JP4079505B2 - Novel process for the preparation of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol - Google Patents

Novel process for the preparation of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol Download PDF

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JP4079505B2
JP4079505B2 JP11871198A JP11871198A JP4079505B2 JP 4079505 B2 JP4079505 B2 JP 4079505B2 JP 11871198 A JP11871198 A JP 11871198A JP 11871198 A JP11871198 A JP 11871198A JP 4079505 B2 JP4079505 B2 JP 4079505B2
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ethyl
octylphenyl
diol
propane
acetoxymethyl
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JPH11310556A (en
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正 三品
邦知 安達
利行 小原
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田辺三菱製薬株式会社
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Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof useful as an immunosuppressant and a method for producing an intermediate thereof. .
[0002]
[Prior art]
2-Amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof is disclosed in, for example, an organ or bone marrow according to International Publication WO 94/08943. It is described that it is useful as an inhibitor of rejection in transplantation, and as a therapeutic agent for various autoimmune diseases such as psoriasis and Behcet's disease and rheumatic diseases. In this publication, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a salt thereof is produced in 8 steps using phenethyl acetate as a raw material compound. The following two methods are described.
[0003]
[Chemical 1]
[0004]
(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 iodinated 2- (4-octylphenyl) ethyl are described as oily substances. Furthermore, 2-amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol is described as an exemplary compound in the publication.
[0005]
On the other hand, Journal of American Chemical Society (J. Am. Chem. Soc.) Vol. 76, 1909, 1954 and Journal of Chemical Society (J. Chem. Soc.), Page 890, 1955, A method is described in which acetamide malonate is condensed in the presence of a base to produce diethyl 2-phenylethyl acetamide malonate.
[0006]
In addition, International Publication WO 96/06068 describes a production method represented by the following formula using a Friedel-Crafts reaction.
[0007]
[Chemical formula 2]
[0008]
[Problems to be solved by the invention]
In the process for producing 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof described in International Publication WO 94/08943 In addition to the long number of production steps, there are many intermediates that are liquid at room temperature, so that purification by recrystallization is difficult, which is not preferable as an industrial production method. Therefore, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a salt thereof can be produced with fewer steps, and further can be purified by recrystallization at room temperature. An object of the present invention is to provide an industrially advantageous production method via an intermediate which is a solid.
[0009]
[Means for Solving the Problems]
That is, the present invention
Step A in which diethyl acetamide malonate is reacted with (2-haloethyl) benzene in the presence of a basic compound to give diethyl 2-acetamido-2-phenylethyl malonate.
Step B in which diethyl 2-acetamido-2-phenylethyl malonate is reduced and further acetylated to 2-acetamido-2-acetoxymethyl-4-phenylbutyl acetate.
2-acetamide-2-acetoxymethyl-4-phenylbutyl acetate A step of introducing an octanoyl group into the para-position of the phenyl group of 2-acetamide-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate C, Step D wherein 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate is reduced to 2-acetamido-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate
2-Acetamido-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate is hydrolyzed to give 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or its Step E to make a pharmaceutically acceptable salt,
2-Acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate was hydrolyzed to give 2-amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol And process F, and
2-amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol is reduced to 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof, comprising the step G of 3-diol or a pharmaceutically acceptable salt thereof. Relates to the manufacturing method.
[0010]
Furthermore, as a method for producing 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof, 2-acetamido- Process H in which 2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate is hydrolyzed to 2-acetamido-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol 2-acetamido-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol is reduced to 2-acetamido-2- [2- (4-octylphenyl) ethyl] propane-1 , 3-diol to process I,
2-Acetamido-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol was hydrolyzed to give 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1, Step J to give 3-diol or a pharmaceutically acceptable salt thereof, and 2-acetamido-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate was hydrolyzed to give 2-acetamido-2- [2- The process K made into (4-octylphenyl) ethyl] propane-1,3-diol can also be mentioned, and these processes are also included in the present invention. In addition, the manufacturing method of this invention is as the following Formula.
[0011]
[Chemical Formula 3]
[0012]
DETAILED DESCRIPTION OF THE INVENTION
Pharmaceutically acceptable salts of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol include inorganic acids such as hydrochloride, hydrobromide, sulfate and the like. Or salts with organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate, benzenesulfonate, etc., preferably hydrochloric acid Salt.
[0013]
Process A is manufactured according to Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 76, 1909, 1954 and Journal of Chemical Society, page 890, 1955. Can do. 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 a reaction solvent, in addition to ethanol, tertiary butyl alcohol, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane, dioxane, toluene and the like or a mixture thereof A solvent can be used.
[0014]
In the reduction reaction of the ester in the step B, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, borane, diisopropylaluminum hydride and the like can be used as a reducing agent. . As the reaction solvent, methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol, diethyl ether, tetrahydrofuran, dimethoxyethane, 2-methoxyethyl ether, dioxane, toluene, or a mixed solvent thereof can be used. The reaction temperature of this reaction varies depending on the reagent used, but is the boiling point of the solvent used from −20 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.
[0015]
As the acetylating reagent in Step B, acetic anhydride or acetyl halides such as acetyl chloride and acetyl bromide can be used. The reaction solvent may be any solvent as long as it is inert 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 may be used. preferable. Furthermore, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine and the like can also be used as the catalyst, and it is preferable to carry out the reaction using these catalysts. The reaction temperature of this reaction varies depending on the reagent used, but is the boiling point of the solvent used from −20 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.
[0016]
In the Friedel-Crafts reaction in Step C, examples of the reagent for introducing an octanoyl group include octanoyl halides such as octanoyl chloride and octanoyl bromide or 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 to be used, any solvent can be used as long as it is inert in the reaction. 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, but is the boiling point of the solvent used from −20 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.
[0017]
The reduction reaction of the ketone in Step D is performed by a known reduction method in the field of synthetic organic chemistry, for example, Clementen reduction using a metal under acidic conditions, Birch reduction in an amine solution, reduction with hydrosilane, or catalytic reduction. Of these, the catalytic reduction method is preferred. The catalytic reduction reaction is performed by using hydrogen and a palladium-based catalyst (palladium, palladium-carbon, etc.) or platinum as the catalyst, or using Raney nickel. Among them, it is preferable to use a palladium-based catalyst in the presence of hydrogen. The solvent to be used may be any solvent that is inert 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. Further, 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 the boiling point of the solvent used from -20 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.
[0018]
The hydrolysis reaction of the acetyl group in the step E can be performed in the presence of a base or an acid. When the reaction is performed in the presence of a base, the base to be used is preferably sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide or the like, and the solvent to be used is any solvent that is inert in the reaction. Of these, water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane and the like, or a mixed solvent thereof are preferable. In the case where the reaction is carried out in the presence of an acid, examples of the acid used include hydrochloric acid, sulfuric acid, acetic acid and the like. Among them, hydrochloric acid is preferable, and any solvent can be used as long as it is inert in the reaction. Of these, 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. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.
[0019]
The reagent, solvent and reaction conditions in step F are the same as in step E.
As the reduction reaction of the ketone in the step G, known reduction methods in the field of synthetic organic chemistry, for example, Clementen reduction using a metal under acidic conditions, Wolffschner reduction using hydrazine under basic conditions, Birch reduction in an amine solution The reduction is carried out by hydrosilane reduction or catalytic reduction, among which the catalytic reduction method is preferred. The catalytic reduction reaction is performed by using hydrogen and a palladium-based catalyst (palladium, palladium-carbon, etc.) or platinum as the catalyst, or using Raney nickel. Among them, it is preferable to use a palladium-based catalyst in the presence of hydrogen. The solvent used may be any solvent that is inert in the reaction, but water, methanol, ethanol, isopropyl alcohol, acetic acid, tetrahydrofuran, dioxane 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. When hydrochloric acid is added, the target product can be obtained as a hydrochloride. The reaction temperature of this reaction varies depending on the catalyst used, but is the boiling point of the solvent used from -20 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.
[0020]
The ester bond hydrolysis reaction in Step H can be performed 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 inert in the reaction. Ethanol, isopropyl alcohol, tetrahydrofuran, dioxane, acetone, acetonitrile and the like, or a mixed solvent thereof is preferable. The reaction temperature is preferably from room temperature to 50 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.
[0021]
Examples of the reduction reaction of ketones in Step I include reduction reactions commonly used in the field of organic synthetic chemistry, such as Clementen reduction using a metal under acidic conditions, Wolffschner reduction using hydrazine under basic conditions, and birch in an amine solution. The reduction, hydrosilane reduction or catalytic reduction is carried out, and among these, the catalytic reduction, clementen reduction or hydrosilane reduction is preferred. The catalytic reduction reaction is carried out by using hydrogen and a palladium-based catalyst (palladium, palladium-carbon, etc.) or platinum as the catalyst, or 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 inert in the reaction, but water, methanol, ethanol, isopropyl alcohol, acetic acid, tetrahydrofuran, dioxane and the like or a mixed solvent thereof is preferable. Further, 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 the boiling point of the solvent used from -20 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally. As a Clementen reduction reagent, it is preferable to use zinc or zinc amalgam as the metal and hydrochloric acid or acetic acid as the 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 varies depending on the reagent used, but is the boiling point of the solvent used from −20 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally. In the reduction reaction with hydrosilane, triethylsilane is preferred as a reagent. This reaction is carried out under acidic conditions, and mineral acids, trifluoroacetic acid, Lewis acids such as boron trifluoride, etc. are used, among which trifluoroacetic acid is preferred. The reaction temperature of this reaction varies depending on the reagent used, but is the boiling point of the solvent used from −20 ° C. Although reaction time changes with reaction conditions, it is 1 to 24 hours normally.
[0022]
The reagent, solvent, and reaction temperature for the amide bond hydrolysis reaction in Step J are the same as those in Step E.
The reagent, solvent, and reaction temperature of the ester bond hydrolysis reaction in Step K are the same as those in Step H.
2-Amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol produced by the production method of the present invention can be prepared with an appropriate solvent (methanol, ethanol, diethyl ether, Dioxane, etc.), acids (hydrochloric acid, hydrobromic acid, inorganic acids such as sulfuric acid or organic acids such as acetic acid, fumaric acid, maleic acid, benzoic acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid, etc.) To give an acid addition salt.
[0023]
The target product obtained in each reaction of 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 an excellent immunosuppressive action. , 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]
【Example】
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.
Example
Step A: Diethyl 2-acetamido-2- (2-phenylethyl) malonate
Sodium hydride (12.0 g) was dispersed in N, N-dimethylformamide (50 ml), and 5 ml of diethyl acetamide malonate (66.2 g) dissolved in N, N-dimethylformamide (200 ml) was added thereto. The mixture was added dropwise with stirring at 2 ° C. 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 over 30 minutes at room temperature. 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 elution solvent to obtain diethyl 2-acetamido-2- (2-phenylethyl) malonate (36 g) as colorless crystals. Melting point 115-117 ° C
IR (KBr): 3236, 1745, 1635 cm-1
1H-NMR (CDClThree): 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), 4.19 (2H, q, J = 7.3 Hz), 6.74 (1H, br.s), 7.11-7.26 (5H, m)
MS m / e: 321
Step B: 2-Acetamide-2-acetoxymethyl-4-phenylbutyl acetate
Lithium aluminum hydride (3.78 g) was suspended in tetrahydrofuran (200 ml), and diethyl 2-acetamido-2- (2-phenylethyl) malonate (16.0 g) dissolved in tetrahydrofuran (100 ml) was added at 5 ° C. The solution was added dropwise with stirring over time. After stirring at room temperature for 3 hours, 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 and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, a saturated aqueous sodium hydrogen carbonate solution, a saturated saline solution, dilute hydrochloric acid, and a saturated saline solution in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-acetamido-2-acetoxymethyl-4-phenylbutyl acetate (9.34 g). Melting point 116-117 ° C
IR (KBr): 2925, 1485, 1070, 1010 cm-1
1H-NMR (CDClThree): 1.94 (3H, s), 2.07 (6H, s), 2.20 (2H, m), 2.59 (2H, m), 4.33 (4H, s), 5.64 (1H, 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 (19.8 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 over 30 minutes at room temperature. After stirring at room temperature for 12 hours, the mixture was stirred at 50 ° C. for 1 hour and poured into ice water. The mixture was extracted with ethyl ether, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography using hexane-ethyl acetate as an elution solvent to give 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate (8.30 g) as pale yellow crystals. Obtained. Melting point 70-74 ° C
IR (KBr): 3314, 1651, 1610, 1259 cm-1
1H-NMR (CDClThree): 0.86 (3H, t, J = 6.5 Hz), 1.26-1.32 (8H, m), 1.69 (2H, t, J = 6.8 Hz), 1.96 (3H) , 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 (4 H, s), 5.69 (1 H, br. S), 7.26 (2 H, d, J = 7.8 Hz), 7.85 (2 H, d, J = 7) .8Hz)
MS m / e: 447
Step D: 2-acetamido-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate
2-Acetamide-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate (150 mg) is dissolved in ethanol (10 ml), acetic acid (10 ml) and 10% palladium-carbon (40 mg) are added, and the mixture is added. Was hydrogenated under stirring using an atmospheric pressure catalytic reduction device. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and then dissolved in ethyl acetate. The solution was washed with aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give 2-acetamido-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate (106 mg) as colorless crystals. Melting point 104-106 ° C
IR (KBr): 3311, 2922, 1738, 1651, 1556, 1259, 1230, 1057 cm-1
1H-NMR (CDClThree): 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 (4H, s), 5.64 ( 1H, br.s), 7.08 (4H, s)
Step E: 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol
To an aqueous solution (100 ml) of lithium hydroxide (7.2 g) was added a methanol solution (100 ml) of 2-acetamido-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate (8.25 g). Heated under reflux for 2 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated 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) ethyl] propane-1,3-diol as colorless crystals.
Melting point 240 ° C. (decomposition), 103-105 ° C. (clearing)
1H-NMR (DMSO-d6): 0.86 (3H, t, J = 6 Hz), 1.1-1.85 (14H, m), 2.38-2.79 (this chemical shift overlaps 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
To a solution of lithium hydroxide (7 g) in water (150 ml), 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate dissolved in a mixed solvent of methanol (200 ml) and tetrahydrofuran (100 ml) ( 8.30 g) was added 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 and concentrated under reduced pressure. The product was recrystallized from a mixed solvent of hexane-ethyl acetate 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, 1604, 1508 cm-1
1H-NMR (CDClThree): 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), 2.91 (2H, t, J = 7.3 Hz), 3.50 (2H, d, J = 10.7 Hz), 3.59 (2H, d, J = 10. 7 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz) MSm / e: 321
Step G: 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride
2-Amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol (100 mg) was dissolved in ethanol, and 1N hydrochloric acid (0.4 ml) and 10% palladium-carbon (30 mg) were dissolved. ) And the mixture was hydrogenated with stirring using a normal pressure catalytic reduction device. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol-ethyl ether to obtain 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. (clearing)
IR (KBr): 3371, 3267, 3035, 2922, 2850, 1601, 1518, 1070, 1045 cm-1
1H-NMR (DMSO-d6): 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 overlaps that of DMSO), 3.5-3.6 (4H, m), 5.36 (2H, t, J = 5 Hz ), 7.10 (4H, s), 7.85 (3H, br. S)
Step H: 2-Acetamide-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol
An aqueous solution of sodium hydroxide is added to 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate dissolved in a mixed solvent of methanol and tetrahydrofuran, and the mixture is stirred at room temperature. The mixture is neutralized, 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-Acetamide-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol
2-Acetamide-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol is dissolved in ethanol, acetic acid and 10% palladium-carbon are added, and the mixture is subjected to an atmospheric pressure catalytic reduction device. And react with hydrogen under stirring. 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 66-68 ° C
Step J: 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol
To a solution of sodium hydroxide is added 2-acetamide-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol in methanol and the mixture is heated at reflux for 2 hours. The mixture is concentrated under reduced pressure and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated 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 (clearing)
1H-NMR (DMSO-d6): 0.86 (3H, t, J = 6 Hz), 1.1-1.85 (14H, m), 2.38-2.79 (this chemical shift overlaps 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
An aqueous solution of sodium hydroxide is added to 2-acetamido-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate dissolved in methanol 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 is recrystallized from ethyl acetate to give 2-acetamido-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol as colorless crystals. Melting point 66-68 ° C
[0025]
【The invention's effect】
The production method of the present invention comprises 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmacologically useful thereof as an immunosuppressant compared with the conventional production method. Since an acceptable salt can be produced in a short process, and all the intermediates obtained in each production process can be isolated as crystals, it is very useful as an industrial production method.

Claims (5)

  1. Diethyl acetamide malonate is reacted with (2-haloethyl) benzene in the presence of a basic compound to give diethyl 2-acetamido-2-phenylethyl malonate, which is reduced and further acetylated to give 2-acetamide. 2-acetamide-2-acetoxymethyl-4- (4-octanoyl), characterized in that 2-acetoxymethyl-4-phenylbutyl acetate is introduced, and then an octanoyl group is introduced into the para position of the phenyl group of this compound Process for producing phenyl) butyl acetate.
  2. Diethyl acetamide malonate is reacted with (2-haloethyl) benzene in the presence of a basic compound to give diethyl 2-acetamido-2-phenylethyl malonate, which is reduced and further acetylated to give 2-acetamide. 2-acetoxymethyl-4-phenylbutyl acetate, and then introducing an octanoyl group into the para position of the phenyl group of this compound to give 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate This is hydrolyzed to 2-amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol, and then reduced to 2-amino- 2- [2- (4-Octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof Production method.
  3. Diethyl acetamide malonate is reacted with (2-haloethyl) benzene in the presence of a basic compound to give diethyl 2-acetamido-2-phenylethyl malonate, which is reduced and further acetylated to give 2-acetamide. 2-acetoxymethyl-4-phenylbutyl acetate, and then introducing an octanoyl group into the para position of the phenyl group of this compound to give 2-acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate This is reduced to 2-acetamido-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate and then hydrolyzed to 2-amino-2- [2- ( 4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof Manufacturing method.
  4. 2-Acetamido-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate was hydrolyzed to give 2-amino-2- [2- (4-octanoylphenyl) ethyl] propane-1,3-diol And then reducing this, a process for producing 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof.
  5. 2-Acetamide-2-acetoxymethyl-4- (4-octanoylphenyl) butyl acetate is reduced to 2-acetamide-2-acetoxymethyl-4- (4-octylphenyl) butyl acetate, which is then hydrolyzed. A process for producing 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable salt thereof, which decomposes.
JP11871198A 1998-04-28 1998-04-28 Novel process for the preparation of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol Expired - Fee Related JP4079505B2 (en)

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WO2014111836A1 (en) * 2013-01-17 2014-07-24 Shilpa Medicare Limited Process for preparation of fingolimod and its salts
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