JPS61137850A - Production of d-or l-n2-t-butoxycarbonyllysine - Google Patents

Abstract

PURPOSE:To obtain the title compound useful as a peptide synthesis reagent, easily at a low cost, by hydrolyzing D- or L-alpha-t-tuboxycarbonylamino-epsilon- caprolactam. CONSTITUTION:The objective compound can be produced by reacting D- or L-alpha-t-butoxycarbonylamino-epsilon-caprolactam in a solvent such as water and alcohol under alkaline condition at room temperature -120 deg.C, preferably 40-80 deg.C for 1-100hr. The alkali to be added to the reaction system is preferably an alkali metal hydroxide, and is added preferably in an amount of 0.9-3.0 equivalent based on the starting material in the form of a 1.0-1.5N aqueous solution.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing D- or L-N''-t-butoxycarbonyl lysine.

[Conventional technology]

Conventionally, as a method for producing NU-t-butoxycarbonyl-lysine, N6-benzyloxycarbonyl-N!
A method of hydrogenolyzing -t-ptoxycargenyl-lysine in methanol using 10% palladium-supported activated carbon as a catalyst is known [Herpetica Himica Aku II (He1v, Chin, Acta) No. 46]. Vol. 870-889, 1963].

[Problem that the invention seeks to solve]

This method hardly involves racemization and utilizes the difference in reactivity of the protecting groups protecting the amino groups at the 2- and 6-positions.
Although this is an excellent method for obtaining 2-t-butoxycarbonyl-L-IJ lysine, the raw material N6-benzyloxycarbonyl-N''-t-7'toxycarbonyl-L-I
To obtain J-lysine, it is necessary to go through several complicated steps. That is, after protecting the amino group at position 2 of LIJ dine with a copper complex or with a formyl group, 6
It is necessary to go through a complicated process of benzyloxycarbonylating only the amine group at position 2, then removing the protecting group for the amino group at position 2 to return it to an amino group, and then t-butoxycarbonylation anew. Therefore, the obtained target product must be expensive.

Moreover, expensive D-lysine must be used to obtain the D-derivative.

Therefore, an object of the present invention is to provide a method for selectively producing L- or D-N2-t-butoxycarbonyl lysine through simple steps and at a lower cost.

[Means for solving problems]

The above objects of the invention can be achieved by hydrolyzing D- or L-α-t-butoxycarbonylamino-ξ-caprolactam.

Hereinafter, specific configurations, examples, and effects of the present invention will be described.

L- or D-a-t-poxycarbonylamino-C-caprolactam, which is a raw material of the present invention, is obtained by t-butoxycarbonylation of DL-a-amino-ε-caprolactam, which is an industrial raw material for L-lydi/. After the optical resolution, DL-α-amino-ε-caprolactam can be easily obtained by performing t-butoxycarbonylation after optical resolution.

In hydrolysis, two cleavages, cleavage of the lactam ring and cleavage of the urethane bond in the side chain, may occur, and therefore, it is carried out under conditions that only the former cleavage occurs selectively. This condition is to make the reaction system alkaline.

As the alkali added to the reaction system, alkali metal hydroxides or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide can be used. preferable.

The amount of alkali used is usually D- or L-.

-t-butoxycarbonylamino-C-caprolactam 0.9 to 3.0 equivalents, preferably LO to zO
That's right. If the amount of alkali used is less than 0.6 g equivalent, the reaction will not be completed, and if it exceeds 3.0 equivalent, side reactions may occur.

Although an aqueous solution having an alkali concentration of 0.5 to 3.0 normal can be used, an aqueous solution having an alkali concentration of LO to L5 normal is particularly preferable.

If the alkaline aqueous solution is less than 0.5N, the reaction will be extremely slow, and if it exceeds 3.0N, cleavage of the urethane bond in the side chain or racemization will be promoted, which is not preferable.

The reaction is usually carried out in the presence of a solvent. Usually, water is sufficient as the solvent, but if necessary, alcohols such as methanol and ethanol may also be present, which are inert to the hydrolysis reaction and raw materials and which are mixed with water (64).

The reaction temperature is usually room temperature to 120°C, particularly preferably 4°C.
The temperature is 0 to 80°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.

Although the reaction time varies depending on the reaction temperature, solvent layer, etc., it is sufficient as long as it is sufficient to substantially complete the reaction. It usually ranges from 1 hour to 100 hours. The reaction method is not particularly limited, but preferably D- or L-a-t-butoxycarbonylamino-ε-caprolactam, an alkali,
A method can be adopted in which a solvent is charged into a reactor and heated in the above-mentioned temperature range while stirring.

When the reaction is finished, L- or D-N! -t-butoxycarbonyl lysine is isolated. The isolation method is not particularly limited, but for example, an organic solvent that first separates the reaction solution from water;
For example, unreacted raw materials and by-products soluble in organic solvents are removed by extraction with chloroform, diethyl ether, ethyl acetate, etc. The extracted aqueous layer is subjected to ion exchange treatment to remove by-produced L- or Q-lysine and basic by-products.

That is, after adjusting a strong ion exchange resin to an ammonium type, it is packed in a column, and the aqueous layer is passed through the column. If the unadsorbed effluent is concentrated under reduced pressure, L- or D-
N2-t-ptogicycarbonyl lysine is obtained.

〔Example〕

The present invention will be explained below with reference to Examples. In the examples, the optical purity was analyzed by acid hydrolysis of the above-mentioned L- or D
- After conversion to lysine, gas chromatography was performed.

That is, L- or D-lysine is replaced with L- or D-N
! .

After induction into N6-dibentafluorodiglopionyl lysine isopropyl ester, it was analyzed using a glass capillary column 0A-300 (manufactured by Sumitomo Chemical).

Example 1 (Synthesis of L-a-t-butoxycarbonylamino-ε-caprolactam) 38.5% of L-α-amino-ε-caprolactam was added to 14 four-loaf flasks equipped with a Dimroth condenser, a stirrer, a thermometer, and a dropping funnel. 4F (0.3 mol) and 300 ml of toluene were charged and stirred at room temperature. 2-
813 f (0.33 mol) of (t-butoxycarbonyloxyimino)-2-phenylacetonitrile was dissolved in 300 ml of toluene, added dropwise over about 1 hour, and further stirred for 3 hours.

After the reaction was completed, toluene was removed under reduced pressure, petroleum ether and diethyl ether were added, and the mixture was kept in a refrigerator overnight.

The precipitated crystals were separated by mouth filtration to obtain 54.3F of crude 1α-t-butoxycarbonylamino-ε-caprolactam.

The crude crystals were recrystallized from a mixed solvent of ethyl acetate and cyclohexane.

(Synthesis of N'-t-butoxycarbonyl-L-lysine) In a 300d three-necked flask equipped with a Dimroth condenser, a stirrer, and a thermometer, 2λ8f (0
, 1 mol) and l normal hydroxide) IJium aqueous solution 150 s? The reaction was continued at 50°C for 70 hours.

After the reaction was completed, the reaction solution was cooled to room temperature and extracted with 50 ml of chloroform. Water layer with strong ion exchange resin 5KI
B (strong cation exchange resin, ammonium M manufactured by Mitsubishi Kasei Co., Ltd.) 300 dC was passed through the aqueous solution 1 that was not adsorbed.
4 was concentrated under reduced pressure to obtain crude N'-t-butoxycarbonyl-lysine 19.8F. The yield was 80.5%. N! was purified by recrystallizing crude Nt-butoxycarbonyl-lysine with a mixed solvent of ethanol and cyclohexane. -t-butoxycarbonyl-L-lysine 17
．． Obtained 2F.

[α]D+8.02 (C=2.acetic acid), mp 194
~195°C, optical purity 98.2%.

Example 2 In the same apparatus as in Example 1, D-, -t-butoxycarbonylamino-C-capro2cutam was added to 22.8F (0.1 mol) and 100% of a 2N aqueous sodium hydroxide solution. 100 ml of ethanol was charged and reacted at 60°C for 50 hours. After the reaction was completed, ethanol was removed under reduced pressure. The remaining aqueous solution was extracted with 5 Q ml of chloroform and treated with a strong ion exchange resin in the same manner as in Example 1 to obtain crude N''-
t-Butquine carbonyl-[)-1J Jin L7.5f
I got it. The yield was 712%.

Purified N''-t-butyccarbonyl-D-lysine was obtained by recrystallization with a mixed solvent of ethanol and cyclohexane.

(-), D+8.01 (C=2.acetic acid), mp 1
94-195.5°C, optical purity 9&O%.

〔Effect of the invention〕

(1) Simply hydrolyzing D- or L-α-t-poxycarbonylamino-ε-caprolactam is important as a peptide synthesis reagent. r-IX L-N
'-t-ptoxycatv〆nyllysine can be FJ.

(2) The raw material D- or L-a-t-butoxycarbonylamino-ε-caprolactam can be easily obtained from DL, -α-amino-ε-caprolactam, which is an industrial raw material for L-lysine.

(3) Therefore, 〇-Matko can be obtained from L-N''-t by a simple operation from inexpensive L-α-amino-ε-caprolactam.
A carbonyl relisine can be obtained.

Patent application Daitoshi Co., Ltd.

Claims (1)

[Claims] D- or L-α-t-butoxycarbonylamino-ε
-D characterized by hydrolyzing caprolactam-
Or a method for producing L-N^2-t-butoxycarbonyl lysine.