JPH11310556A - Novel process for producing 2-amino-2-(2-(4octylphenyl) ethyl) propane-1,3-diol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel production process for 2-amino-2-[2-(4octylphenyl) ethyl]propane-1,3-diol that is useful as an immunosuppressant agent. SOLUTION: The 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol can produced by reacting diethyl acetamidemalonate with a (2-haloethyl)benzene to form 2-acetamide-2-phenyl-ethyl malonate, after reduction, acetyulating it, further introducing an octyanoyl group to give 2-acetamide-2-acetoxymethyl-4-(4 octanoylphenyl)butyl acetate followed by hydrolysis and reduction of the product, as the intermediates in the individual steps can be crystallized and the production steps can be shortened.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 2-amino-2- [2- (4-octylphenyl) useful as an immunosuppressant.
Ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof and a method for producing an intermediate thereof.

[0002]

2. Description of the Related Art 2-Amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof is disclosed, for example, in International Publication W.
O94 / 08943 describes that it is useful as an inhibitor of rejection in organ or bone marrow transplantation and as a therapeutic agent for various autoimmune diseases such as psoriasis and Behcet's disease and rheumatic diseases. The publication discloses 2-amino-2- [2- (4-octylphenyl)
As the method for producing [ethyl] propane-1,3-diol or a salt thereof, the following two methods are described in which phenethyl acetate is used as a starting compound to produce the compound in a total of eight steps.

[0003]

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(In the formula, Ac represents acetyl, Me represents methyl, and Et represents ethyl.) Among the intermediates in the above production method, 2- (4-octanoylphenyl) ethyl acetate, 2- (4- Octylphenyl) ethyl acetate, 2- (4-octylphenyl) ethanol, 2- (4-octylphenyl) ethyl methanesulfonate and 2- (4-
Octylphenyl) ethyl is described as an oil. Further, the publication discloses 2-amino-2- [2
-(4-octanoylphenyl) ethyl] propane-
1,3-diol is described as an exemplary compound.

On the other hand, the Journal of American Chemical Society (J. Am. Chem. So
c. 76, 1909, 1954 and Journal of Chemical Society (J. Chem. So
c. P. 890, 1955 describes a method for producing diethyl 2-phenylethylacetamide malonate by condensing phenethyl bromide and diethyl acetamide malonate in the presence of a base.

[0006] WO 96/06068 describes a production method represented by the following formula using a Friedel-Crafts reaction.

[0007]

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[0008]

[Problems to be Solved by the Invention] International Publication WO94 / 0
2-amino-2- [2-
(4-octylphenyl) ethyl] propane-1,3-
In a method for producing a diol or a pharmaceutically acceptable acid addition salt thereof, in addition to a long number of production steps, purification by recrystallization is difficult due to a large number of intermediates which are liquid at room temperature. Not preferred. Therefore, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a salt thereof can be produced in fewer steps, and furthermore, room temperature at which purification by recrystallization is possible. And to provide an industrially advantageous production method via an intermediate which is a solid.

[0009]

That is, the present invention relates to a method of reacting diethyl acetamide malonate with (2-haloethyl) benzene in the presence of a basic compound to obtain diethyl acetamide malonate.
Step A for preparing 2-acetamido-2-phenylethylmalonate, reduction of diethyl 2-acetamido-2-phenylethylmalonate, and further acetylation to give 2-acetamido-2-acetoxymethyl-4-phenylbutyl
Step B to be acetate, 2-acetamido-2-acetoxymethyl-4-phenylbutyl An octanoyl group is introduced at the para-position of the phenyl group of acetate to give 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl). ) Step C to be butyl acetate, 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate is reduced to give 2-acetamido-2-acetoxymethyl-4- (4-octylphenyl) butyl Step D to be acetate, 2-acetamide-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate is hydrolyzed to give 2-amino-2-
[2- (4-octylphenyl) ethyl] propane-
Step E of preparing 1,3-diol or a pharmaceutically acceptable salt thereof, 2-acetamido-2-acetoxymethyl-4-
Step F of hydrolyzing (4-octanoylphenyl) butyl acetate to give 2-amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol, and 2-amino-2 -[2- (4-octanoylphenyl) ethyl] propane-1,3-diol is reduced to give 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a mixture thereof. 2-Amino-consisting of Step G to make a pharmaceutically acceptable salt
The present invention relates to a method for producing 2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof.

[0010] Further, as a method for producing 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof, the above-mentioned production steps are followed. -Acetamide-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate is hydrolyzed to give 2-acetamido-2- [2- (4-
Step H to give octanoylphenyl) ethyl] propane-1,3-diol H, 2-acetamide-2- [2- (4
-Octanoylphenyl) ethyl] propane-1,3-
The diol is reduced to give 2-acetamido-2- [2- (4-
Step I to give [octylphenyl) ethyl] propane-1,3-diol, 2-acetamide-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol is hydrolyzed to give 2-amino- Step J of 2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof, and 2-acetamido-2-acetoxymethyl-4- (4-octylphenyl) ) Step K) of hydrolyzing butyl acetate to give 2-acetamido-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol, and these steps are also included in the present invention. Is done. The production method of the present invention is as follows.

[0011]

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[0012]

DETAILED DESCRIPTION OF THE INVENTION The pharmaceutically acceptable salts of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol include hydrochloride, hydrobromide, Salts with inorganic acids such as sulfate, or salts with organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate, benzenesulfonate And preferably a hydrochloride.

Process A is for Journal of American
Chemical Society (J. Am. Chem. So
c. 76, 1909, 1954, and the Journal of Chemical Society (J. Chem. S.).
oc. ) Page 890, 1955. As the basic compound used in the reaction, sodium hydride, potassium tertiary butoxy, lithium diisopropylamide and the like can be used in addition to sodium or sodium ethoxide. As the reaction solvent,
In addition to ethanol, tertiary butyl alcohol, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane, dioxane, toluene, or a mixed solvent thereof can be used. it can.

In the reduction reaction of the ester in the step B, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium sodium bis (2-methoxyethoxy) aluminum, borane, diisopropylaluminum hydride, etc. are used as a reducing agent. be able to. Reaction solvents include methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol, diethyl ether, tetrahydrofuran, dimethoxyethane,
2-methoxyethyl ether, dioxane, toluene and the like or a mixed solvent thereof can be used. The reaction temperature of this reaction varies depending on the reagent used, but is from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction conditions, but is usually 1 to 24 hours.

As the acetylating reagent in the step B,
Acetic anhydride or acetyl halides such as acetyl chloride and acetyl bromide can be used. As the reaction solvent,
Any solvent may be used as long as it is an inert solvent in the reaction. Among them, pyridine, dichloromethane, chloroform, tetrahydrofuran, dioxane, toluene, acetonitrile, N, N-dimethylformamide, ethyl acetate and the like or a mixed solvent thereof are preferable. Further, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine and the like can be used as a catalyst, and it is preferable to carry out the reaction using these catalysts. The reaction temperature of this reaction depends on the reagent used, but is from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction conditions, but is usually 1 to 24.
Time.

In the Friedel-Crafts reaction of step C, examples of the reagent for introducing an octanoyl group include octanoyl halides such as octanoyl chloride and octanoyl bromide, and octanoic anhydride, with octanoyl halide being preferred. Examples of the acid catalyst used in the reaction include Lewis acids such as anhydrous aluminum trichloride, anhydrous aluminum tribromide, anhydrous zinc chloride, anhydrous ferric chloride, anhydrous titanium tetrachloride, and boron trifluoride. As the solvent used,
Any solvent may be used as long as it is an inert solvent in the reaction, and among them, 1,2-dichloroethane, dichloromethane, chloroform and the like are preferable. The reaction temperature of this reaction varies depending on the acid catalyst used and the reagent for introducing the octanoyl group,
It is the boiling point of the solvent used from -20 ° C. The reaction time varies depending on the reaction conditions, but is usually 1 to 24 hours.

The reduction reaction of the ketone in the step D includes known reduction methods in the field of synthetic organic chemistry, such as Clementen reduction using a metal under acidic conditions, Birch reduction in an amine solution, reduction with hydrosilane or catalytic reduction. The catalytic reduction method is particularly preferred. The catalytic reduction reaction is carried out by using hydrogen and a palladium catalyst (such as palladium or palladium carbon) or platinum as a catalyst, or by using Raney nickel. Among them, it is preferable to use a palladium catalyst in the presence of hydrogen. Any solvent may be used as long as it is an inert solvent in the reaction, but methanol, ethanol, isopropyl alcohol, ethyl acetate, acetic acid, tetrahydrofuran, dioxane, toluene and the like or a mixed solvent thereof is preferable. The reaction can be accelerated by adding an acid such as hydrochloric acid or acetic acid. The reaction temperature of this reaction varies depending on the catalyst used, but is from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction conditions, but is usually 1-2.
4 hours.

The hydrolysis of the acetyl group in step E can be carried out in the presence of a base or an acid. When the reaction is performed in the presence of a base, the base used is preferably sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, or the like, and the solvent used is any solvent that is inert in the reaction. Among them, water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane and the like or a mixed solvent thereof is preferable. When the reaction is performed in the presence of an acid, examples of the acid used include hydrochloric acid, sulfuric acid, and acetic acid. Among them, hydrochloric acid is preferable, and any solvent may be used as long as it is an inert solvent in the reaction. Among them, water, methanol, ethanol, isopropyl alcohol and the like or a mixed solvent thereof is preferable. The reaction temperature is preferably from 50 ° C. to the boiling point of the solvent. The reaction time varies depending on the reaction conditions, but is usually 1 to 24 hours.

The reagents, solvents and reaction conditions in step F are the same as in step E. Examples of the reduction reaction of the ketone in the step G include a known reduction method in the field of synthetic organic chemistry, for example, Clementen reduction using a metal under acidic conditions, Borfkishner reduction using hydrazine under basic conditions, Birch reduction in an amine solution. Performed by reduction with hydrosilane or catalytic reduction,
Among them, the method of catalytic reduction is preferred. The catalytic reduction reaction is carried out by using hydrogen and a palladium catalyst (such as palladium or palladium carbon) or platinum as a catalyst, or by using Raney nickel. Among them, it is preferable to use a palladium catalyst in the presence of hydrogen. The solvent used may be any solvent as long as it is an inert solvent in the reaction, but water, methanol, ethanol,
Isopropyl alcohol, acetic acid, tetrahydrofuran,
Dioxane or the like or a mixed solvent thereof is preferable. The reaction can be accelerated by adding an acid such as hydrochloric acid or acetic acid, and when hydrochloric acid is added, the desired product can be obtained as a hydrochloride. The reaction temperature of this reaction varies depending on the catalyst used, but is from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction conditions, but is usually 1-2.
4 hours.

The hydrolysis of the ester bond in the step H can be carried out in the presence of a base. As the base to be used, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, ammonia and the like are preferable. As the solvent to be used, any solvent may be used as long as it is an inert solvent in the reaction. , Ethanol, isopropyl alcohol, tetrahydrofuran, dioxane, acetone, acetonitrile and the like or a mixed solvent thereof is preferred. The reaction temperature is preferably from room temperature to 50 ° C. The reaction time varies depending on the reaction conditions.
~ 24 hours.

The reduction reaction of the ketone in the step I includes a reduction reaction usually used in the field of synthetic organic chemistry, for example, a Kremensen reduction using a metal under acidic conditions,
It is carried out by a Borfkishner reduction using hydrazine under basic conditions, a birch reduction in an amine solution, a reduction with hydrosilane or a catalytic reduction, and among them, a method of catalytic reduction, Clementen reduction or reduction with hydrosilane is preferred. The catalytic reduction reaction is carried out by using hydrogen and a palladium-based catalyst (palladium, palladium-carbon, etc.) or platinum as a catalyst, or by using Raney nickel. Among them, it is preferable to use a palladium-based catalyst in the presence of hydrogen. The solvent used in this reaction may be any solvent as long as it is an inert solvent in the reaction, but water, methanol, ethanol, isopropyl alcohol, acetic acid, tetrahydrofuran, dioxane and the like or a mixed solvent thereof are preferable. The reaction can be accelerated by adding an acid such as hydrochloric acid or acetic acid. The reaction temperature of this reaction varies depending on the catalyst used, but is from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction conditions, but is usually 1 to 24 hours. As a reagent for Clementen reduction, it is preferable to use zinc or zinc amalgam as a metal and to use hydrochloric acid or acetic acid as an acid. As a solvent for this reaction, water,
Methanol, ethanol, isopropyl alcohol, acetic acid, tetrahydrofuran, dioxane and the like, or a mixed solvent thereof can be used. The reaction temperature of this reaction is
Although it depends on the reagent used, the boiling point of the solvent used is from -20 ° C. The reaction time varies depending on the reaction conditions, but is usually 1 to 24 hours. The reduction reaction with hydrosilane is
Triethylsilane is preferred as the reagent. This reaction is carried out under acidic conditions, and a mineral acid, trifluoroacetic acid or a Lewis acid such as boron trifluoride is used, among which trifluoroacetic acid is preferred. The reaction temperature of this reaction depends on the reagent used, but is from -20 ° C to the boiling point of the solvent used. The reaction time varies depending on the reaction conditions.
24 hours.

The reagent, solvent and reaction temperature for the hydrolysis reaction of the amide bond in step J are the same as those in step E. The reagent, solvent and reaction temperature for the ester bond hydrolysis reaction in Step K are the same as those in Step H. 2-amino-2- produced by the production method of the present invention
[2- (4-octylphenyl) ethyl] propane-
1,3-diol may be used in a suitable solvent (methanol, ethanol, diethyl ether, dioxane, etc.) as necessary.
Medium, treated with acid (inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or organic acid such as acetic acid, fumaric acid, maleic acid, benzoic acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid, etc.) Thereby, an acid addition salt can be obtained.

The target product obtained by each reaction in the above steps can be isolated and purified by appropriately combining ordinary means such as centrifugation, concentration, liquid separation, washing, drying, recrystallization and distillation. 2-Amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof produced by the production method of the present invention exhibits excellent immunosuppressive activity. Suppression of rejection after organ or bone marrow transplantation and maintenance immunotherapy, or rheumatic diseases such as rheumatoid arthritis, eye diseases such as Behcet's disease or uveitis, psoriasis, atopic dermatitis, contact dermatitis and allergic It can be used for the prevention or treatment of various autoimmune diseases or allergic diseases including dermatitis such as dermatitis.

[0024]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. Examples Step A: Diethyl 2-acetamide-2- (2-phenylethyl) malonate Disperse sodium hydride (12.0 g) in N, N-dimethylformamide (50 ml) and add thereto N, N-dimethylformamide (200 ml), diethyl acetamide malonate (66.2 g) was added dropwise at 5 ° C. with stirring over 2 hours. After stirring at room temperature for 2 hours, phenethyl bromide (44.4 g) dissolved in N, N-dimethylformamide (40 ml) was added dropwise to the mixture at room temperature over 30 minutes. After stirring for 12 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexane-ethyl acetate as an eluent to give diethyl 2-acetamide-2- (2-phenylethyl) malonate (36 g) as colorless crystals. Mp 115-117 ℃ IR (KBr): 3236,1745,1635cm -1 1 H-NMR (CDCl 3): 1.22 (6H, t, J
= 7.3 Hz), 1.96 (3H, s), 2.44-
2.48 (2H, m), 2.65-2.69 (2H,
m), 4.17 (2H, q, J = 7.3 Hz), 4.1
9 (2H, q, J = 7.3 Hz), 6.74 (1H, b
r. s), 7.11-7.26 (5H, m) MS m / e: 321 Step B: 2-acetamido-2-acetoxymethyl-4-
Lithium aluminum hydride (3.78 g) was suspended in phenylbutyl acetate tetrahydrofuran (200 ml), and diethyl 2-acetamido-2- (2-phenylethyl) malonate (16.0) dissolved in tetrahydrofuran (100 ml).
g) was added dropwise at 5 ° C. over 1 hour with stirring. 3 at room temperature
After stirring for an hour, a saturated sodium sulfate solution was added to the mixture, and the suspension was filtered. The filtrate was concentrated under reduced pressure, and pyridine (216 ml) and acetic anhydride (48 ml) were added. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure,
Extracted with ethyl acetate. The organic layer was washed successively with a saturated saline solution, a saturated aqueous solution of sodium hydrogen carbonate, a saturated saline solution, dilute hydrochloric acid and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-acetamide-2-acetoxymethyl-4-phenylbutyl acetate (9.34).
g) was obtained. Melting point 116-117 ° C IR (KBr): 2925, 1485, 1070, 10
^{10cm -1 1 H-NMR (CDCl} 3): 1.94 (3H, s),
2.07 (6H, s), 2.20 (2H, m), 2.5
9 (2H, m), 4.33 (4H, s), 5.64 (1
H, br. s), 7.15-7.28 (5H, m) MS m / e: 321 Step C: 2-acetamido-2-acetoxymethyl-4-
(4-Octanoylphenyl) butyl acetate To a suspension of aluminum chloride (31.0 g) in 1,2-dichloroethane (360 ml) was added octanoyl chloride (1).
9.8 ml) at room temperature. After stirring for 2 hours, 2-acetamido-2-acetoxymethyl-4-phenylbutyl acetate (9.34 g) dissolved in 1,2-dichloroethane (100 ml) was added to the mixture at room temperature over 30 minutes. After stirring for 12 hours at room temperature, the mixture is
The mixture was stirred at 0 ° C for 1 hour and poured into ice water. The mixture was extracted with ethyl ether, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography using hexane-ethyl acetate as the eluting solvent to give 2-yellow crystals.
Acetamide-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate (8.30 g) was obtained. 70-74 ° C IR (KBr): 3314, 1651, 1610, 12
^{59cm -1 1 H-NMR (CDCl} 3): 0.86 (3H, t, J
= 6.5 Hz), 1.26-1.32 (8H, m),
1.69 (2H, t, J = 6.8 Hz), 1.96 (3
H, s), 2.08 (6H, s), 2.19-2.23
(2H, m), 2.62-2.66 (2H, m), 2.
92 (2H, t, J = 6.8 Hz), 4.32 (4H,
s), 5.69 (1H, br.s), 7.26 (2H,
d, J = 7.8 Hz), 7.85 (2H, d, J = 7.
8 Hz) MSm / e: 447 Step D: 2-acetamide-2-acetoxymethyl-4-
(4-octylphenyl) butyl acetate 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate (150 m
g) was dissolved in ethanol (10 ml) and acetic acid (10 m
l) and 10% palladium-carbon (40 mg) were added, and the mixture was hydrogenated with stirring using a normal pressure catalytic reduction apparatus. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give colorless crystals of 2-acetamido-2-acetoxymethyl-4- (4-
Octylphenyl) butyl acetate (106mg)
I got 104-106 ° C IR (KBr): 3311,2222,1738,16
^{51,1556,1259,1230,1057cm -1 1 H-NMR (CDCl} 3): 0.87 (3H, t, J
= 6.6 Hz), 1.2-1.35 (10H, m),
1.5-1.7 (2H, m), 1.94 (3H, s),
2.08 (6H, s), 2.1-2.25 (2H,
m), 2.5-2.65 (4H, m), 4.34 (4
H, s), 5.64 (1H, br.s), 7.08 (4
H, s) Step E: 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol Aqueous solution (100 ml) of lithium hydroxide (7.2 g)
2-acetamide-2-acetoxymethyl-4- (4
-Octylphenyl) butyl acetate (8.25
g) in methanol (100 ml) was added and the mixture was heated under reflux for 2 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was recrystallized from ethyl acetate to give 2-amino-2- [2- (4-octylphenyl) as colorless crystals.
[Ethyl] propane-1,3-diol was obtained. Melting point 240 ° C. (decomposition), 103-105 ° C. (clear) ¹ H-NMR (DMSO-d ₆ ): 0.86 (3H,
t, J = 6 Hz), 1.1-1.85 (14H, m),
2.38-2.79 (this chemical shift overlaps with that of DMSO), 3.5-3.6 (4H, m), 5.
36 (2H, t, J = 5 Hz), 7.06 (4H,
s), 7.84 (3H, br.s) Step F: 2-Amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol Lithium hydroxide (7 g) in water ( 150 ml) solution, methanol (200 ml) and tetrahydrofuran (100
ml) of 2-acetamide-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate (8.30 g) dissolved in a mixed solvent was added thereto, and the mixture was heated under reflux for 3 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate,
Concentrated under reduced pressure. The product was recrystallized from a hexane-ethyl acetate mixed solvent to give 2-amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol (2.0 g) as colorless crystals. Obtained.
Melting point 116-117 ° C IR (KBr): 3350, 2926, 1678, 16
^{04,1508cm -1 1 H-NMR (CDCl} 3):
0.86 (3H, t, J = 6.9 Hz), 1.26
1.32 (8H, m), 1.68-1.72 (8H,
m), 2.69 (2H, t, J = 8.3 Hz), 2.9
1 (2H, t, J = 7.3 Hz), 3.50 (2H,
d, J = 10.7 Hz), 3.59 (2H, d, J = 1)
0.7Hz), 7.26 (2H, d, J = 8.3H)
z), 7.86 (2H, d, J = 8.3 Hz) MSm / e: 321 Step G: 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloric acid Salt 2-amino-2- [2- (4-octanoylphenyl)
Ethyl] propane-1,3-diol (100 mg) was dissolved in ethanol, and 1N hydrochloric acid (0.4 ml) was added.
% Palladium-carbon (30 mg) was added, and the mixture was hydrogenated with stirring using an atmospheric pressure catalytic reduction device. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol-ethyl ether to give 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride (82 mg) as colorless crystals. Melting point 240 ° C (decomposition), 110-112 ° C (clear) IR (KBr): 3371, 3267, 3035, 29
22,2850,1601,1518,1070,10
^{45cm -1 1 H-NMR (DMSO} -d 6): 0.85 (3H,
t, J = 6.6 Hz), 1.2-1.3 (10H,
m), 1.45-1.6 (2H, m), 1.7-1.8
(2H, m), 2.45-2.6 (this chemical shift is
MS-SO), 3.5-3.6 (4
H, m), 5.36 (2H, t, J = 5 Hz), 7.1
0 (4H, s), 7.85 (3H, br.s) Step H: Mixing of 2-acetamide-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol methanol and tetrahydrofuran An aqueous solution of sodium hydroxide is added to 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate dissolved in a solvent, and the mixture is stirred at room temperature. After neutralization, the mixture is concentrated under reduced pressure and extracted with ethyl acetate.
The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product is recrystallized from hexane-ethyl acetate to give 2-acetamido-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol as colorless crystals. Step I: 2-acetamido-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol 2-acetamido-2- [2- (4-octanoylphenyl) ethyl] propane-1,3 The diol is dissolved in ethanol, acetic acid and 10% palladium-carbon are added, and the mixture is reacted with hydrogen under stirring using a normal pressure catalytic reduction device. The reaction is filtered and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to give 2-acetamido-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol as colorless crystals. Melting point 66-6
8 ° C. Step J: 2-Amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol An aqueous solution of sodium hydroxide was treated with 2-acetamide-2-
[2- (4-octylphenyl) ethyl] propane-
A solution of 1,3-diol in methanol is added and the mixture is heated under reflux for 2 hours. The mixture was concentrated under reduced pressure,
Extract with ethyl acetate. Wash the organic layer with saturated saline,
After drying over anhydrous magnesium sulfate, concentrate under reduced pressure. The product is recrystallized from ethanol-water to give 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol as colorless crystals. Melting point 240 ° C. (decomposition), 103-105 ° C. (clear) ¹ H-NMR (DMSO-d ₆ ): 0.86 (3H,
t, J = 6 Hz), 1.1-1.85 (14H, m),
2.38-2.79 (this chemical shift overlaps with that of DMSO), 3.5-3.6 (4H, m), 5.
36 (2H, t, J = 5 Hz), 7.06 (4H,
s), 7.84 (3H, br.s) Step K: 2-Acetamide-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol 2-Acetamide-2- dissolved in methanol An aqueous solution of sodium hydroxide is added to acetoxymethyl-4- (4-octylphenyl) butyl acetate and the mixture is stirred at room temperature. The mixture is concentrated under reduced pressure and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was recrystallized from ethyl acetate to give 2-acetamide-2- [2- (4
-Octylphenyl) ethyl] propane-1,3-diol. Melting point 66-68 ° C

[0025]

Industrial Applicability The production method of the present invention, compared with the conventional production method, is useful as an immunosuppressant for 2-amino-2- [2-
(4-octylphenyl) ethyl] propane-1,3-
Since the diol or a pharmaceutically acceptable salt thereof can be produced in a short process, and furthermore, all the intermediates obtained in each production process can be isolated as crystals, it is very industrially applicable. Useful.

Claims (5)

[Claims] (1) Diethyl acetamide malonate is converted to (2-
(Haloethyl) benzene in the presence of a basic compound to give diethyl 2-acetamido-2-phenylethylmalonate, which is reduced and then acetylated to give 2-acetamido-2-acetoxymethyl-4-phenylbutyl. 2-acetamide-2-acetoxymethyl-4- (4-acetate) characterized by introducing an octanoyl group at the para-position of the phenyl group of this compound.
A process for producing octanoylphenyl) butyl acetate. 2. The method of claim 2, wherein the diethyl acetamide malonate is (2-
(Haloethyl) benzene in the presence of a basic compound to give diethyl 2-acetamido-2-phenylethylmalonate, which is reduced and then acetylated to give 2-acetamido-2-acetoxymethyl-4-phenylbutyl. Then, an octanoyl group was introduced at the para-position of the phenyl group of the compound to give 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate, which was hydrolyzed to give 2
-Amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol, which is then reduced, wherein 2-amino-2- [2- (4-
[Octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof. 3. The method of claim 2, wherein the diethyl acetamide malonate is (2-
(Haloethyl) benzene in the presence of a basic compound to give diethyl 2-acetamido-2-phenylethylmalonate, which is reduced and then acetylated to give 2-acetamido-2-acetoxymethyl-4-phenylbutyl. Then, an octanoyl group was introduced into the para-position of the phenyl group of the compound to give 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate, which was reduced to give 2-acetamide -2-acetoxymethyl-4- (4-octylphenyl) butyl acetate, which is then hydrolyzed to give 2-amino-2- [2- (4-
[Octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof. (4) 2-acetamide-2-acetoxymethyl-
Hydrolysis of 4- (4-octanoylphenyl) butyl acetate to 2-amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol, which is then reduced. 2-amino-characterized by
A method for producing 2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof. (5) 2-acetamido-2-acetoxymethyl-
4- (4-Octanoylphenyl) butyl acetate is reduced to give 2-acetamide-2-acetoxymethyl-4
2- (4-octylphenyl) butyl acetate, which is then hydrolyzed.
A method for producing 2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof.