JP2003128629A - Method for producing optically active 6-halogeno-3,5- dihydroxyhexanoic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an optically active 6-halogeno-3- oxo-5-hydroxyhexanoic acid derivative by easy operation without needing a cryogenic reactor and an incubator. SOLUTION: An optically active 6-halogeno-3,5-dihydroxyhexanoic acid derivative is produced by asymmetrically hydrogenating the optically active 6- halogeno-3-oxo-5-hydroxyhexanoic acid derivative using very inexpensive hydrogen as a reducing agent in the presence of a catalyst of a RuBr2 BIANP complex prepared from a ruthenium-optically active phosphine complex, particularly an optically active phosphine 2,2'-bisdiarylphophino-1,1'-binaphthyl (BINAP) and a ruthenium complex.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active 6-halogeno-3,5-dihydroxyhexanoic acid derivative. More specifically, the optically active 6-halogeno-3-
The carbonyl group of the oxo-5-hydroxyhexanoic acid derivative is stereoselectively reduced to give an optically active 6-halogeno-3,
It relates to a method for producing a 5-dihydroxyhexanoic acid derivative. Optically active 6-halogeno-3,5-dihydroxyhexanoic acid derivatives, especially 6-chloro-3,5-dihydroxyhexanoic acid derivatives, are pharmaceutical intermediates, especially HMG-
It is a compound useful as a CoA reductase inhibitor intermediate.

[0002]

2. Description of the Related Art Conventionally, as an optically active 6-halogeno-3-oxo-5-hydroxyhexanoic acid derivative, the carbonyl group of a 6-chloro-3-oxo-5-hydroxyhexanoic acid derivative is stereoselectively reduced to give an optically active compound. Active 6-chloro-
As a method for producing a 3,5-dihydroxyhexanoic acid derivative, (mono) stereoselective reduction using sodium borohydride and triethylborane (US52)
78313), and (ii) a method of stereoselectively reducing using a microorganism exhibiting a reducing activity (WO00 / 08011). In addition, as a similar reaction, (3) 6
-Benzyloxy-5-tetrahydropyranyloxy-3-oxohexanoate tert-butyl was reacted with ruthenium-optically active phosphine complex Ru ₂ Cl ₄ [BINA
P] ₂ N (CH ₂ CH ₃ ) ₃ as a catalyst for asymmetric hydrogenation (JP-A-6-65226), (4) 6-tert-butoxy-5-hydroxy-3-oxohexanoic acid ter
A method (JP-A-2-289537) for asymmetric hydrogenation of t-butyl ester using the same catalyst as in (3) has been reported.

[0003]

[Problems to be Solved by the Invention] However, (1)
The method (2) cannot be said to be economical because the reaction does not proceed with high stereoselectivity unless the reaction is carried out at an extremely low temperature near -80 ° C and a relatively expensive reaction reagent is used. In addition, the method (2) has excellent yield and stereoselectivity, but requires a culture device because it is a microbial reaction and leaves room for improvement in post-treatment of the reaction solution. ing. Further, the method (3) is different from the substrate of the present invention in that the substituent at the 6-position and the hydroxyl group at the 5-position are protected,
In addition, the method (4) is different from the substrate of the present application in the substituent at the 6-position. Neither (3) nor (4) is described about reactivity with respect to the substrate of the present application and stereoselectivity. In the method (4), the hydroxyl group at the 5-position is unprotected, but the reaction is carried out under a high pressure of hydrogen pressure of 50 kg / cm ² , and the reaction yield and selectivity are satisfactory. I can't say. As described above, all of the conventional methods have problems to be improved, do not require cryogenic reaction equipment, culture equipment, etc., are easy to post-treat, and are economical, optically active 6-halogeno-3. Development of a method for producing a 5,5-dihydroxyhexanoic acid derivative has been desired.

[0004]

In the present invention, in view of the above situation, as a result of intensive studies to solve the above problems, as a result, an extremely inexpensive hydrogen was used as a reducing agent, and a ruthenium-optically active phosphine complex, Particularly, optically active 2,2'-bisdiarylphosphino-1,1'-binaphthyl (BIN
Referred to as AP) and Ru prepared by a ruthenium complex
Under the catalytic action of Br ₂ BIANP complex, the optically active 6-
The inventors have found that it is possible to asymmetrically hydrogenate a halogeno-3-oxo-5-hydroxyhexanoic acid derivative to produce an optically active 6-halogeno-3,5-dihydroxyhexanoic acid derivative, and have completed the present invention.

That is, the present invention provides the following formula (1):

[0006]

[Chemical 5]

(In the formula, R ₁ is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted group having 6 to 20 carbon atoms. Represents an aryl group, and X represents a halogen atom) and is optically active 6-halogeno-3-oxo-
A 5-hydroxyhexanoic acid derivative, particularly a 6-chloro-3-oxo-5-hydroxyhexanoic acid derivative in which X is a chlorine atom, is used as a catalyst with a ruthenium-optically active phosphine complex as a catalyst, and particularly an optically active 2,2′- Asymmetric hydrogenation using a RuBr ₂ BINAP complex prepared from bisdiarylphosphino-1,1′-binaphthyl (BINAP) and a ruthenium complex as a catalyst, represented by the following formula (2):

[0008]

[Chemical 6]

A method for producing an optically active 6-halogeno-3,5-dihydroxyhexanoic acid derivative represented by the formula (wherein R ₁ and X are the same as above).

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
In the optically active 6-halogeno-3-oxo-5-hydroxyhexanoic acid derivative represented by the above formula (1), R ₁
Is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms,
A substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms,
Alternatively, it represents a substituted or unsubstituted aryl group having 6 to 20 carbon atoms.

The substituted or unsubstituted alkyl group having 1 to 10 carbon atoms is not particularly limited and includes, for example, a methyl group,
Ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group,
Examples thereof include a cyclohexyl group, and a t-butyl group is preferable.

The substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms is not particularly limited, and examples thereof include a benzyl group, a p-hydroxybenzyl group and a p-methoxybenzyl group. The substituted or unsubstituted aryl group having 6 to 20 carbon atoms is not particularly limited, and examples thereof include a phenyl group, an o-methylphenyl group, a m-methylphenyl group, a p-methylphenyl group, an o-methoxyphenyl group,
Examples thereof include m-methoxyphenyl group, p-methoxyphenyl group, naphthyl group, anthracenyl group, 2-furyl group, 2-thiophenyl, 2-pyridyl group and 3-pyridyl group.

In the compound represented by the above formula (1),
X is a halogen atom, and examples thereof include a chlorine atom, a bromine atom, an iodine atom and the like, and a chlorine atom is preferable from the viewpoint of easiness of substrate preparation.

As the optically active 6-halogeno-3-oxo-5-hydroxyhexanoic acid derivative represented by the above formula (1), the optically active 6-chloro-3-oxo-5-hydroxyhexanoic acid derivative is, for example, WO00. Prepared from acetic acid ester and magnesium chloride diisopropylamide according to the method described in J.
It can be prepared from ethyl-chloro-3-hydroxybutyrate.

In the optically active 6-halogeno-3,5-dihydroxyhexanoic acid derivative represented by the above formula (2), R ₁ is the same as defined in the above formula (1).

The ruthenium-optically active phosphine complex used as a hydrogenation catalyst is represented by the following formula (3):

[0017]

[Chemical 7]

A complex represented by the following formula (4) Ru (P-P) Y2 (arene) (4) (wherein P-P represents an optically active phosphine ligand, and
Rene represents an aromatic ligand) or a complex represented by the following formula (5)

[0019]

[Chemical 8]

Examples thereof include complexes represented by:

In the above formulas (3), (4) and (5), the phosphine ligand is an optically active bisphosphine, for example, an optically active 2,2'-bisdiarylphosphino-1,1. '-Binaphtyl (called BINAP),
Optically active 1,2-bis (trans-2,5-dialkylphosphorano) benzene (referred to as DuPhos), optically active 1,2-bis (trans-2,5-dialkylphosphorano) ethane (referred to as BPE), Alternatively, optically active bis (tert-butylmethylphosphino) ethane (B
⁽ referred to as isP ^* ) and the like. Preferably, it is an optically active 2,2′-bisdiarylphosphino-1,1′-binaphthyl.

The aryl group in the optically active 2,2'-bisdiarylphosphino-1,1'-binaphthyl is phenyl group, o-methylphenyl group, m-methylphenyl group, p-methylphenyl group, o- Methoxyphenyl group, m-methoxyphenyl group, p-methoxyphenyl group, naphthyl group, anthracenyl group, 2-furyl group, 2
-Thiophenyl, 2-pyridyl group, 3-pyridyl group and the like can be mentioned, with preference given to phenyl group.

In the above formulas (3) and (4), Y is preferably a halogen atom such as iodine atom, bromine atom or chlorine atom, more preferably bromine atom.

In the above formula (4), arene represents an aromatic compound and is not particularly limited, and examples thereof include benzene, toluene, xylene, cumene, cymene, mesitylene, anisole and naphthalene. For ease of use, benzene, mesitylene and cymene are preferred.

The following methods are known as methods for preparing the ruthenium-optically active phosphine complex represented by the above formula (3). (1) Easy to obtain [Ru (COD) (methyl
lyl) ₂ ] (which represents cycloocta-1,5-diene) and an optically active bisphosphine are mixed and heated to obtain a ruthenium-optically active phosphine complex in which Y is a methylallyl group in formula (3), or Further, a method of reacting with a HBr solution to form a ruthenium-optically active phosphine complex in which Y is a bromine atom in the formula (3) (Tetrahedron Asymmetry (19)
94) 5, p. 655). (II) By reacting [RuCl ₂ (COD)] _n with optically active bisphosphine in the presence of triethylamine, and then reacting with sodium acetate, Y in the formula (3)
Is an acetoxy group as a ruthenium-optically active phosphine complex, or an aqueous solution of hydrogen halide is further added to this to obtain a ruthenium-optically active phosphine complex in which Y is a halogen atom in formula (3) (JA.
m. Chem. Soc. (1986) Volume 108, 711
7). (3) Ru (acac) ₃ (wherein acac represents an acetylacetonato group) and an optically active bisphosphine are reacted to form a ruthenium-optically active phosphine complex in which Y is an acetylacetonate group in the formula (3). Method (Organometallics. (1993) 12
Vol., P. 1467). Among them, the above method (1) is preferable.

As a method of preparing the ruthenium-optically active phosphine complex represented by the above formula (4), [RuY
₂ (Arene)] ₂ and an optically active bisphosphine are known to be heated in dimethylformamide (JO
rg. Chem. (1992) 57, 4053).

In the above formula (5), Z is a halogen atom, and examples thereof include an iodine atom, a bromine atom and a chlorine atom. A chlorine atom is preferred.

As a method for preparing the ruthenium-optically active phosphine complex represented by the above formula (5), [RuCl
₂ (COD)] _n and optically active bisphosphine in the presence of triethylamine (Organometal)
lics (1996) Vol. 15, page 1521).

Among the complexes represented by the above formulas (3) to (5), as the catalyst used in the asymmetric hydrogenation reaction of the present invention, the reaction can be carried out under high stereoselectivity, high yield and low hydrogen pressure. From the standpoint of practicability, the complex of the above formula (3) or (4) is preferable, the complex of the above (3) is more preferable, and the RuBr ₂ BINAP complex is further preferable.

Next, regarding the step of producing the optically active 6-halogeno-3,5-dihydroxyhexanoic acid derivative represented by the above formula (2) by asymmetrically reducing the compound represented by the above formula (1) explain.

The equivalent amount of the asymmetric catalyst is not particularly limited as long as the reaction proceeds sufficiently. The preferable amount of the catalyst used varies depending on the type of the catalyst and the solvent and the reaction conditions, but in consideration of the reaction rate and the economical efficiency, 1/50 to 1/100000 equivalents relative to the compound represented by the above formula (1), and It is preferably 1/100 to 1/10000 equivalent.

In the above reaction, the hydrogen pressure is preferably 1-100 kg / cm ² , and more preferably 1-1.
It is 0 kg / cm ² .

Examples of the reaction solvent include dichloromethane, chloroform, toluene, benzene, tetrahydrofuran, diethyl ether, ethyl acetate, N, N-dimethylformamide, formamide, acetone, butanol, isopropanol, ethanol, methanol, water and the like. Further, the above solvents may be used alone or in combination. Water, methanol, or a mixed solvent of methanol and water is preferable, and a mixed solvent of methanol and water is more preferable.

The ratio of the above methanol-water mixed solvent can be arbitrarily selected, but is preferably 1 as methanol / water.
00/1 to 1/1, and more preferably 20/1 to
It is 4/1.

The above reaction is carried out, for example, in the above solvent at -50 ° C.
Although it can be selected from mild conditions of up to 150 ° C, it is preferably 0 ° C to 50 ° C from the viewpoint of improving the yield. The reaction can be performed by reacting for about 30 minutes to 24 hours.

As the post-treatment of the above reaction, for example, the reaction mixture is purified by silica gel chromatography or recrystallization to obtain the desired optically active 6-halogeno-3,5-dihydroxyhexanoic acid derivative. it can.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

[0038]

Example (Example 1) (3R, 5S) -6-chloro-
3,5-dihydroxyhexanoic acid tert-butyl ester
Preparation of Ter (S) -6-chloro-3-oxo-5-hydroxyhexanoic acid tert-butyl ester (118 mg, 0.5
_{^{0mmol), RuBisP * Br 2 (}} 2.5mg, 0.
0050 mmol) (BisP ^* is (S, S) bis (t
tert-Butylmethylphosphino) ethane) was added with 2 mL of a methanol-water (10/1) solution and completely dissolved under argon. After performing hydrogen substitution 3 times at -78 ° C and raising the temperature to 50 ° C, hydrogen pressure (5.0 kg / c
m ² ) and reacted for 20 hours. After hydrogen is discarded, the mixture is concentrated, purified by silica gel column chromatography, and then treated with 6-chloro-3,5-dihydroxyhexanoic acid te.
The rt-butyl ester was obtained in 79.7 mg (67%). From the NMR analysis, the ratio of diastereomers is (3
R, 5S) :( 3S, 5S) = 66: 34. ¹ H-NMR (500 MHz, CDCl ₃ ) (3R, 5
S) δ 1.47 (s, 9H), 1.65 to 1.80.
(M, 2H), 2.43 (d, J = 5.8Hz, 2
H), 3.50-3.58 (m, 2H), 3.72 (b
r, 1H), 3.83 (br, 1H), 4.05-4.
15 (m, 1H), 4.20-4.30 (m, 1H).
(3S, 5S) δ 1.47 (s, 9H), 1.69-
1.72 (m, 2H), 2.43 (d, J = 5.8H
z, 2H), 3.13 (br, 1H), 3.56 (b
r, 1H), 3.55 (dd, J = 10.4, 6.4H
z, 1H), 3.62 (dd, J = 11.0, 4.9H)
z, 1H), 4.05-4.15 (m, 1H), 4.2.
8-4.35 (m, 1H).

(Example 2) (3R, 5S) -6-chloro
Tert-butyl -3,5-dihydroxyhexanoate
Preparation of Stell (S) -6-Chloro-3-oxo-5-hydroxyhexanoic acid tert-butyl ester (118 mg, 0.5
0 mmol), RuBr ₂ (R) -BINAP (4.4 m
g, 0.0050 mmol) (BINAP is 2,2'-
2 ml of a methanol-water (10/1) solution was added to bisdiphenylphosphino-1,1′-binaphthyl),
It was completely dissolved under argon. After performing hydrogen substitution 3 times at −78 ° C. and heating up to 50 ° C., hydrogen pressure (5.0 k
The reaction was carried out at g / cm ² for 20 hours. After hydrogen was discarded, the mixture was concentrated and purified by silica gel column chromatography to give 6-chloro-3,5-dihydroxyhexanoic acid tert-butyl ester (93.3 mg, 78%). From the NMR analysis, the ratio of diastereomers is (3
R, 5S) :( 3S, 5S) = 94: 6.

(Example 3) (3S, 5S) -6-chloro
Tert-butyl -3,5-dihydroxyhexanoate
Preparation of Stell (S) -6-Chloro-3-oxo-5-hydroxyhexanoic acid tert-butyl ester (118 mg, 0.5
0 mmol), RuBr ₂ (S) -BINAP (4.4 m
g, 0.0050 mmol) in methanol-water (10 /
1) 2 mL of the solution was added and completely dissolved under argon. Hydrogen substitution was carried out 3 times at -78 ° C, the temperature was raised to 50 ° C, and then the reaction was carried out at hydrogen pressure (5.0 kg / cm ² ) for 20 hours. After hydrogen is discarded, the mixture is concentrated and purified by silica gel column chromatography to give 6-chloro-3,5.
-Dihydroxyhexanoic acid tert-butyl ester was obtained in 98.3 mg (82%). From the NMR analysis, the ratio of diastereomers is (3R, 5S) :( 3S, 5S)
= 8: 92.

(Example 4) (3S, 5S) -6-chloro
Tert-butyl -3,5-dihydroxyhexanoate
Preparation of Stell (S) -6-Chloro-3-oxo-5-hydroxyhexanoic acid tert-butyl ester (118 mg, 0.5
0 mmol), RuBr ₂ (S) -BINAP (4.4 m
g, 0.0050 mmol) in methanol single solvent (2
mL) was added and completely dissolved under argon. -78
Hydrogen substitution was carried out 3 times at 0 ° C, the temperature was raised to 50 ° C, and then the reaction was carried out at hydrogen pressure (5.0 kg / cm ² ) for 20 hours. After hydrogen was discarded, the mixture was concentrated and purified by silica gel column chromatography to give 6-chloro-3,5-dihydroxyhexanoic acid tert-butyl ester (29.9 m).
Obtained in g (25%). From the NMR analysis, the ratio of diastereomers is (3R, 5S) :( 3S, 5S) = 5: 95.
Met.

(Example 5) (3S, 5S) -6-chloro
Tert-Butyl-3,5-dihydroxyhexanoate
Preparation of Stell (S) -6-Chloro-3-oxo-5-hydroxyhexanoic acid tert-butyl ester (118 mg, 0.5
_{0mmol), RuBr 2 (S,} S) -Me-DuPho
s (MeDuPhos is 1,2-bis (trans-
Represents 2,5-dimethylphosphorano) benzene) (2.
8 mg, 0.0050 mmol) in methanol-water (1
2 mL of 0/1) solution was added and completely dissolved under argon. Hydrogen substitution was carried out 3 times at -78 ° C, the temperature was raised to 50 ° C, and then the reaction was carried out at hydrogen pressure (5.0 kg / cm ² ) for 20 hours. After hydrogen is discarded, the mixture is concentrated and purified by silica gel column chromatography to give 6-chloro-3,
4-0.8 mg (34%) of 5-dihydroxyhexanoic acid tert-butyl ester was obtained. From the NMR analysis, the ratio of diastereomers is (3R, 5S) :( 3S, 5
S) = 15: 85.

[0043]

INDUSTRIAL APPLICABILITY Since the present invention has the above-mentioned constitution, an asymmetric hydrogenation of an easily prepared optically active 6-halogeno-3-oxo-5-hydroxyhexanoic acid derivative using a ruthenium-optically active phosphine complex as a catalyst. By doing so, 6-halogeno-3,5 can be reduced extremely efficiently and economically.
It is possible to produce dihydroxyhexanoic acid derivatives.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4H006 AA02 AB84 AC41 AC81 BA23                       BA37 BA48 BA61 BB14 BB31                       BJ50 BM10 BM72 BN10 KA01                       KF20                 4H039 CA60 CF30

Claims (10)

[Claims] 1. The following formula (1): (In the formula, R ₁ represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms. , X represents a halogen atom), and asymmetric hydrogenation of an optically active 6-halogeno-3-oxo-5-hydroxyhexanoic acid derivative with a ruthenium-optically active phosphine complex as a catalyst. Formula (2) below A method for producing an optically active 6-halogeno-3,5-dihydroxyhexanoic acid derivative represented by the formula (wherein R ₁ and X are the same as above). 2. The method according to claim 1, wherein X is a chlorine atom. 3. A ruthenium-optically active phosphine complex represented by the following formula (3): A complex represented by the following formula (4) Ru (P-P) Y ₂ (arene) (4) (wherein P-P represents an optically active phosphine ligand, ar
ene represents an aromatic ligand), or
The following formula (5) The method according to claim 1 or 2, wherein the complex represented by 4. The optically active phosphine ligand is an optically active 2,2′-bisdiarylphosphino-1,1′-binaphthyl (denoted as BINAP), or an optically active bis (ter).
t-Butylmethylphosphino) ethane (denoted by BisP *) or optically active 1,2-bis (trans-2,5)
-Dialkylphosphorano) benzene (denoted as DuPhos), or optically active 1,2-bis (trans-2,5)
The process according to claim 3, which is -dialkylphosphorano) ethane (denoted as BPE). 5. The optically active phosphine ligand is 2,2′-bisdiarylphosphino-1,1′-binaphthyl (BI
The method according to claim 3, which is represented by NAP). 6. The production method according to claim 3, wherein a complex in which Y is a bromine atom in the formula (3) is used as the catalyst. 7. As a catalyst, RuBr ₂ in which the optically active phosphine ligand in formula (3) is 2,2′-bisdiarylphosphino-1,1′-binaphthyl (BINAP) and X is a bromine atom. The production method according to claim 3, wherein a BINAP complex is used. 8. The production method according to claim 1, wherein the reaction is carried out at a hydrogen pressure of 1 to 10 kg / cm ² . 9. The production method according to claim 1, wherein the reaction is carried out at a reaction temperature of 0 to 60 ° C. 10. The production method according to claim 1, wherein a mixed solvent of methanol and water is used as a reaction solvent.