JPS5929045B2 - Production method of optically active substances - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing optically active substances.

More particularly, the present invention relates to the reduction reaction of PrOchiral or racemic compounds using aminoalane monomers and iminoalane polymers to obtain optically active substances. BACKGROUND OF THE INVENTION The synthesis of optically active compounds such as alcohols and amines with high steric purity has become one of the important synthetic methods from both technical and economical points of view.

In terms of obtaining natural products by partial or total synthesis, direct synthesis of optically active compounds without the need to consider separation of optical enantiomers has become increasingly attractive in recent years.

Currently, asymmetric synthesis with the highest optical purity can be carried out by enzyme or microbial reactions, but there are various problems when using such methods.
For example, in many applications, such as when prochiral compounds such as ketones and imines or racemic compounds such as epoxides and trialkylphosphine oxides are asymmetrically hydrogenated with optically active complex metal hydrides to obtain corresponding optically active alcohols and amines. He is very interested in the use of chemical synthesis.

To date, direct or indirect asymmetric reactions of said substances using hydrides of elements belonging to group 3 of the periodic table have been proposed for hydrogen transfer reactions from aluminum and lithium hydrides in the presence of optically active alcohols. Only reduction reactions have been reported.

Generally, such reactions proceed through the formation of the corresponding metal alkoxy hydride, but with low optical yields and
Furthermore, the selection of reaction conditions is severely limited due to the low solubility of the reagents. The highest reported optical yield is approximately 4
5 to 50%. The optical yield is expressed by the formula (α).

B. - Calculated using 100.

(a) Max The inventors proposed that instead of aluminum alkoxy hydrides, which are optically active due to the presence of asymmetric alkoxy groups, the general formula H2AlNRlR2, HAI(NRlR2)2, (HA
INR) n (where R, .Rl and R2 are alkyl, aryl or cycloalkyl groups, and n is an integer of 4 or more), with at least one Al-N direct bond per aluminum atom; and one Al-H
The third substituent containing a bond and bonding to the aluminum atom is halogen, -H, -N(R)2, -0R,
Moreover, when using an optically active aminoalane or polyiminoalane in which the asymmetric center is in a primary or secondary amine group containing at least one optically active alkyl group, the optically active The present inventors have discovered that it is possible to carry out an asymmetric synthesis reaction that transfers hydrogen from aluminum hydride, leading to the present invention.

When the above derivatives are used in the asymmetric hydrogenation reaction of prochiral ketones, imines, N-substituted imines, oximes or racemic alkylene oxides and trialkylphosphine oxides, the corresponding optical activity is achieved with very high optical yields. A reduced product is obtained.

The optical yield was 85%. The above derivatives have good solubility in various solvents even at low temperatures;
It can be used as a reducing agent even under conditions where lH3, LiAlH4 or other hydrides cannot give good results.

Aminoalane and iminoalane can be converted into optically active primary or secondary amines and AlH3.D by the following reaction.
Alternatively, it is prepared using LiAlH4 as a raw material. [D-Lewis base; (CH3)3N, (C2H5)3N, etc.] Amines include, for example, bornylamine, sec-butylamine, phenethylamine, tanthylamine, and primary amines in which the substituent is optically active or in which at least one of the substituents is N
- It is an optically active group such as methylphenethyl azamine, pipecoline, desoxyefedrin, or methylefedrin, and is a secondary amine in which other substituents are chiral or achiral.

' Some of the alanes prepared as described above are shown below.

The above compounds are used in the reduction reaction of prochiral compounds (substrates) such as ketones, imines, oximes, etc. in various solvents at temperatures of +50 to -100° C., depending on the nature of the solvent and substrate.

Under these conditions the optical yield is 85%. The reaction mechanism is as follows. [Al-H*] After completion of the optically active dialkylaminoalane or polyiminoalane reaction, the asymmetric amine is almost completely recovered with an unmeasurable racemization index.

This fact rules out the possibility of hydrogen transfer from the asymmetric carbon atom when the amine is C 2 .

The advantages of using the aminoalane according to the invention are much higher than in other processes using metal hydrides, which can undergo conventional asymmetric hydrogenation reactions under wide temperature conditions and in various solvents. It is possible to carry out the reaction in optical yield and to almost completely recover the reagents that give rise to the optical properties.

Example 1 0 acetophenone dissolved in 100 ml ethyl ether
．． 215 mol were slowly added dropwise into a solution containing 0.11 mol of N-methylphenethylaminoalane in 600 ml of ether, cooled to 0.degree.

After 4 hours, it was hydrolyzed with water and ice by maintaining the pH≦4 with HCl.

The organic layer was separated, the aqueous layer was extracted three times with 100 ml of ether, and the extracts were combined and concentrated. 60% of the remaining oily substance
The semicarbazide was reacted with HCl and sodium acetate in a water-ethanol (1:4) solution at <0>C.

By diluting with plenty of water and then cooling to 0°C,
Separate unreacted acetophenone as semicarbazone,
I got a lot.

The clear solution was extracted 4 times with 100 ml of ether,
The extracts were combined, dried over Na2sO4, and then the solvent was distilled off. Remove the residue in vacuum (0.1-0.15 mmHg)
It was distilled with. [α]B. Ob8. =-5.51 (optical yield 12.5%) of phenylmethyl carbinol 23.
67 was obtained with a yield of 90%.

[α
〕ingredient! 60bs. =-29.9 and (EtOHlc=5)
9,17 of N-methylphenethylamine.HCI was obtained with a yield of 93%.

The amino hydrochloride used for dialkylaminoalane synthesis is [α]÷R6Ob8. =-30.00(EtOH, c-
5) It was. Example 2 By operating according to Example 1, acetophenone and N-methylphenethylaminoalane (2:1) were reacted in ethyl ether at -73<0>C.

The corresponding carbinol was obtained with a yield of 57.5%. [
α〕8,0bs. = -37.2 (optical yield 85%).

Example 3 Following the procedure of Example 1, acetophenone and N-methylphenethylamine (2:1) were reacted in toluene at 0°C.

The corresponding carbinol was obtained with a yield of 88%. [α]
8.0 bs. =-12.048. The optical yield was 27.4%. Example 4
Following the procedure of Example 1, acetophenone and N-methylphenethylamine (2:1) were reacted in toluene at -70°C.

The corresponding carbinol was obtained with a yield of 63.5%. [
α]8,0b8. = 32.6, and the optical yield was 74%.

Example 5 At -70°C, N(n-butyl)imino-2
-11.47 y of butanone were added to a solution containing 16.3 y of N-methylphenethylaminoalane in ether.

After the reaction was completed, hydrolysis was carried out using ice and alkali. The ether layer was separated and the aqueous layer was extracted three times with ether. The ether extracts were combined, dried over Na2sO4, and then evaporated under reduced pressure. Secondary butylamine was obtained from a 12 mm fraction of the remaining oil in a yield of 40-45%. [α]8.0b8. −+2.95 and an optical yield of 18%. Example 6 By the procedure of Example 1, acetophenone and
Pipecorinoalane (2:1) in tetrahydrofuran
The reaction was carried out at 70°C.

The corresponding carbinol was obtained with a yield of 60%. [α]
8.05,. The yield was 119.8 (optical yield 22.5%).

Example 7 By the procedure of Example 1, acetophenone and
Phenethyl iminoalane was reacted in ether at 0°C.

The corresponding carbinol was obtained with a yield of 80%. [α]
8.0b8. The yield was 1+4.42 (optical yield 14.4%). Example 8 0.3 N-methylphenethylaminoalane in benzene
At 25°C, a solution containing 1 mol of 3-methyl-1
-Phenyl-1-phospho-30benzene-1-oxide (1) A jig of benzene solution was added.

After addition, the mixture was left at room temperature for 3 hours with stirring, and then hydrolyzed with ice and alkali.

The benzene layer was extracted, dried with KOH, and then evaporated under reduced pressure.

N-methylphenethylamine was collected by distillation at 0.1 mmHg (boiling point 0.1-48°C, yield 70
~75%, optical yield 98%).

The next fraction is 3-methyl-1-phenyl-1-phospho-3
-Cyclobenzene ().

Yield -55-60%, [α]8.0b8. 1+6.78
The maximum specific rotation of this phosphine is unknown. Example 9 Isobutyl methyl ketoxime 13.27 (0.11
5 mol) was slowly added to a solution containing 20.87 (0.13 m0) of N-methylphenethylaminoalane in 250 ml ether at 0° C. over 1 hour 30 minutes.

The solution was refluxed for 3 hours and then hydrolyzed with ice.

After making the pH of the solution alkaline, ether (100 m
Extracted three times at 0. The extracts were combined, dried with KOH, and then evaporated.

The residue was distilled at 15 mmHg.

Different fractions were analyzed by GLC. Iso-butylmethylamine was obtained with a yield of 50%. [α]B. Ob8. The yield was -10.63 (according to a scientific paper -10.71, optical yield 5.9%). N-methylphenethylamine could be isolated as a hydrochloride from the distillation residue, and the yield was 90%.

The optical purity of the obtained amine was 98 for the starting time value.
%Met. Measurements of specific rotation were performed on pure samples and not on diluted samples.

Claims (1)

[Claims] 1 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R and R^ I are mutually different groups,
alkyl group or phenyl group), general formula (II)▲
There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^III and R^IV are mutually different alkyl groups, and R^II is hydrogen or an alkyl group), or the general formula (III) R^VR ^VIR^VIIP^*: (In the formula, R^V, R^VI and R^VII are mutually different groups, and are an alkyl group or a phenyl group, and two of them combine to form a ring. In the method for producing an optically active substance represented by the general formula (I ^ I)
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R and R^ I have the same meanings as above) A ketone, general formula (II^ I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Formula Middle, R^III and R^IV have the same meanings as above,
R^VII is hydrogen, an alkyl group or a hydroxyl group) or an N-substituted imine or ketoxime and the general formula (III^ I) R^VR^VIR^VIIP=O (wherein R^V, The corresponding prochiral compound or racemic compound selected from the group consisting of trialkylphosphine oxides having the same meanings as above) with the general formula H_2AlNR_1R_2, ▲Mathematical formula, chemical formula, table, etc.▼ or (HAlNR_3)
_n (wherein R_1, R_2 and R_3 are an alkyl group, an aryl group or a cycloalkyl group, and n is an integer of 4 or more), with at least one Al-N direct bond and one Al-N direct bond per aluminum atom. Al-H
The third substituent containing a bond and bonding to the aluminum atom is halogen, -H, -N(R_3)_2 or -OR
_3 (where R_3 has the same meaning as above) and reacts with an optically active aminoalane or polyiminoalane whose asymmetric center is in a primary or secondary amine group containing at least one optically active alkyl group. 1. A method for producing an optically active substance, the method comprising the steps of: