JPS625942A - Production of l-or d-n2-benzyloxycarbonyllysine - Google Patents

Abstract

PURPOSE:To selectively and efficiently obtain high-purity L- or D-N<2>- benzyloxycarbonyllysine, by hydrolyzing L- or D-alpha-benzyloxycarbonylamino-epsilon- caprolactam. CONSTITUTION:DL-alpha-Amino-epsilon-caprolactam is benzyloxycarbonylated and then subjected to optical resolution to give L- or D-epsilon-benzyloxycarbonylamino-epsilon- caprolactam, which is hydrolyzed in a solvent (e.g., water or methanol) at room temperature-120 deg.C for 1-100hr by treating the reaction system with hydrochloric acid, sulfuric acid, etc., into an acidic condition, to give the aimed substance. The amount of the acid used is 0.9-10 equivalents, preferably 1.0-7 equivalents based on the starting raw material and its concentration is 0.3-5 normals in an aqueous solution.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing 17- or D-N2-benzyloxycarbonyl lysine.

[Conventional technology]

Conventionally, as a method for producing L-4 or l) -N"-benzyloxycarbonyl lysine, N8-benzilitine-L
-Lysine was reacted with benzyloxycarbonyl chloride to give N2-benzyloxycarbonyl-N6-benzylidene-1,-lysine, and the benzylidene group was removed with acid to produce N2-benzyloxycarbonyl-L-I.
A method to obtain J Shinwo is known. (J, An,
Chem, Soc,, 83゜[Problem to be solved by the invention] N6-penzylidene-L-lysine is isomerized, 6
It has a property that a portion of the benzylidene group at the position is rearranged to the 2-position to generate N2-benzylidene-L-lysine. Therefore, in the conventional method of synthesizing N2-benzyloxycarbonyl-lysine using N6-penzylidey-L-IJ syn as a starting material, N6-benzyloxycarbonyl-L-lysine with benzyloxycarbonylation at the 6-position is synthesized.
- Since lysine is produced as a by-product, not only the production rate of N2-benzyloxycarbonyl-L-lysine decreases, but also a purification operation is required to remove the by-produced N6-benzyloxycarbonyl-L-lysine. Ta. In addition, in order to suppress isomerization, it is necessary to operate at a low temperature of several tens of degrees below zero, which not only slows down the reaction rate and requires a long reaction time, but also makes it difficult to operate. The law has many flaws.

Therefore, an object of the present invention is to provide a method for selectively and efficiently producing highly purified N2-benzyloxycarbonyl-L-lysine or N2-benzyloxycarbonyl-D-lysine.

[Means and effects for solving the problems] The above objects of the present invention can be achieved by hydrolyzing L- or 1)-a-benzyloxycarbonylamino-ε-caprolactam.

Hereinafter, a specific configuration of the present invention will be explained.

L- or D-α-benzyloxycarbonylamino-ε-caprolactam, which is the raw material of the present invention, is obtained by optical resolution after benzyloxycarbonylating DL-α-amino-ε-caprolactam, which is an industrial raw material for L-lysine. Alternatively, it can be easily obtained by optically resolving DL-α-amiso-ε-caprolactam and then subjecting it to benzyloxycarbonylation.

In the hydrolysis reaction of the present invention, two cleavages, cleavage of the lactam ring and cleavage of the urethane bond in the side chain, may occur, so the hydrolysis reaction is performed under conditions in which only the former cleavage occurs selectively and racemization occurs. It is preferable to carry out the experiment under conditions where no

This condition is to make the reaction system acidic.

When the reaction system is made alkaline, cleavage of urethane bonds occurs more easily, resulting in the desired L- or D-N2
-The yield of benzyloxycarbonyl lysine tends to decrease. In addition, racemization tends to occur in alkaline conditions.

In order to make the reaction system acidic, mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid are preferably used as the acid added to the reaction system, and hydrochloric acid is particularly preferably used.

The amount of acid used is preferably 0 with respect to L- or D-α-benzyloxycarbonylamino-ε-caprolactam.
．． The amount is 9 to 10 equivalents, more preferably 1.0 to 7 equivalents. The amount of acid used is 0. If it is less than g equivalent, the reaction tends not to be completed, and conversely, if it exceeds IO equivalent, side reactions tend to occur.

Although an aqueous solution having an acid concentration of 0.3 to 5N can be used, an aqueous solution having an acid concentration of 0.5 to 2N is particularly preferable. 0.
If the acid aqueous solution is less than 3N, the reaction will be extremely slow.
If it exceeds 5N, it is not preferable because it promotes cleavage and racemization of the urethane bond in the side chain.

The reaction is usually carried out in the presence of a solvent.

The reaction solvent is usually only water, but in order to improve the mixing state of the reaction solution, alcohols such as methanol and ethanol, benzene, toluene, tetrahydrofuran, p-
Dioxane etc. can be present together. When alcohols coexist, the reaction produces D- or D-N.
2-Benzyloxycarbonyl lysine reacts with alcohol to produce an ester as a by-product, but this can be easily converted into L- or D-N''-benzyloxycarbonyl lysine and alcohol by distilling off the alcohol from the reaction solution during the reaction. It can be decomposed.

The reaction temperature is room temperature to 120°C, particularly preferably 40°C.
~100°C. If the reaction temperature is lower than room temperature, the reaction rate will be slow, and if it exceeds 120°C, cleavage of urethane bonds and racemization will be promoted.

The reaction time varies depending on the reaction temperature, amount of solvent, etc., but it is sufficient as long as it is sufficient to substantially complete the reaction, and is usually 1.
-100 hours.

The reaction method is arbitrary, but usually L- or D-a-
A method can be adopted in which benzyloxycarbonylamino-ε-caprolactam, an acid, and a solvent are charged into a reactor and heated in the above temperature range while stirring.

After the reaction is completed, L- or D -N''-benzyloxycarbonyl lysine can be isolated usually by the following method. First, the reaction solution is extracted with a water-insoluble organic I medium such as chloroform, diethyl ether, ethyl acetate, etc. to remove unreacted raw materials and by-products soluble in organic solvents.
The raffinate water I- is neutralized with ammonia and then concentrated and crystallized to obtain +f L- or l) = N2-benzyloxycarbonyl lysine.

〔Example〕

Next, the present invention will be specifically explained with reference to Examples.

Example 1 L-a-benzyloxycarbonylamino-ε-caprolactam 3. O
l F (11,5 mmol), IN-hydrochloric acid aqueous solution 46
m1 was charged, and the reaction was continued at 90°C for 12 hours.

After the reaction was completed, the reaction solution was cooled to room temperature. Add 2 to this solution
After adding 5 g/8% aqueous ammonia, the mixture was extracted twice with 10 g/chloroform. The aqueous layer of the raffinate is concentrated and crystallized, and N
2-benzyloxycarbo= # -L-lysine 1.
91j' was obtained. The yield was 60%.

(a) D-13,9° (C=2.0.2N-HC4)M
p 224-225°C Example 2 L-α-benzyloxycarbonylamino-ε-caprolactam 3.01 F (11.5 mmol), l N
A mixture of 46 ml of -IJi acid aqueous solution and 20*1 methanol was reacted at 90° C. for 10 hours while distilling methanol off.

The reaction solution was treated in the same manner as in Example 1 to obtain 1.79f of N2-benzyloxycarbonyl-L-lysine. The yield was 58%.

(ff) Sweet-13.8° (C=2.0.2N-) IC4
) IVI p 224-226°C [Effects of the Invention] According to the present invention, high purity N2-benzyloxycarbonyl-L-lysine or N2-benzyloxycarbonyl-1) IJ lysine can be selectively and efficiently produced. can.

Patent application Daitoshi Co., Ltd.

Claims (1)

[Claims] L- or D-α-benzyloxycarbonylamino-
L characterized by hydrolyzing ε-caprolactam
- or a method for producing D-N^2-benzyloxycarbonyl lysine.