JPS61186350A - Optically active amino alcohol and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is 1-5C alkoxy or H; R2 is 1-5C alkyl; excluding the case that R1 is 5-methoxy and R2 is methyl; *represents asymmetric carbon atom). EXAMPLE:(-)-Erythro-2-amino-1-(2,4-dimethoxyphenyl)-1-propanol-. USE:Useful as an asymmetric modifier of boron hydride-type reducing agent. PREPARATION:The compound of formula I can be produced by reacting the amino alcohol of formula II with an optically active alpha-oxyacid derivative in a solvent, separating the resultant two kinds of diastereomers taking advantage of the solubility difference, etc., optionally refining the product by recrystallization, etc., decomposing with an alkali, and extracting with an organic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the general formula (I) [wherein R1 represents an alkoxyl group having 1 to 5 carbon atoms or a hydrogen atom, and R2 represents an alkyl group having 1 to 6 carbon atoms]. However, this excludes the case where R1 is a 5-methoxy group and R2 is a methyl group. This invention relates to an optically active amino alcohol (hereinafter referred to as the compound of the present invention) represented by the symbol (the symbol means an asymmetric carbon) and a method for producing the same.

The compound of the present invention is used as a raw material for an asymmetrically modified borohydride reducing agent used in producing an optically active alcohol derivative from a ketone compound, for example, general formula (2) (% formula %) [wherein R8 is represents an alkyl group, a cycloalkyl group or a cycloalkenyl group, a mataha, a haloken atom,
Represents an alkyl group, a haloalkyl group, a cyano group, an alkoxyl group, a phenoxy group, or a phenyl group which may be substituted with a phenyl group. R4 represents an imidazol-1-yl group or a 1,2.4-)lyazol-1-yl group. R5 represents a t-butyl group or a 1,1-dimethyl-2-phenylethyl group in which the benzene ring may be substituted with a halogen atom. ] The general formula (
g) (In the 4C formula, Ra, R4, Rs and * represent the same meanings as above.) It is used to produce an optically active α,β-unsaturated alcohol derivative represented by the following.

The present inventors have conducted extensive studies on chiral modifiers of reducing agents used when producing optically active alcohol derivatives by asymmetric reduction of ketone compounds, and have found that the general formula (1
It has been discovered that the metal compound of the present invention represented by ) is extremely excellent as an asymmetric modifier for boron hydride reducing agents, leading to the present invention.

The present invention will be explained below.

In the compound of the present invention represented by the general formula (I), the substituent R1 includes, for example, a methoxy group, an ethoxy group, or a hydrogen atom, and the substituent R2 includes, for example, a methyl group or an ethyl group.

Next, a method for producing the compound of the present invention will be described.

The compound of the present invention has the general formula (If) In formula C, R1 and R2 have the same meanings as above.

] The 211-class diastereomers obtained by reacting the amino alcohol represented by, for example, with an optically active α-oxyacid derivative in a solvent are separated, for example, by the difference in solubility, and are recrystallized or column-coated as necessary. It is obtained by purifying it by operations such as chromatography, decomposing it with an alkali, and extracting it with an organic solvent. If necessary, the obtained compound of the present invention is purified by operations such as recrystallization and column chromatography.

In the above method for producing the compound of the present invention, the reaction solvent used is, for example, an aliphatic lower alcohol such as methanol, ethanol, isopropanol, or an aliphatic lower ketone such as acetone, water, or a mixture thereof. Similar solvents are used. Examples of extraction solvents include chloroform, methylene chloride, toluene, and ethyl ether.

Specific examples of optically active α-oxyacid derivatives include tartaric acid, pantolactone, mandelic acid, malic acid, and the like. When using vantolactone, an alkali salt of optically active pantoic acid obtained by treating vantolactone with an alkali such as sodium hydroxide or potassium hydroxide and a mineral acid salt of an amino alcohol represented by the above general formula (provided) may be reacted with.

Further, as the alkali, for example, sodium hydroxide or potassium hydroxide is used.

The compound of the present invention may be purified, if necessary, in the form of a mineral acid salt such as a hydrochloride.

Racemic amino alcohols represented by the general formula (It) are, for example, W, H, Hartung et al., J, Am
.

Chem, Soc,, Dan, 4149-4160 (1
931).

The present invention will be described in detail below with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 Yama-erythro 2-amino-1-(2,4-dimethoxyphenyl)-1-propatur (Erythro/Threo=9
8.9/1.138.48y (0.04 mol) and water 60- to D-H-vantolactone 5.21N (0.04
After stirring at 80-90"C for 1 hour, it was concentrated under reduced pressure to give methanol-ethanol 50flt (1:
4), 5.44 diastereomeric salts of D-H-pantoic acid were obtained ([a]D-16
,0°(c=1.0.water)). Furthermore, ethanol 50-
But if you recrystallize it again, 3.641 8-erythro 2
-Amino-1-(2゜4-dimethoxyphenyl)-1-
D-H-pantoate of propatool was obtained ([
α]D-19.4° (C=1.0, water). The resulting diastereomeric salt was decomposed with a solution of 1 g of potassium hydroxide in 10 d of water, and extracted with methylene chloride to yield 2.07 t of 8-
Erythro 2-amino-1-(2,4-dimethoxyphenyl)-1-propatur (Erymelo/Threo=99.
610.4) was obtained (m, p, 92-98°c
). Optical purity as determined by high performance liquid chromatography analysis was 98.6%. This amino alcohol was dissolved in a mixed solvent of diethyl ether and methylene chloride, and hydrogen chloride gas was passed through it.
4-dimethoxyphenyl)-1-propatur hydrochloride 2
．． 86F was obtained (m, p, 188-188.5
°C (decomposed), [lZ]D-84,0° (c =
1. Os water)).

Optical purity by high performance liquid chromatography analysis In: 9
It was 8.6%.

Example 2 Yama-erythro 2-amino-1-(2-methoxyphenyl)-1-propatur (Erythro/Threo=98.0
/2.0) 14.05 f and 10.09 f of D-H-vantolactone were heated and stirred in 100% water for 1 hour, concentrated under reduced pressure, and recrystallized with isopropanol 110% to yield 5.09g. D-8-pantoic acid salt of (t)-erythro 2-amino-1-(2-methoxyphenyl)-1-propatur was obtained ([α]D+ 22
．． 9° (C=0.9.water)).

The obtained diastereomeric salt was converted into potassium hydroxide A1.61
g(7) When decomposed with a 20-solution of water and extracted with chloroform, 2.589 ((1)-erythro-2-amino-1
-(2-methoxyphenyl)-1-propatol was obtained. This amino alcohol was dissolved in a diethyl ether-chloroform solvent and hydrogen chloride gas was passed to remove the generated hydrochloride and dried. Tool hydrochloric acid tlEm was obtained ([αJD+26.5°(
C=1. O1 water)).

When analyzed by high performance liquid chromatography as a diastereomeric salt of the confirmed conductor, the optical purity was 62.6%. When the recrystallized P solution was concentrated under reduced pressure, 20.28f of H-erythro 2-7 minnow 1-(2-methoxyphenyl)-
1-propatol DH-pantoin maussed ([alo +1.29° (c=i, o, water)). After recrystallizing this with inbropanol and separating the P, the P solution was concentrated under reduced pressure to obtain potassium hydroxide: 3.761 (7) water: 47
When decomposed with tne solution and extracted with chloroform, 6.
79f of H-erythro 2-amino-1-(2-methoxyphenyl)-1-propatol was obtained.

The obtained amino alcohol was converted into a diastereomer of a sugar derivative, and when analyzed by high performance liquid chromatography, the optical purity was found to be 44.6%. Furthermore, when this amino alcohol was dissolved in diethyl ether-chloroform and hydrogen chloride gas was passed through it, 8-erythro-2-amino-1-(
2-Methoxyphenyl)-1-propatur hydrochloride was obtained, and 1.761 8-erythro 2-amino-1-(2-methoxyphenyl) was obtained from the P solution after 8 times of re-M crystallization with ethanol. -Propatool Hydrochloride '1m ([
a]p=87.7° (C==1.0.water)). Optical purity is 98.0% when analyzed by high performance liquid chromatography.
Met.

Example 8 (To)-Erythro 2-amino-1-(2,5-jethoxyphenyl)-1-propatur (Erimero/Threo=98.4/1.6) 20.5 (0,0918 mol) ) was added to a 50 m solution of L -(+)-tartaric acid 1B, 789 (0,0918 mol) in hot methanol, crystals precipitated.Furthermore, 140 ad of methanol was added, redissolved, and then released. The cooled and precipitated crystals were filtered to obtain 12.4 Bl of crystals ([a
1D+28.0° (c=1.0.water)).

Further recrystallization with methanol 150-7,44 f
The (i)-erythro 2-amino-1-(2,6-jethoxyphenyl>-1-propatur)-(t)-tartrate was obtained ((alo + 81.8°((:
=1.0. water)). After decomposing this salt with a 10% aqueous sodium hydroxide solution and extracting it with methylene chloride, 4.7
51 (+)-erythro 2-amino-1-(2,5-
jetoxyphenyl)-1-propertool (Erimero/
Threo=10010) was obtained.

When this was dissolved in diethyl ether and hydrogen chloride gas was passed through it, (t)-erythro 2-amino-1-(2,5-jethoxyphenyl)-1-propatur hydrochloride 5.4 (
l was obtained (m, p, 186.5-188.5"
C, [ff1D+29.1° (C=1.0.water)). Optical purity determined by high performance liquid chromatography analysis is 99.
It was 0% or more.

Example 4 (to)-Erythro 2-amino-1-(2-ethoxyphenyl)-1-propatur (Erythro 99% or moreJu1
15 mg of 1.19N hot methanol was added to L-(-1-)-
Adding 8.60 f of tartaric acid to a 20-m solution of hot methanol and collecting the cold crystals gave 10.449 L-(ho)-tartrate (Ialn + 6.8° (C = 1.01).
water)). Furthermore, when this salt is recrystallized with methanol, [α
]Crystal 4 where D is -8.4° (c = 1.0 + water)
．． 50f was obtained, which was decomposed with a 20% aqueous sodium hydroxide solution and extracted with chloroform to yield 2.799 8-erythro-2-amino-1-(2-ethoxyphenyl)-1-.
The property tool was obtained ([α]I) −16,4°(c
= 1.0, C)icza)).

When analyzed by high performance liquid chromatography as a diastereomer with a sugar derivative, the optical purity was 63.2%. The obtained amino alcohol was dissolved in diethyl ether-chloroform and hydrogen chloride gas was passed through it to give -1-erythro-2-amino-1-(2-ethoxyphenyl)-1-.
Propatur hydrochloride 3.18 II was obtained. Furthermore, when recrystallized four times with isopropanol, 1.02f crystals were obtained ([αID -48,6 (c = 1.0. water)
). Optical purity was 97.8%.

Reference example 1 2-amino-1-(2,5-jethoxyphenyl)-1
-Propanone hydrochloride a 11 (0,114 mol) was dissolved in 450 ml of water, and at 8-7"C, 2.15 f (0,0568 mol) of sodium borohydride was added, and after stirring while keeping warm for 2 hours, concentrated hydrochloric acid was added. The aqueous layer was made alkaline with a 25% aqueous sodium hydroxide solution and extracted with chloroform, resulting in a concentration of 24.1 F.
-Erythro 2-amino-1-(2,5-jethoxyphenyl)-1-propanone hydrochloride (Erythro/Threo = 98.6/6.4).

When recrystallized with toluene, 21.0 g of crystals were obtained (
Elimero/Threo = 98.4/1.6).

m, p, 108-109°C nmr:X
, f)ytoJL/ (CDCzs, δ(ppm)
) 0.99 (d, 3) 1), 1.87 (t, 6) I)
, 1.4-2.2 (broad.

2) 1), 8.24 (m, M), 8.98 (q, 4) 1
), 4.72 (d, H), 6.74 (2H), 6.96
()I) Reference Example 2 201 (0,0988 mol) of 2-amino-1-(2-ethoxyphenyl)-1-propanone hydrochloride was dissolved in 800 mol of water.
-Sodium borohydride 1.7 at 5-8°C dissolved in
7F (0,0468 mol) was added and the mixture was stirred while keeping it warm for 1 hour, and then allowed to stand overnight at room temperature. After making the reaction solution acidic with concentrated hydrochloric acid,
When made alkaline with 25% sodium hydroxide aqueous solution, erythro 2-amino-1-(2-ethoxyphenyl)
-1-Fc1 was obtained as a Panorca crystal, and when F was removed, washed with water and dried, a crystal of 18.40F was obtained (Erimero/Threo = 98°4/1.6). When recrystallized with toluene, 12
．． A crystal of 89f was obtained (99% or more of elimero).

m-1), 89-91-C nmr spectrum (CDC18:δ(ppm1 >0.
99 (d, 81”1), 1.40 (t, 3) 1), 1.
6-2.4 (broad.

211), 8.24 (m, H), a, 99 (q, 2) i
), 4.76(d,)i), 6.7~7.04(m,
2M), 7.05 to 7.45 (m, 2H) Reference Example 3 Under nitrogen atmosphere, (kererythro 2-amino-1-(2
,5-jethoxyphenyl)-1-propatur hydrochloride (optical purity 99% or more) 0.4676&(1,8 mmol) was suspended in 1,2-dichloroethane 5-, -25
Cool to 0.0681y of sodium borohydride
(1.8 mmol) in dimethylformamide was added and brought to room temperature from -25"C for 3 hours. Next, to this suspension was added 20'c"'C-ε)-1- (2,4-
dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-8-
On (E/Z=97.6/2.4) 0.8 9
9 (1.2 mmol) in 4 m of 1,2-dichloroethane was added and stirred for 24 hours. Next, 10% hydrochloric acid 8- was added and decomposed by stirring at 45"C. After washing the organic layer with water,
When mirabilite is dried and concentrated under reduced pressure, 0.89jF H-(E)
-(2,4-dichlorophenyl)-2-(1,2,4-
Crude crystals of triazol-1-yl)-4,4-dimethyl-1-penten-3-ol were obtained. The reaction rate was 99.5% by gas chromatography, and the product composition was 96.7% of 8-alcohol and 8.7% of 2-alcohol.
It was 8%. High performance liquid chromatography using an optically active column revealed that the enantiomeric ratio of the 8-alcohol was 90.8% (H) and 9.796 (H).

Reference Example 4 Under nitrogen atmosphere, -1erythro 2-amino-1-(2,
4-dimethoxyphenyl)-1-propanol hydrochloride (
Optical purity 98.6%) 0.4459y (1.8 mmol) was suspended in 1,2-dichloroethane 5-, -25-
Cool to C and add 0.0681f of sodium borohydride (
A solution of 1.8 mmol) of dimethylformamide 1d was added thereto, and the mixture was warmed to room temperature from -25°C over 2.5 hours. Next, this suspension was heated at 20°C to
, 4-dimethyl-1-penten-3-one (E/Z=9
8.9/1.1) 0.851 (1.2 mmol) in 1.2-dichloroethane 4-solution was added and stirred for 26 hours. Next, add 8fILt of 10% hydrochloric acid and heat at 45°C.
The mixture was stirred and disassembled. The organic layer was washed with water, dried with mirabilite, and concentrated under reduced pressure to obtain (-1-1-εl-1-(4-chlorophenyl)
-2-(1,2,4,-triazol-1-yl)-4
, 4-dimethyl-1-penten-8-ol crude crystals 0
．． I got 35 no. Gas chromatography showed that the reaction rate was 97.8%, and the product composition was 8-alcohol 9
5.7% and 4.8% di-alcohol. By high performance liquid chromatography using an optically active column, the enantiomeric ratio of the 8-alcohol was determined to be 85.0
% and 15.0%.

Claims (6)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 represents an alkoxyl group having 1 to 5 carbon atoms or a hydrogen atom, and R_2 represents an alkyl group having 1 to 5 carbon atoms. represents a group. However, R_1 is a 5-methoxy group, and R
Except when _2 is a methyl group. *mark means asymmetric carbon. An optically active amino alcohol represented by ]. (2) The compound according to claim 1, wherein in the general formula (I), R_1 is a methoxy group, an ethoxy group, or a hydrogen atom. (3) In the general formula (I), R_2 is a methyl group or an ethyl group.
Compounds described in Section. (4) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, R_1 represents an alkoxyl group having 1 to 5 carbon atoms or a hydrogen atom, and R_2 represents an alkyl group having 1 to 5 carbon atoms. represents a group. However, R_1 is a 5-methoxy group, and R
Except when _2 is a methyl group. ] General formula (I) characterized by optical resolution of a racemic alcohol represented by using an optically active α-oxy acid derivative ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 and R_2 represent the same meanings as above, and the * mark means an asymmetric carbon. ] A method for producing an optically active amino alcohol. (5) In the general formulas (I) and (II), R_
5. The production method according to claim 4, wherein 1 is a methoxy group, an ethoxy group, or a hydrogen atom. (6) In the general formulas (I) and (II), R_
Claim 4, wherein 2 is a methyl group or an ethyl group
The manufacturing method according to item or item 5.