JPH09100285A - Production of optically active 5-hydroxy-3-oxo-6-heptynoic acid ester derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently produce the subject compound useful as a synthetic intermediate, etc., for a blood cholesterol lowering agent by reacting a specific aldehyde with a diketene in the presence of a Ti or an Al compound and an optically active Schiff base. SOLUTION: An aldehyde represented by formula I (R<1> is silyl) (e.g. trimethylsilyl-2-popynal) is reacted with a diketene represented by formula II in the presence of a metallic compound, comprising titanium or aluminum and having at least one group represented by the formula OR<2a> [R<2a> us a (substitutes) hydrocarbon] (e.g. titanium tetraisopropoxide) and an optically active Schiff base represented by formula III (R<3> to R<8> are each an alkyl, an aryl, etc.; R<9> is H, an alkyl, an aryl, an alkyloxy, an aryloxy, a halogen, nitro, cyano, etc.; (k) is 1-3] or a complex compound of the metallic compound with the Schiff base to afford an optically active 5-hydroxy-3-oxo-6-heptynoic acid ester derivative represented by formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing an optically active 5-hydroxy-3-oxo-6-heptate derivative. The aforementioned optically active 5-hydroxy-3-oxo-6-heptate derivative is a series of blood cholesterol lowering agents [3-hydroxy-3.
-Methylglutaryl coenzyme A (HMG-CoA)
It is useful as an intermediate in the synthesis of [reductase inhibitors] [Breten of the Chemical Society]
Bulletin of the Chemical Society o
f Japan, 1995, 68, 2649-2656)).

[0002]

2. Description of the Related Art Conventionally, an optically active 5-
As a method for producing a hydroxy-3-oxo-6-heptic acid ester derivative, there is a method as shown below. Terarahedron Asymmetry
ymmetry, 1991, Volume 2, pages 943 to 944) requires 6 steps using a tartaric acid derivative as a starting material, and (3R) -3,4-epoxy-
Total yield of 1- (tert-butyldimethylsilyl) -1-butyne 1
A method of obtaining 8% is disclosed. Bulletin of the Chemical Society
Bulletin of the Chemical Society o
f Japan, 1995, 68, 2649-2656), using (3R) -3,4-epoxy-1- (tert-butyldimethylsilyl) -1-butyne obtained above as a starting material, Process required, 5-
A method for obtaining a hydroxy-3-oxo-6-heptate derivative with a total yield of 35% is disclosed. The method that combines these is industrially satisfactory in that it requires 8 long steps, uses compounds that are difficult to handle (such as boron tribromide), and has a low total yield of 6%. It wasn't possible.

Therefore, the known production method has been unsatisfactory as a method for obtaining an optically active 5-hydroxy-3-oxo-6-heptate derivative according to the present invention.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have earnestly studied to establish an industrial production method of an optically active 5-hydroxy-3-oxo-6-heptate derivative, and as a result, a metal compound, It was found that when an aldehyde and diketene are reacted in the presence of an optically active Schiff base, an optically active 5-hydroxy-3-oxo-6-heptate derivative can be obtained in high yield. Completed the invention.

Therefore, the present invention provides a metal compound, an aldehyde and a diketene in the presence of an optically active Schiff base.
Optically active 5-hydroxy-3-oxo-6 by reaction
-To provide a method for producing a heptate derivative.

[0006]

The present invention provides an aldehyde represented by the following general formula (I): R ¹ -C≡C-CHO (I) [wherein R ¹ represents a silyl group]. And the following formula:

[0007]

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The diketene represented by the formula (II) represents at least one group represented by the general formula (II): —OR ^2a (II) (wherein R ^2a represents an optionally substituted hydrocarbon group). By reacting in the presence of a metal compound of titanium or aluminum having the same or a complex compound obtained by the reaction of the metal compound and an optically active Schiff base.
I):

Embedded image (In the formula, R ¹ has the same meaning as described above, and R ² represents an optionally substituted hydrocarbon group.) Optically active 5-hydroxy-3-oxo-6-heptic acid ester derivative Manufacturing method.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION

The aldehydes represented by the general formula (I) used in the production method of the present invention and the optically active 5 represented by the general formula (III) which is the object compound of the production method of the present invention.
R ¹ in the -hydroxy-3-oxo-6-heptate derivative is represented by the general formula (VII)

[0011]

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(Wherein R ¹⁰ , R ¹¹ and R ¹² are each independently an alkyl group or an optionally substituted phenyl group), and the alkyl group has 1 to 10 carbon atoms. The alkyl group having 10 is preferably an unsubstituted phenyl group as an optionally substituted phenyl group, and more preferably an alkyl group having 1 to 6 carbon atoms or a phenyl group.

The optically active 5-hydroxy-3- (3-hydroxy) represented by the general formula (III) which is the object compound of the production method of the present invention.
R in oxo-6-heptate derivative
² is an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or a halogen atom, a cyano group, a nitro group and an alkyl group having 1 to 6 carbon atoms. An aryl group having 6 to 15 carbon atoms or having 7 to 2 carbon atoms having at least one substituent selected from the group consisting of
It is preferably 0 aralkyl group.

In the metal compound having at least one group represented by the general formula (II) used in the production method of the present invention, R ^2a is an alkyl group having 1 to 12 carbon atoms or an aryl group having 6 to 15 carbon atoms. Group, aralkyl group having 7 to 20 carbon atoms or halogen atom, cyano group, nitro group and 1 carbon atom
It is preferably an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms and having at least one substituent selected from the group consisting of alkyl groups having 6 to 6 carbon atoms.

The metal compound having at least one group represented by the general formula (II) used in the production method of the present invention is represented by the titanium compound represented by the general formula (IV) or the general formula (V). Aluminum compounds such as Ti (OR ^2a ) ₄ , Ti (OR ^2a ) ₃ A, Ti
(OR ^2a ) ₂ A ₂ , Al (OR ^2a ) ₃ , Al (OR ^2a )
Is preferably a metal compound represented by ₂ A, the metal compound is _{^{Ti (OR 2a) 4, Ti}} (OR 2a) 3 A,
The metal compound represented by Al (OR ^2a ) ₃ or Al (OR ^2a ) ₂ A is more preferable, and the metal compound is T
Most preferably, it is a metal compound represented by i (OR ^2a ) ₄ or Al (OR ^2a ) ₃ .

Ti (OR) having at least one group represented by the general formula (II) used in the production method of the present invention.
R ^2a in the titanium compound represented by ^2a) ₄ is an alkyl group having 1 to 12 carbon atoms, ants having 6 to 15 carbon atoms - group,
C6 having at least one substituent selected from the group consisting of an aralkyl group having 7 to 20 carbon atoms or a halogen atom, a cyano group, a nitro group and an alkyl group having 1 to 6 carbon atoms.
It is preferably an aryl group having from 15 to 15 or an aralkyl group having from 7 to 20 carbon atoms.

The optically active 5-hydroxy-3- (3-hydroxy) represented by the general formula (III) which is the target compound of the production method of the present invention.
R in oxo-6-heptate derivative
² is R ^2a in the titanium compound represented by the general formula (IV) and the aluminum compound represented by the general formula (V).
And are preferably the same.

The general formula (V
The optically active Schiff base represented by I) is preferably
R in optically active Schiff bases^Three, R^Four, R^Five,
R⁶, R ⁷And R⁸, Each independently, a hydrogen atom,
An alkyl group, an aryl group or an aralkyl group, and
R^FiveAnd R⁶The carbon atom attached to R and R⁷And R⁸Joined to
At least one of the carbon atoms is an asymmetric carbon atom,
R⁹Is a hydrogen atom, alkyl group, aryl group, aralkyl
Group, alkyloxy group, aryloxy group, halogen source
Child, nitro group, cyano group, alkyloxycarboniolu
A group, an aryloxycarbonyl group or an acyloxy group
, And k is an integer of 1 to 3
Schiff base, more preferably R⁶Is a hydrogen atom
And R^FourAnd R^FiveIs a hydrogen atom, alkyl group or
A nyl group;^Three, R⁷, R⁸And R⁹Respectively
Independently, an optically active Schit that represents a hydrogen atom or an alkyl group.
It is a base.

Further, in the production method of the present invention, the above metal compound made of titanium or aluminum having at least one group represented by the general formula (II) and the general formula (V
The reaction is preferably carried out in the presence of a complex compound represented by I) with an optically active Schiff base, and the reaction is carried out after the complex compound of the metal compound and the optically active Schiff base is formed. Is more preferable. Further, in the production method of the present invention, it is optimal to carry out the reaction in the temperature range of -40 to 40 ° C.

The main reaction in the production method of the present invention is, for example, reaction formula (I) shown below.

[0021]

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Can be represented by R ¹ in the aldehydes represented by the general formula (I) [hereinafter also referred to as the compound (I)] used in the production method of the present invention is represented by the general formula (VI
I) a silyl group represented by R in the silyl group
¹⁰ , R ¹¹ and R ¹² represent an alkyl group or an aryl group which may be substituted. The alkyl group having 1 to 10 carbon atoms represented by R ¹⁰ , R ¹¹ and R ¹² is, for example, a methyl group, an ethyl group, a propyl group (including each isomer), a butyl group (including each isomer), a pentyl group. (Including each isomer), Hexyl group (Including each isomer), Heptyl group (Including each isomer), Octyl group (Including each isomer), Nonyl group (Including each isomer), Decyl group (Including each isomer),
An alkyl group having 1 to 6 carbon atoms is preferable, and a methyl group, an ethyl group, a propyl group (including each isomer), and a butyl group (including each isomer) are more preferable.

R ¹⁰ and R ¹¹ represented by the general formula (VII)
And the optionally substituted aryl group represented by R ¹² is an unsubstituted phenyl group or a substituted phenyl group. Examples of the substituent of the substituted phenyl group include a halogen atom such as a chlorine atom and a bromine atom, an alkyl group such as a methyl group and an ethyl group, and a chlorine atom or a methyl group is preferable. R ¹⁰ , R
The optionally substituted aryl group represented by ¹¹ and R ¹² is most preferably a phenyl group.

Specific examples of the aldehydes represented by the general formula (I) having such a substituent include, for example, 3-trimethylsilyl-2-propanal 3-dimethylethylsilyl-2-propanal 3 -Dimethylisopropylsilyl-2-propanal 3-tert-butyldimethylsilyl-2-propanal 3-triethylsilyl-2-propanal 3-triisopropylsilyl-2-propanal 3-dimethyloctylsilyl- 2-propenyl 3-dimethylphenylsilyl-2-propynal 3-diphenylmethylsilyl-2-propinal 3-triphenylsilyl-2-propinal can be mentioned,

3-Trimethylsilyl-2-propanal 3-Dimethylethylsilyl-2-propanal 3-Dimethylisopropylsilyl-2-propanal 3-t-butyldimethylsilyl-2-propanal 3-triethyl Silyl-2-propanal 3-Triisopropylsilyl-2-propanal 3-Dimethylphenylsilyl-2-propanal 3-Diphenylmethylsilyl-2-propanal 3-Triphenylsilyl-2-propynal Preferred,

3-Trimethylsilyl-2-propenyl 3-tert-butyldimethylsilyl-2-propanyl 3-dimethylphenylsilyl-2-propinal is more preferred.

Aldehydes represented by the general formula (I) used in the production method of the present invention include, for example, 3-trimethylsilylpropyn-1-al, which is organic.
Synthesis (Organic Synthesis, 1
1985, 64, 182-188), using propargyl alcohol as a starting material to obtain 3-trimethylsilyl-2-propan-1-ol. I can. Next, the Journal of the American Chemical Society (Journal of t
he American Chemical Society, 1994, 116, 6121 ~
3-trimethylsilyl-2-propanal can be obtained according to the method disclosed in (6129).

In the production method of the present invention, the metal compound represented by the general formula (II) and comprising titanium or aluminum having at least one —R ^2a group has the general formula (IV) T
i (OR ^2a ) _m A _4-m (IV) (provided that R ^2a and A have the same meanings as described above) [hereinafter also referred to as metal compound (IV)] or general formula (V) A metal compound represented by Al (OR ^2a ) _n A _3-n (V) (wherein R ^2a and A have the same meanings as described above) [hereinafter also referred to as a metal compound (V)].

The metal compound represented by the general formula (IV) (I
The ^optionally substituted hydrocarbon group represented by R ^2a in V) is at least one selected from the group consisting of an alkyl group, an optionally substituted aryl group, and an optionally substituted aralkyl group. Indicates a group

The metal compound represented by the general formula (IV) (I
Examples of the alkyl group represented by R ^2a in V) include a linear or branched alkyl group having 1 to 12 carbon atoms, preferably a methyl group, an ethyl group or a propyl group (each isomer is Included), a butyl group (including each isomer), and a pentyl group (including each isomer). The ^optionally substituted aryl group represented by R ^2a in the metal compound (IV) represented by the general formula (IV) is an unsubstituted aryl group or a substituted aryl group. . Examples of the “unsubstituted aryl group represented by R ^2a ” in the metal compound (IV) include aryl groups having 6 to 15 carbon atoms, such as phenyl group and naphthalene group. Group is preferred, and phenyl group is more preferred. Examples of the aryl group of the “substituted aryl group represented by R ^2a ” in the metal compound (IV) include the above aryl groups, and the substituted aryl group represented by R ^2a. Examples of the substituent of "ru group" include a halogen atom, a cyano group, a nitro group, and an alkyl group having 1 to 6 carbon atoms.

The metal compound represented by the general formula (IV) (I
The optionally substituted aralkyl group represented by R ^2a in V) is an unsubstituted aralkyl group or a substituted aralkyl group. The “unsubstituted aralkyl group represented by R ^2a ” in the metal compound (IV) is, for example, a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group or the like having 7 to 2 carbon atoms.
An aralkyl group of 0 can be mentioned, and a benzyl group is preferable. Examples of the aralkyl group of the “substituted aralkyl group represented by R ^2a ” in the metal compound (IV) include the above aralkyl groups, and the substituent of the “substituted aralkyl group represented by R ^2a ” is Examples thereof include a halogen atom, a cyano group, a nitro group, and an alkyl group having 1 to 6 carbon atoms.

The metal compound represented by the general formula (IV) (I
A in V) represents a halogen atom or an alkyl group. Examples of the halogen atom represented by A in the metal compound (V) include a fluorine atom, a chlorine atom, a bromine atom and a yo-yo.
Examples thereof include a halogen atom such as a do atom, and a chlorine atom is preferable. Examples of the alkyl group represented by A in the metal compound (IV) include a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group (each isomer group). A butyl group (including each isomer) and a pentyl group (including each isomer). A in metal compound (IV)
Is preferably the above halogen atom.

Metal compound (I) represented by compound (IV)
N in V) represents an integer of 1, 2, 3 or 4, preferably 2, 3 or 4, more preferably 3 or 4, and most preferably 4.

The metal compound (IV) having R ^2a and A is titanium tetraethoxide or titanium tetran.
-Propoxide, titanium tetraisopropoxide,
Preference is given to titanium tetraalkoxides such as titanium n-butoxide, titanium tetra n-pentoxide and titanium haloalkoxides such as titanium halotrioxide, and the abovementioned titanium tetraalkoxides are more preferred. Such a metal compound (IV), for example, titanium monochlorotriisopropoxide is prepared according to the method described in Chemische Berichte (Vol. 118, No. 4, 1421-1440, 1985). it can.

^{Alternatively} , R ^2a and A in the metal compound represented by the general formula (V) [hereinafter also referred to as compound (V)] have the same meanings as described above. N in the compound (V) is 1,
It represents an integer of 2 or 3, preferably 2 or 3, and more preferably 3.

The metal compound (V) having R ^2a and X is preferably an aluminum haloalkoxide such as aluminum trialkoxide and aluminum monohalodialkoxide, and aluminum triisopropoxide and aluminum monologide. Isopropoxide is more preferred.

Such metal compound (V), for example, aluminum monochlorodiisopropoxide can be produced by the following method. In a methylene chloride solution of diethylaluminum chloride in the presence of argon gas,
The cooled isopropanol is added to obtain a mixed solution.
The resulting mixed solution is warmed to room temperature and stirred for 1 hour to produce aluminum monochlorodipropoxide. The reaction solution containing aluminum monochlorodiisopropoxide can be directly used in the production method of the present invention.

General formula (VI) used in the present invention
R ³ , R ⁴ in the optically active Schiff base represented by
R ⁵ , R ⁶ , R ⁷ and R ⁸ each independently represent a hydrogen atom, an alkyl group, an aryl group or an aralkyl group. ^{R 3, R 4, R 5} , alkyl group represented by R ^6, R ⁷ and R ^8, ant - group, the aralkyl group the alkyl group, ant - a group or an aralkyl group. Moreover, at least one of the carbon atoms bonded to R ⁵ and R ⁶ and the carbon atoms bonded to R ⁷ and R ⁸ is an asymmetric carbon atom.

R ⁹ in the optically active Schiff base represented by the general formula (VI) is a hydrogen atom, an alkyl group or an aryl group.
Group, an alkyloxy group, an aralkyl group, an aryloxy group, a halogen atom, a nitro group, a cyano group, an alkyloxycarbonyl group, an aryloxycarbonyl group or an acyloxy group. Examples of the alkyl group, aryl group, aralkyl group and halogen atom represented by R ⁹ include the above alkyl group, aryl group, aralkyl group and halogen atom. Examples of the alkyloxy group represented by R ⁹ include a methoxy group, an ethoxy group, and a propyloxy group (including each isomer). Examples of the aryloxy group represented by R ⁹ include a phenoxy group and a naphthyloxy group. Examples of the alkyloxycarbonyl group represented by R ⁹ include a methoxycarbonyl group, an ethoxycarbonyl group, and a propyloxycarbonyl group. Examples of the aryloxycarbonyl group represented by R ⁹ include a phenoxycarbonyl group and a naphthyloxycarbonyl group. Examples of the acyloxy group represented by R ⁹ include an acetoxy group, a propionyloxy group and a benzoyloxy group. K in the optically active Schiff base represented by the general formula (VI) is an integer of 1, 2, and 3,
Preferably it is 1. The substitution position of R ⁹ is arbitrary.

An optically active Schottky represented by the general formula (VI)
R suitable as a base^Three, R^Four, R^Five, R⁶, R⁷,
R⁸And R⁹The combination of⁶Is a hydrogen atom
Represents R^FourAnd R^FiveIs a hydrogen atom, an alkyl group or phenyl
And R represents^Three, R⁷, R ⁸And R⁹Is German
It is a combination that vertically shows a hydrogen atom or an alkyl group.

The general formula used in the production method of the present invention (
VI) in the optically active Schiff base represented by R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹
As the "optically active Schiff base represented by the general formula (VI)" having, the following compounds are preferable.

(S) -2- [N- (3'-tert-butylsalicylidene) amino] -3-methyl-1-butanol, (R) -2- [N-
(3'-tert-Butylsalicylidene) amino] -3-methyl-1-
Butanol, (S) -2- [N-salicylideneamino] -3-
Methyl-1-butanol, (R) -2- [N-salicylideneamino] -3-methyl-1-butanol, (S) -2- [N- (3'-tert-
Butylsalicylidene) amino] -3,3-dimethyl-1-butanol, (R) -2- [N- (3'-tert-butylsalicylidene) amino] -3,3-dimethyl-1 -Butanol, (S) -2- [N-
(3 ', 5'-di-tert-butylsalicylidene) amino] -3-methyl-1-butanol, (R) -2- [N- (3', 5'-di-tert-butyl Salicylidene) amino] -3-methyl-1-butanol,
(S) -2- [N- (3'-tert-butylsalicylidene) amino] -1
-Propanol, (R) -2- [N- (3'-tert-butylsalicylidene) amino] -1-propanol, (S) -2- [N- (3'-ter
t-Butylsalicylidene) amino] -1-butanol, (R)-
2- [N- (3'-tert-butylsalicylidene) amino] -1-butanol, (S) -2- [N- (3'-tert-butylsalicylidene)
Amino] -4-methyl-1-pentanol, (R) -2- [N- (3 ′
-tert-Butylsalicylidene) amino] -4-methyl-1-pentanol, (S) -2- [N- (3'-tert-butylsalicylidene) amino] -2-phenyl-1- Ethanol, (R) -2- [N
-(3'-tert-Butylsalicylidene) amino] -2-phenyl
-1-Ethanol, (S) -2- [N- (3'-tert-butylsalicylidene) amino] -1-tert-butyl-1-ethanol, (R) -2-
[N- (3'-tert-butylsalicylidene) amino] -1-tert-
Butyl-1-ethanol, (S) -2- [N- (3 ', 5'-di-tert-butyl-7'-phenylsalicylidene) amino] -3-methyl-1
-Butanol (R) -2- [N- (3 ', 5'-di-tert-butyl-7'-phenylsalicylidene) amino] -3-methyl-1-butanol, (S) -2-
[N- (3'-tert-butyl-7'-phenylsalicylidene) amino] -3-methyl-1-butanal, (R) -2- [N- (3'-tert-
Butyl-7'-phenylsalicylidene) amino] -3-methyl
-1-Butanol, (S) -2- [N- (3 ', 5'-di-tert-butyl-
7'-methylsalicylidene) amino] -3-methyl-1-butanal, (R) -2- [N- (3 ', 5'-di-tert-butyl-7'-methylsalicylidene ) Amino] -3-methyl-1-butanal,
(S) -2- [N- (3'-tert-butyl-7'-methylsalicylidene)
Amino] -3-methyl-1-butanal, (R) -2- [N- (3'-t
ert-Butyl-7'-methylsalicylidene) amino] -3-methyl-1-butanal

As the "optically active Schiff base represented by the general formula (VI)", the following compounds are more preferable. (S) -2- [N- (3'-tert-butylsalicylidene) amino] -3
-Methyl-1-butanol, (S) -2- [N-salicylideneamino] -3-methyl-1-butanol, (S) -2- [N- (3 ', 5'-
Di-tert-butylsalicylidene) amino] -3-methyl-1-
Butanol, (S) -2- [N- (3'-tert-butylsalicylidene) amino] -1-propanol, (S) -2- [N- (3'-tert-
Butylsalicylidene) amino] -1-butanol, (R) -2-
[N- (3'-tert-butylsalicylidene) amino] -1-butanol, (S) -2- [N- (3'-tert-butylsalicylidene) amino] -4-methyl- 1-pentanol, (S) -2- [N- (3'-t
ert-Butylsalicylidene) Amino] -2-phenyl-1-ethanol, (S) -2- [N- (3'-tert-butylsalicylidene)
Amino] -3,3-dimethyl-1-butanol, (R) -2- [N-
(3'-tert-Butylsalicylidene) amino] -3,3-dimethyl-1-butanol. (S) -2- (N-3,5-di-t-butyl-7-
Phenylsalicylidene) amino-3-methyl-1-butano-
(R) -2- (N-3,5-di-t-butyl-7-phenylsalicylidene) amino-3-methyl-1-butanol (R) -2- [N- (3 ' , 5'-Di-tert-butyl-7'-methylsalicylidene) amino] -3-methyl-1-butanal, (S) -2- [N
-(3 ', 5'-di-tert-butyl-7'-methylsalicylidene) amino] -3-methyl-1-butanal,

The optically active Schiff base represented by the general formula (VI) used in the production method of the present invention is, for example,
(S) -2- [N- (3'-tert-butylsalicylidene) amino] -3
-Methyl-1-butanol is a product of Journal of Organic Chemistry,
It can be produced as follows according to the production method described in 1993, Vol. 58, No. 6, pp. 1515-1522).

As the manufacturing method thereof, for example, the general formula (V
III)

[0046]

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A hydroxyaldehyde represented by the formula (wherein R ³ , R ⁴ , R ⁹ and k have the same meanings as described above), and a general formula (IX)

[0048]

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It is easily produced by a method of reacting with an optically active β-amino alcohol represented by the formula (wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ have the same meanings as described above). You can

The optically active Schiff base represented by the general formula (VI) used in the production method of the present invention uses only one of the optical isomers, and the optically active 5-hydroxy-3-oxo is used accordingly. One of the optical isomers of the -6-heptate derivative is produced. Any optically active Schiff base may be used in the present invention.

The target compound produced by the process of the present invention, 5-hydroxy-, represented by the general formula (III)
In the 3-oxo-6-heptate derivative,
R ¹ has the same meaning as described above. R ² may represent at least one group selected from the group consisting of an alkyl group having the same meaning as R ^2a , an optionally substituted aryl group, and an optionally substituted aralkyl group, and R ² And R ^2a
Are preferably the same group. Such R ¹ , R
Examples of the "5-hydroxy-3-oxo-6-heptic acid ester derivative represented by the general formula (III)" having ² include aldehydes and metal compounds (I
V) [or metal compound (V)]. In addition, the 5-hydroxy-3-oxo-6-heptynate derivative represented by the general formula (III) has tautomers of keto and enol forms, but in the production method of the present invention, 5-hydroxy-3-oxo-6-
The heptate derivative may be a keto form or an enol form.

In the present invention, diketene is a liquid substance, and when an aldehyde or a metal compound (IV) [or compound (V)] is a liquid substance, an organic solvent is not particularly required to carry out the reaction. However, the reaction can also be carried out using an organic solvent. Aldehydes and compounds (I
When V) [or compound (V)] is not a liquid substance, it may be dissolved in a solvent and added to the reaction. The solvent used in the present invention is not particularly limited as long as it does not participate in the reaction, for example, methylene chloride, a halogen-based solvent such as chloroform, an aromatic solvent such as benzene, toluene, xylene, pentane, hexane, heptane, etc. Aliphatic hydrocarbon solvent, diethyl ether, diisopropyl ether,
Examples thereof include ether solvents such as tetrahydrofuran, nitrile solvents such as acetonitrile and propionitrile.

The aldehydes represented by the general formula (I) used in the production method of the present invention are usually used in a proportion of 0.2 to 10 mol per 1 mol of the optically active Schiff base. The amount is preferably 0.5 to 5.0 mol, and the amount is preferably 0.5 to 5.0 mol.

The diketene used in the production method of the present invention may be used in an amount of usually 0.1 to 15 mol based on 1 mol of the optically active Schiff base. Amounts of up to 10.0 mol are preferred.

The amount of the metal compound (IV) represented by the general formula (IV) or the metal compound (V) represented by the general formula (V) used in the production method of the present invention is
0.8 to 1.2 per 1 mol of the optically active Schiff base
The amount may be a molar ratio, and 0.85 to 1.15
Amounts in molar proportions are preferred.

The reaction method in the production method of the present invention is as follows:
Aldehydes and diketene may be added as they are to a mixed solution of the above solvent in which an optically active Schiff base and a metal compound [compound (IV) or compound (V)] are mixed, or the above solvent. May be added after being dissolved in.

The above-mentioned organic solvent is used as the reaction solvent in the production method of the present invention, and the amount of the solvent used is not particularly limited, but the amount of the solvent used is 0 relative to the optically active Schiff base (weight). The amount is preferably 0.01 to 100 times (weight ratio), preferably 0.1 to 50 times (weight ratio), and preferably 1 to 20 times (weight ratio). Is more preferable.

The reaction temperature in the production method of the present invention varies depending on the amount and type of solvent used, but is usually -40 to 40 ° C.
Is generally, preferably -30 to 30 ° C, and more preferably -25 to 25 ° C.

The reaction in the production method of the present invention can be carried out under the condition that an inert gas such as nitrogen gas, helium gas or argon gas is aerated, but preferably nitrogen gas or argon gas is aerated. Do under conditions.

In the production method of the present invention, the method for obtaining the desired compound from the reaction mixture containing the purified optically active 5-hydroxy-3-oxo-6-heptate derivative is a combination of ordinary washing operation and separation operation. All you have to do is
For example, it is preferable to obtain a target compound by a method using solvent extraction, washing, concentration under reduced pressure, column chromatography and the like after neutralizing the reaction mixture by adding a dilute acid aqueous solution.

In the isolation operation, the acid used is
Examples thereof include inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid, with hydrochloric acid being preferred. The concentration of the acid used is not particularly limited, but an acid having a concentration of 0.05N to 10N is preferably used, an acid having a concentration of 0.1N to 10N is preferably used, and It is further preferred to use an acid at a concentration of 2.0N. The amount of these acids used varies depending on the concentration and type of the acid. For example, when 1N-hydrochloric acid is used, the amount is 1 to 50 times (volume ratio) the reaction mixture (volume). Good and double to 25
The amount that doubles (volume ratio) is preferable.

The preferred embodiments of the present invention described above are as follows.

(1) Aldehydes represented by the general formula (I) and an optically active compound represented by the general formula (III)
The method for producing an optically active 5-hydroxy-3-oxo-6-heptate derivative as described above, wherein R ¹ in the hydroxy-3-oxo-6-heptate derivative is a silyl group.

(2) R ^2a in the metal compound is an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or a halogen atom,
The above shows an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, which has at least one substituent selected from the group consisting of a cyano group, a nitro group and an alkyl group having 1 to 6 carbon atoms. A method for producing the optically active 5-hydroxy-3-oxo-6-heptic acid ester derivative described.

(3) The optically active 5-hydroxy-3-oxo-6- as described above, wherein the metal compound is titanium tetraalkoxide or titanium halotrioxide.
Method for producing heptate derivative.

(4) The method for producing an optically active 5-hydroxy-3-oxo-6-heptic acid ester derivative as described above, wherein the metal compound is titanium tetraalkoxide.

(5) Titanium tetraalkoxide is
The above-mentioned optically active 5-hydroxy-3-oxo-, which is titanium tetraethoxide, titanium tetra n-propoxide, titanium tetraisopropoxide, titanium n-butoxide, or titanium tetra n-pentoxide.
A method for producing a 6-heptate derivative.

(6) R ² in the optically active 5-hydroxy-3-oxo-6-heptate derivative represented by the general formula (III) is a titanium compound represented by the general formula (IV) or a general compound The method for producing an optically active 5-hydroxy-3-oxo-6-heptate derivative which is the same as R ^2a in the aluminum compound represented by formula (V).

(7) R in the above general formula (VI)
⁶ represents a hydrogen atom, R ⁴ and R ⁵ represent a hydrogen atom, an alkyl group or a phenyl group, and R ³ , R ⁷ , R ⁸ and R ⁹
Each independently represents a hydrogen atom or an alkyl group, and is the optically active 5-hydroxy-3-oxo-6.
-A method for producing a heptate derivative.

(8) The optically active 5-hydroxy-3-oxo-6 as described above, wherein the above reaction is carried out in the presence of a complex compound of the above metal compound and the above optically active Schiff base.
-A method for producing a heptate derivative.

(9) The above-mentioned optically active 5-hydroxy-3, which is carried out in the temperature range of -40 to 40 ° C.
-Method for producing oxo-6-heptate derivative.

[0072]

According to the present invention, the aldehydes and diketene of the general formula (I) and the metal compound (IV) of the general formula (IV) or the metal compound (V) of the general formula (V) are When the reaction is carried out in the presence of the optically active Schiff base of the general formula (VI), the optically active 5-hydroxy-3-oxo-6-heptate derivative of the general formula (III) can be easily obtained. . Optically active 5-hydroxy-3-
The oxo-6-heptate derivative is useful as an intermediate when synthesizing a blood cholesterol lowering agent [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor] Therefore, an optically active blood cholesterol lowering agent can be easily produced.

[0073]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited thereto. The optical purity (% ee) in the examples was determined by performing the HPLC analysis described below. Analysis conditions are: column; CHIRALPAKAD, elution solvent; (hexane: ethanol = 99: 1) + 0.01% trifluoroacetic acid, flow rate; 1.0 ml / min, detection wavelength;
254 nm, retention time, 11 minutes (minor component), 12 minutes (major component). The yield (%) in the examples was calculated by the formula (I) [[5-hydroxy-3-oxo-6-heptate derivative (mol) / aldehyde derivative (mol)] X100].

Example 1 While passing argon gas through the Schlenk tube,
(S) -2- (N-3,5-di-tert-butyl-7-phenylsalicylidene) amino-3-methyl-1-butanol 0.85 g
(2.15 mmol) and 5 ml of methylene chloride were added, and 0.58 ml (1.95 mmol) of titanium tetraisopropoxide was further added at room temperature (20
℃) and stirred and mixed at the same temperature for 1 hour. Thereafter, the Schlenk tube was cooled to -40 ° C. The methylene chloride solution was further mixed with 3-trimethylsilyl-2-propena-
0.3 ml (1.95 mmol) and 0.3 ml of diketene (3.9 mmol) were added,
The mixture was reacted at 40 ° C. for 96 hours with stirring. After completion of the reaction, the obtained reaction mixture was added to a mixed solution of 1N-hydrochloric acid + ether mixed solution and extracted with ethyl acetate to obtain an organic layer. The obtained organic layer was dried under reduced pressure to obtain a crude product.
The obtained crude product was purified by silica gel chromatography to obtain 330 mg of isopropyl 7-trimethylsilyl-5-hydroxy-3-oxoheptate as a pale yellow oil (yield: 69%, optical purity: 92). % Ee).

[Α] _D ²² -32.0 ° (c1.0, C
HCl ₃ ) IR (neat) 3500, 2968, 1714, 1
^{252,842cm -1 1 H-NMR (CDCl} 3) δ: 0.16 (s, 9H), 1.26 (d, J = 6.7
Hz, 6H), 2.95 (d, J = 4.3Hz, 1
H), 2.96 (d, J = 7.9 Hz, 1H), 3.4
6 (s, 2H), 4.81 (dd, J = 4.3 Hz,
7.9 Hz, 1 H), 5.06 (sept, J = 6.7)
Hz, 1H)

Example 2 While ventilating argon gas,
(S) -2- (N-3-di-tert-butyl-7-salicylidene)
Amino-3-methyl-1-butanol 0.28 g (1.07
5 ml of methylene chloride) and 0.3 ml (0.97 mmol) of titanium tetraisopropoxide were further added at room temperature (20 ° C.), and the mixture was stirred and mixed at the same temperature for 1 hour. Thereafter, the Schlenk tube was cooled to -40 ° C. To the methylene chloride solution was further added 0.15 ml (0.97 mmol) of 3-trimethylsilyl-2-propanal and 0.15 of diketene.
Milliliter (1.95 mmol) was added, and the mixture was reacted by stirring at -40 ° C for 96 hours. After completion of the reaction, the obtained reaction mixture was added to a mixed solution of 1N-hydrochloric acid + ether mixed solution and extracted with ethyl acetate to obtain an organic layer. The obtained organic layer was dried under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel chromatography,
100 mg of isopropyl 7-trimethylsilyl-5-hydroxy-3-oxoheptate was obtained as a pale yellow oil (yield: 44%, optical purity: 81% ee).

Claims (4)

[Claims] 1. An aldehyde represented by the following general formula (I): R ¹ -C≡C-CHO (I) [wherein R ¹ represents a silyl group], and the following formula: ] And titanium having at least one group represented by the general formula (II): —OR ^2a (II) (wherein R ^2a represents a hydrocarbon group which may be substituted). Alternatively, by reacting in the presence of a metal compound made of aluminum and an optically active Schiff base, or in the presence of a complex compound obtained by the reaction of the metal compound and an optically active Schiff base, the following general formula ( III): (In the formula, R ¹ has the same meaning as described above, and R ² represents an optionally substituted hydrocarbon group.) Optically active 5-hydroxy-3-oxo-6-heptic acid ester derivative Manufacturing method. 2. The metal compound is represented by the general formula (IV): Ti (OR ^2a ) _m A _4-m (IV) (wherein R ^2a has the same meaning as described above, A is a halogen atom or a carbon number of 1). Or a general formula (V): Al (OR ^2a ) _n A _3-n (V) (formula) R ^2a and A have the same meanings as described above, and n is 1 to 3
Is an aluminum compound represented by the formula), and the method for producing an optically active 5-hydroxy-3-oxo-6-heptic acid ester derivative according to claim 1. 3. The optically active Schiff base has the following general formula (VI): (However, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are
Each independently represents an alkyl group, an aryl group or an aralkyl group, and has a carbon atom bonded to R ⁵ and R ⁶ and R ^7;
And at least one of the carbon atoms bonded to R ⁸ is an asymmetric carbon atom, and R ⁹ is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an alkyloxy group, an aryloxy group, a halogen atom or a nitro group. , A cyano group, an alkyloxycarbonyl group, an aryloxycarbonyl group or an acyloxy group, and k represents an integer of 1 to 3).
A process for producing a 3-oxo-6-heptate derivative. 4. The reaction is performed after forming a complex compound of the metal compound and the optically active Schiff base.
The optically active 5-hydroxy-3-oxo-6-
Method for producing heptate derivative.