JPH1045746A - Production of optically active compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an optically active compound useful as an intermediate for pharmaceutics, such as α-adrenaline blocker, and cholesterol depressant, by a reaction of a cathecol, etc., with an optically active glycidyl nitrobenzenesulfonic ester in an organic solvent in the presence of a base. SOLUTION: This optically active compound of formula II is obtained by a reaction of a compound of formula I (the ring E is a benzene ring, which may have further 1-4 substituents, for example, cathecol) with an optically active glycidyl nitrobenzenesulfonic ester in an organic solvent in the presence of such a base as an alkali metal carbonate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active compound useful as an intermediate for pharmaceuticals such as α-adrenergic blockers and cholesterol lowering agents.

[0002]

2. Description of the Related Art An optically active compound intended in the present invention, namely, an optically active 2-hydroxymethyl-2,3-dihydro compound
Examples of the method for producing a -1,4-benzodioxane derivative include: 1) reacting catechol with (2S) -3-benzyloxy-1,2-propanediol tosylate in ethanol in the presence of sodium methoxide; (Journal ofMedici
nal Chemistry, 20, 880-885 (1977)); 2) A method using a reaction between catechol and epichlorohydrin (Journal of Medicinal Chemistry, 30, 49-57).
(1987)); 3) catechol and optically active glycidyl tosylate,
Reaction in an organic solvent in the presence of sodium hydride or potassium carbonate (Journal of Medicinal Chemist
ry, 32, 1402-1407 (1989); Tetrahedron Letter, 29,
3671-3674 (1988)); 4) Racemic 2-hydroxymethyl-2,3-dihydro-1,4-
A method of optically resolving benzodioxane with lipase (Tetrahedron Letter, 33, 6283-6286 (1992)) and the like are known. However, a method for producing an optically active compound of the present invention using an optically active form of glycidyl 3-nitrobenzenesulfonic acid ester is not known.

[0003]

The above-mentioned conventional production methods are optically active compounds useful as intermediates of pharmaceuticals such as α-adrenergic blockers and cholesterol lowering agents in terms of yield, optical purity and the like. It is hard to say that this is a satisfactory production method for producing an optically active 2-hydroxymethyl-2,3-dihydro-1,4-benzodioxane derivative. Therefore, there is a need for a method capable of producing the derivative in a stereoselective and high yield manner.

[0004]

According to the present invention, there is provided a compound of the formula (I)

Embedded image Wherein ring E represents a benzene ring which may further have 1 to 4 substituents;
Compound (I)) and an optically active form of glycidyl 3-nitrobenzenesulfonate in an organic solvent in the presence of a base;

Embedded image Wherein the ring E has the same meaning as described above (hereinafter, abbreviated as compound (II)).

In the formula (I), the substituents on the ring E include a halogen atom, a hydrocarbon group, a thiol group which may be substituted, an acyl group, a hydroxyl group which may be substituted, a nitro group and a cyano group. And an optionally substituted amino group.

[0006] Halogen atoms include fluorine, chlorine, bromine and iodine. As the hydrocarbon group, C
_1-15 hydrocarbon group, for example, C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _4-10 cyclo group Examples include an alkadienyl group, a C _6-14 aryl group, and a C _7-10 aralkyl group. Preferred examples of the C _1-10 alkyl group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, 1-ethyl Propyl, hexyl, isohexyl,
1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,
3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, decyl and the like.
Preferred examples of the C _2-10 alkenyl group include, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3
-Pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like. Preferred examples of the C _2-10 alkynyl group include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,
-Pentynyl, 3-pentynyl, 4-pentynyl, 1-
Hexinyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like can be mentioned.

Preferred examples of the C _3-10 cycloalkyl group include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.
2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl,
Bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl and the like can be mentioned. Preferred examples of the C _3-10 cycloalkenyl group include, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. . Preferred examples of the C _4-10 cycloalkadienyl group include, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. Is mentioned. C _6-14
Preferable examples of the aryl group include, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Preferable examples of the C _7-10 aralkyl group include, for example, benzyl, phenethyl and the like.

In the optionally substituted thiol group, examples of the substituted thiol group include C _1-10 alkylthio, C _3-10 cycloalkylthio, C _2-10 alkenylthio, and C _3-10 cyclothio. Alkenylthio group, C _7-10
Aralkylthio group, C _2-4 alkanoylthio group, C _6-14
Arylthio groups and the like. Preferred examples of the C _1-10 alkylthio group include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, tert.-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, Heptylthio, nonylthio and the like. Preferable examples of the C _3-10 cycloalkylthio group include, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. Preferable examples of the C _2-10 alkenylthio group include, for example, allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio and the like. Preferable examples of the C _3-10 cycloalkenylthio group include, for example, 2-cyclopentenylthio, 2-cyclohexenylthio and the like. Preferable examples of the C _7-10 aralkylthio group include benzylthio, phenethylthio and the like. Preferable examples of the C _2-4 alkanoylthio group include, for example, acetylthio, propionylthio, butyrylthio, isobutyrylthio and the like.
Preferable examples of the C _6-14 arylthio group include, for example, phenylthio, naphthylthio and the like.

Examples of the acyl group include C _1-13 acyl groups such as formyl, C _2-10 alkanoyl group, C _3-10 alkenoyl group, C _4-10 cycloalkanoyl group, C _4-10 cycloalkenoyl group, _6-12 aromatic carbonyl groups and the like. Suitable examples of the C _2-10 alkanoyl group include, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like. Preferred examples of the C _3-10 alkenoyl group include, for example, acryloyl, methacryloyl, crotonoyl, isocrotonoyl and the like. Preferable examples of the C _4-10 cycloalkanoyl group include, for example, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl and the like. Preferred examples of the C _4-10 cycloalkenoyl group include, for example, 2-cyclohexenecarbonyl. Preferable examples of the C _6-12 aromatic carbonyl group include benzoyl, naphthoyl and the like.

In the optionally substituted hydroxyl group, the substituted hydroxyl group includes, for example, C
_1-10 alkoxy group, C _3-10 cycloalkyloxy group, C
_Examples thereof include a _2-10 alkenyloxy group, a C _3-10 cycloalkenyloxy group, a C _7-10 aralkyloxy group, a C _2-4 alkanoyloxy group, and a C _6-14 aryloxy group. C
Preferred examples of the _1-10 alkoxy group include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, Heptyloxy, nonyloxy and the like can be mentioned. Preferable examples of the C _3-10 cycloalkyloxy group include cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Preferred examples of the C _2-10 alkenyloxy group include, for example, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like. Preferable examples of the C _3-10 cycloalkenyloxy group include, for example, 2-cyclopentenyloxy, 2-cyclohexenyloxy and the like. Preferred examples of the C _7-10 aralkyloxy group include:
For example, benzyloxy, phenethyloxy and the like can be mentioned. Preferred examples of the C _2-4 alkanoyloxy group include:
For example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and the like can be mentioned. Preferable examples of the C _6-14 aryloxy group include phenoxy, naphthyloxy and the like.

In the optionally substituted amino group,
Substituted amino groups include N-mono-substituted amino groups and N, N-di-substituted amino groups. Examples of the substituent in the substituted amino group include the aforementioned C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group,
A C _6-14 aryl group and a C _2-10 alkanoyl group. Preferable examples of the substituted amino group include, for example, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino and the like. Can be

In the formula (I), the substituent on ring E is preferably a halogen atom, a C _1-10 alkyl group, a hydroxyl group, a C _1-10 alkoxy group or a nitro group. The number of substituents on the ring E is 1 to 4,
Preferably it is one or two. In the formula (I), the ring E is preferably a benzene ring optionally having one nitro group, more preferably an unsubstituted benzene ring.

Hereinafter, the production method of the present invention will be described in detail.
The optically active form of compound (II) is produced by reacting compound (I) with an optically active form of glycidyl 3-nitrobenzenesulfonate in an organic solvent in the presence of a base. As the compound (I), a compound known in the literature, for example, a compound commercially available as a reagent can be used.

As the organic solvent, an organic solvent which does not adversely affect the reaction is used. Such solvents include:
For example, ethers such as diethyl ether, diisopropyl ether, and tetrahydrofuran; aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as chloroform and dichloromethane; ketones such as acetone and methyl ethyl ketone; Esters; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These organic solvents may be mixed and used at an appropriate ratio. The organic solvent is preferably an ether, and more preferably dimethylformamide. The amount of the organic solvent to be used is preferably appropriately selected depending on the individual reaction. For example, 1 to 100 parts by weight, preferably 5 to 100 parts by weight, per 1 part by weight of compound (I)
To 50 parts by weight.

The optically active form of glycidyl 3-nitrobenzenesulfonate is (2R)-(-)-glycidyl 3-nitrobenzenesulfonate (hereinafter referred to as "2R-(-)-glycidyl 3-nitrobenzenesulfonate").
Either (R) -glycidyl nosylate) or (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (hereinafter sometimes abbreviated as (S) -glycidyl nosylate) Good. When the former is used, the S form of the compound (II) is obtained, and when the latter is used, the R form of the compound (II) is obtained. Where glycidyl
The optically active form of 3-nitrobenzenesulfonic acid ester is generally available as a reagent, and is commercially available, for example, as (R) -glycidyl nosylate or (S) -glycidyl nosylate from Daiso Corporation. Glycidyl
The amount of the optically active form of 3-nitrobenzenesulfonic acid ester to be used is, for example, 0.1 to 5 equivalents, preferably 0.5 to 2 equivalents, relative to compound (I).

Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as potassium carbonate; alkali metal hydrides such as sodium hydride; alkyl alkali metals such as butyl lithium; Alkali metal alkoxides such as ethoxide; and alkali metal amides such as sodium amide. The base is preferably an alkali metal carbonate, more preferably potassium carbonate. The amount of the base to be used is, for example, 0.1 to 5 equivalents, preferably 0.5 to 2 equivalents, relative to compound (I).
Is equivalent.

The reaction temperature is usually from 0 ° C. to the boiling point of the organic solvent used, preferably room temperature (1 to 3).
0 ° C) to 80 ° C. The reaction time is generally 0.5 to 48 hours, preferably 1 to 20 hours. The optically active compound (II) thus obtained can be obtained by a known isolation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction,
By crystallization, recrystallization, phase transfer, chromatography, etc.
It can be isolated and purified.

The compound (I) obtained by the production method of the present invention
Optically active isomers of I), particularly compounds (I
The optically active isomer I) is an important intermediate when synthesizing various pharmaceuticals and agricultural chemicals having an asymmetric carbon, and includes, for example, prosimpal, piperoxane, N- [2- (2, 6-
Dimethoxyphenoxy) ethyl] -1,4-benzodioxane-
It is extremely useful for the synthesis of α-adrenergic blockers such as 2-methylamine hydrochloride (WB4101), antigastritis drugs, antispasmodics, and anxiolytics.

Embedded image In addition, as shown in the following formula, an optically active compound of compound (II) in which ring E is unsubstituted is, for example, Journal of Medicinal Chemis
try), Vol. 30, pages 49-57 (1987).
It can be oxidized to an optically active 2,3-dihydro-1,4-benzodioxane-2-carboxylic acid derivative, and 4-amino
It is also useful as a raw material for -2- [4- (1,4-benzodioxan-2-ylcarbonyl) piperazin-1-yl] -6,7-dimethoxyquinazoline (Doxazosin).

Embedded image

[0019]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited thereto. The NMR spectra in the examples were measured with a 90 MHz spectrometer manufactured by Hitachi, Ltd. using tetramethylsilane as an internal or external standard, and represented by δ values (ppm). The optical purity of the optically active compound was determined by a high performance liquid chromatography method. That is, an optically active column, elution conditions, and the like for separating each enantiomer are appropriately selected to determine the peak area [S ₁ , S ₂ (where S ₁ > S ₂ )] of each enantiomer. It was expressed by calculating body excess (enantiomeric excess, hereinafter abbreviated as ee). Optical purity = [(S ₁ −S ₂ ) / (S ₁ + S ₂ )] × 100
(% Ee) The optical purity in Examples and Comparative Examples was calculated using high performance liquid chromatography under the following conditions. Column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries) Moving bed: n-hexane / 2-propanol = 96/4 (v /
v) Flow rate: 0.8 ml / min Detection: UV (280 nm) Temperature: 26 ° C. Injection: 5.0 ml (2.0 mg / ml) The literature values in the examples are based on the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry). Chemist
ry), 20, 880-885 (1977).

[0020]

【Example】

Example 1 To 5.29 g (48 mmol) of catechol, 10.4 g (40 mmol) of (S) -glycidyl nosylate, 6.63 g of potassium carbonate (48 m
mol) and 70 ml of dimethylformamide, and
Stirred for hours. The reaction solution was added to ice water and extracted with diethyl ether. After the ether layer was dried over magnesium sulfate, it was concentrated to dryness under reduced pressure. When the residue was analyzed by high performance liquid chromatography, the amount of (R) -2-hydroxymethyl-2,3-dihydro-1,4-benzodioxane produced was 4.
The amount was 57 g (yield 86.3%). The optical purity was 97.0% based on the results of analysis by high performance liquid chromatography.
% ee was calculated. The residue was purified by silica gel chromatography (310 g, eluted with chloroform) and recrystallized from a mixed solvent of diethyl ether and hexane (volume ratio: 1/1) to give (R) -2-hydroxymethyl-2,3 1.88 g of colorless needle crystals of -dihydro-1,4-benzodioxane were obtained. Its optical purity was 99.4% ee. The mother liquor was recrystallized to obtain 0.38 g of colorless needle crystals of (R) -2-hydroxymethyl-2,3-dihydro-1,4-benzodioxane. Its optical purity was 99.2% ee. ¹ H-NMR (CDCl ₃ , 90MHz) δ 1.9 (1H, br s), 3.8-4.0
(2H, m), 4.1-4.3 (3H, m), 6.87 (4H, m) .IR (KBr) 3400, 1600, 1505, 1280 cm ^-1 .mp 74-75 ° C (diethyl ether / n-hexane) [Literature values
[Α] _D ²⁵ = + 32.5 ° (c = 0.1, EtOH) [Literature value + 34.0 °
(c = 0.1, EtOH)).

Example 2 To 12.74 g (116 mmol) of catechol, 25.0 g (96.4 mmol) of (R) -glycidyl nosylate and 16.0 g of potassium carbonate
(116 mmol) and 170 ml of dimethylformamide, and add
The mixture was stirred at ℃ for 4.5 hours. The reaction solution was added to ice water and extracted with diethyl ether. After the ether layer was dried over magnesium sulfate, it was concentrated to dryness under reduced pressure. When the residue was analyzed by high performance liquid chromatography, the amount of (S) -2-hydroxymethyl-2,3-dihydro-1,4-benzodioxane produced was 10.11 g (yield 63.1%). The optical purity was calculated to be 95.6% ee based on the result of analysis by high performance liquid chromatography. The residue was purified by silica gel chromatography (750 g, eluted with diisopropyl ether) and recrystallized from a mixed solvent of diethyl ether and hexane (volume ratio: 1/1) to give (S) -2-hydroxymethyl-2, 5.87 g of colorless needle crystals of 3-dihydro-1,4-benzodioxane were obtained. Its optical purity was 99.4% ee. Recrystallization from the mother liquor resulted in an additional 2.02 g
Colorless needle crystals of (S) -2-hydroxymethyl-2,3-dihydro-1,4-benzodioxane were obtained. Its optical purity is 90.
It was 2% ee.

Example 3 To 3.72 g (24 mmol) of 4-nitrocatechol, 5.18 g (20 mmol) of (S) -glycidyl nosylate and 3.32 g of potassium carbonate
(24 mmol) and 30 ml of dimethylformamide.
The mixture was stirred at ℃ for 18 hours. The reaction solution was added to ice water and extracted with diethyl ether. After the ether layer was dried over sodium sulfate, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (120 g, eluted with chloroform / acetone) to give 2.18 g of crystals of (R) -nitro-2-hydroxymethyl-2,3-dihydro-1,4-benzodioxane
(51.6% yield). This was further recrystallized from toluene to obtain 1.15 g of colorless needle crystals. ¹ H-NMR (CDCl ₃ , 90MHz) δ 1.8-2.0 (1H, br s), 3.8-
4.0 (2H, m), 4.15-4.48 (3H, m), 6.92-7.00 (1H, m),
7.75-7.83 (1H, m). IR (KBr) 3350, 1610, 1510, 1530, 1360, 1290 cm ^-1 . Mp 101-103 ° C (toluene). [Α] _D ²⁶ = + 74.5 ° (c = 0.1, EtOH)

Comparative Example 1 0.457 g (2.0 mmol) of (S) -glycidyl tosylate and 0.332 g of potassium carbonate were added to 0.264 g (2.4 mmol) of catechol.
(2.4 mmol) and 3.5 ml of dimethylformamide.
The mixture was stirred at ℃ for 7 hours. The reaction solution was added to ice water and extracted with diethyl ether. The ether layer was dried over sodium sulfate and then concentrated to dryness under reduced pressure to obtain 0.52 g of an oil.
When the residue was analyzed by high performance liquid chromatography,
The amount of (R) -2-hydroxymethyl-2,3-dihydro-1,4-benzodioxane produced was 0.182 g (54.8% yield).
Its optical purity was 73.7% ee based on the result of analysis by high performance liquid chromatography.

[0024]

According to the production method of the present invention, optically active compounds useful as intermediates of pharmaceuticals such as α-adrenergic blockers and cholesterol lowering agents can be produced in a stereoselective and high yield. it can.

Claims (6)

[Claims] 1. A compound of the formula (I) [Wherein ring E represents a benzene ring which may further have 1 to 4 substituents] and an optically active form of glycidyl 3-nitrobenzenesulfonic acid ester in an organic solvent Wherein the reaction is carried out in the presence of a base. [Wherein ring E has the same meaning as described above]. 2. The substituent is a halogen atom, a hydrocarbon group, an optionally substituted thiol group, an acyl group, an optionally substituted hydroxyl group, a nitro group, a cyano group or an optionally substituted amino group. The production method according to claim 1, which is a group. 3. The method according to claim 1, wherein the substituent is a halogen atom, a C _1-10 alkyl group, a hydroxyl group, a C _1-10 alkoxy group or a nitro group. 4. The process according to claim 1, wherein the ring E is a benzene ring optionally having one nitro group. 5. The method according to claim 1, wherein the organic solvent is an ether. 6. The method according to claim 1, wherein the base is an alkali metal carbonate.