JPH0859576A - Method for producing optically active aminoketone and aminoalcohol - Google Patents

Abstract

PURPOSE: To obtain the subject compounds useful as synthetic intermediates for medicines, agrichemicals, etc., or as optical resolving agents under mild conditions by a new one step method comprising directly reacting an α-amino acid derivative with an excessive amount of a Grignard reagent. CONSTITUTION: One mole of an α-amino acid derivative of formula I (R<1> is alkyl, amino-protecting group; R<2> is 1-8C alkyl, aryl, etc.; C* is asymmetric carbon atom) is reacted with five or more moles of a Grignard reagent of formula: R<3> MgX (R<3> is 6-20C hydrocarbon; X is halogen) usually in a solution below the refluxing temperature of the solution, preferably at 15-50 deg.C, to obtain the objective compound of formula II. The reaction solvent is preferably THF. When e.g. N-benzyloxycarbonyl-L-serine and phenylmagnesium bromide are used as the starting raw material of formula I and as the Grignard reagent, respectively, (2S)-2-benzyloxycarbonylamino-3-hydroxy-1-phenylpropane is obtained as the compound of formula II.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for synthesizing optically active aminoketones and optically active aminoalcohols, which are compounds useful as synthetic intermediates for drugs, agricultural chemicals, etc. or as optical resolving agents.

[0002]

2. Description of the Related Art As a method for synthesizing N-protected-α-aminoketones starting from N-protected-α-amino acid, the carboxyl group of the amino acid is converted to acid chloride and then reacted with benzene and Friedel-Crafts reaction. Method (J.Am.Chem.So
c. , 103 , 6157 (1981)), a method in which a carboxyl group of an amino acid is treated with an alkyllithium reagent to form a lithium salt and then reacted with a Grignard reagent (J. Or.
g. Chem., 54 , 1866 (1989)). Further, as a method for producing an α-amino alcohol, a method of reacting an α-amino acid or an ester thereof with a specific Grignard reaction agent (Japanese Patent Laid-Open No. S60-12065)
50-29535 and JP-A-56-65848) are known.

Further, as a synthetic method of N-protected-β-amino alcohols, a method of reducing amino ketones
(J. Org. Chem. , 54 , 1866 (1989)), a method of treating an N-protected-amino acid ester with diisobutylaluminum hydride followed by a Grignard reagent (J. Org. Chem., 57 , 5469).
(1992)) A method of reacting an acid chloride of N-protected-aminoaldehyde or N-protected-amino acid with a Grignard reagent is known.

[0004]

When an aminoketone derivative is obtained, acylation by the Friedel-Crafts reaction is not practical because there are many restrictions on the protecting group, the type of amino acid side chain, and the structure of the product to be acylated. Further, the method using alkyllithium requires complicated reactions such as reaction at a low temperature, for example, -78 ° C, and is a two-step reaction, and there are many restrictions on protecting groups and side chain functional groups.

Further, in the case of obtaining an amino alcohol derivative, in the method using diisobutylaluminum hydride and a Grignard reagent, only one of the diastereomers of the erythro form and the threo form can be obtained, and the amino aldehyde or acid chloride is passed through. The methods had problems such as racemization and instability.

[0006]

Means for Solving the Problems As a result of repeated studies by the present inventors, a more convenient and general method for producing compounds having the structures of the above-mentioned general formulas (3) and (4) was developed. ,
We succeeded in achieving that task with the following configuration. According to the present invention, by directly reacting an α-amino acid derivative with a large excess of Grignard reagent, the desired optically active aminoketone can be obtained in one step under mild conditions, and further reducing conditions can be selected. Thus, an optically active amino alcohol can be stereoselectively obtained from the aminoketone.

That is, the present invention provides a compound represented by the general formula (1) R ¹ —NH—C ^* H (R ² ) —COOH (1) (wherein R ¹ represents an alkyl group or an amino-protecting group). ,
R ² represents an optionally substituted alkyl, aryl or aralkyl group having 1 to 8 carbon atoms, and R ¹ and R ²
They are linked - (CH _{2) 3} - or -CH ₂ -CH (OH)
-CH ₂ - shows the. C ^* represents an asymmetric carbon atom. ) In the α-amino acid derivative represented by the general formula (2) R ³ MgX ··· (2) (In the formula, X is a halogen atom, and R ³ has a substituent having 6 to 20 carbon atoms. It is a hydrocarbon group which may be present.)
The compound of the general formula (3) R ¹ —NH—C ^* H (R ² ) —COR ³ ·, which comprises reacting at least 5 mol of the Grignard reagent represented by (3) (In the formula, R ¹ , R ² , R ³ and C ^* are as defined above.)
The method for producing an optically active aminoketone represented by the formula and a compound represented by the general formula (4) R, which comprises reducing the obtained optically active aminoketone or presenting a reducing agent in advance when reacting the general formulas (1) and (2). ^{1 -NH-C * H (R} 2) -C * H (OH) R 3 ···· (4) ( ^{wherein, R 1, R 2, R} 3 and C ^* are as defined above.)
The gist is the method for producing an optically active amino alcohol represented by.

The present invention will be described in detail below. The amino acid used as a raw material of the α-amino acid derivative of the general formula (1) of the present invention may be a natural product or a synthetic product,
The L-form, the D-form or the racemic form can be used. The alkyl group as the substituent R ^{1 in} the general formula (1) is an alkyl group having 1 to 8 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl and n-.
Examples thereof include linear or branched alkyl groups such as butyl, i-butyl, t-butyl, cycloalkyl groups such as cyclohexyl, aralkyl groups such as benzyl, and aryl groups such as phenyl. Further, the amino protecting group is one used in peptide synthesis, and examples thereof include a benzyloxycarbonyl group, a t-butyloxycarbonyl group,
Examples thereof include a benzenesulfonyl group and a fluorenylmethyloxycarbonyl group, but other groups may be used as long as the reactivity with the Grignard reagent is low.

The substituent R ² in the general formula (1) has 1 carbon atom.
~ 8 alkyl, aryl, and aralkyl groups, which may have a substituent. Specifically, these are
Is the side chain of an amino acid, methyl (-CH _3), ethyl (-C ₂ H _5), n- propyl (-C ₃ H _7), i- propyl _{(-CH (CH 3) 2)} , n- butyl (-C ₄ H _9), i
- butyl _{(-CH 2 -CH (CH 3)} 2), 1 -methylstyrene propyl _{(-CH (CH 3) -CH 2} CH 3), benzyl _{(-CH 2 -C 6 H 5)} , cyclohexyl (-C ₆ H ₁₁ ),
Cyclohexylmethyl _{(-CH 2 -C 6 H 11)} , hydroxymethyl (-CH ₂ OH), 2- hydroxyethyl (-
CH ₂ CH ₂ OH), 1-hydroxyethyl (-CH (O
H) CH _3), 4- hydroxybenzyl (-CH ₂ -C ₆
H ₄ -OH), 3,4- dihydroxy-benzyl (-CH _{2
-C 6 H 4 - (OH)} 2), mercaptomethyl (-CH ₂ S
H), mercaptoethyl _{(-CH 2 CH 2 SH),} 2- methylthioethyl _{(-CH 2 CH 2 SCH 3)} , carboxymethyl (-CH ₂ COOH), aminocarbonyl methyl (-CH ₂ CONH _2), carboxyethyl (-CH ₂ C
H ₂ COOH), aminocarbonyl ethyl (-CH ₂ CH
₂ CONH _2), 4- aminobutyl (- (CH _{2) 4} N
H _2), 4-imidazolylmethyl (-CH ₂ -C ₃ H
₃ N ₂ ), 3-indolylmethyl (-CH ₂ -C ₈ H
₆ N), 3-aminopropyl (-CH ₂ CH ₂ CH ₂ N
H ₂₎ group, more _{- (CH 2) 3 -NH-} C (NH) -
NH _2, - (CH ₂₎ a ₃ -NH-CO-NH ₂ and the like. When the amino acid has a carboxyl group in the side chain such as aspartic acid and glutamic acid, those protected with an orthoester prior to the reaction, or when it has an amino group in the side chain such as lysine, And those protected by the amino-protecting group of. Further, R ¹ and R ² are linked to each other to form — (CH ₂ ) ₃ — or —CH ₂ —CH (OH) —.
CH ₂ - exhibit binding is the case of proline or hydroxyproline.

As R ³ of the Grignard reagent of the general formula (2), an alkyl group having 6 to 20 carbon atoms such as n-hexyl, cyclohexyl and n-octyl; an alkenyl group having 6 to 20 carbon atoms; phenyl, methylphenyl , An aryl group which may have a substituent such as methoxyphenyl and propoxyphenyl; methoxyphenyl, methylcarbonylphenyl,
Substitution in which a functional group such as a phenyl group having a 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl, -NHZ (Z is an amino-protecting group) group is protected by a protecting group which is inactive to the Grignard reagent. Groups are exemplified. Also, X
Examples of the halogen atom represented by include chlorine, bromine and the like. Specific examples include n-hexyl magnesium bromide and phenyl magnesium bromide. In the present invention, it is necessary to use the Grignard reagent in an amount of at least 5 times, preferably 8 times to 10 times the molar amount of the substrate α-amino acid derivative.

This reaction is usually carried out in a solution, but the solvent used is not particularly limited as long as it is inert to the reaction, and usually tetrahydrofuran, diethyl ether,
Ethers such as dioxane, diglyme, etc. are used. Of these, tetrahydrofuran is more preferable from the viewpoint of solubility of the substrate. The reaction temperature is usually 0 ° C. to the reflux temperature or lower, preferably about 15 ° C. to 50 ° C., because the reaction progresses slowly under ice-free conditions and is not practical, and on the other hand, when it is too high, side reactions may occur. In particular, when the substrate has poor solubility such as tyrosine, it is preferable to appropriately heat. The reaction time varies depending on the reaction conditions applied, but is at least 30 minutes, usually 1 to 20 hours. In the present invention, the order of adding the α-amino acid derivative of the substrate and the Grignard reagent is not particularly limited, and the Grignard reagent may be added to the α-amino acid derivative or vice versa.

When the optically active aminoketones formed are obtained after the reaction, the excess Grignard reagent in the reaction solution is decomposed with an aqueous solution of dilute hydrochloric acid, dilute sulfuric acid, acetic acid or citric acid, and then separated. A crude product is obtained by a commonly used method and, if necessary, purified by a recrystallization method, column chromatography or the like. In the present invention, when producing optically active amino alcohols, the optically active amino ketones obtained as described above are reduced with a reducing agent. At that time, the aminoketones may or may not be isolated from the reaction product solution with the Grignard reagent.

As the reducing agent, various metal-hydrogen complex compounds such as sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, or K-selectride (K-Se) can be used.
lectride), L-Selectride, and the like, and boranes such as diborane and triethylamine-borane can also be used. Although the amount of the reducing agent used varies depending on the type of the reducing agent and the substance to be reduced, it is usually used in an amount equivalent to twice the molar amount of the substance to be reduced. The reduction reaction is appropriately selected between -78 ° C and 50 ° C. Also,
By carrying out the reaction between the α-amino acid derivative and the Grignard reagent in the presence of a reducing agent, an optically active amino alcohol can be produced from the α-amino acid derivative in a single step. In that case, the reducing agent is added after the addition of the Grignard reagent. It is preferable to add.

In the present invention, the ratio of the diastereomer mixture of the optically active amino alcohol obtained varies depending on the reaction conditions such as the type and amount of reducing agent used, the type of solvent and the reaction temperature. By combining them, stereoselective reduction is possible, and either an erythro body or a threo body can be obtained with high selectivity. For example, when K-selectride or diisobutylaluminum hydride is used as the reducing agent, one of the isomers having a diastereomeric relationship with each other is preferentially produced in an ether solvent such as tetrahydrofuran.

After completion of the reaction, the optically active amino alcohols formed are isolated by first removing the reducing agent and the excess Grignard reagent present in the reaction solution from water or diluted hydrochloric acid, diluted sulfuric acid, acetic acid or citric acid. Decompose with aqueous solution. Then, a crude product is obtained from the obtained product solution by a commonly used method such as extraction, liquid separation, distillation or the like, and if necessary, purified by a recrystallization method, column chromatography or the like. When the produced optically active amino alcohol is a diastereomer mixture, its molar ratio is determined by NMR, HPLC.
Etc., and can be separated into each diastereomer by a recrystallization method, chromatography or the like.

As described above, according to the method of the present invention, the desired optically active aminoketone can be produced in a simple process by causing an excess amount of the Grignard reagent to directly act on the α-amino acid derivative under mild conditions. Further, when the aminoketone is reduced to produce an optically active aminoalcohol, the aminoalcohol can be stereoselectively obtained by appropriately selecting the type of reducing agent, the type of solvent, the reaction conditions and the like. it can. The thus obtained optically active aminoketone and optically active amino alcohol are useful as synthetic intermediates for medicines and agricultural chemicals, or as optical resolving agents.

[0017]

EXAMPLES The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0018]

Example 1 N-benzyloxycarbonyl-L-serine (479 m) dissolved in 2 ml of tetrahydrofuran in a tetrahydrofuran solution of phenylmagnesium bromide (1M, 16 ml) under an argon atmosphere under ice cooling.
g, 2.0 mmol) was added dropwise over 2 minutes. After stirring overnight at room temperature, the mixture was poured into ice water containing 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure (2S) -2-
Benzyloxycarbonylamino-3-hydroxy-1
548 mg of phenylpropanone as pale yellow crystals
Obtained (yield 91.5%). The sample recrystallized from ethyl acetate-hexane was white needle-shaped and had m.p. p. 109 ℃,
It was [α] ²⁰ _D -5.7 ° (cl, CH ₃ OH). ¹
It was confirmed by 1 H-NMR spectrum that the compound was (2S) -2-benzyloxycarbonylamino-3-hydroxy-1-phenylpropanone.

[0019]

Example 2 In place of N-benzyloxycarbonyl-L-serine in Example 1, N-benzyloxy-D
-(2R) -2-benzyloxycarbonylamino-3-hydroxy-1-, except that serine was used.
Phenylpropanone as pale yellow crystals, yield 85.4%
Got with. [Α] ²⁰ _D + 5.7 ° (cl, CH ₃ OH) m.p. p. 10
9 ° C

[0020]

Example 3 (2S) -2-Dimethylethoxycarbonylamino-3-hydroxy-1-phenylpropanone was collected as a colorless oil from N-tert-butoxycarbonyl-L-serine in the same manner as in Example 1. The yield was 79.6%. The product was confirmed by [α] ²⁰ _D −24.4 ° (cl, CH ₃ OH) ¹ H-NMR spectrum.

[0021]

Example 4 (2S) -2-benzenesulfonylamino-3-hydroxy-1-phenylpropanone was obtained as white crystals from N-benzenesulfonyl-L-serine in the same manner as in Example 1 in a yield of 65.9%. Got with. The product was confirmed by [α] ²⁰ _D + 51.4 ° (cl, CH ₃ OH) ¹ H-NMR spectrum.

[0022]

Example 5 N-benzyloxycarbonyl-L-serine (239 m) dissolved in 2 ml of tetrahydrofuran in a tetrahydrofuran solution of phenylmagnesium bromide (1M, 9 ml) under ice cooling in an argon atmosphere.
g, 1.0 mmol) was added dropwise over 2 minutes, sodium borohydride (76 mg, 2.0 mmol) was then added, and the mixture was stirred overnight at room temperature. The mixture was poured into ice water containing 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium hydrogen carbonate solution, water, and saturated saline,
Dry over anhydrous sodium sulfate and evaporate the solvent under reduced pressure to 2
-Benzyloxycarbonylamino-1-phenyl-
The crude product of 1,3-propanediol was obtained as a colorless oil. Purified by silica gel column chromatography (methylene chloride-methanol), (2S) -2-
Benzyloxycarbonylamino-1-phenyl-1,
3-Propanediol (threo: erythro = 1: 1) was obtained with a yield of 60%. ^The product was confirmed by ¹ H-NMR spectrum.

[0023]

Example 6 (2S) -2-benzyloxycarbonylamino-3-hydroxy-1-phenylpropanone (400 mg) obtained in Example 1 was added to ethanol (10 m).
l) and sodium borohydride (11
4 mg) was added. After stirring overnight at room temperature, the reaction was stopped by adding a 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. When the desiccant was filtered off and the solvent was distilled off under reduced pressure, (2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol (threo:
Erythro = 1: 2) was quantitatively obtained. ^The product was confirmed by ¹ H-NMR spectrum.

[0024]

Example 7 Using N-benzyloxycarbonyl-L-tyrosine (2 mmol) as a starting material, phenylmagnesium bromide was reacted according to Example 1. Since the reaction solution was suspended, tetrohydrofuran (20 ml) was added. The product solution was purified by silica gel chromatography (methylene chloride-methanol) to give (2S) -2-benzyloxycarbonylamino-3- (4-hydroxyphenyl) -1-phenyl-1-propanone as white crystals in a yield of 9 Earned in%. The product was confirmed by [α] ²⁰ _D + 31.2 ° (cl, CH ₃ OH) ¹ H-NMR spectrum.

[0025]

Example 8 Using N-benzyloxycarbonyl-D-serine (10.0 mmol) as a starting material, and following the procedure of Example 1, n-hexyl magnesium bromide (1M, 60 ml).
Was reacted. As a result, (2R) -2-benzyloxycarbonylamino-1-hydroxy-3-nonanone was obtained as a colorless oil in a yield of 65%. ^The product was confirmed by ¹ H-NMR spectrum.

[0026]

Example 9 A solution of (2S) -2-benzyloxycarbonylamino-3-hydroxy-1-phenylpropanone obtained in Example 1 in tetrahydrofuran (2 mmol, 1
2 ml) was added dropwise a tetrahydrofuran solution of K-selectride (1M, 8 ml) at −78 ° C. for 10 minutes in an argon atmosphere. The mixture was stirred as it was for 2 hours and then at room temperature for 1 hour. The reaction was stopped by adding 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to give 2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol as white crystals in a yield of 82%, (1R, 2S) -2-benzyloxy. Carbonylamino-1-phenyl-1,3-propanediol was obtained with a diastereomeric excess of 90% or more. ^The product was confirmed by ¹ H-NMR spectrum.

[0027]

[Example 10] (2S) -2-Benzyloxycarbonylamino-3-hydroxy-1-phenylpropanone (2 mmol) was used as a raw material, and according to Example 10, -78 ° C.
Was reacted with an n-hexane solution of diisobutylaluminum hydride (1M, 8 ml). As a result, 2
-Benzyloxycarbonylamino-1-phenyl-
Reaction yield of 1,3-propanediol as white crystals 8
0% of (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol was obtained with a diastereomeric excess of 90% or more. ¹ H-NMR
The product was confirmed by spectrum.

[0028]

According to the method of the present invention, α-
An optically active aminoketone can be produced by a very simple process of directly reacting an excess amount of Grignard reagent with an amino acid derivative, and further, when the aminoketone is reduced to produce an optically active aminoalcohol, the kind of the reducing agent is used. The amino alcohol can be stereoselectively obtained by appropriately selecting the type of solvent, reaction conditions and the like. INDUSTRIAL APPLICABILITY The method of the present invention is an effective method for producing an optically active aminoketone and an optically active amino alcohol, which are useful as synthetic intermediates for medicines and agricultural chemicals or as optical resolving agents.

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Claims (6)

[Claims] 1. General formula (1) R ¹ —NH—C ^* H (R ² ) —COOH (1) (wherein R ¹ represents an alkyl group or an amino-protecting group,
R ² represents an optionally substituted alkyl, aryl or aralkyl group having 1 to 8 carbon atoms, and R ¹ and R ²
They are linked - (CH _{2) 3} - or -CH ₂ -CH (OH)
-CH ₂ - shows the. C ^* represents an asymmetric carbon atom. ) In the α-amino acid derivative represented by the general formula (2) R ³ MgX ··· (2) (In the formula, X is a halogen atom, and R ³ has a substituent having 6 to 20 carbon atoms. It is a hydrocarbon group which may be present.)
The Grignard reagent represented by the formula (3) R ¹ —NH—C ^* H (R ² ) is used in an amount of at least 5 mol with respect to the α-amino acid derivative, and is reacted at a reflux temperature or lower. -COR ³ ... (3) (In the formula, R ¹ , R ² , R ³ and C ^* are as defined above.)
A method for producing an optically active aminoketone represented by: 2. The α-amino acid derivative represented by the general formula (1) is used at least 5 mol of the Grignard reagent represented by the general formula (2) with respect to the α-amino acid derivative, and reacted at a reflux temperature or lower. To produce an optically active aminoketone represented by the general formula (3), and then to reduce the aminoketone, the general formula (4) R ¹ —NH—C ^* H (R ² ) —C ^* H (OH ) R ³ ... (4) (In the formula, R ¹ , R ² , R ³ and C ^* are as defined above.)
And a method for producing an optically active amino alcohol. 3. A Grignard reagent represented by the general formula (2) is used in the α-amino acid derivative represented by the general formula (1) in an amount of at least 5 mol with respect to the α-amino acid derivative, and at a reflux temperature or lower. General formula (4) characterized by reacting in the presence of a reducing agent R ¹ —NH—C ^* H (R ² ) —C ^* H (OH) R ³ ... (4) (wherein R ¹ , R ² , R ³ and C ^* are as defined above.)
And a method for producing an optically active amino alcohol. 4. In the general formula (1), R ¹ is a benzyloxycarbonyl group, a t-butyloxycarbonyl group,
The method according to claim 1, wherein the α-amino acid derivative is an amino-protecting group selected from a fluorenylmethyloxycarbonyl group, a benzenesulfonyl group and a phthaloyl group. 5. An optically active aminoketone represented by the general formula (3) is reduced in a cyclic ether solvent in the presence of a borohydride reducing agent to give a threo form of the optically active aminoalcohol represented by the general formula (4). The manufacturing method according to claim 2, wherein the manufacturing is performed selectively. 6. An erythro body of an optically active aminoalcohol represented by the general formula (4) is selected by reducing an optically active aminoketone represented by the general formula (3) in an alcohol solvent in the presence of a borohydride reducing agent. The manufacturing method according to claim 2, wherein the manufacturing method is carried out.