JPS6148488B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active α-hydroxyaldehydes.

More specifically, the present invention is based on the general formula (1) (In the formula, A represents an aryl group, B represents an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, or a group containing a functional group in their organic moiety) (hereinafter abbreviated as aminal) ) to the general formula (2) R-Mg-X (2) (wherein, R is an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, an aryl group, or a group containing a functional group in the organic moiety thereof, and X is (representing a halogen), and R is a Grignard reagent larger than B or smaller than B in the above general formula (1) is reacted, and then hydrolyzed. (In the formula, B and R have the same meanings as above.) When R is larger than B, it is the opposite of the compound of general formula (1), and when R is smaller than B, it is represented by the general formula ( The present invention relates to a method for producing optically active α-hydroxy aldehydes having the same absolute configuration as the compound 1).

Examples of the compound represented by the general formula (1) that is the object of the present invention include B as a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-amyl group, 2-propenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group , 4-methyl-4-pentenyl group, ethynyl group, propargyl group, 2-butynyl group, 2-pentynyl group, 3-pentynyl group, benzyl group, phenethyl group, phenylpropyl group, etc., and R is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-amyl group, vinyl group, 2-propenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 4-pentenyl group , 4-methyl-4-pentenyl group, ethynyl group, propargyl group, 2-butynyl group, 2
-pentynyl group, 3-pentynyl group, benzyl group, phenethyl group, phenylpropyl group, phenyl group, p-tolyl group and the like.

α-Hydroxyaldehydes, which are the subject of the present invention, can be used as intermediate raw materials for pharmaceuticals and agricultural chemicals, and the method for producing optically active forms thereof is particularly important. Atrolactamide, which can be derived from eg 2-hydroxy-2-phenylpropionaldehyde, is used as a medicine.

Conventionally, there are few examples regarding the production of optically active α-hydroxyaldehydes, for example, J.Amer.Chem.
Soc., 100 , 1514 (1978).
Although a method for producing -phenylpropionaldehyde derivatives is described, it is not easy to produce an optically active source, the number of production steps is large, and the optical purity of the obtained product is only 44%.

As a result of extensive studies, the present inventors found that if the Grignard reagent represented by the general formula (2) is reacted with the optically active aminal represented by the general formula (1) and then hydrolyzed, α -Hydroxyaldehyde is obtained, and its configuration is the same as that of the aminal when R of the Grignard reagent is smaller than the substituent B of the optically active aminal, and conversely, the configuration is the opposite of that of the aminal when it is larger than the substituent B of the optically active aminal. The present invention was completed by discovering that α-hydroxyaldehydes having a steric configuration can be obtained.

The optically active aminal of general formula (1) used in the present invention can be produced, for example, using optically active 2-(N-substituted aminomethyl)pyrrolidine and a glyoxylic acid ester derivative as raw materials. Examples of compounds represented by general formula (1) include methyl group, ethyl group, n-propyl group, isopropyl group, n-
Alkyl groups such as butyl group, isobutyl group, n-amyl group, 2-propenyl group, 2-butenyl group,
Alkenyl groups such as 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 4-methyl-4-pentenyl group, ethynyl group, propargyl group, 2-butynyl group, 2-pentynyl group, 3 Examples include alkynyl groups such as -pentynyl groups, aralkyl groups such as benzyl groups, phenethyl groups, and phenylpropyl groups, and those containing functional groups in their organic moieties.

The Grignard reagent of general formula (2) as used in the present invention refers to a Grignard reagent that is generally called, for example, R is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-amyl group, etc. an alkylmagnesium halide having
vinyl group, 2-propenyl group, 2-butenyl group,
Alkenylmagnesium halide having 3-butenyl group, 2-pentenyl group, 4-pentenyl group, 4-methyl-4-pentenyl group, etc., ethynyl group, propargyl group, 2-butynyl group, 2-pentynyl group, 3-pentynyl group Alkynyl magnesium halide with benzyl group, phenethyl group, phenylpropyl group etc., phenyl group, p-
In addition to arylmagnesium halides having tolyl groups, etc., those containing functional groups in their organic moieties may also be used.

The solvent used when reacting the Grignard reagent may be a solvent commonly used in a Grignard reaction, such as ether, tetrahydrofuran, or a mixed solvent containing these. The reaction temperature can be lower than the boiling point of the solvent used. In order to obtain a product with a high optical yield, it is desirable that the reaction temperature is low.

Optically active α-hydroxyaldehyde can be produced by reacting with a Grignard reagent and then hydrolyzing it, but after reacting with a Grignard reagent, it is converted into a derivative such as an ether and then hydrolyzed to produce an α-hydroxyaldehyde derivative. can also be produced (see Examples 2 and 3 and 5).

Hydrolysis is usually carried out at a temperature of 0°C to 100°C, but lower temperatures are preferred in view of the stability of the optically active α-hydroxyaldehyde produced.

Thus, for example, an optically active α-hydroxyaldehyde obtained via the (S)-aminal represented by the general formula (1) using (S)-2-(N-substituted aminomethyl)pyrrolidine as an asymmetric source can be expressed by the general formula ( When substituent R shown in 3) is larger than substituent B, it has an R configuration, and conversely, when substituent R is smaller than substituent B, it has an S configuration. Therefore, by appropriately combining the substituent B of the aminal used in the present invention and the substituent R of the Grignard reagent, α-hydroxyaldehydes having any steric configuration can be produced. For example, 2-hydroxy-
When producing 2-methylbutyraldehyde,
If an ethyl Grignard reagent is reacted with an aminal in which substituent B shown in general formula (1) is a methyl group and the configuration is S, an aminal having the configuration R is obtained, while substituent B is an ethyl group. If an aminal is reacted with a methyl Grignard reagent, an S configuration is obtained (see Examples 2 and 5).

Generally, when attempting to produce a compound having a configuration opposite to that of the product obtained in asymmetric synthesis, the enantiomer must be used as the chiral source in many cases. In such cases, the enantiomer of the chiral source is often unavailable or very expensive, which is industrially disadvantageous.

However, in the present invention, optically active α-hydroxyaldehydes having any steric configuration can be produced by combining the substituent B of the optically active aminal and the substituent R of the Grignard reagent, and the aminals used in this case are listed as reference examples. They can be easily produced using the same chiral source. Furthermore, the chiral source can be easily recovered and reused after the reaction, and the method of the present invention has great industrial benefits as a method for producing optically active α-hydroxyaldehydes.

Further, if racemic aminal is used in the method of the present invention, racemic α-hydroxyaldehyde can be obtained, so the present invention can also be applied to a method for producing racemic α-hydroxyaldehyde.

The invention will be specifically explained in the following examples.

Example 1 5-(S)-2-acetyl-3-phenyl-1.
3-Diazabicyclo[3.3.0]octane 258
mg was dissolved in 5 ml of ether, cooled to -70°C, and twice the equivalent of an ether solution of phenylmagnesium bromide was added thereto, followed by reaction for 1 hour. 3 ml of saturated ammonium chloride aqueous solution was added, and the temperature was raised to room temperature. The ether layer was separated, washed with 1N aqueous sodium hydroxide solution, 11 ml of 2% hydrochloric acid was added, and the mixture was reacted at 0°C for 12 hours. The ether layer was separated, washed with saturated brine, and dried over Glauber's salt. The ether was distilled off under reduced pressure, and the resulting residue was purified with a silica gel column to obtain 128 mg (76%) of (R)-2-hydroxy-2.
-Phenylpropionaldehyde was obtained. [α]
Optical yield at D = -255° (C = 1.060, benzene)
It was 99%.

Example 2 5-(S)-2-acetyl-3-phenyl-1.
3-diazabicyclo[3.3.0]octane 1.41
g was dissolved in 27 ml of ether, cooled to -70°C, and 1.5 equivalents of an ether solution of ethylmagnesium bromide was added dropwise. After reacting at -70°C for 1 hour, 10 ml of saturated ammonium chloride aqueous solution was added, and the temperature was raised to room temperature. The ether layer was separated, washed with saturated brine, and dried over Glauber's salt. The ether was distilled off under reduced pressure, and the resulting residue was dissolved in 20 ml of dimethylformamide.

Add 0.53 g of sodium hydride (55%) and stir at 60°C for 2 hours, then add 2.09 g of benzyl bromide.
The reaction was allowed to proceed for 1 hour. Water and ether were added to the reaction mixture for extraction, and the ether layer was washed with saturated brine and dried over sodium sulfate. The ether was distilled off under reduced pressure, and the resulting residue was purified with an alumina column, then 60 ml of 2% hydrochloric acid and 60 ml of ether were added and reacted at 0°C for 4 hours.
The ether layer was separated, washed with saturated brine, and dried over Glauber's salt. The ether was distilled off under reduced pressure, and the resulting residue was purified by silica gel preparative TLC to obtain 506 mg (43%) of (R)-2-benzyloxy-2-methylbutyraldehyde.

[α]D=+39° (C=1.027, benzene) and the optical yield was 78%. The optical yield was determined by deriving 2-methylbutane-1,2-diol whose optical rotation was known. nmr peaks are δ (ppm) = 0.9 (3H, triplet), 1.3 (3H, singlet), 1.8
(2H, quartet), 4.4 (2H, singlet),
They were 7.2 (5H, singlet) and 9.5 (1H, singlet).

Example 3 5-(S)-2-acetyl-3-phenyl-1.
3-Diazabicyclo[3.3.0]octane 1.00
g was dissolved in 20 ml of tetrahydrofuran, cooled to -70°C, 2.7 equivalents of a solution of vinyl magnesium bromide in tetrahydrofuran was added, and the mixture was reacted for 20 hours. The reaction temperature was gradually raised to 0°C. 10 ml of saturated ammonium chloride aqueous solution was added, and the temperature was raised to room temperature. The reaction solution was extracted with ether, washed with saturated brine, and dried over Glauber's salt. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 7 ml of dimethylformamide. Sodium hydride (55%) 0.38g
After stirring at 60°C for 2 hours, 1.49 g of benzyl bromide was added and reacted for 1 hour. Water and ether were added to the reaction mixture for extraction, and the ether layer was washed with saturated brine and dried over sodium sulfate. After distilling off the ether under reduced pressure and purifying the resulting residue with an alumina column, the 2%
40 ml of hydrochloric acid and 40 ml of ether were added and reacted at 0°C for 12 hours. The ether layer was separated, washed with saturated brine, and dried over sodium sulfate. The ether was distilled off under reduced pressure, and the resulting residue was subjected to silica gel proprietary TLC.
to obtain 367 mg (44%) of (R)-2-benzyloxy-2-methyl-3-butenal.

[α]D=+156° (C=0.963, benzene), and the optical yield was 93%. The optical yield was determined by deriving 2-methylbutane-1,2-diol whose optical rotation was known. The nmr peaks are δ (ppm) = 1.4 (3H, singlet), 4.4 (2H, singlet), 5.1~
They were 5.7 (3H, multiplet), 7.2 (5H, singlet), and 9.8 (1H, singlet).

Example 4 5-(S)-2-acetyl-3-phenyl-1.
Same as Example 1 except that 5-(S)-2-propionyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane was used instead of 3-diazabicyclo[3.3.0]octane. Do the same, (R)-
2-Hydroxy-2-phenylbutyraldehyde was obtained (yield 80%). [α]D=-256°(C=
1.147, benzene), and the optical yield was 100%.

Example 5 5-(S)-2-acetyl-3-phenyl-1.
5-(S)-2-propionyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane was used instead of 3-diazabicyclo[3.3.0]octane, and methylmagnesium was used as the Grignard reagent. The same procedure as in Example 2 was carried out except that iodide was used, and (S)-2-benzyloxy-2-methylbutyraldehyde was obtained (yield 41%).

[α]D=-39° (C=1.002, benzene) and the optical yield was 78%.

Example 6 5-(S)-2-acetyl-3-phenyl-1.
Same as Example 1 except that 5-(S)-2-isobutyryl-3-phenyl-1,3-diazabicyclo[3.3.0]octane was used instead of 3-diazabicyclo[3.3.0]octane. Do the same, (R)-
2-Hydroxy-2-phenyl-3-methylbutyraldehyde was obtained (yield 75%). [α]D=-
Optical yield is 94% at 308° (C = 1.340, benzene)
That's all.

Example 7 528 mg of 5-(S)-2-(5'-methyl-5'-hexenoyl)-3-phenyl-1,3-diazabicyclo[3.3.0]octane was dissolved in 10 ml of ether to give -70 The mixture was cooled to 0.degree. C., and 1.5 equivalents of an ether solution of methylmagnesium bromide was added dropwise. −
After reacting at 70°C for 1 hour, 5 ml of saturated ammonium chloride aqueous solution was added and the temperature was raised to room temperature. The ether layer was separated, 17 ml of 2% hydrochloric acid was added, and the mixture was reacted at 0°C for 3 hours. The ether layer was separated, washed with saturated brine, and dried over Glauber's salt. Ether was distilled off under reduced pressure to obtain 250 mg (yield 90%) of (S)-2-hydroxy-2,6-dimethyl-6-heptenal. The optical yield is 88% and the nmr peak is δ
(ppm) = 1.3 (3H, singlet), 1.7 (3H, singlet), 1.4~1.8 (4H, multiplet),
2.0 (2H, triplet), 3.3 (1H, singlet), 4.6 (2H, broad singlet), 9.4
(1H, singlet).

Example 8 5-(S)-2-acetyl-3-phenyl-1.
3-Diazabicyclo[3.3.0]octane 643
Dissolve mg in 15 ml of ether, cool to -73°C,
-1.5 times equivalent of an ether solution of methyl-4-pentenylmagnesium bromide was added.

A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was heated to room temperature. The aqueous layer was separated, the ether layer was cooled to 0°C, 30 ml of 2% hydrochloric acid was added, and the mixture was reacted for 2.5 hours. The ether layer was separated and the aqueous layer was extracted with ether. The obtained ether layers were mixed, washed with saturated brine, and dried over Glauber's salt.

Ether was distilled off under reduced pressure to give 405 mg (yield 93%).
(R)-2-hydroxy-2,6-dimethyl-
6-heptenal was obtained. The optical yield was 100%.

Example 9 5-(S)-2-[3-(2,5-dimethoxy-
505 mg of 3,4,6-trimethylphenyl)propanoyl]-3-phenyl-1,3-diazabicyclo[3,3,0]octane was dissolved in ether and cooled to -100°C. Next, about 3 times the equivalent of methylmagnesium iodite was added, and after 30 minutes, a saturated aqueous ammonium chloride solution was added to separate the layers.

13 ml of 2% hydrochloric acid was added to the ether layer, and the mixture was stirred at 0°C for 2 hours. After extraction with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and then the solvent was distilled off. The residue was purified with a silica gel column,
181 mg (54%) of (S)-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanal were obtained.

The nmr (CCl ₄ ) peak is δ (ppm) = 1.20 (3H,
singlet), 1.56 to 1.85 (2H, multiplet), 2.05 (9H, singlet), 2.16 to 2.80
(2H, multiplet), 3.40 (1H, singlet), 3.46 (3H, singlet), 3.51 (3H, singlet), 9.25 (1H, singlet) [α] _D +39.6° (C0.53, benzene) Optics The yield was 96%.

Example 10 5-(S)-2-acetyl-3-phenyl-1.
3-Diazabicyclo[3.3.0]octane 709
mg was dissolved in ether and then cooled to -100°C.
About 3 times the equivalent of 2-(2,5-dimethoxy-
3,4,6-trimethylphenyl)ethylmagnesium bromide was added. After 30 minutes, a saturated aqueous ammonium chloride solution was added and the mixture was separated.

Add 30ml of 2% hydrochloric acid to the obtained ether layer and
Stirred at ℃ for 2 hours. Next, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over Glauber's salt, and then the solvent was distilled off. The residue was purified with a silica gel column to give 451 mg.
(52%) of (R)-4-(2,5-dimethoxy-
3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanal was obtained.

[α] _D -38.0 (C=0.52, benzene), the optical yield was 93%.

Reference example 1 (S)-2-(anilinomethyl)pyrrolidine 2.64
g and 1.89 g of methyl hydroxymethoxyacetate in 30 ml
dissolved in benzene and removed water azeotropically for 30 min.
The mixture was heated to reflux for a minute. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 75 ml of tetrahydrofuran. 1.57 g of anhydrous magnesium chloride was heated under reflux for 10 minutes and then cooled to -70°C. Add dropwise 1.36 times equivalent of ether solution of methylmagnesium bromide 1
After reacting for an hour, saturated ammonium chloride aqueous solution
10 ml was added and the temperature was raised to room temperature. The reaction solution was extracted with ether, washed with saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified using an alumina column to obtain 2.499 g (72%) of 5-(S).
-2-acetyl-3-phenyl-1,3-diazabicyclo[3,3,0]octane was obtained.

Reference Example 2 The same procedure as Reference Example 1 was carried out except that ethylmagnesium bromide was used as the Grignard reagent, and 5-
(S)-2-propionyl-3-phenyl-1,3
-Diazabicyclo[3.3.0]octane was obtained (yield 28%).

Claims (1)

[Claims] 1 General formula (1) (In the formula, A represents an aryl group, and B represents an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, or a group containing a functional group in the organic moiety thereof). -Mg-X (2) (wherein R represents an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, an aryl group, or a group containing a functional group in the organic moiety thereof, and X represents a halogen), General formula (3), characterized in that R is reacted with a Grignard reagent larger than B or smaller than B in the above general formula (1), and then hydrolyzed. (In the formula, B and R have the same meanings as above.) When R is larger than B, it is the opposite of the compound of general formula (1), and when R is smaller than B, it is represented by the general formula ( A method for producing optically active α-hydroxy aldehydes having the same absolute configuration as the compound of 1).