JP3118061B2 - Production method of optically active hydroxylamine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing an optically active hydroxylamine useful as an intermediate of a raw material for pharmaceuticals by hydrosilylation of nitrones.

[0002]

2. Description of the Related Art Hydroxylamine is useful as various raw materials for synthesis because it produces amines by reduction and causes various addition reactions such as oxime formation and nitrile formation. Among them, particularly, optically active hydroxylamine can be easily derived into optically active amines and the like, and is therefore useful as a raw material for synthesis of pharmaceuticals and the like. Heretofore, various methods have been known as methods for producing such optically active hydroxylamine, but no method based on hydrosilylation of nitrones has been known.

[0003]

An object of the present invention is to provide a method for producing optically active hydroxylamine by a hydrosilylation reaction of nitrones.

[0004]

The present inventors have conducted various studies on catalysts for asymmetric hydrosilylation reactions.
The inventors have found that an optically active hydroxylamine can be efficiently obtained by hydrosilylation of nitrones by using a complex of a metal selected from ruthenium, palladium and nickel having an asymmetric ligand as a catalyst, and completed the present invention.

The present invention is represented by the following reaction formula.

[0006]

Embedded image

(Wherein R ¹ , R ² and R ³ are the same or different and each may have an alkyl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent. Represents an optionally substituted aryl group or an optionally substituted alkoxycarbonyl group, or R ² and R ³ together form an optionally substituted heterocyclic ring. Means an asymmetric carbon atom)

[0008] That is, the present invention is characterized in that a nitrone represented by the general formula (1) is reacted with a hydrosilane using a complex of a metal selected from ruthenium, palladium and nickel having an asymmetric ligand as a catalyst. This is a method for producing an optically active hydroxylamine represented by the general formula (2).

The nitrones (1) which are the starting compounds of the method of the present invention are, for example, represented by the following general formula (3)

[0010]

Embedded image

Wherein R ¹ , R ² and R ³ have the same meaning as described above,
_It can be obtained efficiently by oxidizing with ₂ WO ₄ as a catalyst using hydrogen peroxide. [S. Muraha
shi et al .; Org. Chem. , 55, 1736
-1744 (1990)].

In the above general formulas (1) to (3), R ¹ and R ²
And the alkyl group represented by R ³ include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
linear or branched alkyl groups such as n-butyl group and tert-butyl group; cyclic alkyl groups such as cyclopentyl group and cyclohexyl group; and aralkyl groups such as benzyl group and benzhydryl group. Examples of the aryl group include a phenyl group and a naphthyl group, and examples of the alkoxycarbonyl group include a methoxycarbonyl group and an ethoxycarbonyl group. The heterocyclic ring formed by R ² and R ³ together is a monocyclic ring such as 1-pyrroline or 2,3,4,5-tetrahydropyridine; 3,4-dihydroquinoline, Examples include fused rings such as dihydroisoquinoline. Examples of these groups and groups that can be substituted on the heterocycle include a halogen atom, an alkyl group, and an alkoxy group.

In the method of the present invention, a complex of a metal selected from ruthenium, palladium and nickel having an asymmetric ligand is used as a catalyst. Preferable examples of the complex include a ruthenium complex in which two asymmetric phosphine compounds and two phosphite compounds are coordinated.

Specific examples of the ligand include 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane (abbreviated as DIOP), 2,3-bis (Diphenylphosphino) butane (abbreviated as CHIRAPHOS), 1,2-bis (diphenylphosphino) propane (abbreviated as PROPHOS), 2,2'-bis (diphenylphosphino)-
1,1′-binaphthyl (abbreviated as BINAP), 2,
2'-bis [di- (p-tolyl) phosphino) -1,
1'-binaphthyl (abbreviated as Tol-BINAP),
N, N-dimethyl-1- [1 ', 2-bis (diphenylphosphino) ferrocenyl] ethylamine (BPPFA
, 2,4-tert-butyl-4- (diphenylphosphino) -2- (diphenylphosphinomethyl) -1-pyrrolidinecarboxylate (abbreviated as BPPM), 2,4-bis (diphenylphosphino) Fino) pentane (abbreviated as BDPP), 1,2-bis [(o-methoxyphenyl) phenylphosphino] ethane (DIP
AMP). Among these, particularly preferred complexes are a ruthenium-optically active phosphine represented by the formula (4) Ru ₂ Cl ₄ (Tol-BINAP) ₂ (NEt ₃ ) (where Et represents an ethyl group). Complexes may be mentioned.

All of these catalysts have compounds having different absolute configurations, that is, (+)-form and (-)-form. In the method of the present invention, by selecting any of these, the desired absolute form is obtained. The configuration hydroxylamine (2) can be obtained.

The amount of these catalysts used is usually 0.001 mol per mol of the nitrones (1) as the starting compound.
The range is preferably 1 mol to 0.1 mol, more preferably 0.005 mol to 0.01 mol. If the amount is less than 0.001 mol, the effect as a catalyst is not sufficiently exhibited, and if the amount is more than 0.1 mol, it becomes uneconomical.

The hydrosilanes used in the method of the present invention are not particularly limited as long as they can cause a hydrosilylation reaction. For example, dimethylsilane, diethylsilane, diphenylsilane, 1-naphthylphenylsilane, methylphenylsilane And dihydrosilanes such as phenylsilane, and diphenylsilane is particularly preferred.

The amount of the hydrosilane to be used is generally preferably in the range of 1 mol to 5 mol per 1 mol of the starting compound, nitrone (1).

The method of the present invention is usually carried out in the presence or absence of a solvent. Examples of the solvent that can be used include an aprotic polar solvent and a non-polar solvent, and specific examples include dioxane, tetrahydrofuran, methylene chloride, and toluene.

The reaction temperature and the reaction time vary depending on the type of the starting compound, the nitrone (1), the type of the catalyst, and other reaction conditions, but are usually from -80 ° C to 100 ° C, about 2 hours to 2 hours.
Preferably, it is 15 hours.

After the completion of the reaction, the obtained product is treated by a known method such as separation and extraction, distillation, and various chromatographic purification methods to obtain the desired optically active hydroxylamine (2). it can. Further, the obtained optically active hydroxylamine is treated with a corresponding optically active secondary amine by a known method such as reduction using zinc and hydrochloric acid.
It can be easily converted to a tertiary amine, which is useful as an intermediate for the synthesis of pharmaceuticals such as alkaloids.

[0022]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited thereto.
In addition, the measurement conditions of the physical property value are as follows. Melting point: Measured in an open capillary in a sulfuric acid bath. Nuclear magnetic resonance spectrum: JEOL JNM-GSX-2
70 (manufactured by JEOL Ltd.), ¹ H-NMR was 2
70 MHz, ¹³ C-NMR was 67.9 Hz, and the solvent was measured using CDCl ₃ .

Example 1 (S)-(-)-N- [1- (4'-chlorophenyl)
Preparation of [Ethyl] -N-methylhydroxylamine: (E) -N-
[1- (4'-Chlorophenyl) ethylidene] methylamine N-oxide 0.176 g (0.96 mmol)
Was added thereto, 1 ml of distilled tetrahydrofuran was added thereto, and the mixture was freeze-degassed with liquid nitrogen three times. In addition, Ru ₂ C
_{l 4 ((-) - Tol} -BINAP) 2 (NEt 3) 0.
017 g (0.0094 mmol) was added, and freeze degassing was performed three times with liquid nitrogen. To this mixture, 0.40 ml (2.2 mmol) of diphenylsilane was added under an argon atmosphere, and the mixture was stirred and reacted at 35 ° C. for 2 hours. After terminating the reaction by adding 10 ml of a 1M aqueous hydrochloric acid solution, ether 10 was added.
Extraction was performed three times with ml to remove the silyl derivative. The aqueous layer was separated, neutralized with sodium hydrogen carbonate, and then added with 10 ml of ether.
Extraction three times to separate the ether layer. The obtained ether layer was dried over anhydrous sodium sulfate, and the ether was removed under reduced pressure to obtain the desired N- [1- (4'-chlorophenyl).
Ethyl] -N-methylhydroxylamine crude crystals
136 g (0.73 mmol, yield 76%) were obtained. The optical purity of the product is determined by silica gel column chromatography and then purified by high performance liquid chromatography using a chiral column [CHIRALPAK AD ^™ (manufactured by Daicel Chemical Industries, Ltd.); 4.6 mm × 250 mm, developing solvent: hexane: isopropyl alcohol = 98: 2 (volume ratio)] and found to be 69% ee.
The absolute configuration was determined by deriving the product to a known amine. That is, N- [1- (4'-chlorophenyl) ethyl] -N-methylamine, which is a corresponding secondary amine, was obtained by a reduction reaction using zinc and hydrochloric acid, and the optical rotation of this compound was measured. α] ²⁵ _D = −65.2 °
(Neat), which is calculated from the literature value [S. Takena
Ka et al .; Chem. Soc. Chem. Comm
un. , P. 830 (1978)], and the product was determined to be the (S)-(-)-form. The physical properties of the product were as follows. Melting point: 108.0-109.0 ° C. Nuclear magnetic resonance spectrum: ¹ H-NMR (CDCl ₃ ) δ ppm: 1.44 (d, J = 6.6 Hz, 3H), 2.49 (s, 3H), 3.64 (q, J = 6.6 Hz, 1H ),
7.22-7.31 (m, 5H) ¹³ C-NMR (CDCl ₃ ) δppm: 19.9, 45.8, 68.5, 128.6, 129.3, 133.2, 140.7

Examples 2 to 14 In the same manner as in Example 1, Ru ₂ Cl ₄ ((−)
-ToI-BINAP) using ₂ (NEt _3), shown in Table 1 to Table 4 the results of producing an optically active hydroxylamine to hydrosilylation by diphenylsilane various nitrone. Tables 5 to 7 show physical properties of the products.
In the table, what is described as liquid in the column of melting point means that the product is liquid and the melting point cannot be measured. In the following examples, unless otherwise specified, the amount of the catalyst used was 1 mol%, the amount of the hydrosilane used was 2 equivalents to the nitrones, and the reaction time was 2 hours.

[0025]

[Table 1]

[0026]

[Table 2]

[0027]

[Table 3]

[0028]

[Table 4]

[0029]

[Table 5]

[0030]

[Table 6]

[0031]

[Table 7]

[0032]

[0033]

Examples 18 to 21 Similarly, various ruthenium-optically active phosphine complexes were used as catalysts, and the (E) -N-
Table 1 shows the results of the production of optically active N- [1- (4'-chlorophenyl) ethyl] -N-methylhydroxylamine by hydrosilylation of [1- (4'-chlorophenyl) ethylidene] methylamine N-oxide with diphenylsilane. It is shown in FIG. In the table, Ac represents an acetyl group.

[0035]

[Table 9]

Examples 22 to 25 Similarly, as a catalyst, Ru ₂ Cl ₄ ((−)-Tol-
Using (BINAP) ₂ (NEt ₃ ), (E) -N- [1- (4′-chlorophenyl) ethylidene] methylamine N-oxide used in Example 1 was hydrosilylated with various hydrosilanes to give (S)-. (-)-N- [1-
Table 10 shows the results of the production of (4'-chlorophenyl) ethyl] -N-methylhydroxylamine. In each case, the solvent was methylene chloride and the reaction temperature was 35 ° C.

[0037]

[Table 10]

[0038]

According to the method of the present invention, optically active hydroxylamine can be easily obtained in high yield, and the optically active hydroxylamine obtained by the method of the present invention can be prepared by a known method. Since it can be easily converted to a secondary amine and a pharmaceutical synthetic intermediate such as an alkaloid can be obtained, it greatly contributes to industrial benefits.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 207/46 C07D 207/46 211/94 211/94 217/08 217/08 // C07B 61/00 300 C07B 61/00 300 C07M 7:00 (56) References JP-A-63-23840 (JP, A) JP-A-62-19557 (JP, A) JP-A-60-89492 (JP, A) JP-A-56-29594 (JP) , A) JP-A-54-39059 (JP, A) JP-A-52-17405 (JP, A) Edited by The Chemical Society of Japan, "Chemical Handbook Basic Edition, Revised 4th Edition", September 30, 1993, Issued by Maruzen Co., Ltd. and opened the back cover. (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 239/10 C07B 53/00 C07C 239/12 C07C 239/18 C07B 61/00 300

Claims (1)

(57) [Claims] 1. A compound of the general formula (1) (Wherein, R ¹ , R ² and R ³ are the same or different, and may have an alkyl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent. A nitrone which represents an aryl group or an alkoxycarbonyl group which may have a substituent, or R ² and R ³ together form a heterocyclic ring which may have a substituent) And reacting a hydrosilane with a metal complex selected from ruthenium, palladium and nickel having an asymmetric ligand as a catalyst. (Wherein, R ¹ , R ² and R ³ have the same meaning as described above, and * means an asymmetric carbon atom).