JPH09124564A - Optically active compound mixture and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an optically active compound mixture which comprises a specific optically active amino alcohol and an optically active amino alcohol ester having the reverse configuration to the former and is useful as an optical resolution agent or a chiral auxiliary for synthesizing optically active medicines and agrochemicals. SOLUTION: This optically active compound mixture comprises (A) an optically active isomer of a compound (A') of the formula I (X and Y are each a (substituted) alkyl, an aryl; X and Y may incorporate to form a (substituted) alkylene or an alkylene containing hetero atoms; n is 3-6) and (B) a compound which is) a compound (B') of formula II (Z is an acyl) and has the reverse optically active configuration as that of the component A. For example, the objective mixture is prepared by allowing a microorganism in Pseudomonas, Alcaligenes, Mucol, Phizopus, Aspergillus, or Phycomycetes, or a biochemical catalyst originating from these microorganisms to act on a dl-isomer of compound A' or B' in the presence of an acyl donor or an acyl acceptor thereby effecting asymmetric esterification or asymmetric deacylation.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a chiral auxiliary agent for synthesizing an optical resolving agent and an optically active pharmaceutical and agrochemical.
ary) and the like, and an optically active amino alcohol and a method for producing the same.

[0002]

2. Description of the Related Art A general method for producing optically active amino alcohols obtained by the method of the present invention is not known.

[0003]

SUMMARY OF THE INVENTION Accordingly, the object of the present invention is to obtain an optically active amino alcohol or amino alcohol ester from an optically inactive (dl-) amino alcohol or its ester. To get.

[0004]

That is, the present invention has the general formula [I]

Embedded image (In the formula, n is an integer of 3 to 6, and X and Y are the same or different alkyl groups, substituted alkyl groups or aryl groups, and are substituted or unsubstituted alkylene chains or alkylene chains containing a hetero atom. Can be formed) and an optically active amino alcohol represented by the following general formula [II] having the opposite configuration.

Embedded image (In the formula, n is an integer of 3 to 6, Z is an acyl group, X and Y are the same or different alkyl groups, substituted alkyl groups or aryl groups, and a substituted or unsubstituted alkylene chain or A alkylene chain containing a hetero atom can be formed.) A mixture of an optically active amino alcohol ester represented by the formula) and a method for producing the mixture according to claims 2 to 4.

D represented by the above formula [I] as a raw material substrate
For example, 1-amino alcohol is described in known materials [J. Me
d. Chem. 32, 1217 (1989); Prakt.
Chem. 32, 69 (1966); Chem. Abstr. 8
5,77722z] and the like, cis or trans 2- (dimethylamino) cyclopentanol,
2- (ethylpropylamino)-, 2- (benzylmethylamino)-, 2- (diisopropylamino)-, 2-
(1-Piperidinyl)-, 2- (1-pyrrolidinyl)
-, 2- (4-phenyl-1-piperidinyl)-, 2-
(4-Methyl-1-piperazinyl)-, 2- (4-morpholinyl)-and 2- (4-thiamorpholinyl) -cyclohexanol and 2- (methylphenylamino)
Cyclooctanol and the like.

Examples of the acyl donor compound include, for example,
Vinyl acetate, vinyl propionate, vinyl laurate,
Vinyl compounds such as monochlorovinyl acetate and diketene;
Examples thereof include organic acid anhydrides such as acetic anhydride, propionic anhydride, and succinic anhydride; esters such as butyl acetate and ethyl monochloroacetate; triglycerides such as triacetin, tributyrin, and triolein. These acyl-donating compounds are generally used in an amount in the range of about 0.3 to 3 mol per mol of dl-amino alcohol as a substrate. The preferred amount used is in the range of 0.6 to 2 mol.

Further, the dl-aminoalcohol ester represented by the above formula [II] used as a raw material substrate is, for example, an acylated product of the aminoalcohol represented by the above formula [I], in other words, Organic acid esters, the organic acid relating to the esterification, for example, acetic acid, butyric acid,
Saturated or unsaturated fatty acids such as octanoic acid and oleic acid,
Alternatively, monochloroacetic acid and the like are typical. The above formula [I
The substrate represented by [I] is a known material “Can. J. Chem.
1, 469 (1973); Org. Chem.33,3
480 (1968)]. As the acyl acceptor compound, water and methanol, ethanol,
Examples thereof include alcohols such as butanol.
These are usually used in excess.

The biochemical catalyst used in the process of the present invention is a dl-aminoalco-catalyst in the presence of an acyl donor compound.
Or a dl-amino alcohol ester [II] in the presence of an acyl acceptor compound.
Is a microorganism or enzyme capable of asymmetrically deacylating a. Examples of such microorganisms include microorganisms belonging to the genera Pseudomonas, Alcaligenes, Mucor, Rhizopus, Aspergillus or Phycomyces. Furthermore, enzymes obtained from these microorganisms can also be used. Pseudomonas is preferred in both cases. As these enzymes, those modified such as immobilization can also be used.

The biochemical catalyst can be reused. The optically active mixture of alcohol [I] and ester [II] obtained by asymmetric esterification and asymmetric deacylation is usually a mixture of compounds having mutually opposite configurations. Also, depending on the type of microorganism, there are those that are good at asymmetric esterification, those that are good at asymmetric deacylation, and those that can do both, and in some cases give the opposite optically active mixture. You can use them properly according to your purpose.

In carrying out the method of the present invention, in the case of asymmetric esterification, an acyl donor compound and a biochemical catalyst are added to dl-aminoalcohol [I] as a substrate, preferably with shaking. Perform by stirring or stirring. Use of a solvent is not essential, but hexane, octane, cyclohexane, benzene, aliphatic and aromatic hydrocarbon solvents such as toluene, diethyl ether, tetrahydrofuran, ether solvents such as dioxane, dichloromethane, chloroform, A halo-containing solvent such as trichlorethylene can be appropriately used. Further, in the case of asymmetric deacylation, an acyl acceptor compound and a biochemical catalyst are added to dl-aminoalcohol ester [II] as a substrate,
Preferably, it is performed by shaking or stirring. The use of buffering agents such as phosphate buffers is often desirable.

Optically active amino alcohol [I] and amino alcohol ester [II] can be separated and obtained from the mixture obtained by the method of the present invention by operations such as chromatography, distillation or extraction.

[0012]

According to the process of the present invention, it is industrially advantageous to prepare optically active substance mixtures of either (dl-) aminoalcohol or (dl-) aminoalcohol ester. You can

[0013]

Now, the present invention will be described in further detail with reference to specific examples. Example 1 A mixture of vinyl acetate (2.58 g, 30 mmol) and dl-trans-2- (1-piperidinyl) cyclohexanol (1.83 g, 10 mmol) was added to Amano P [Sch. -A lipase of Domonas origin, manufactured by Amano Pharmaceutical Co., Ltd.] (0.4 g) was added, and the mixture was stirred at room temperature overnight. The enzyme was recovered by filtration, and the filtrate was concentrated to obtain an optically active mixture. Toluene (15 ml) and water (10 ml) were added to this mixture, and 6N hydrochloric acid (0.8 ml,
4.8 mmol was added and stirred. Allow to stand and separate the toluene layer, dehydrate and concentrate to obtain acetic acid (R, R) -2- (1-
Piperidinyl) cyclohexyl (1.0 g, 4.4 mmol) was obtained. The aqueous layer is made alkaline with 5N aqueous sodium hydroxide solution, extracted with toluene, dehydrated and concentrated,
(S, S) -2- (1-Piperidinyl) cyclohexanol (0.8 g, 4.4 mmol) was obtained.

Example 2 Monochlorovinyl acetate (3.62 g, 30 mmol) and d
To a mixture of l-trans-2- (1-piperidinyl) cyclohexanol (1.83 g, 10 mmol), Amano P was added.
(0.2 g) was added, and the mixture was stirred at room temperature overnight. Example 1
Monochloroacetic acid (R, R) -2-
(1-Piperidinyl) cyclohexyl (1.1 g, 4.
2 mmol) and (S, S) -2- (1-piperidinyl) cyclohexanol (0.8 g, 4.4 mmol) were obtained.

Example 3 Acetic acid d was added to 0.1 M phosphate buffer (pH 7, 25 ml).
1-trans-2- (1-piperidinyl) cyclohexyl (2.25 g, 10 mmol) was added and the pH was adjusted with 6N hydrochloric acid.
Adjusted to 7. Amano P (60 mg) was added, and the mixture was stirred overnight at room temperature to obtain an optically active mixture. Extract with toluene, dehydrate and concentrate to acetic acid (S, S) -trans-2-
(1-Piperidinyl) cyclohexyl (1.0 g, 4.
4 mmol) was obtained. The aqueous layer was made alkaline with 5N aqueous sodium hydroxide solution, extracted with toluene, dehydrated and concentrated to give (R, R) -trans-2- (1-piperidinyl) cyclohexanol (0.85 g, 4 0.6 mmol)
I got

Example 4 Butyric acid d was added to 0.1 M phosphate buffer (pH 7, 25 ml).
1-cis-2- (1-piperidinyl) cyclohexyl (2.53 g, 10 mmol) was added, and the pH was adjusted to 7 with 6N hydrochloric acid.
And Amano P (60 mg) was added, and the mixture was shaken overnight at room temperature to obtain an optically active mixture. Extracted with toluene,
After dehydration and concentration, (S, R) -cis-2- (1-piperidinyl) cyclohexyl butyrate (1.1 g, 4.35 mmol) was obtained. The aqueous layer was made alkaline with 5N sodium hydroxide, extracted with toluene, dehydrated and concentrated (R,
S) -cis-2- (1-piperidinyl) cyclohexanol (0.8 g, 4.4 mmol) was obtained.

[0017]

According to the method of the present invention, amino alcohols of high optical purity can be easily obtained.

Claims (4)

[Claims] 1. A compound of the general formula [I] (In the formula, n is an integer of 3 to 6, and X and Y are the same or different alkyl groups, substituted alkyl groups or aryl groups, and are substituted or unsubstituted alkylene chains or alkylene chains containing a hetero atom. Can be formed) and an optically active isomer of amino alcohol represented by the following general formula [II] having the opposite configuration. (In the formula, n is an integer of 3 to 6, Z is an acyl group, X and Y are the same or different alkyl groups, substituted alkyl groups or aryl groups, and a substituted or unsubstituted alkylene chain or A mixture of optically active isomers of amino alcohol ester represented by the formula (1) which can form an alkylene chain containing a hetero atom. 2. An amino alcohol represented by the general formula [I].
2. The process for producing a mixture according to claim 1, wherein the asymmetric esterification is carried out by acting a biochemical catalyst on the dl-form of acetylene in the presence of an acyl-donating compound. 3. An amino alcohol represented by the general formula [II].
The method for producing a mixture according to claim 1, wherein the asymmetric deacylation is carried out by reacting the dl-form of the ruster with a biochemical catalyst in the presence of an acyl acceptor compound. 4. The method according to claim 2 or 3, wherein the biochemical catalyst is a microorganism of each genus of Pseudomonas, Alcaligenes, Mucor, Rhizopus, Aspergillus or Phycomyces or an enzyme derived from the microorganism.