JPH06172256A - Production of 3-hydroxybutyric acid derivative - Google Patents

Abstract

PURPOSE:To efficiently and economically produce an optically active 3-hydroxy acid derivative useful as an intermediate for synthesizing medicines and agrichemicals from an optically active malic acid. CONSTITUTION:An optically active (R) or (S)-malic acid derivative of formula I (R<1> and R<2> are H, substitutable alkyl, aralkyl or aryl) is reduced by using a metal hydride (preferably sodium baron hydride) to give an optically active (R) or (S)-3,4-dihydroxybutyric acid of formula II. After the compound of formula II is formed, an acid is added to the reaction solution, the excessive reducing agent is decomposed and the reaction solution is acidified to pH<=2. The compound of formula II is subjected to ring formation under heating at 50-120 deg.C to give an optically active (R) or (S)-3-hydroxy-gamma-butyrolactone of formula III. Or the compound of formula II is reacted with a brominating agent and an alcohol of the formula R<3>OH (R<3> is 1-5C alkyl) at 20-100 deg.C to give an optically active (R) or (S)-4-bromo-3-hydroxybutyric ester of formula IV.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an optically active compound which is a compound useful as an intermediate for synthesizing pharmaceuticals, agricultural chemicals and the like.
The present invention relates to a method for efficiently producing (R) or (S) -3,4-dihydroxybutyric acid, 3-hydroxy-γ-butyrolactone and 4-bromo-3-hydroxybutyric acid ester.

[0002]

BACKGROUND OF THE INVENTION As a method for producing optically active 3,4-dihydroxybutyric acid or its ester, (1) 3-chloro-
Method by cyanation of 1,2-propanediol (JP-A-2-42050), (2) Method of reducing malic acid diester using borane dimethyl sulfide complex [Chemistry Letters, 138]
9-1392 (1984)], as a method for producing 3-hydroxy-γ-butyrolactone, (3) acetylmalic anhydride is treated with MeOH, then reduced with sodium borohydride, and subsequently cyclized with an acid. Method [Synthetic Communications
ns), 16 (2), 183-190 (1986)], and a method for producing a 4-bromo-3-hydroxybutyric acid ester derivative, (4) 4-bromo-3-ketobutyric acid ester is reduced by baker's yeast reduction. Method for producing (S) -4-bromo-3-hydroxybutyric acid ester by asymmetric hydrogenation [Tetrahedron Letters, Vol. 26, Vol. 1
No. 101-104 (1985)], (5) Ruthenium-optically active phosphine complex as a catalyst, 4-bromo-3-
A method for producing an optically active 4-bromo-3-hydroxybutyric acid ester by asymmetrically hydrogenating a ketobutyric acid ester (Japanese Patent Laid-Open No. 1-211551), (6) L- by oxidizing ascorbic acid with hydrogen peroxide A threonine calcium salt was prepared, which was reacted with a hydrobromic acid acetic acid solution and an alcohol, and further reduced with palladium carbon to give (R)
Method for producing 4-bromo-3-hydroxybutyric acid ester [Acta Chemica Scandinavia (Acta Chem.
Scand. ) B37, 341-344 (1983)], (7) 3
-Synthesis from hydroxy-γ-butyrolactone and 3,4-dihydroxybutyric acid ester (JP-A-4-149)
No. 151) is known.

[0003]

These methods require multiple steps, use of expensive reagents, the availability of optically active raw materials is not easy, and the optical purity of the product is unsatisfactory. It has problems to be solved, such as being sufficient, and is used as an industrial production method of optically active 3,4-dihydroxybutyric acid, 3-hydroxy-γ-butyrolactone and 4-bromo-3-hydroxybutyric acid ester. Is not always practical.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have found that the 1-position carboxyl group of optically active malic acid, which is easily available,
Surprisingly, by protecting OH and -OH at the 2-position with a ketal- or acetal-type protecting group such as isopropylidene group and then reducing with a metal hydride,
Easily and selectively reducing the 1-position carboxyl group to give 3,4
-Can be converted to dihydroxybutyric acid, which subsequently
Optically active 3-hydroxy-when cyclized by acid treatment
It has been found that γ-butyrolactone is also easily obtained upon treatment with alcohol and brominating agent to give 4-bromo-3-hydroxybutyrate.

That is, the present invention has the structural formula (I)

[Chemical 3] [In the formula, R ¹ and R ² each represent a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group. ] Optical activity (R) or (S)
An optical activity (R) or (S) represented by the structural formula (II) HO—CH ₂ —CHOH—CH ₂ —COOH, characterized by reducing a malic acid derivative using a metal hydride as a reducing agent. It relates to a method for producing -3,4-dihydroxybutyric acid.

The present invention further provides (1) a cyclization under acidic conditions subsequent to the above reduction.
(III)

[Chemical 4] A method for producing optically active (R) or (S) -3-hydroxy-γ-butyrolactone; and (2) brominating agent and structural formula (IV) R ³ OH [wherein R ³ has 1 carbon atom Represents an alkyl group of ~ 5. ]
In structural formula _{(V) Br-CH 2 -CHOH} -CH 2 -COOR 3 [ wherein, characterized in that is reacted with alcohol represented, R ³ are as defined above. ] Optical activity represented by
It also relates to a method for producing (R) or (S) -4-bromo-3-hydroxybutyric acid ester.

R ¹ and R ² in the structural formula (I) are hydrogen atom, or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, trichloro. To mention an unsubstituted or substituted alkyl group such as a methyl group, an unsubstituted or substituted aralkyl group such as a benzyl group or a p-nitrobenzyl group, or an unsubstituted or substituted aryl group such as a phenyl group or a tolyl group. You can

Various methods are available for synthesizing the compound represented by the structural formula (I) by protecting malic acid.
For example, malic acid can be easily protected with an isopropylidene group by reacting it with 2,2-dimethoxypropane in the presence of acetone. Malic acid derivative (I)
Either the (R) form or the (S) form can be used as a starting material in the method of the present invention.

As the metal hydride used as the reducing agent, sodium borohydride, lithium borohydride,
Potassium borohydride, lithium aluminum hydride,
Sodium trimethoxyborohydride and the like can be preferably used, and sodium borohydride gives preferable results. The amount of the reducing agent used depends on the kind, but is preferably 1 to 5 molar equivalents, and particularly preferably 2 to 3 molar equivalents, relative to the malic acid derivative (I).

As the reaction solvent, lower alcohols such as methanol, ethanol and isopropanol can be used alone or as a mixed solvent, or a mixed solvent of alcohol and an aprotic solvent such as tetrahydrofuran, ether and dioxane can be used. . The solvent is selected in consideration of the solubility and decomposition rate of the reducing agent used, and when sodium borohydride is used as the reducing agent, for example, ethanol, isopropanol, or a methanol / isopropanol mixed solvent is preferable.

The reduction reaction can be carried out, for example, by adding an alcohol solution of malic acid derivative (I) to an alcohol solution of sodium borohydride at 0 to 150 ° C., preferably 10 to 80 ° C. to cause a reaction. it can. After the reduction, to isolate 3,4-dihydroxybutyric acid (II) from the reaction solution, for example, an acid such as hydrochloric acid or sulfuric acid is added to the reaction solution to decompose the excess reducing agent, and the pH is preferably 2 to 4
After acidification, it is purified by a conventional method.

When the compound is converted to 3-hydroxy-γ-butyrolactone (III) after reduction, an acid such as hydrochloric acid or sulfuric acid is added to the reduction reaction solution to decompose excess reducing agent, and preferably,
After acidification to pH 2 or less and heating at 40 to 150 ° C., more preferably 50 to 120 ° C. for cyclization, post treatment by a conventional method is performed.

4-Bromo-3-hydroxybutyric acid ester
To obtain (V), after the reduction, an acid is optionally added to decompose an excess reducing agent, and then a brominating agent and an alcohol are used.
(IV) is added, preferably 20-4 at 20-100 ° C.
After reacting for 0 hour, the product is isolated and purified by a conventional method. As a brominating agent, a hydrogen bromide reagent, for example, hydrobromic acetic acid solution, hydrobromic acid / sulfuric acid, or sodium bromide /
Sulfuric acid or the like is preferably used in an amount of 1 to 10 equivalents based on the malic acid derivative (I) used for the reduction. Particularly, a hydrobromide acetic acid solution is preferable. As the alcohol of the formula (IV), a lower alcohol having 1 to 5 carbon atoms (that is, R ³ is an alkyl group having 1 to 5 carbon atoms), for example, methanol, ethanol, n-propanol, isopropanol, n-butanol. , Isobutanol, etc. are preferably used in an amount of 1 to 30 equivalents relative to the malic acid derivative (I).

The above-mentioned cyclization and bromination / esterification according to the invention may be carried out subsequent to the reduction reaction or after isolation of the reduction product (II). Further, after the reduction, cyclization, or bromination / esterification according to the present invention, the reaction mixture can be used as it is, or after the product is isolated and purified, it can be used in a synthetic reaction of a drug or the like. Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

[0015]

【Example】

Reference Example 2,2-Dimethyl-5-oxo-1,3-dioxolane-
Preparation of 4 (S) -acetic acid: A solution of 40.2 g (0.3 mol) of (S) -malic acid and 36.9 ml (0.3 mol) of 2,2-dimethoxypropane (DMP) in 18.5 ml of acetone. Four
Stirred at 0 ° C. for 2 hours. Ethyl acetate 20
After adding 0 ml and concentrating under reduced pressure at 40 ° C, further DMP3
6.9 ml was added and stirred at 40 ° C. for 5 hours. The solution was concentrated under reduced pressure again, 36.9 ml of DMP was added, and the mixture was stirred at room temperature for 3 days. 200 ml of ethyl acetate and 12 ml of hexane were precipitated.
Recrystallized from 0 ml, 40.6 g (yield 77.7%) of 2,
2-dimethyl-5-oxo-1,3-dioxolane-4
(S) -acetic acid was obtained. m. p. 109-111 ° C. ¹ H-NMR (90 MHz, CDCl ₃ ): δ1.57 (s, 3
H), 1.64 (s, 3H), 2.83 to 3.04 (m, 2
H), 4.71 to 4.73 (m, 3H) FT-IR (KBr): 3271, 1767, 1281,
1128, 804 cm ^-1

Example 1 Preparation of (S) -3,4-dihydroxybutyric acid: 2,2-dimethyl-5-oxo-1,3-dioxolane-4 (S) -acetic acid 5.226 g (30 mmol) of methanol ( A solution of 6.09 ml) / isopropanol (11.1 ml) was added to a solution of 3.402 g (90 mmol) of sodium borohydride in isopropanol (7 ml) at room temperature, and the mixture was stirred at room temperature for 3 hours. Then, 1N hydrochloric acid was added to adjust the pH to 3 and then concentrated under reduced pressure. 150 ml of ethanol was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure. 50 ml of ethanol was added to the obtained residue again,
After filtration, the filtrate was concentrated under reduced pressure to obtain a residue containing (S) -3,4-dihydroxybutyric acid. This was subjected to silica gel column chromatography (hexane: acetone = 1: 1) to obtain 2.75 g of (S) -3,4-dihydroxybutyric acid. Yield 76.4%. [α] _D ²⁰ = −27.9 (C = 0.96, CH ₃ OH) ¹ H-NMR (90 MHz, CDCl ₃ , CD ₃ OD): δ
2.47 to 2.63 (m, 2H), 3.6 (d, 2H, J = 5H
z), 3.97 to 4.3 (m, 1H), 4.77 to 5.32
(m, 3H) IR (cm ^-1 ) (neat): 3300, 2900, 1710,
1390, 1180, 1030

Example 2 Preparation of (S) -3-hydroxy-γ-butyrolactone: 2,
2-dimethyl-5-oxo-1,3-dioxolane-4
(S) -Acetic acid 3.256 g (18.7 mmol) of methanol
The (3.8 ml) / isopropanol (7 ml) solution was added to a solution of 1.77 g (46.7 mmol) sodium borohydride in isopropanol (7 ml) at room temperature, and the mixture was stirred at room temperature for 2 hours. Then, 4.3 ml of concentrated hydrochloric acid was added, the mixture was stirred at 100 ° C. for 2 hours, 60 ml of isopropanol was added, and the mixture was filtered and washed. The filtrate was concentrated under reduced pressure, 25 ml of methanol was added, and the concentration under reduced pressure was repeated twice. Ethyl acetate 1
0 ml was added, and the mixture was stirred at 80 ° C. for 2 hours and dried over sodium sulfate. The obtained solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: acetone =
5: 1) to give 1.45 g of pure (S) -3-hydroxy-γ-butyrolactone. Yield 76.2%. [α] _D ²⁰ = −82 ° (C = 2.0, EtOH) ¹ H-NMR (90 MHz, CDCl ₃ ): δ2.54 (m, 1)
H), 2.78 (dd, 1H, J = 18Hz, J = 6Hz), 4.
2-4.7 (m, 4H) IR (neat): 3350, 2971, 2908, 177
5, 1404, 1372, 1175, 1086, 104
9,685 cm ^-1

Example 3 Preparation of (S) -3-hydroxy-γ-butyrolactone: 2,
2-dimethyl-5-oxo-1,3-dioxolane-4
(S) -Acetic acid 1.74 g (10 mmol) of ethanol (8.7 m
l) The solution was cooled to 0 ° C. sodium borohydride 1.
It was added to a solution of 13 g (30 mmol) of ethanol (8.7 ml), and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. Then, add 2.76 ml of concentrated hydrochloric acid and stir at 100 ° C. for 2 hours,
The operation of adding 50 ml of ethanol and concentrating under reduced pressure was repeated twice. After adding 50 ml of ethyl acetate, filtering and washing, the filtrate was concentrated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (hexane: acetone = 5: 1) to give 797 mg of pure (S). -3-Hydroxy-γ-butyrolactone was obtained. Yield 78.1%. The physical properties were in agreement with those of Example 2.

Example 4 Preparation of (S) -3-hydroxy-γ-butyrolactone: 2
A solution of 1.926 g (30 mmol) of trichloromethyl-5-oxo-1,3-dioxolane-4 (S) -acetic acid in isopropanol (4.4 ml) was cooled to 0 ° C. 1.13 g (30 mmol) of sodium borohydride. ) Isopropanol
(4.4 ml) added to the solution and stirred at room temperature for 2 hours. Then, 2.76 ml of concentrated hydrochloric acid was added, the mixture was stirred at 100 ° C. for 2 hours, 30 ml of isopropanol was added, filtration and washing were performed, and the operation of concentrating the filtrate under reduced pressure was repeated twice. 10 ml of ethyl acetate was added, and the mixture was stirred at 80 ° C. for 2 hours and then dried over sodium sulfate. The resulting solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (hexane: acetone = 5: 1) to obtain 702 mg of pure (S) -3-hydroxy-γ-butyrolactone. Yield 68.8
%. The physical properties were in agreement with those of Example 2.

Example 5 Preparation of methyl (S) -4-bromo-3-hydroxybutyrate:
2,2-Dimethyl-5-oxo-1,3-dioxolane-
4 (S) -acetic acid 3.256 g (18.7 mmol) of methanol
The (3.8 ml) / isopropanol (7 ml) solution was added to a solution of 1.77 g (46.7 mmol) sodium borohydride in isopropanol (7 ml) at room temperature, and the mixture was stirred at room temperature for 2 hours. Then, 4.3 ml of concentrated hydrochloric acid was added, the solution was concentrated under reduced pressure, 21.6 ml of 30% hydrobromic acetic acid solution was added, and the mixture was stirred at room temperature for 24 hours. 40 ml of methanol in the obtained solution
Was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the obtained oily substance was partitioned between ethyl acetate and water, the pH of the aqueous layer was adjusted to 7 by adding an aqueous sodium carbonate solution, the organic layer was separated, and further extracted with ethyl acetate. did. After drying over anhydrous sodium sulfate, concentration under reduced pressure and crude (S) -bromo-3-
Methyl hydroxybutyrate was obtained as an oil. The oily matter was subjected to column chromatography on silica gel (hexane: ethyl acetate = 4: 1) to obtain 2.43 g of methyl (S) -4-bromo-3-hydroxybutyrate. Yield 66%. [α] _D ²⁰ = -10.84 (C = 1, MeOH) ¹ H-NMR (90 MHz, CDCl ₃ ): δ2.66 (d, 2)
H, J = 6Hz), 3.31 (s, 1H), 3.42 (d, 2H,
J = 5 Hz), 3.71 (s, 3H), 4.12 to 4.38
(m, 1H) IR (CCl ₄ solution): 3500, 2950, 1730, 1
440, 1200, 1180, 1040 cm ^-1

[0021]

INDUSTRIAL APPLICABILITY By the method of the present invention, optically active 3,4-dihydroxybutyric acid, 3-hydroxy-γ-butyrolactone and 4-bromo-3-hydroxybutyric acid ester useful as intermediates for pharmaceuticals, agricultural chemicals, etc. It can be efficiently and economically produced from an active malic acid derivative.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07C 67/08 67/307 69/675 9279-4H C07D 307/32

Claims (5)

[Claims] 1. Structural formula (I): [In the formula, R ¹ and R ² each represent a hydrogen atom or an optionally substituted alkyl, aralkyl or aryl group. ] Optical activity (R) or (S)
An optical activity (R) or (S) represented by the structural formula (II) HO—CH ₂ —CHOH—CH ₂ —COOH, characterized by reducing a malic acid derivative using a metal hydride as a reducing agent. A method for producing -3,4-dihydroxybutyric acid. 2. An optical activity represented by the structural formula (I).
The structural formula (II) is obtained by reducing the (R) or (S) -malic acid derivative using a metal hydride as a reducing agent.
The optically active (R) or (S) -3,4-dihydroxybutyric acid represented by the formula (III) is characterized in that it is cyclized under acidic conditions. A method for producing optically active (R) or (S) -3-hydroxy-γ-butyrolactone represented by: 3. An optical activity represented by the structural formula (I).
The structural formula (II) is obtained by reducing the (R) or (S) -malic acid derivative using a metal hydride as a reducing agent.
In after the optically active (R) or (S)-3,4-dihydroxy butyric acid represented, brominating agent and structural formula (IV) in R ³ OH [wherein, R ³ is an alkyl group having 1 to 5 carbon atoms Represents ]
In structural formula _{(V) Br-CH 2 -CHOH} -CH 2 -COOR 3 [ wherein, characterized in that is reacted with alcohol represented, R ³ are as defined above. ] Optical activity represented by
A method for producing (R) or (S) -4-bromo-3-hydroxybutyric acid ester. 4. The method according to claim ¹ , wherein R ¹ and R ² are both methyl groups. 5. The production method according to claim 1, wherein sodium borohydride is used as the metal hydride.