JPH0532680A - Optical resolution of optically active glutaric acid ester derivative - Google Patents

Abstract

PURPOSE:To perform optical resolution of a specific racemic mixed solution in high yield and optical purity by reacting the racemic mixed solution with (+)-dehydroabietylamine, thereby forming (+)-dehydroabietylamine salt of R(-)- glutaric acid ester. CONSTITUTION:A racemic mixed solution of a glutaric acid of formula [R<1> is hydroxyl-protecting group; R<2> is (substituted) lower alkyl; * represents asymmetric carbon atom] is treated with (+)-dehydroabietylamine to form (+)- dehydroabietylamine salt of R(+)-glutaric acid ester and effect the optical resolution of optically active glutaric acid ester derivative. The produced salt is subjected to salt-decomposition to recover R(-)-glutaric acid ester and S(+)- glutaric acid ester.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention provides a method for producing an optically active 3-hydroxyglutaric acid monoester useful as a raw material for various pharmaceutical products. For example, optically active HMG-
The optically active 3-hydroxyglutarate monoester provided by the present invention is extremely important in order to be able to produce a CoA reductase inhibitor in high yield and on a large scale.

[0002]

2. Description of the Related Art As a method for producing an optically active substance of this type,
Asymmetric synthesis methods and enzymatic hydrolysis methods of ester moieties are well known. However, such asymmetric synthesis methods conventionally used require various special reagents or require complicated reaction steps. Further, the method using an enzyme has difficulty in setting the acceptability of the reaction product of the enzyme and the condition setting of the enzyme reaction. Therefore, there are few known examples of easily obtaining an active substance having high optical purity by these methods.

[0003]

Obtaining a compound having a high optical purity is extremely important for the synthesis of various compounds including pharmaceuticals. The present invention is a method for efficiently obtaining an optically active substance by optically resolving a racemic 3-hydroxyglutarate monoester.

[0004]

Means for Solving the Problems As a result of intensive studies on the above circumstances, the present inventors have found an optical resolution method for obtaining an optically active substance useful as an intermediate. That is, the invention provides formula I:

[Chemical 2] (Wherein R ¹ represents a hydroxy protecting group, R ² represents a lower alkyl which may have a substituent, and * represents an asymmetric carbon atom, respectively). Is.

That is, this manufacturing method is shown by the following method. One optically active optical resolving agent was added to racemic-3-tert-butyldimethylsilyloxyglutaric acid monomethyl ester, the optically active substance of the same kind as that added was separated, and the other optically active substance was separated from the mother liquor. Is the way to get. More specifically, racemic-3-tert-butyldimethylsilyloxyglutaric acid monomethyl ester has (+)-D
By reacting with HAA, a (+) DHAA salt of R (-)-3-tert-butyldimethylsilyloxyglutarate monomethyl ester is obtained, and the salt is decomposed to give R (-)-3-tert. -Butyldimethylsilyloxyglutarate monomethyl ester (I-1) is obtained. Further
After separating the (+)-DHAA salt, the mother liquor is treated to obtain S (+)-3-tert-butyldimethylsilyloxyglutarate monomethyl ester (I-2).

In the present specification, the hydroxy protecting group includes
Methyl, tert-butyl, allyl, benzyl, tetrahydropyranyl, tert-butyldimethylsilyloxy, tert
Examples of the present invention include an ether-forming protective group such as -butyldiphenylsilyloxy, an ester-forming protective group such as acetyl and benzoyl, and a sulfonate ester-forming protective group such as methylsulfonyl, p-toluenesulfonyl and phenylsulfonyl. In, an ether-forming protecting group, especially tert-butyldimethylsilyloxy is preferred.

The term "lower alkyl which may have a substituent (s)" generally means a linear or branched carbon atom of 1 to 6
Of alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec
-Butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, n-hexyl and isohexyl, and the like,
Each may be substituted with halogen or an amino group.

The present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the scope of the present invention. The abbreviations used in the examples have the following meanings. Me: Methyl Et: Ethyl TBDMS: tert-Butyldimethylsilyl DHAA: Dehydroabietylamine

[Chemical 3]

Reference Example (±) -3-tert-butyldimethylsilyloxygluta
Acid monomethyl ester 1

[Chemical 4] 30.0 g of crude acid anhydride are dissolved in 500 ml of methanol and refluxed for 4 hours. It was evaporated to dryness under reduced pressure, the residue was dissolved in toluene and subjected to silica gel column chromatography (toluene / ethyl acetate = 4/1), the eluate was concentrated under reduced pressure, and the residue was removed from pentane under ice cooling. Crystallization gives 27.2 g of the desired compound as colorless crystals (melting point: 54
~55 ℃) IR (Nujol): 1700, 1730 cm -1 Elemental analysis (%) C ₁₂ H calcd _{24 O 5 Si: C, 52.12} ; H, 8.75 Found: C, 51.90; H, 8.72 1 HNMR (CDCl ₃ , 200M) δ: 0.07 (3H, s); 0.08 (3H,
s); 0.85 (9H, s); 2.60 (4H, m); 3.68 (3H, s); 4.55 (1
H, m)

Example 1 R-(-)-3-tert-butyldimethylsilyloxyglucurone
Tal acid monomethyl ester le (I-1)

[Chemical 5] (1) R-(-)-3-tert-butyldimethylsilylio
(+) DHAA salt of monomethyl xyglutaric acid ester
10.0 g (36 mmol) of 2 (+) DHAA was dissolved in 50 ml of methanol, and 10.0 g (35 mmol) of racemic (±) -3-tert-butyldimethylsilyloxyglutaric acid monomethyl ester 1 was added thereto. Dry to dryness under reduced pressure.
The residue is dissolved in 100 ml of pentane, seeds are planted, and the mixture is allowed to stand under ice cooling overnight. The precipitated crystals are collected by filtration and have a melting point of 129 to 1
(+) DHAA of R-(−)-3-tert-butyldimethylsilyloxyglutarate monomethyl ester at 30 ° C.
8.41 g of salt 2 are obtained. [Α] _D + 9.0 ° (C = 2.0, 25.0 ° C., MeOH) ¹ HNMR (200M, CDCl ₃ ) δ: 0.04 (3H, s); 0.06
(3H, s); 0.84 (9H, s); 0.97 (3H, s); 1.21 (6H, d, J = 7H
z); 1.22 (3H, s); 1.30 ~ 1.85 (8H, m); 2.20 ~ 2.95 (11
H, m); 3.64 (3H, s); 4.48 (1H, m); 6.68 ~ 7.30 (3H, m) Elemental analysis value (%) Calculated as C ₃₂ H ₅₅ NO ₅ Si: C, 68.40; H, 9.87; N, 2.49 Experimental value: C, 68.18; H, 9.74; N, 2.57

(2) Synthesis of (I-1) 8.41 g of the obtained (+) DHAA salt 2 was suspended in 100 ml of ether, and 4N-HCl-ethyl acetate solution 1 was added thereto.
Add 0 ml and stir. Further, 100 ml of pentane was added and stirred, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue is dissolved in toluene and subjected to silica gel column chromatography (toluene / ethyl acetate = 2/1) to obtain 4.10 g of the target compound (I-1) as an oily substance having an optical purity of 96% ee or more. [Α] _D −5.8 ° (C = 4.1, 25.0 ° C., MeOH) ¹ HNMR (200M, CDCl ₃ ) δ: 0.07 (3H, S); 0.08 (3H,
s); 0.85 (9H, s); 2.60 (4H, m); 3.68 (3H, s); 4.55 (1
H, m)

Further, the optical purity of the obtained compound (I-
1) is reacted with R (+) 1-phenethylamine-DCC-1-hydroxybenztriazol to give H
It was confirmed from NMR according to the method of ethcock (J. Org. Chem., 49 , 3657 (1984)). ¹ HNMR (200M, CDCl ₃ ) δ: 0.07 (3H, s); 0.11 (3H,
s); 0.86 (9H, s); 1.47 (3H, d, J = 7Hz); 2.35 ~ 2.60 (4
H, m); 3.65 (3H, s); 4.50 (1H, m); 5.12 (1H, m); 6.57
(1H, br, d, J = 7Hz); 7.32 (5H, m)

Example 2 S-(+)-3-tert-butyldimethylsilyloxyglucurone
Tal acid monomethyl Es ether (I-2)

[Chemical 6] (1) S-(+)-3-tert-butyldimethylsilyloxy
Siglutaric acid monomethyl ester S (-)-1-phene
The mother liquor from which the tilamine salt 3 compound 2 was obtained is dried and dissolved in 200 ml of ether. 4N-HCl-ethyl acetate solution 1 under stirring
0 ml was added, the precipitate was filtered off, the filtrate was concentrated and subjected to silica gel column chromatography (toluene / ethyl acetate = 2/1), and the eluate was concentrated under reduced pressure. The residue is dissolved in 20 ml of pentane and left standing at -20 ° C for two nights. The precipitated crystals were filtered off and the solvent in the filtrate was distilled off to give crude (1-2) 3.80 as an oily substance having an optical purity of 93% ee.
get g. This compound 1.00 g (3.62 mmol), S-
(-)-1-Phenethylamine 440 μl (3.50 mmol)
Was dissolved in 3 ml of ether, 6 ml of pentane was added, and the mixture was allowed to stand at room temperature for 1 hour. The precipitated crystals are collected by filtration to obtain 1.27 g of compound 3 (melting point: 104-105 ° C). [Α] _D + 11.2 ° (C = 1.00, 24.0 ° C, MeOH) Elemental analysis value (%) Calculated as C ₂₀ H ₃₅ NO ₅ Si: C, 60.42; H, 8.87; N, 3.52 Experimental value: C , 60.34; H, 8.85; N, 3.61 ¹ HNMR (200M, CDCl ₃ ) δ: 0.04 (3H, s); 0.05 (3H,
s); 0.84 (9H, s); 1.50 (3H, d, J = 6Hz); 2.30 to 2.60 (4
H, m); 3.65 (3H, s); 4.11 (1H, qJ = 6Hz); 7.25 ~ 7.40
(5H, m)

(2) Synthesis of compound (I-2) 1.27 g of compound 3 was suspended in 50 ml of ether, 2 ml of 4N-HCl-ethyl acetate solution was added thereto, and the mixture was stirred at room temperature for 2 hours.
Stir for 0 minutes. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in pentane, and the residue was purified by silica gel (toluene / ethyl acetate = 2/1). Target compound (I-2) 86 with 98% ee
I get 1 mg. [Α] _D + 5.8 ° (C = 4.1, 25.0 ° C., MeOH) ¹ HNMR (200M, CDCl ₃ ) δ: 0.07 (3H, s); 0.08 (3H,
s); 0.85 (9H, s); 2.60 (4H, m); 3.68 (3H, s); 4.55 (1
H, m) optical purity is the same as R (+) 1-phenethylamine-
The reaction was carried out with DCC-1-hydroxicbenztriazole and confirmed as an amide derivative by the method of Heatcock. ¹ HNMR (200M, CDCl ₃ ) δ: 0.03 (3H,
s); 0.07 (3H, s); 0.79 (9
H, s); 1.50 (3H, d, J = 7Hz);
2.35-2.62 (4H, m); 3.69 (3
H, s); 4.50 (1H, m); 5.11
(1H, m); 6.56 (1H, brd, J = 7H
z); 7.32 (5H, m)

Claims (4)

[Claims] 1. General formula (I): (Wherein R ¹ represents a hydroxy protecting group, R ² represents a lower alkyl which may have a substituent, and * represents an asymmetric carbon atom, respectively) to a racemic mixed solution of the glutaric acid ester (+ ) -Dehydroabietylamine,
A method for recovering an optically active glutaric acid ester, which comprises producing a (+)-dehydroabiethylamine salt of an R (-) glutaric acid ester. 2. The method for recovering R (−) glutaric acid ester according to claim 1, wherein the salt produced is decomposed. 3. The recovery of S (+) glutaric acid ester according to claim 1, wherein the mother liquor is reacted with an amine to form an amine salt of S (+) glutaric acid ester, and the salt is further decomposed. Method. 4. The amine is phenethylamine.
The method described.