JPS61148155A - Production of d-or l-n6-carbobenzoxyllysine - Google Patents

Abstract

PURPOSE:To obtain the titled compound from inexpensive raw materials while reducing amounts of formic acid, acetic anhydride, etc., used, by reacting D- or L-lysine hydrochloride with acetic acid, etc., in the presence of both an alkali metal salt of an organic acid and formic acid under a specific condition. CONSTITUTION:D- of L-Lysine hydrochloride is reacted with an organic acid anhydride selected from acetic anhydride and acetic formic anhydride in the presence of both an alkali metal salt of an organic acid and formic acid at 0-20 deg.C to give a compound shown by the formula. Then, this compound is reacted with carbobenzoxyl chloride while being kept at 8.5-10.5pH, to give D- or L-N<16>-carbobenzoxyl-N<2>-formyllysine. Further, it is heated to give D- or L-N<6>-carbobenzoxyllysine.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing D- or L-N''-carbobenzoxylysine.

[Conventional technology]

Conventionally, as a method for producing D- or L-N@-carbobenzoxylysine, D- or LIJ dine is reacted with copper carbonate to protect the amino group at the first position as a copper complex, and then
A method of reacting with carbobenzoxyl chloride is known (JP-A-48-44231).

[Problem that the invention seeks to solve]

Although this method is a useful method for selectively reacting only the amine group present at the 6th position of the two amino groups present in lysine, it is a useful method for decomposing copper complex salts.
It is necessary to process waste liquid containing copper ions, which are heavy metal ions, and complicated operations are required to reduce the content of copper ions in the product. I had a problem.

Therefore, an object of the present invention is to establish a method for producing D- or L-N'-carbobenzoxylysine that eliminates the above-mentioned problems.

[Means and effects for solving the problems] The object of the present invention is to combine D- or L-lysine hydrochloride with acetic anhydride and acetic formic anhydride in the presence of an alkali metal salt of an organic acid and formic acid. organic acid anhydride and 0 to 20℃
to obtain D- or L-N2-formyl lysine represented by the following formula:
to obtain D- or L-Ns-carbobenzoxy-N2-formyl lysine by reacting with carbobenzoxyl chloride while maintaining the temperature of
This can be achieved by heating formyl lysine.

The present invention will be explained in detail below.

D- or L-lysine hydrochloride used in the present invention is
Either lysine hydrochloride or lysine dihydrochloride may be used,
Preferred is gin-hydrochloride. Moreover, they can be used in either the D-form or the D-form.

Preferred specific examples of the alkali metal salts of organic acids used in the present invention are formic acid, potassium formate,
Lithium formate, sodium acetate, potassium acetate,
Particularly preferred are sodium formate and potassium formate.

The amount of the alkali metal salt of an organic acid to be used is sufficient to neutralize lysine hydrochloride, for example, 1 equivalent for lysine hydrochloride, and 2 equivalents for lysine dihydrochloride.

The amount of formic acid used is 5 to 20 equivalents, preferably 8 to 11 equivalents, relative to lysine. If the amount of formic acid used is less than 5 equivalents, lysine hydrochloride and the alkali metal salt of an organic acid will not dissolve, resulting in a low reaction yield. If the amount exceeds 20, the reaction will not be affected, but more raw materials than necessary will be used. In addition, unreacted formic acid remaining in the reaction system after the completion of the reaction can be recovered by distillation under reduced pressure and used again.

The amount of acetic anhydride to be used is 1 to 5 times the amount of lysine, preferably 2 to 3 times the amount of lysine.

The amount of acetic formic anhydride to be used is 1 to 4 times the mole, preferably 11 to 2 times the mole of lysine.

The reaction time may be sufficient to substantially complete the reaction, but is usually 0.5 to 2.0 hours.

The reaction temperature is 0-20°C.

After the reaction is completed, water is added to the reaction solution to decompose acetic anhydride or acetic formic anhydride and acetic acid and formic acid are concentrated under reduced pressure, or directly concentrated under reduced pressure to form D- or L-N''-.
Obtain a concentrate of formyl lysine. In addition, when concentrating under reduced pressure, the distilled formic acid can be used again in the present invention as it is.

The D- or L-N2-formylysine thus obtained is then N4-carbobenzoxylated. D- or L
-N2-formyl lysine may be used after being purified, or may be used as a concentrate.

The N'-carbopentyl quintylation reaction is carried out at pH 8.5-1.
0.5, preferably in the range of 9.5 to IO. The pH is adjusted by adding an alkaline compound to the reaction system. Alkaline compounds typically include sodium hydroxide, potassium hydroxide, and lithium hydroxide.

The amount of alkaline compound used is usually O as the concentration of the aqueous solution.
15 to 5, preferably LO to 2.0 normal.

The amount of carbobenzoxyl chloride used is D- or L
The amount is 1 to 15 equivalents, preferably 1 to 11 equivalents, relative to -N''-formyl lysine.

The reaction temperature is 0-20°C, preferably 5-15°C.

The reaction time may be sufficient to substantially complete the reaction, but is usually 0.5 to 5 hours.

When the carbobenzoxyl chloride reaction is completed, D
- or L-N6-carpopenzoxy-N2-formyllysine is obtained, but it is practical to subject it to the heating reaction as it is without isolating it.

The heating reaction is usually carried out by adding an acid to pH 1 to 3, preferably 15.
Do it in ~2. As the acid, hydrochloric acid or sulfuric acid is usually used. When the pH is less than 1, side reactions occur and the target product cannot be obtained in good yield, and when it exceeds 3, the reaction rate tends to decrease.

Reaction temperature is 80-120℃, preferably 90-105℃
It is.

The reaction time may be sufficient to substantially complete the reaction, but is usually 0.5 to 5 hours.

After the reaction is completed, the reaction solution is cooled to room temperature, and then diluted with diethyl ether,
yt, "'"5""48"11 (After taking it out, the pH of the aqueous layer was adjusted to 6.5-7, and the precipitated crystals were separated by mouth filtration, resulting in D- or L-N8-carbobenzoxylysine. can get.

〔Example〕

The present invention will be specifically explained below using Example t.

Example 1 500II equipped with a dropping funnel, thermometer and stirrer
230.1 F (5 mol) of L9 gin-hydrochloride 9 L3 F (0.5 mol) were charged and cooled to 5-1 (1° C.).
Added 0f (0.5 mol) over 10 minutes, then 5
~1 (stirred at Ic.

Next, acetic anhydride 102.1F (10 mol) was added at 5 to 10°C.
The mixture was added dropwise over a period of 30 minutes, and the mixture was further stirred at 10 to 20°C for 1 hour. After the reaction was completed, 10 d of water was added and the mixture was stirred at room temperature for 1 hour. Then, it was concentrated under reduced pressure using an evaporator.

While cooling the concentrate to 5-15°C, the pH was adjusted to 10 with 2N sodium hydroxide.

500 equipped with two dropping funnels, thermometer and stirrer
Add the above adjustment solution to +w14 flasks and heat to 5-15°C.
The mixture was stirred while cooling.

97.8f of carbobenzoxyl chloride in the dropping funnel
(0.58 mol) and 300 ml of 2N sodium hydroxide
After maintaining the pH at 1o, lbopenzoquine chloride was added dropwise over about 30 minutes, and the reaction was continued for an additional 2 hours.

After the reaction was completed, the pH was adjusted to ~2 with concentrated hydrochloric acid, and then heated under reflux for 2 hours. Next, the reaction solution was cooled to room temperature and extracted with 200 gt of ethyl acetate, and the aqueous layer was adjusted to pH 6.5 to 7.0 with 2N sodium hydroxide and stirred for 1 hour.

The precipitated crystals were split and dried to obtain N6-carbobenzoxyl-L-ridyyizs, 5f.

The yield was 89.5%.

Example 2 Gi M276.1p (6 mol) and L-lysine hydrochloride 913f (0.5 mol) were charged into the same apparatus as in Example 1, and cooled to 5-10°C. Potassium formate42. IN
(0.5 mol) was added over 10 minutes, and then
Stir at ~1O<0>C.

Then acetic acid formic anhydride 57.2 F (0.65 mol)
was added dropwise over 30 minutes at 5-10°C, and then for another 1 hour at 10-10°C.
The mixture was stirred at 20°C. After the reaction was completed, 10 ml of water was added and the mixture was stirred at room temperature for 1 hour, concentrated in the same manner as in Example 1, reacted with carbobenzoxyl chloride, and heated to form N6-carbobenzoxyl L + ) 129.3p of gin was obtained.

The yield was 92.2%.

〔Effect of the invention〕

The present invention exhibits the following effects.

(1) Since L IJ resin acid salt, which is an inexpensive raw material, is used as it is, the compound according to the present invention can be obtained at low cost.

(2) The amount of formic acid and acetic anhydride used can be small.

(3) When acetic acid formic anhydride is used, the compound according to the present invention can be obtained at a lower cost.

Kaede Gatoshi Co., Ltd.

Claims (1)

[Claims] D- or L-lysine hydrochloride and an organic acid anhydride selected from acetic anhydride and acetic formic anhydride are reacted at 0 to 20°C in the presence of an alkali metal salt of an organic acid and formic acid. to obtain D- or L-N^2-formyl lysine represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼;
reacting with carbobenzoxyl chloride while maintaining the temperature between 5 and 10.5 to obtain D- or L-N^6-carbobenzoxyl-N^2-formyl lysine; Benzoxyl-N^
A method for producing D- or L-N^6-carbobenzoxylysine, which comprises heating 2-formyllysine.