JPH0229071B2 - - Google Patents

Description

[Detailed Description of the Invention] (Industrial Application Field) The present invention relates to the general formula (However, R ¹ represents an optionally substituted aryl group or nitrogen-containing heterocyclic group, -NHY represents an optionally protected amino group.) Optically active 1-substituted-2-aminopropane represented by Or related to the manufacturing method of the salt.

The object of the present invention is useful as a synthetic intermediate for various pharmaceutical compounds, for example, in the general formula ()
Optical activity 1 where R ¹ is p-methoxyphenyl group
-(p-Methoxyphenyl)-2-aminopropane is an optically active compound with excellent bronchodilator action8-
Hydroxy-5-{1-hydroxy-2-[N-
It is a compound useful as an intermediate for the synthesis of (2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril (Japanese Patent Application Laid-Open No. 60-208965).

(Prior art) Conventionally, as a method for producing optically active 1-substituted-2-aminopropane, for example, (a) p-methoxyphenylacetone and optically active 1-methylbenzylamine are condensed, and then asymmetric reduction is performed. optically active N-(α
-phenethyl)-(p-methoxyphenylisopropyl)amine is prepared, and then the phenethyl group is removed to obtain optically active 1-(p-methoxyphenyl).
-Asymmetric induction method to obtain 2-aminopropane {Journal of the Medicinal Chemistry [J.Med.Chem., 16 , 480 (1973)]} or (b) racemic 1-(p-methoxyf) A method of optically resolving enyl)-2-aminopropane with d-tartaric acid {Chemical Pharmaceutical Bulletin [Chem.Pharm.Bull., 26 , 1123 (1978)], etc. is known. However, according to method (a) of these methods, in order to produce optically active 1-(p-methoxyphenyl)-2-aminopropane, theoretically more than the same mole of optically active 1-methylbenzyl is always required. An amine had to be used, and method (b) had the technical disadvantage that the split yield of the target product was extremely poor, ranging from 6 to 16%.

(Problems to be Solved by the Invention) Unlike such conventional techniques, the present invention uses optically active amino acid esters, which are industrially available in large quantities and easily, as a raw material compound, and optically pure 1- The present invention provides an industrially advantageous method for producing substituted-2-aminopropanes (2).

(Structure and Effects of the Invention) According to the present invention, the optically active 1-substituted-2-aminopropane () or a salt thereof has the general formula (1) (However, R ¹ is an optionally substituted aryl group or nitrogen-containing heterocyclic group, R ² is an ester residue, and -NHY is an optionally protected amino group.) -Substituted-2-aminopropionic acid ester or its salt is reduced to form the general formula (However, R ¹ and -NHY have the same meanings as above.) An optically active 3-substituted-2-aminopropanol represented by the formula (However, R ¹ and -NHY have the same meanings as above, and OZ represents a protected hydroxyl group.) After obtaining the optically active 3-substituted-2-aminopropanol derivative or its salt represented by ( 2) Reducing the aminopropanol derivative () or its salt in the presence of a metal halide, or (3) Reacting the aminopropanol derivative () or its salt with a metal halide to obtain the general formula (However, R ¹ and -NHY have the same meanings as above, and X represents a halogen atom.) After obtaining the optically active 3-substituted-2-aminopropyl halide or its salt, this is reduced. It can be manufactured by

As the raw material compound () of the present invention, optically active amino acid esters that are easily available industrially can be used.
For example, esters of various natural or non-natural amino acids, such as optically active phenylalanine, tyrosine, p-methoxyphenylalanine, tryptophan, and histidine, with protected or unprotected amino groups may be used. Can be done.

In the starting compound (), when the amino group is a protected amino group, the protecting group includes, for example, a lower alkanoyl group such as an acetyl group or a propionyl group; a substituted or unsubstituted benzoyl group such as a benzoyl group; methoxycarbonyl group, lower alkoxycarbonyl group such as ethoxycarbonyl group, tert-butoxycarbonyl group;
Mono-, di-, or tri-halogenated lower alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl group; substituted or unsubstituted benzyloxycarbonyl groups such as benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group ; Substituted or unsubstituted phenyl lower alkyl groups such as benzyl group and p-methoxybenzyl group; Di- or tri-phenyl lower alkyl groups such as benzhydryl group and trityl group; Substituted or unsubstituted phenylsulfonyl groups such as tosyl group; o
Any substituted or unsubstituted phenylsulfenyl group such as -nitrophenylsulfenyl group can be used.

Further, as the ester residue in the raw material compound (), for example, lower alkyl groups such as methyl group, ethyl group, and propyl group are preferably mentioned.

On the other hand, in compound (), examples of the group Z include lower alkanoyl groups such as formyl group and acetyl group; substituted or unsubstituted phenylsulfonyl groups such as phenylsulfonyl group and p-trienesulfonyl group; naphthalenesulfonyl group; methylsulfonyl group. A hydroxyl group-protecting group such as a lower alkylsulfonyl group such as an ethylsulfonyl group or an ethylsulfonyl group can be suitably used.

Examples of the salts of compounds () to () include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, methanesulfonate, ethanesulfonate, and p-toluenesulfone. Mention may be made of organic acid addition salts such as acid salts and the like.

Reduction of the compound () or a salt thereof can be carried out in a solvent in the presence of a reducing agent. As the solvent, for example, water, methanol, ethanol, isopropanol, n-propanol, or a mixture thereof can be suitably used, and as the reducing agent, for example, sodium borohydride, potassium borohydride, lithium borohydride, etc. Alkali metal borohydrides such as can be suitably used. This reaction is preferably carried out at a temperature of 0 to 100°C, particularly 0 to 20°C.

Protection of the hydroxyl group in the compound () or a salt thereof can be carried out by a conventional method depending on the type of protecting group. For example, when the protecting group is a tosyl group, the reaction can be carried out by reacting the compound () with a tosyl halide in a solvent in the presence of a base and a catalyst. Preferred examples of tosyl halide include tosyl chloride. Preferred solvents include benzene, toluene, ethyl acetate, chloroform, dichloromethane, etc., and preferred bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and potassium carbonate metals such as sodium carbonate and potassium carbonate. can be used. In addition, examples of the catalyst include n-tetrabutylammonium chloride, n-tetrabutylammonium bromide,
Preferred examples include quaternary ammonium salts such as n-tetrabutylammonium sulfate. This reaction is preferably carried out at a temperature of 0 to 50°C, particularly 0 to 20°C.

The target compound () or its salt can be produced by reducing the thus obtained compound () or its salt in the presence of a metal halide, or alternatively,
It can also be produced by once reacting the compound () or its salt with a metal halide to form the corresponding propyl halide () or its salt, and then reducing this.

When reducing the compound () or a salt thereof in the presence of a metal halide, the reaction can be carried out in a solvent in the presence of a reducing agent. Suitable solvents include, for example, water, tetrahydrofuran, monomethylene glycol, dimethylene glycol, acetic acid, dilute hydrochloric acid, or mixtures thereof. Examples of metal halides include alkali metal halides such as sodium iodide, sodium bromide, and sodium chloride, with sodium iodide being particularly preferred. Examples of reducing agents include metal zinc, zinc-copper alloy, metal magnesium, divalent chromium metal salts (such as chromium chloride (di
chromium sulfate (bivalent), chromium acetate (bivalent))
etc. can be mentioned suitably. The amount of metal halide used is 1 to 5 per compound () or its salt.
The amount of the reducing agent used is preferably 1 to 10 times the molar amount of the compound () or its salt. This reaction is carried out at 20-100℃, especially at 50℃.
Preferably it is carried out at ~100°C.

On the other hand, the reaction between the compound () or its salt and the metal halide can be carried out in a solvent. Suitable solvents include, for example, water, tetrahydrofuran, monomethylene glycol, dimethylene glycol, or mixtures thereof. As the metal halide, for example, any of those exemplified when the above-mentioned compound () is subjected to a reduction reaction in the presence of a metal halide can be suitably used. The amount of metal halide used is 1 to 5 per compound () or its salt.
A double molar amount is preferred. This reaction is 20-100
Preferably, the reaction is carried out at a temperature of 50-100°C.

Reduction of the compound () or a salt thereof can be carried out in a solvent in the presence of a reducing agent. As the solvent, for example, any of the solvents exemplified in the explanation of the reaction between the compound () or its salt and a metal halide can be used. As the reducing agent, for example, metal zinc, zinc-copper alloy, metal magnesium, divalent chromium metal salts (for example, chromium chloride (divalent), chromium sulfate (divalent), chromium acetate (divalent), etc.) are preferably used. The amount used is preferably 1 to 10 times the molar amount of the compound () or its salt. This reaction is carried out at 20 to 100℃, especially 50 to 100℃.
It is preferable to carry out.

Furthermore, in the case where the amino group in the optically active 1-substituted-2-aminopropane () or its salt obtained as described above is a protected amino group, the removal of the protecting group can be carried out by removing the protecting group. It can be carried out by conventional methods depending on the type, for example, by means of hydrolysis, electrolytic reduction, base treatment, acid treatment, catalytic reduction, oxidation reaction, etc. More specifically, for example, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group,
Protective groups such as benzyl group and p-methoxybenzyl group can be removed under normal pressure or elevated pressure in the presence of a suitable catalyst such as colloidal palladium, palladium on carbon or palladium black. Also, protecting groups such as benzoyl groups can be removed by treatment with, for example, ammonia, mono- or di-substituted lower alkyl amines, or sodium lower alkoxide. Protecting groups such as acetyl group, tert-butoxycarbonyl group, benzhydryl group, trityl group, o-nitrophenylsulfenyl group, etc. are, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, In addition, protecting groups such as ethoxycarbonyl groups can be removed by treatment with hydrochloric acid, etc., and by hydrolysis with a base such as potassium hydroxide or an acid such as hydrochloric acid or hydrobromic acid. can. Protective groups such as tosyl groups can be removed by electrolytic reduction or treatment with a base.

Since all of the above reactions in the method of the present invention proceed without racemization, if an optically active form is used as the raw material compound (2) or its salt, the compound (2) or its salt can also be obtained as an optically active form.
Therefore, compared to conventionally known methods, the method of the present invention can produce highly purified optically active 1-substituted-2-aminopropane () from easily available optically active amino acid esters in good yields, making it easier for pharmaceutical synthesis. This method is characterized in that it can be a preferred industrial production method for compounds () useful as intermediates.

Example 1 (1) 300 g of L-tyrosine is suspended in 2.6 g of ethanol, 320 ml of thionyl chloride is added dropwise over 1 hour while stirring under ice cooling, and the suspension is stirred overnight at room temperature. The solvent was distilled off from the solution, ether was added to the residue, and the precipitated crystals were collected by filtration. By washing the crystals with ether and drying them, L-
Pale yellow crystals of tyrosine ethyl ester/hydrochloride
Gain 416g. Yield: Quantitative mp 170-170.5℃ IRν ^nujol _nax (cm ^-1 ): 3340, 1735 NMR (DMSO-d ₆ , δ): 1.13 (3H, t, J=
7Hz), 4.09 (2H, q, J = 7Hz), 6.70 and 7.01 (2H, d, J = 8.5Hz) (2) Add 2 ethyl acetate, 1.4 water and 460 g potassium carbonate to 416 g of this product, cool on ice, While stirring, 282 g of benzyloxycarbonyl chloride is added over 50 minutes. After stirring at the same temperature for 30 minutes, separate the ethyl acetate layer. The ethyl acetate layer is washed successively with water, dilute hydrochloric acid and water, and dried. After removing the insoluble matter by filtration, the solvent was distilled off to obtain 585.5 g of a pale yellow oily substance of L-N-benzyloxycarbonyl tyrosine ethyl ester.

(3) 2.6 dimethyl sulfoxide per 585.5 g of this product,
Add 685 g of potassium carbonate and 423 g of methyl iodide, and stir at room temperature overnight. After the reaction, benzene 6
is added, and the mixture is washed successively with water, 3.3% aqueous sodium hydroxide solution, water, and saturated saline.
After drying, insoluble matter is filtered off. By distilling off the solvent under reduced pressure, a pale yellow oil of (S)-3-(4-methoxyphenyl)-2-benzyloxycarbonylaminopropionic acid ethyl ester was obtained.
Gain 605g. Yield: Quantitative (4) Add 94 g of sodium borohydride to 1 ethanol under ice cooling and stirring. Add 302.5 g of this product in two ethanol solutions at once to the mixture, stir at 8°C for 30 minutes, and then return to room temperature. The temperature of the mixture was maintained at around 25°C and stirred for 7 hours.
0.75 ml of acetone is added dropwise to the solution under cooling, and then 206 ml of concentrated hydrochloric acid is added dropwise. 5ml of 10% hydrochloric acid
After adding 200 ml of water to make the pH of the solution slightly acidic, insoluble matter was filtered off. The filtrate is concentrated under reduced pressure and then extracted with ethyl acetate. The extract is washed successively with water, aqueous sodium hydroxide solution, and saturated brine. After drying the extract and removing insoluble matter by filtration, the solvent is distilled off under reduced pressure. By recrystallizing the residue from ethyl acetate-n-hexane, (S)-3-(4-methoxyphenyl)-
223.5 g of colorless crystals of 2-benzyloxycarbonylaminopropanol were obtained. Yield: 85.6% mp 93-99℃ [α] ²⁰ _D -39.5゜ (C = 1.11, methanol) IRν ^nujol _nax (cm ^-1 ): 3450, 3400, 3350, 3305,
1685, 1660 Mass (m/e): 315 (M ⁺ ) NMR (CDCl ₃ , δ): 2.70 (2H, d, J = 6.5
Hz), 3.72 (3H, S), 5.02 (2H, S), 6.74 and 7.04 (2H, dJ=8.5Hz), 7.24 (5H, S) (5) 7.35 g of this product, 50 ml of dichloromethane and 5% hydroxide Mix with 50 ml of aqueous sodium solution, and add 4.90 g of p-trienesulfonyl chloride to the mixture under ice cooling. 1.75 g of n-tetrabutylammonium sulfate was added to the mixture under ice cooling, and after stirring at the same temperature for 1 hour, 0.2 g of p-toluenesulfonyl chloride was added, and the mixture was stirred at room temperature for 1 hour. Ether is added to the reaction solution, washed with water, dried, and insoluble materials are removed by filtration. The solvent was distilled off from the filtrate under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane to give (S)-3-(4-methoxyphenyl)-2-benzyloxycarbonylamino-1-( 11.36 g of colorless needle crystals of p-toluenesulfonyl)propanol are obtained. yield:
Quantitative mp 80-81℃ [α] ²⁰ _D -31.9゜ (C = 1.04, methanol) IRν ^CHCl _3nax (cm ^-1 ): 3440, 1715, 1610 Mass (m/e): 297 (M ⁺ ) NMR ( CDCl ₃ , δ): 2.41 (3H, S), 3.71 (3H,
S), 4.98 (2H, S), 6.5-7.9 (13H, m) (6) A mixture of 34 g of this product, 54 g of sodium iodide, 500 ml of tetrahydrofuran, and 25 ml of water is refluxed for 2.5 hours while stirring. The solvent is distilled off from the reaction solution, and the residue is extracted with benzene. The extract is washed successively with water, an aqueous sodium hydroxide solution, an aqueous sodium thiosulfate solution, and water, and after drying, the solvent is distilled off under reduced pressure. By crystallizing the residue from ethyl acetate-n-hexane, (S)-3-
18.8 g of colorless needle-like crystals of (4-methoxyphenyl)-2-benzyloxycarbonylaminopropyliodide are obtained. Yield: 61% mp 82-84°C (recrystallized from ethyl acetate-n-hexane) [α] ²⁰ _D -4.8° (C = 1.04, methanol) IRν ^nujol _nax (cm ^-1 ): 3320, 1690 Mass ( m/e): 425 (M ⁺ ) NMR (CDCl ₃ , δ): 3.78 (3H, S), 5.10 (2H, S), 6.82 and 7.16 (2H, d, J = 8.5Hz), 7.34 (5H, S) (7) 2.13g of this product, 20ml of dimethoxyethane, 1ml of water
and 1.64 g of powdered zinc are refluxed for 30 minutes under stirring. Insoluble matter is filtered off and washed with ethanol. The filtrate and washing liquid are combined and the solvent is distilled off under reduced pressure. The residue is extracted with ethyl acetate, and the extract is washed successively with dilute hydrochloric acid, an aqueous sodium hydroxide solution, and water, and after drying, the solvent is distilled off. By purifying the residue using silica gel column chromatography (solvent: ethyl acetate:hexane = 1:6), colorless (R)-1-(4-methoxyphenyl)-2-benzyloxycarbonylaminopropane was obtained. Obtain 1.22 g of solid. Yield: 81.6% mp 87.5-88°C (recrystallized from ethyl acetate-n-hexane) [α] ²⁰ _D -26.2° (C = 1.0, methanol) IRν ^nujol _nax (cm ^-1 ): 3320, 1685 Mass ( m/e): 299 (M ⁺ ) NMR (CDCl ₃ , δ): 1.10 (3H, d, J = 6.4
Hz), 2.60 to 2.80 (2H, m), 3.77 (3H, S), 5.07 (2H, S), 6.79 and 7.08 (2H, d, J = 9Hz), 7.32 (5H, S) (8) This product Add 0.24 g of 10% palladium carbon, 15 ml of tetrahydrofuran and 2 ml of 10% hydrochloric acid to 1.05 g,
Catalytic reduction is carried out by treating at room temperature under hydrogen gas pressure (1 atm) for 3.5 hours. After filtering off the catalyst from the reaction solution, the solvent is distilled off from the filtrate under reduced pressure. The residue was crystallized from ethanol-diethyl ether to obtain 590 mg of colorless prismatic crystals of (R)-1-(4-methoxyphenyl)-2-aminopropane hydrochloride. Yield: 83.6
% mp 251-253℃ (Literature value: mp 251-253℃ ^* ) [α] ²⁰ _D -23.0゜ (C = 2.03, H ₂ O) (Literature value: [α] ²⁵ _D -22.5゜ (C = 2.0 , H ₂ O) ^** ) {＊, ＊＊: Journal of the Medicinal Chemistry [J.Med.Chem., 16 , 480
(1973)] IRν ^nujol _nax (cm ^-1 ): 2700-2500, 2030, 1610 Mass (m/e): 165 (M ⁺ , faint), 122, 121,
44 NMR (D ₂ O, δ): 1.34 (3H, d, J = 6.5 Hz), 2.93 (2H, d, J = 7 Hz), 3.88 (3H, S), 7.05 and 7.33 (2H, d, J = 8.5Hz) Example 2 (1) (S)-3- obtained in Example 1-(4) above
Add 1.68 g of benzene to 220.5 g of (4-methoxyphenyl)-2-benzyloxycarbonylaminopropanol and dissolve at 35°C. to the solution
After adding 1.12 g of a 10% aqueous sodium hydroxide solution and 143 g of p-toluenesulfonyl chloride at about 20°C, a solution of 47 g of n-tetrabutylammonium sulfate in 200 ml of water is added dropwise at 12°C.
The mixed solution is stirred for 35 minutes under ice cooling (liquid temperature 17-19°C). The benzene layer is separated, washed with water, and then dried. By distilling off the solvent from the benzene layer under reduced pressure, (S)-3-(4-methoxyphenyl)-2-benzyloxycarbonylamino-
341 g of a colorless solid of 1-(p-toluenesulfonyl)propanol are obtained. Yield: Quantitative The physical constants of this product matched those of the compound obtained in Example 1-(5) above.

(2) 28.2g of this product, 390ml of tetrahydrofuran, water
Add 40 g of powdered zinc to a mixture of 13.5 ml and 45 g of sodium iodide and reflux for 2 hours. Insoluble matter is filtered off from the reaction solution and washed with ethanol. The filtrate and washing liquid are combined and the solvent is distilled off under reduced pressure.
Ethyl acetate is added to the residue for extraction, and the extract is washed successively with water, dilute hydrochloric acid, water, aqueous sodium hydroxide solution, and water. After drying the extract and removing insoluble matter by filtration, the solvent was distilled off from the filtrate under reduced pressure to obtain (R)-1-(4-methoxyphenyl).
17.8 g of a colorless solid of -2-benzyloxycarbonylaminopropane was obtained. Yield: 99.4% The physical constants of this product matched those of the compound obtained in Example 1-(7) above.

(3) Colorless prism crystals of (R)-1-(4-methoxyphenyl)-2-aminopropane hydrochloride were obtained by treating 1.05 g of this product in the same manner as in Example 1-(8). .

The physical constants of this product matched those of the compound obtained in Example 1-(8).

Claims (1)

[Claims] 1. General formula (However, R ¹ is an optionally substituted aryl group or nitrogen-containing heterocyclic group, -NHY is an optionally protected amino group, and OZ is a protected hydroxyl group.) -Substituted-2-aminopropanol derivative or its salt is reduced in the presence of a metal halide, or the compound () or its salt is reacted with a metal halide to obtain the general formula (However, R ¹ and -NHY have the same meanings as above, and X represents a halogen atom.) After obtaining the optically active 3-substituted-2-aminopropyl halide or its salt, this is reduced. A general formula characterized by (However, R ¹ and -NHY have the same meanings as above.) A method for producing optically active 1-substituted-2-aminopropane or a salt thereof. 2 (1) General formula (However, R ¹ is an optionally substituted aryl group or nitrogen-containing heterocyclic group, R ² is an ester residue, and -NHY is an optionally protected amino group.) -Substituted-2-aminopropionic acid ester or its salt is reduced and the hydroxyl group of the product is protected to form the general formula (However, R ¹ and -NHY have the same meanings as above, and OZ represents a protected hydroxyl group.) After producing the optically active 3-substituted-2-aminopropanol derivative or its salt represented by ( 2) Reducing the compound () or a salt thereof in the presence of a metal halide, or (3) Reacting the propanol derivative () or a salt thereof with a metal halide to form a compound of the general formula (However, R ¹ and -NHY have the same meanings as above, and X represents a halogen atom.) After producing an optically active 3-substituted-2-aminopropyl halide or a salt thereof, this is reduced. A general formula characterized by (However, R ¹ and -NHY have the same meanings as above.) A method for producing optically active 1-substituted-2-aminopropane or a salt thereof. 3. The manufacturing method according to claim 1 or 2, characterized in that the protecting group is removed from a compound in which -NHY is a protected amino group in the general formula ().