silica gel column chromatography (separation liquid; hexane:
(Ethyl acetate = 95: 5, V / V).
(3R, 6E) -3-[(tert-butyldimethylsilyl)
Oxy] -7- [2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5 '-(methoxymethyl) pyridin-3'-yl] -5-oxo-6-methyl heptenoate Ester 675m
g was obtained (88% yield).

Example 3 2,6-Diisopropyl-4- (4'-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde 427
mg (1.3 mmol) and 550 mg of (R) -3-tert-[(butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester
(1.43 mmol, 99% ee) was dissolved in 5 ml of isopropanol (water content 0.30 Wt%) to obtain an isopropanol solution. The obtained isopropano-
199 mg (1.43 mmol) of potassium carbonate
Was added and stirred at room temperature (22 ° C.) for 8 hours to react.
20 ml of ethyl acetate was added to the obtained reaction solution to obtain a diluted solution. The resulting diluent was washed with 10 milliliters of water (x2). A liquid separation operation was performed from the diluted solution after washing to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered to obtain a filtrate. The obtained filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was separated and purified by silica gel column chromatography (separation liquid; hexane: ethyl acetate = 95: 5, V / V) to give (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy -7- [2 ', 6'-diisopropyl-4'-
613 mg of (4 ″ -fluorophenyl) -5 ′-(methoxymethyl) pyridin-3′-yl] -5-oxo-6-heptenoic acid methyl ester was obtained (80% yield).

Comparative Example 1 2,6-Diisopropyl-4- (4'-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde 427
mg (1.3 mmol) and (R) -3-tert-[(butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl)-
550 mg of 5-oxohexanoic acid methyl ester (1.3
mmol) was dissolved in 3 ml of acetonitrile to obtain an acetonitrile solution. 61.5 mg (1.43 m) of lithium chloride was added to the obtained acetonitrile solution.
mol) and DBU (201 mg, 1.32 mmol) were dissolved in 2.2 ml of an acetonitrile solution, and the mixture was stirred and reacted at room temperature (20 ° C.) for 25 hours.
20 ml of ethyl acetate was added to the obtained reaction solution to obtain a diluted solution. The resulting diluent was washed with 10 milliliters of water (x2). A liquid separation operation was performed from the diluted solution after washing to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered to obtain a filtrate.
The obtained filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue is subjected to silica gel column chromatography (separation liquid;
Separation and purification were performed with hexane: ethyl acetate = 95: 5, V / V) to give (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -7- [2 ', 6'-diisopropyl-. Four'-
105 mg of (4 ″ -fluorophenyl) -5 ′-(methoxymethyl) pyridin-3′-yl] -5-oxo-6-heptenoic acid methyl ester was obtained (yield: 14%).

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-6-107673 (JP, A) JP-A-7-118233 (JP, A) JP-A 8-127557 (JP, A) International publication 94/6746 (WO, A1) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07F 7/18 C07D 213/55

Claims (4)

(57) [Claims] (1) Formula (1) 2,6-diisopropyl-4- (4′-fluorophenyl) -5-methoxymethyl-3-pyridinecarboxaldehyde represented by the formula: (R) -3-[(tert-butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester was added to the solution in the presence of potassium carbonate to remove water from 100 to 20,000 p.
pm in an aliphatic alcohol solvent containing (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -7- [2 ′, 6′-diisopropyl-4 ′-(4 ″ -fluorophenyl) -5 ′
-(Methoxymethyl) pyridin-3'-yl] -5-oxo-6-heptenoic acid methyl ester, which is optically active 3-[(tert-butyldimethylsilyl) oxy] -7- [ 2 ', 6'-diisopropyl-4'-(4 "-fluorophenyl) -5'-
Production method of (methoxymethyl) pyridin-3′-yl] -5-oxo-6-heptenoic acid methyl ester. 2. A method according to claim 1, wherein the aliphatic alcohol is a solvent containing mainly a secondary or tertiary aliphatic alcohols. 3. The method according to claim 1, wherein the aliphatic alcohol solvent has a water content of 100 to
The production method according to claim 1, which contains 15,000 ppm. 4. The fatty alcohol is isopropanol.
The method according to claim 1.