JPS6016928B2 - Production method of optically active amino alcohol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing optically active amino alcohols.

More specifically, it is a method for producing an optically active amino alcohol, which is characterized by reacting an optically active Q-amino acid with phenylmagnesium chloride (PhMgCI) in the presence of tetrahydrofuran (THF).

The formula for this reaction is as follows.

(In the formula, C* represents an asymmetric carbon.

R is an alkyl, aralkyl, or aryl group. Ph is a phenyl group. ) The optically active amino alcohol represented by the general formula (0) is an industrially and academically useful substance.

For example, it is not only useful as an optical resolution agent or an auxiliary agent for asymmetric synthesis, but also can be used directly as a synthetic intermediate for pharmaceuticals and agricultural chemicals. The following method for synthesizing the compound of formula (b) is already known.

That is, phenylmagnesium bromide is allowed to act on optically active alanine, leucine/phenylalanine, phenylglycine ethyl ester or its hydrochloride in diethyl ether.

J. Chem. Soc. , 127, 291 (1925)
: Same magazine, 785 (1926); Pharmaceutical magazine, 4 & 46 (1
928) Reference. The present inventors conducted various studies from an industrial standpoint regarding the method for producing the optically active amino alcohol represented by the general formula (n), and as a result, they came to discover the following new knowledge. That is,
m Instead of Q-amino acid ester as a starting material, Q
-The reaction proceeds smoothly even when amino acids are used.

This allows the step of esterifying the Q-amino acid to be omitted. {2) Phenylmagnesium as a reactant.

Similar results can be obtained by using phenylmagnesium chloride instead of mido. This made it possible to use chlorobenzene, which is much cheaper than bromobenzene, as a raw material for Grignard reagents. {3' In order to achieve the above two points, THF or T is used as a reaction solvent.
A composition containing HF is essential.

This is based on the fact that THF exhibits a particularly excellent solvent effect both in the preparation of phenylmagnesium chloride by the reaction of chlorobenzene and metallic magnesium, and also in the reaction of the Grignard reagent with Q-amino acids. There is. The reaction of phenylalanine or phenylglycine with phenylmagnesium bromide in diethyl ether has already been reported, but the former requires a long reaction time (2 hours) and has a poor yield (about 44%).

In the latter case, under normal reaction conditions, the raw material is completely recovered. J. Chem. Soc. , 123, 79 (1923)
; see Ibid. 127, 292 (1925).

The present invention was completed based on the above new findings.

In other words, the general formula RC*day (N is) COO day (1) (in the formula,
C* represents an asymmetric carbon.

R is an alkyl, aralkyl, or aryl group. ) The general formula RC*day (N ratio) C (Ph) 20 days (0) is characterized by reacting the optically active Q-amino acid represented by (In the formula, C* and R each have the same meanings as above.

Sh is a phenyl group. ) is a method for producing an optically active amino alcohol.

Next, the present invention will be explained in more detail.

The alkyl group in the substituent R of the optically active Q-amino acid of general formula (1), which is a raw material, also includes a cycloalkyl group and a cycloalkylalkyl group.

Examples of R include the following.
That is, C, ~4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, C5-6 cycloalkyl groups such as cyclohexyl, C6-7 cycloalkylalkyl groups such as cyclohexylmethyl, Examples include an aralkyl group such as benzyl or an aryl group such as phenyl. Specific examples of the optically active Q-amino acid of the present invention include the following compounds.

That is, alanine, valine, leucine, isoleucine, phenylalanine or phenylglycine. The substituent R of the optically active amino alcohol of general formula (b) obtained by the present invention is the same as that of general formula (1).

Examples of amino alcohols include the following. That is, 2-amino-1,1-diphenyl-1-propano-'2-amino-1,1-diphenyl-3-methyl-1-butanol 2mamino-1,1-diphenyl-3-methyl-1-bentanol 2-amino-1,1-diphenyl-4-methyl-1-bentano -ru-2-amino-1,1,3-triphenyl-1-f.

Examples include b/fnol 2-ami/-1.1.2 triphenylene-1-ethanol.

Next, a method of implementing the present invention will be explained.

A feature of the present invention is that THF or a composition containing THF is used as a reaction solvent.

Usually it is carried out using only THF, but in some cases it is permissible to add other solvents that do not inhibit the reaction. T.H.
Examples of additives for F include ethers such as diethyl ether, dioxane, dimethyl cellosolve, and dimethyl carbitol, hydrocarbons such as hexane, heptane, benzene, toluene, and xylene, or mixtures of two or more of these. Phenylmagnesium chloride, which is a reactant, is required in an amount of 4 times or more in mole relative to the Q-amino acid.

Usually 4 to 1 sonic molar is used. As a reaction method,
Phenylmagnesium.

Lido may be added to the amino acid or vice versa. The use of finely ground Q-amino acids is advantageous in increasing the rate of dissolution. The reaction temperature is suitably between 20 oo and the reflux temperature of the solvent system used. The target amino alcohol is usually obtained as a crystal by hydrolyzing the reaction mixture and then using a suitable isolation method.

As the purification method, extraction using key acid, various chromatography, recrystallization, etc. are selected and used as appropriate. The present invention will be explained in more detail with reference to Examples below.

Reference Example 1 In a well-dried 500 mm four-necked flask, 24.3 mm (1 atom) of magnesium (shavings), 40 mm (0.355 mol) of chlorobenzene, THFIOO, and separately prepared phenylmagnesium chloride were added. 5 secretions (about 13
mmol) and the inside of the flask was purged with nitrogen.

When the mixture is heated at 72 to 73 qo for 0.5 hours,
Dissolution of magnesium started. A mixture consisting of chlorobenzene 809 (0.711 mol) and THF 200 was added dropwise thereto over 1 hour. Add 3 more reaction mixture
．． A THF solution of phenylmagnesium chloride was obtained by heating under reflux for an hour. The liquid temperature rose to 78 CO, and the amount of remaining magnesium was 0.7 CO. The yield of Grignard reagent is 91% based on chlorobenzene.
Met. Example 1 A THF solution of phenylmagnesium chloride prepared according to Reference Example 1 was ground to 100 to 200 mesh (L
)-Alanine (12.0 mol) was added, and the mixture was heated under reflux for 6 hours.

The temperature of the reaction solution decreased from 76 qo to 7.0 qo. The reaction mixture was added in an amount of 40 to 60 qo to a mixture of 83% of concentrated hydrochloric acid and 300M of water for hydrolysis.

After adjusting the pH of the aqueous layer to 8.5 to 9.0 with N alkali, the aqueous layer was separated. After the organic layer was extracted with 300 μg of 0.3 μg of hydrochloric acid, the aqueous layer was washed with 200 μg of toluene.

When the separated aqueous layer was neutralized with 10 to 15 qo of N alkali 90M, white crystals were precipitated. After taking the product in a furnace, it was washed with water and dried under reduced pressure to obtain 18.5 g of (S)-2-amino-1,1-diphenyl-1-propanol.
Yield 60%. The physical property values were as follows.

[Q].

-86.5o (C I.lu chloroform) mpl01
~10〆○Example 2-4 TEF of phenylmagnesium chloride obtained in Reference Example 1
The Q-amino acid shown in Table 1 (the usage amount is shown in Table 1) was added to the solution.
(Both were ground in a mortar) and heated under reflux.

The reaction times are shown in Table 1. The temperature of the reaction solution is 7500 to 7
It dropped to 2oo. The reaction mixture was mixed with 83 parts of concentrated hydrochloric acid and 3 parts of water.
00M at 40 to 60 ml for hydrolysis.

After adjusting the pH of the aqueous layer to 8.5 to 9.0 with N alkali, the layers were separated. The organic layer was concentrated under reduced pressure and diluted with 200% of toluene. Table 1 shows the obtained toluene solution.
The optically active amino alcohols were obtained using the isolation method shown in .

The names, yields, and physical properties of the products are summarized in Table 1.

In addition, the specific optical rotation [Q]o is approximately 1% in chloroform in both cases.
Measured in solution. Table 1

Claims (1)

[Claims] 1 Optical activity α represented by the general formula RC*H(NH_2)COOH (wherein, C* represents an asymmetric carbon. R is an alkyl, aralkyl, or aryl group) -Characterized by reacting an amino acid with phenylmagnesium chloride (PhMgCl) in the presence of tetrahydrofuran General formula RC*H(NH_2)C(Ph)_2OH (wherein, C
* and R each have the same meaning as above. Ph is a phenyl group. ) Production method of optically active amino alcohol.