JP2002302464A - Optically active halohydrin derivative and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new production intermediate for the production of a 3,4-disubstituted phenylethanol aminotetralin carboxamide derivative or its pharmacologically permissible salt having β2 -adrenaline receptor stimulating action and useful as an agent for preventing imminent abortion and premature birth, a bronchodilator and a pain relieving and stone discharge promoting agent for lithangiuria, and provide a method for the use of the intermediate. SOLUTION: This invention relates to a compound expressed by formula (I) (R<1> is an OH-protecting group; R<2> and R<3> are each independently H or an OH-protecting group; and X is a halogen) and a method for producing a 3,4- disubstituted phenylethanol aminotetralin carboxamide derivative expressed by formula (II) or its pharmacologically permissible salt by using the compound of formula (I).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel intermediate for producing a 3,4-disubstituted phenylethanolaminotetralincarboxylic acid amide derivative or a pharmaceutically acceptable salt thereof, which is useful as a pharmaceutical, and use thereof. About the method.

More specifically, the present invention provides a β _2-
Formula (V), which has an adrenergic receptor stimulating effect and is useful as an agent for preventing imminent flow / premature birth, a bronchodilator, a pain relieving agent for urolithiasis, and a lithotripsy accelerator

Embedded image The present invention relates to a novel intermediate useful for producing a 3,4-disubstituted phenylethanolaminotetralin carboxylic acid amide derivative represented by the following formula or a pharmaceutically acceptable salt thereof, and a method for using the same.

[0003]

2. Description of the Related Art As a method for producing a 3,4-disubstituted phenylethanolaminotetralin carboxylic acid amide derivative represented by the formula (V), WO97 / 30023 discloses (1) Formula (VI)

Embedded image (Wherein R ⁰ is a protecting group for a hydroxyl group and Y is a halogen), and an alkylating agent represented by the formula (VII):

Embedded image (Wherein A is a lower alkylene group and B is a di-lower alkylamino group), and then reduced with sodium borohydride to obtain a diastereomer mixture. Method for separation by chromatography, and (2) Formula (VIII)

Embedded image Wherein R ⁰ has the same meaning as described above, and a compound of formula (IX)

Embedded image Is reacted with an amine represented by a condensing agent to form an amide compound, and a diastereomer mixture obtained by reducing the amide compound with a reagent such as a borane-dimethylsulfide complex is separated by liquid chromatography. , The phenolic hydroxyl group is YA-COB
(Y, A and B have the same meanings as described above), but the optically active halohydrin derivative represented by the formula (I) of the present invention is disclosed. Absent.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide β ₂
3,4-formula (V) having an adrenergic receptor stimulating action and being useful as an agent for preventing imminent flow / premature birth, a bronchodilator, a pain relieving agent for urolithiasis and a calculus accelerating agent
An object of the present invention is to provide a novel optically active intermediate useful for producing a disubstituted phenylethanolaminotetralincarboxylic acid amide derivative or a pharmaceutically acceptable salt thereof in a simple and high yield.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found a novel optically active halohydrin derivative represented by the above formula (I) which has not been described in the literature. It has been found that a 3,4-disubstituted phenylethanolaminotetralincarboxylic acid amide derivative represented by the formula (V) or a pharmaceutically acceptable salt thereof can be easily and efficiently produced using a halohydrin derivative, The present invention has been completed.

That is, the present invention provides the above-mentioned formula (3), which has a β ₂ -adrenoreceptor stimulating action, and is useful as an agent for preventing imminent flow / premature birth, a bronchodilator, a pain relieving agent for urinary lithiasis and a calculus accelerating agent. A novel optically active intermediate useful for producing a 3,4-disubstituted phenylethanolaminotetralincarboxylic acid amide derivative represented by V) or a pharmaceutically acceptable salt thereof, is represented by the following formula (I)

Embedded image Wherein R ¹ is a protecting group for a hydroxyl group, R ² and R ³ are independently a hydrogen atom or a protecting group for a hydroxyl group, and X is a halogen.

Further, the present invention provides a compound of the formula (II)

Embedded image (Wherein R ⁴ , R ⁵ and R ⁶ are the same or different and each is a protecting group for a hydroxyl group, and X is a halogen), and a compound represented by the formula (III)

Embedded image With an amine of the formula (IV)

Embedded image Wherein the protecting groups R ⁴ , R ⁵ and R ⁶ of the compound of formula (IV) are deprotected and then, if necessary, a pharmacologically acceptable salt is formed Formula (V), characterized in that:

Embedded image And a method for producing a 3,4-disubstituted phenylethanolaminotetralincarboxylic acid amide derivative represented by the formula: or a pharmaceutically acceptable salt thereof.

In the present invention, halogen is a chlorine atom,
Represents a bromine atom or an iodine atom, and a protecting group for a hydroxyl group refers to any group that can be introduced to prevent an undesirable reaction from occurring in a hydroxyl group, for example, an aralkyl group, a tri-lower alkylsilyl group, or a lower alkoxy lower group. Examples include an alkyl group, a tetrahydropyranyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and a phenyl lower alkoxycarbonyl group. Here, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, isopropyl, and tert-butyl. The aralkyl group means the lower alkyl substituted with a phenyl group which may be substituted with 1 to 3 halogens or a methoxy group, for example, benzyl, 4-chlorobenzyl, 4-methoxybenzyl, 3,4 -Dimethoxybenzyl and the like. The tri-lower alkylsilyl group means a silyl group trisubstituted by the lower alkyl group, and includes, for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and the like. A lower alkoxy lower alkyl group is one having 1 to 6 carbon atoms.
Means the lower alkyl group substituted with a single linear or branched alkoxy group, for example, methoxymethyl,
1-ethoxyethyl and the like. The lower alkanoyl group means a carbonyl group substituted by the lower alkyl group, and includes, for example, acetyl, isobutyryl, pivaloyl and the like. The lower alkoxycarbonyl group means a carbonyl group substituted by a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like. The phenyl lower alkoxycarbonyl group means the above lower alkoxycarbonyl group substituted with a phenyl group, and examples include benzyloxycarbonyl. Preferred hydroxyl protecting groups include aralkyl groups and tri-lower alkylsilyl groups. The most preferred hydroxyl protecting group is t
tert-butyldimethylsilyl and benzyl.

Hereinafter, the present invention will be described in detail. The compounds represented by formulas (XIII) and (II) of the present invention can be produced according to the following scheme.

Embedded image Wherein R ⁴ , R ⁵ , R ⁶ and X are as defined above.

The phenol derivative represented by the formula (X) used as a starting material in the present invention can be obtained by reacting commercially available 4'-hydroxyacetophenone with formalin in 3'-chloromethyl- 4'-hydroxyacetophenone can be produced by cyanation with sodium cyanide, alkali hydrolysis and esterification.

The compound represented by the above formula (XIII) of the present invention can be produced by carrying out the reaction in the following steps a to c.

(Step a) A phenolic hydroxyl group can be prepared by adding a protecting reagent to a phenol derivative represented by the formula (X) in an inert solvent in the presence of a base or an acid, if necessary, according to a conventional method. To give a methyl ketone derivative represented by the above formula (XI). The introduction of such a hydroxyl-protecting group is described, for example, in T.S. W. G
reen and P.M. G. FIG. H. Wuts, "Protec
five Groups in Organic Syn
thesis ", 3rd edition, and references described therein. When R ⁴ is an aralkyl group, a phenol derivative represented by the above formula (X) and R ⁴ —X (X is as defined above) are mixed with a base (eg, potassium carbonate, sodium carbonate) in an inert solvent. ,
In the presence of an inorganic base such as cesium carbonate) and, if necessary, a catalytic amount of an alkali metal iodide (eg, potassium iodide), usually at 10 to 100 ° C. for 30 minutes to 12
After the reaction, the insolubles are removed if necessary, and then extracted and concentrated by a conventional method to obtain the compound represented by the formula (X)
The methyl ketone derivative represented by I) can be obtained. Examples of the inert solvent that can be used in this reaction include, for example,
Examples thereof include ethers such as diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran, N, N-dimethylformamide, and acetonitrile. These inert solvents can be used alone or as a mixture of two or more. The methyl ketone derivative (XI) can be purified, if necessary, by a conventional purification means such as recrystallization.

(Step b) Next, the methylketone derivative represented by the above formula (XI) is added to a halogenating reagent (for example, chlorine) in an inert solvent, if necessary, in the presence of a catalytic amount of an acid (for example, sulfuric acid or the like). , Bromine, pyrrolidone hydrotribromide, etc.), and after completion of the reaction, extraction and concentration by a conventional method can give the phenacyl halide represented by the formula (XII). Examples of the inert solvent that can be used in this reaction include carboxylic esters such as ethyl acetate, halogenated hydrocarbons such as chloroform, hydrocarbons such as hexane, and the like. Two or more kinds can be used as a mixture. Phenacyl halide (X
II) may be purified and used in the next step, but there is no problem if it is used in the next step without purification.

(Step c) Next, the above formula (XII)
The phenacyl halide represented by in the presence of an optically active amino alcohol in an inert solvent, if necessary, by adding a metal alkoxide, asymmetric reduction using a borohydride reagent, the present invention The halohydrin derivative represented by the formula (XIII) can be produced. Inert solvents usable in this asymmetric reduction reaction include diethyl ether, tetrahydrofuran, 1,2-
Ethers such as dimethoxyethane, dichloromethane,
Examples thereof include halogenated hydrocarbons such as chloroform, and hydrocarbons such as toluene. These inert solvents can be used alone or in combination of two or more. Examples of the optically active amino alcohol include (2R)
-Α, α-diphenyl-2-pyrrolidinemethanol,
(1R, 2S, 3R, 4S) -3-amino-1,7,7
-Trimethylbicyclo [2.2.1] heptane-2-ol and the like can be used, and usually 0.1 to 100 mol%, preferably 1 to 20 mol% with respect to phenacyl halide (XII). It can be appropriately selected from the range and used. As the metal alkoxide, aluminum tri-lower alkoxide (eg, aluminum triethoxide, aluminum triisopropoxide, etc.) and the like can be used. Usually, 1.0 to 1.5 equivalents are used based on the optically active amino alcohol. Is done. As the reducing agent, a borane-dimethyl sulfide complex, a borane-tetrahydrofuran complex, a borane-N, N-diethylaniline complex, and the like can be used, and usually 1 to 3 in terms of boron with respect to phenacyl halide (XII). Used equivalent. To suitably carry out the asymmetric reduction reaction, a metal alkoxide is added to a solution of the optically active amino alcohol in an inert solvent, if necessary, and the mixture is stirred at room temperature for 30 minutes to several hours. Phenacyl halide (XI
I) is added, and the reaction is usually performed at 0 to 70 ° C. for 1 to 12 hours. After the completion of the reaction, the target halohydrin derivative represented by the formula (XIII) can be obtained with extremely high optical purity by extracting and concentrating by a conventional method. The halohydrin derivative (XIII) can be purified, if necessary, by a conventional purification means such as recrystallization.

The optically active amino alcohol used in the asymmetric reduction reaction can be a commercially available product or can be produced according to the method described in the literature (K.T.
anaka et al. Chem. Soc. Perkin
Trans. 1, 1991, 1445-1452
page).

(Step d) When the halohydrin derivative represented by the formula (II) of the present invention is different from R ⁵ and R ⁶ , a different protecting reagent may be added to the halohydrin derivative represented by the formula (XIII) according to a conventional method. When R ⁵ and R ⁶ are the same, the reaction is carried out using an excess amount, for example, 2 to 10 equivalents of a protecting reagent. can do. The introduction of such a hydroxyl-protecting group is described, for example, in T.S. W. Green and P.M. G. FIG. H. Wut
s, “Protective Groups in O
rgnic Synthesis ", 3rd edition, and the references described therein.
When R ⁵ and R ⁶ are a tri-lower alkylsilyl group,
The halohydrin derivative (XIII) and the tri-lower alkyl silylating agent are usually reacted with an inert solvent in the presence of a base in the range of from 0 to
By reacting at 50 ° C. for 1 to 24 hours, the halohydrin derivative of the present invention represented by the formula (II) can be produced. Inert solvents that can be used in this silylation reaction include ethers such as tetrahydrofuran, hydrocarbons such as toluene, ethyl acetate, acetonitonyl,
N, N-dimethylformamide, and the like, and these inert solvents can be used alone or in combination of two or more. Examples of the tri-lower alkyl silylating agent include chlorotrimethylsilane, chlorotriethylsilane, chlorotriisopropylsilane, tert-butyldimethylchlorosilane and the like. As the base, triethylamine, diisopropylethylamine, pyridine,
And imidazole. The tri-lower alkyl silylating agent and the base are usually a halohydrin derivative (XI
It can be suitably selected and used from the range of 2 to 10 equivalents to II). After completion of the reaction, the desired halohydrin derivative (I) is extracted and concentrated by a conventional method.
I) can be obtained. Halohydrin derivative (II)
May be purified and used in the next step, but there is no problem if it is used in the next step without purification.

By using the thus obtained optically active halohydrin derivative represented by the formula (II) and carrying out the reaction of steps ef shown in the following scheme, the above formula (V) which is useful as a pharmaceutical is obtained. V)
A 4-disubstituted phenylethanolaminotetralin carboxylic acid amide derivative can be produced.

Embedded image In the formula, R ⁴ , R ⁵ and R ⁶ independently represent a hydroxyl-protecting group, and X is as defined above.

(Step e) The halohydrin derivative represented by the above formula (II) and the amine represented by the above formula (III) are usually reacted in an inert solvent in the presence of a base in the range of 40 to 13
The compound represented by the formula (IV) can be produced by reacting at 0 ° C. for 1 to 48 hours. Examples of the inert solvent that can be used in this reaction include, for example,
Alcohols such as isopropanol and tert-butanol; ethers such as 1,2-dimethoxyethane;
Examples thereof include chlorobenzene, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, and acetonitrile. A mixture of more than one species can be used. As the base, for example, inorganic bases such as sodium carbonate, potassium carbonate and cesium carbonate, and organic bases such as triethylamine and diisopropylethylamine can be used. The halohydrin derivative (II) and the amine (III) are usually used in equimolar amounts, but one of them may be used in excess. The base can usually be appropriately selected and used from the range of 1 to 5 equivalents to the amine (III). After completion of the reaction, extraction is performed by a conventional method.
The desired compound represented by the above formula (IV) can be obtained by concentration. Compound (IV) may be purified and used in the next step, but may be used in the next step without purification without any problem.

(Step f) Next, the protecting group R ⁴ , R ⁵ and R ⁶ in the compound represented by the formula (IV) are removed sequentially or simultaneously by a conventional method, whereby the compound represented by the formula (V) is removed. 3,4-disubstituted phenylethanolaminotetralin carboxylic acid amide derivative can be led in good yield. Removal of such a hydroxyl protecting group may be, for example,
T. W. Green and P.M. G. FIG. H. Wuts, "P
protective Groups in Organ
ic Synthesis, 3rd Edition, and the references described therein. When the protecting group R ^{4 for the} hydroxyl group is an aralkyl group, and R ⁵ and R ⁶ are tri-lower alkylsilyl groups, the compound (IV) is prepared in an inert solvent in the presence of an acid or a fluoride salt, usually from 0 to
The reaction is carried out at 50 ° C. for 1 to 24 hours to remove the tri-lower alkylsilyl group to obtain a compound of the formula (XIV)

Embedded image Can be converted to the compound represented by Acids that can be used in this reaction include, for example, p-toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, hydrofluoric acid, and the like.
Examples thereof include tetra-n-butylammonium fluoride and pyridine hydrogen fluoride. Acid or fluoride salts are usually
The compound can be appropriately selected from a range of 1 to 5 equivalents to the compound represented by the formula (IV) and used. Inert solvents that can be used in this reaction include ethers such as tetrahydrofuran, ketones such as acetone, methanol,
Examples thereof include alcohols such as isopropanol, acetonitrile, and the like. These inert solvents can be used alone or as a mixture of two or more kinds, and can be used by adding water as needed. After completion of the reaction, the compound represented by the formula (XIV) can be obtained by extraction and concentration by a conventional method. The compound represented by the formula (XIV) can be isolated as an acid addition salt thereof, if necessary. Such an acid addition salt is obtained by dissolving a compound represented by the formula (XIV) in an inert solvent, and adding a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or formic acid, acetic acid, methane, or the like. Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
It can be formed by adding an organic acid such as citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, and oxalic acid. The compound represented by the formula (XIV) may be isolated as an acid addition salt, and if necessary, treated with a base aqueous solution (eg, potassium carbonate aqueous solution) in a water-containing solvent to return to its free form. Can be.

Subsequently, the compound represented by the formula (XIV) is reacted with a metal catalyst (for example, 5 to 5) in an inert solvent under a hydrogen atmosphere.
10% palladium carbon, palladium black, etc.)
Using, usually reacted at 0 to 70 ° C. for 1 to 24 hours,
By removing the aralkyl group, a 3,4-disubstituted phenylethanolaminotetralin carboxylic acid amide derivative represented by the above formula (V) can be produced. Examples of the inert solvent that can be used in this reaction include, for example,
Examples include alcohols such as ethanol. After completion of the reaction, the insolubles are removed and the mixture is concentrated to obtain the desired 3,4-disubstituted phenylethanolaminotetralincarboxylic acid amide derivative (V).
The 3,4-disubstituted phenylethanolaminotetralincarboxylic acid amide derivative represented by the formula (V) can be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. Acid addition salts with organic acids such as sulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, etc. Can be mentioned.

The formula (II) used in the production
The amine derivative represented by I) can be produced by a method described in the literature or a method similar thereto (for example, Eur. J. Med. Chem., 29, 259-
267 (1994); Japanese Patent Publication No. 3-1454
No. 8).

[0022]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The contents of the present invention will be described in more detail with reference examples and examples. The following examples are intended to illustrate the present invention and do not limit the scope of the invention.

[0023]

EXAMPLES Reference Example 1 Methyl 5'-acetyl-2'-hydroxyphenylacetate 136.0 g of 4'-hydroxyacetophenone was suspended in 1000 mL of concentrated hydrochloric acid, and 37% formalin 34 was stirred.
0 mL was added and heated at 50 ° C. for 4 hours. The precipitated crystals were collected by filtration and washed with water to obtain 203.2 g of 3'-chloromethyl-4'-hydroxyacetophenone as red crystals. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.50
(3H, s), 4.75 (2H, s), 6.97 (1
H, d, J = 8.4 Hz), 7.84 (1H, d, J =
8.4 Hz), 7.99 (1H, s), 10.89 (1
H, s).

A mixture of 98.0 g of sodium cyanide and 500 mL of dimethyl sulfoxide was stirred at 60 ° C. for 30 minutes. Under stirring at 60 ° C., 3′-chloromethyl-4′-
203.2 g of hydroxyacetophenone was added over 1 hour. After stirring for an additional hour, sodium hydroxide 14
Add a solution of 0.0 g of water (500 mL), and add
Heated to reflux for an hour. After allowing to cool to room temperature, 2500 mL of water and 500 mL of toluene were added, and the mixture was separated. The aqueous layer was adjusted to pH 3 by adding 400 mL of concentrated hydrochloric acid, and ethyl acetate 10
Extracted three times with 00 mL. Combine organic layers and water 1000
Washed with mL and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, 100 mL of ethyl acetate was added to the residue, and 300 mL of toluene was slowly added dropwise at 50 ° C. while heating and stirring. The obtained crystals were collected by filtration to obtain 97.6 g of 5'-acetyl-2'-hydroxyphenylacetic acid. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.47
(3H, s), 3.55 (2H, s), 6.89 (1
H, d, J = 8.4 Hz), 7.75 (1H, dd, J)
= 2.0, 8.4 Hz), 7.78 (1H, d, J =
2.0 Hz), 10.18 to 10.75 (1H, b
r), 11.81-12.49 (1H, br).

4.9 g of concentrated sulfuric acid was added to a mixture of 97.6 g of 5'-acetyl-2'-hydroxyphenylacetic acid and 200 mL of methanol with stirring, and the mixture was heated under reflux for 1 hour.
A solution of 8.1 g of sodium hydrogen carbonate in water (200 mL) was added, and the mixture was allowed to cool to room temperature with stirring. The precipitated crystals were collected by filtration, washed with methanol-water, dried under reduced pressure, and 5'-acetyl-
90.9 g of methyl 2'-hydroxyphenylacetate was obtained. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.47
(3H, s), 3.60 (3H, s), 3.64 (2
H, s), 6.90 (1H, d, J = 8.4 Hz),
7.77 (1H, dd, J = 2.2, 8.4 Hz),
7.80 (1H, d, J = 2.2 Hz), 10.52
(1H, s).

Reference Example 2 2-[(2S) -2-amino-1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide hydrochloride dihydrate ( 2S) -2-Amino-7-methoxy-1,2,3,4
-10.0 g of tetrahydronaphthalene hydrochloride in 40
The suspension was dissolved in 2.3 g of sodium hydroxide and extracted twice with 20 mL of toluene. The toluene layer was washed with 10 mL of water and concentrated under reduced pressure. 4 in the resulting oil
27 mL of 8% hydrobromic acid was added, and the mixture was heated under reflux at 140 ° C. for 4 hours. After concentration under reduced pressure, the obtained crude crystals were recrystallized from isopropanol to give (2S) -2-amino-7-hydroxy-1,2,3,4-tetrahydronaphthalene / hydrobromide (11.3 g) as white crystals. As obtained. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.65
1.75 (1H, m), 2.04 to 2.11 (1H,
m), 2.67 to 2.78 (3H, m), 2.97 (1
H, dd, J = 4.7, 16.4 Hz), 3.38-
3.45 (1H, m), 6.50 (1H, d, J = 2.
6Hz), 6.57 (1H, dd, J = 2.6, 8.4)
Hz), 6.89 (1H, d, J = 8.4 Hz), 8.
01 (3H, brs), 9.13 (1H, s) Specific rotation: [α] _D ²⁸ = -61.4． (c = 1.0, M
OH).

(2S) -2-amino-7-hydroxy-
11.3 g of 1,2,3,4-tetrahydronaphthalene / hydrobromide in 70 mL of N, N-dimethylformamide
And triethylamine 32 mL with stirring at room temperature.
Was added dropwise over 5 minutes. Under water-cooled stirring, di-carbonate
A solution of 11.1 g of t-butyl in N, N-dimethylformamide (30 mL) was added dropwise over 10 minutes. After stirring overnight at room temperature, 200 mL of water was added to the reaction solution, and the mixture was extracted twice with 100 mL of ethyl acetate.
The extract was washed sequentially with citric acid, water (100 mL each) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure to obtain 12.4 g of (2S) -2-tert-butyloxycarbonylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene as an oil. ¹ H-NMR (CDCl 3) δ ppm: 1.46 (9
H, s), 1.66 to 1.75 (1H, m), 1.98.
~ 2.06 (1H, m), 2.55 (1H, dd, J =
8.2, 16.3 Hz), 2.77 (2H, t, J =
6.5 Hz), 3.03 (1H, dd, J = 3.8, 1
6.3 Hz), 3.86 to 4.00 (1H, br),
4.52 to 4.68 (1H, br), 5.13 to 5.2
8 (1H, br), 6.53 (1H, d, J = 2.6H)
z), 6.62 (1H, dd, J = 2.6, 8.4H
z), 6.93 (1H, d, J = 8.4 Hz) Specific rotation: [α] _D ²⁶ = −67.8 ゜ (c = 1.0, M
OH).

(2S) -2-tert-butyloxycarbonylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene 12.4 g, potassium iodide 8.
5 g was suspended in 50 mL of tetrahydrofuran, and a solution of 3.9 g of sodium hydroxide in water (20 mL) was added. Under stirring at room temperature, a solution of 6.2 g of 2-chloro-N, N-dimethylacetamide in tetrahydrofuran (10 mL) was added, and the mixture was stirred for 30 minutes. Further, 1.7 g of 2-chloro-N, N-dimethylacetamide was added, and the mixture was stirred for 1 hour.
Ethyl acetate (200 mL) was added to the reaction solution, and the mixture was washed successively with water (100 mL) and saturated saline (50 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, crystallized from ethyl acetate-hexane, and 12.3 g of 2-{[(2S) -2-
tert-butyloxycarbonylamino-1,2,2
3,4-tetrahydronaphthalen-7-yl] oxy}
-N, N-dimethylacetamide was obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.45 (9
H, s), 1.68 to 1.75 (1H, m), 2.00
~ 2.07 (1H, m), 2.59 (1H, dd, J =
8.2, 16.3 Hz), 2.80 (2H, t, J =
6.4 Hz), 2.97 (3H, s), 3.05-3.0.
11 (4H, m), 3.89 to 4.01 (1H, b
r), 4.51-4.62 (1H, br), 4.64
(2H, s), 6.64 (1H, d, J = 2.6H
z), 6.75 (1H, dd, J = 2.6, 8.3H
z), 7.00 (1H, d, J = 8.3 Hz) Specific rotation: [α] _D ²⁷ = −60.8 ゜ (c = 1.0, M
OH).

12.29 g of 2-{[(2S) -2-tert-butyloxycarbonylamino-1,2,3,4-tetrahydronaphthalen-7-yl] oxy} -N, N-dimethylacetamide is added to 50 mL of isopropanol.
And 17.5 mL of concentrated hydrochloric acid was added thereto with stirring at room temperature, followed by stirring overnight. The precipitated crystals were collected by filtration, washed with 12.3 mL of isopropanol, and dried under reduced pressure to give 2-[(2S)-
2-amino-1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide
7.94 g of the hydrochloride dihydrate was obtained as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.70-
1.81 (1H, m), 2.10 to 2.18 (1H,
m), 2.68 to 2.87 (6H, m), 2.99 (3
H, s), 3.06 (1H, dd, J = 4.7, 16.
1 Hz), 3.37 to 3.50 (5H, m), 4.74
(2H, s), 6.68 (1H, s), 6.71 (1
H, d, J = 8.4 Hz), 6.99 (1H, d, J =
8.4 Hz), 8.47 (3H, br) Specific rotation: [α] _D ²⁹ = −45.4 ゜ (c = 1.0, M
OH).

Example 1 Methyl (1R) -1- [4-benzyloxy-3- (2-hydroxyethyl) phenyl] -2-bromoethanol 5'-acetyl-2'-hydroxyphenylacetate 9
0.9 g, benzyl chloride 58.0 g, potassium iodide 7.3 g was added to N, N-dimethylformamide 150 mL
And 63.4 g of potassium carbonate was added with stirring at room temperature, followed by stirring at 50 ° C. for 1.5 hours. Water 600
mL was added, and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were recrystallized from ethyl acetate-hexane to give methyl 5'-acetyl-2'-benzyloxyphenylacetate.
01.4 g were obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 2.53 (3
H, s), 3.63 (3H, s), 3.70 (2H,
s), 5.14 (2H, s), 6.95 (1H, d, J
= 8.6 Hz), 7.30 to 7.40 (5H, m),
7.84 (1H, d, J = 2.2 Hz), 7.88 (1
H, dd, J = 2.2, 8.6 Hz,).

32.8 g of methyl 5'-acetyl-2'-benzyloxyphenylacetate was dissolved in 160 mL of ethyl acetate, and stirred at room temperature with 6.2 mL of bromine in hexane (1 mL).
5 mL) solution was added dropwise over 20 minutes. 30 minutes later, water 1
00 mL was carefully added. After liquid separation, the ethyl acetate layer was washed with 50 mL of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give methyl 5'-bromoacetyl-2'-benzyloxyphenylacetate.
9 g were obtained. ¹ H-NMR (CDCl ₃ ) δ ppm: 3.64 (3
H, s), 3.71 (2H, s), 4.39 (2H,
s), 5.17 (2H, s), 6.98 (1H, d, J
= 8.6 Hz), 7.30 to 7.42 (5H, m),
7.88 (1H, d, J = 2.3 Hz), 7.92 (1
H, dd, J = 2.3, 8.6 Hz).

(2R) -α, α-diphenyl-2-pyrrolidine Methanol (76 mg) in tetrahydrofuran (3 mL)
, And 59 mg of aluminum triethoxide was added with stirring at room temperature, and the mixture was stirred for 1 hour. 0.6 mL of borane dimethyl sulfide (10M) was added, and while stirring at room temperature, 1.132 g of methyl 5′-bromoacetyl-2′-benzyloxyphenylacetate was added to tetrahydrofuran (6 m
L) The solution was added dropwise at an internal temperature of 25 ° C or lower. After confirming the disappearance of the raw materials, the mixture was heated to an internal temperature of 50 ° C. and further stirred for 2 hours. After confirming the completion of the reaction, the temperature was returned to room temperature, and 1 mL of methanol was carefully added. After the bubbling subsides, the solvent is distilled off under reduced pressure.
Ethyl acetate 10 mL and 1 mol / L hydrochloric acid 3 m were added to the residue.
L was added. After separating the organic layer, the aqueous layer was further extracted with 10 mL of ethyl acetate. The organic layers were combined, washed with 5 mL of water and 5 mL of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-hexane to give (1R) -1- [4-benzyloxy-3- (2-hydroxyethyl) phenyl].
0.910 g of -2-bromoethanol was obtained as white crystals. Optical purity: 99.9% e. e. (HPLC analysis value) Melting point: 86-87 ° C IR (KBr): 3249, 1568, 1448, 12
^{53cm -1 1 H-NMR (CDCl} 3) δ ppm: 1.85 (1
H, s), 2.89 to 2.95 (3H, m), 3.51.
(1H, dd, J = 8.9, 10.4 Hz), 3.57
(1H, dd, J = 3.6, 10.4 Hz), 3.80
To 3.87 (2H, m), 4.79 to 4.84 (1H,
m), 5.07 (2H, s), 6.90 (1H, d, J
= 8.1 Hz), 7.15 to 7.20 (2H, m),
7.29 to 7.42 (5H, m) Specific rotation: [α] _D ²⁹ = -17.6 ° (c = 1.0, M
OH).

Example 2 (1R) -1- [4-benzyloxy-3- (2-te)
rt-butyldimethylsilyloxyethyl) phenyl]
-2-Bromo-1-tert-butyldimethylsilyloxyethane (1R) -1- [4-benzyloxy-3- (2-hydroxyethyl) phenyl] -2-bromoethanol 3
0.00 g and 29.07 g of imidazole are dissolved in 100 mL of N, N-dimethylformamide, and the mixture is stirred under ice-cooling and stirred.
A solution of 32.18 g of tert-butyldimethylchlorosilane in toluene (32 mL) was added dropwise. After stirring at room temperature for 6 hours, 2.57 g of tert-butyldimethylchlorosilane
Of toluene (2.5 mL) was added, and the mixture was further stirred for 2 hours. 100 mL of water was added to the reaction solution, and ethyl acetate 10
Extracted twice with 0 mL. Combine the organic layers and add 100 mL of water
And twice with 50 mL of saturated saline. Dry over anhydrous magnesium sulfate and concentrate under reduced pressure to give (1R) -1-
[4-benzyloxy-3- (2-tert-butyldimethylsilyloxyethyl) phenyl] -2-bromo-
1-tert-butyldimethylsilyloxyethane 5
8.2 g were obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ ppm: -0.09 (3
H, s), -0.04 (6H, s), 0.10 (3H,
s), 0.85 (9H, s), 0.89 (9H, s),
2.90 (2H, t, J = 7.3 Hz), 3.35-
3.46 (2H, m), 3.80 (2H, t, J = 7.
3 Hz), 4.78 (1H, dd, J = 4.4, 7.9)
Hz), 5.05 (2H, s), 6.86 (1H, d,
J = 8.3 Hz), 7.12 to 7.15 (2H, m),
7.32 to 7.44 (5H, m) Specific rotation: [α] _D ³¹ = −33.0 ° (c = 1.0, M
OH).

Example 3 2-[(2S) -2-({(2R) -2- [4-benzyloxy-3- (2-tert-butyldimethylsilyloxyethyl) phenyl] -2-tert] -Butyldimethylsilyloxyethyl @ amino) -1,2,3,4-
Tetrahydronaphthalen-7-yloxy] -N, N-
Dimethylacetamide (1R) -1- [4-benzyloxy-3- (2-te
rt-butyldimethylsilyloxyethyl) phenyl]
-2-bromo-1-tert-butyldimethylsilyloxyethane 58.2 g, 2-[(2S) -2-amino-
1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide hydrochloride dihydrate (30.2 g) and potassium carbonate (18.9 g) are suspended in N, N-dimethylacetamide (85 mL). After introducing argon gas at room temperature for 10 minutes, the mixture was heated at 120 ° C. in an argon atmosphere.
For 6 hours. After returning to room temperature, water 200
mL was added, and the mixture was extracted twice with 200 mL of ethyl acetate. The organic layers were combined, and twice with 100 mL of water, 100 mL of saturated saline.
Washed sequentially with mL. After drying over anhydrous magnesium sulfate,
After concentration under reduced pressure, 2-[(2S) -2-(− ２ (2R) -2
-[4-Benzyloxy-3- (2-tert-butyldimethylsilyloxyethyl) phenyl] -2-ter
t-butyldimethylsilyloxyethyl @ amino)-
1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide (68.6 g) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ ppm: -0.16 (3
H, s), -0.04 (6H, s), 0.03 (3H,
s), 0.85 (9H, s), 0.88 (9H, s),
1.49 to 1.59 (1H, m), 1,63 to 1.75
(2H, m), 1.99 to 2.02 (1H, s), 2.
52 to 2.96 (9H, m), 2.97 (3H, s),
3.08 (3H, s), 3.81 (2H, t, J = 7.
4 Hz), 4.64 (2H, s), 4.75 (1H, d
d, J = 4.2, 8.2 Hz), 5.05 (2H,
s), 6.66 (1H, d, J = 2.6 Hz), 6.7.
3 (1H, dd, J = 2.6, 8.4 Hz), 6.85
(1H, d, J = 8.3 Hz), 6.98 (1H, d,
J = 8.4 Hz), 7.12 (1H, dd, J = 2.
1,8.3 Hz), 7.15 (1H, d, J = 2.1H)
z), 7.32 to 7.44 (5H, m) Specific rotation: [α] _D ³¹ = −56.9 ° (c = 0.7, M
OH).

Example 4 2-[(2S) -2-({(2R) -2- [4-benzyloxy-3- (2-hydroxyethyl) phenyl]-
2-hydroxyethyl {amino) -1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide oxalate monohydrate 2-[(2S) -2-({ (2R) -2- [4-benzyloxy-3- (2-tert-butyldimethylsilyloxyethyl) phenyl] -2-tert-butyldimethylsilyloxyethyl @ amino) -1,2,3,4-
Tetrahydronaphthalen-7-yloxy] -N, N-
Dissolve 68.6 g of dimethylacetamide in 480 mL of tetrahydrofuran and 24 mL of water, and stir at room temperature under stirring.
-48.7 g of toluenesulfonic acid monohydrate was added, and the mixture was stirred overnight. Potassium carbonate 38.9g water (300mL)
The solution was added and extracted with 300 mL of ethyl acetate and 300 mL of 10% ethanol-ethyl acetate. The organic layers were combined, washed with a solution of potassium carbonate (11.8 g) in water (200 mL), and 10% saline (200 ml), and then concentrated under reduced pressure. Dissolve the obtained oil in 120 mL of ethanol,
Under stirring at 50 ° C., a solution of 10.7 g of oxalic acid dihydrate in ethanol (95 mL) was added. After crystallization, 430 mL of toluene was added at room temperature, and the mixture was stirred for 3 hours, and then allowed to stand overnight. The precipitated crystals were collected by filtration, dried, and dried at 2-[(2S)-
2-({(2R) -2- [4-benzyloxy-3-
36. (2-Hydroxyethyl) phenyl] -2-hydroxyethyl {amino) -1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide oxalate monohydrate 7 g were obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.71 to 1.
87 (1H, m), 2.21 to 2.31 (1H, m),
2.61 to 3.25 (14H, m), 3.39 to 3.5
0 (1H, m), 3.61 (2H, t, J = 7.3H
z), 4.73 (2H, s), 4.92 (1H, d, J
= 9.1 Hz), 5.13 (2H, s), 6.66 (1
H, s), 6.70 (1H, d, J = 8.4 Hz),
6.99 (1H, d, J = 8.5 Hz), 7.03 (1
H, d, J = 8.4 Hz), 7.22 (1H, d, J =
8.5 Hz), 7.25 (1 H, s), 7.34 (1
H, t, J = 7.2 Hz), 7.38 to 7.45 (4
H, m) Specific rotation: [α] _D ²⁹ = -67.8． (c = 1.0, M
OH).

Example 5 2-[(2S) -2-({(2R) -2- [4-hydroxy-3- (2-hydroxyethyl) phenyl] -2-]
(Hydroxyethyl {amino) -1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide.0.5 sulfate A solution of 24.3 g of potassium carbonate in water (200 mL) and ethanol containing 10% -In a mixture of 200 mL of ethyl acetate,
Under stirring at 40 ° C., 2-[(2S) -2-(｛(2R)-
2- [4-benzyloxy-3- (2-hydroxyethyl) phenyl] -2-hydroxyethyl {amino)-
1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide oxalate
36.7 g of monohydrate was added and stirred for 1 hour. After separating the organic layer, the aqueous layer was diluted with 10% ethanol-ethyl acetate 100%.
Extracted twice with mL. Combine the organic layers and add 50
Washed with mL and concentrated under reduced pressure. The obtained oil was dissolved in 150 mL of ethanol, and 3.7 g of 10% palladium carbon (50% water-containing product) was added.
Stirred at C for 8 hours. The palladium carbon was filtered and concentrated under reduced pressure. Dissolve the residue in 100 mL of ethanol,
Stir at room temperature. After crystallization, 50 mL of hexane was added and the mixture was stirred overnight. The precipitated crystals were collected by filtration and dried under reduced pressure.
The obtained crystals were dissolved in 130 mL of methanol,
26.0 mL of a 2 mol / L sulfuric acid aqueous solution was added under stirring. The mixture was allowed to cool to room temperature and stirred overnight. The precipitated crystals were collected by filtration, dried under reduced pressure, and dried at 2-[(2S) -2-(｛(2R)
-2-hydroxy-2- [4-hydroxy-3- (2-
Hydroxyethyl) phenyl] ethyl @ amino) -1,
2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide.0.5 sulfate 2
1.47 g were obtained as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.55
1.75 (1H, m), 2.05 to 2.15 (1H,
m), 2.60-3.25 (15H, m), 3.56
(2H, t, J = 7.3 Hz), 4.60 to 4.80
(3H, m), 6.62 (1H, d, J = 2.6H
z), 6.67 (1H, dd, J = 2.6, 8.4H
z), 6.75 (1H, d, J = 8.2 Hz), 6.9
6 (1H, d, J = 8.4 Hz), 7.03 (1H, d
d, J = 2.1, 8.2 Hz), 7.09 (1H, d,
J = 2.1 Hz), 9.25 (1H, brs) Specific rotation: [α] _D ²⁵ = −70.8 ゜ (c = 1.0, H ₂
O).

[0037]

The optically active halohydrin derivative represented by the formula (II) of the present invention is converted to a compound of the formula (V)
3,4-disubstituted phenylethanolaminotetralin carboxylic acid amide derivative or a pharmacologically acceptable salt thereof can be produced in a simple and high yield, and the halohydrin derivative is an imminent flow / premature birth inhibitor, It is useful as a production intermediate for bronchodilators, urolithiasis pain relievers and lithotriptors.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme Court ゛ (Reference) C07M 7:00 C07M 7:00 (72) Inventor Takehiro Ishikawa 1158-1 Heights Toyoshina, Toyoshina-cho, Minamiazumi-gun, Nagano Prefecture Jennen B-102 (72) Inventor Toshihiro Nishimura 4511 F-term Kashiwabara, Hodaka-cho, Minamiazumi-gun, Nagano Pref.

Claims (7)

[Claims] 1. A compound of the formula (I) (Wherein, R ¹ is a protecting group for a hydroxyl group, R ² and R ³ are each independently a hydrogen atom or a protecting group for a hydroxyl group, and X is a halogen). Wherein R ¹ is an aralkyl group, R ² and R
The compound according to claim 1, wherein ³ is a hydrogen atom. 3. R ¹ is an aralkyl group, R ² and R
The compound according to claim 1, wherein ³ is a tri-lower alkylsilyl group. 4. The compound according to claim 1, wherein R ¹ is benzyl, R ² and R ³ are hydrogen atoms, and X is a bromine atom. 5. The compound according to claim 1, wherein R ¹ is benzyl, R ² and R ³ are tert-butyldimethylsilyl, and X is a bromine atom. 6. A compound of the formula (II) Wherein R ⁴ , R ⁵ and R ⁶ are the same or different, and may be the same or different protecting groups for a hydroxyl group, and X is a halogen, and a compound represented by the formula (III): By reacting with an amine of the formula (IV) Wherein the protecting groups R ⁴ , R ⁵ and R ⁶ of the compound of formula (IV) are deprotected and then, if necessary, a pharmacologically acceptable salt is formed Wherein the formula (V) is A method for producing a 3,4-disubstituted phenylethanolaminotetralincarboxylic acid amide derivative represented by the formula: or a pharmaceutically acceptable salt thereof. 7. R ⁴ is an aralkyl group, R ⁵ and R
^The method according to claim 6, wherein ⁶ is a tri-lower alkylsilyl group.