JPS62132849A - Production of d-or l-n-t-butoxycarbonyl-o-benzylserine - Google Patents

Abstract

PURPOSE:To obtain the titled compound which is a kind of protected amino acid useful for peptide synthesis, suppressing racemization in high yield, by adding a specific reaction reagent to the reaction system, thereby suppressing the hydrolysis of benzyl halide even in a system containing water. CONSTITUTION:An aqueous solution of an alkali metal hydroxide is added to a reaction system containing D- or L-N-t-butoxycarbonylserine and a benzyl halide or, as an alternative method, a benzyl halide and an aqueous solution of an alkali metal hydroxide are simultaneously added to a reaction system containing D- or L-N-t-butoxycarbonylserine and the components are made to react with each other in a solvent such as dimethylformamide at 0-30 deg.C for 0.5-3hr to obtain the objective compound. Since alkali metal hydroxide has high solubility in aqueous solvent, the reaction can be carried out without using a large amount of solvent and the recovery of the solvent is facilitated.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to D- or L-Nt-butoxycarbonyl-〇-benzylserine (hereinafter referred to as Boc-0), which is a type of protected amino acid used in peptide synthesis. -Bzl -D
-Ser Boc -0-Bzl -L -Se
(abbreviated as r)).

[Conventional technology]

Conventionally, Boc -0-Bzl -D -Ser or B
oC-O-Bzl -L -Ser (As a D production method, optically active N-t-butoxycarbonylserine is reacted with benzyl halide in a non-aqueous system in the presence of an alkali metal hydroxide in an aprotic polar solvent. A method is known (Japanese Patent Publication No. 53-43947).

[Problem that the invention seeks to solve]

In conventional methods, O-benzylation was carried out in a non-aqueous system in order to avoid hydrolysis of benzyl halide by an alkali metal hydroxide.

However, in non-aqueous solvents, the solubility of alkali metal hydroxides is low, and even if an aprotic polar solvent that can relatively dissolve alkali metal hydroxides among non-aqueous solvents is used, the required amount cannot be obtained. A large amount of solvent is required to dissolve alkali metal hydroxides. In addition, solvent recovery must be performed at low temperatures to avoid racemization of reaction products, but it is not easy to recover large amounts of high-boiling point aprotic polar solvents.Furthermore, alkali metal water It is also difficult to handle oxides in solid form.As described above, there are many problems that need to be solved with conventional methods.

[Means and effects for solving the problem] As a result of various studies, the present inventors have found that by carrying out the reaction using a method of adding reaction reagents that is completely different from the conventional method, benzyl Hydrolysis of Ride is suppressed and D- or L
-Nt-butoxycarbonylserine (under JJ, Boc
-D-5er or Boc-L-Ser)
was found to be O-benzylated in high yield, and racemization did not occur, and the present invention was achieved based on this discovery.

That is, the present invention provides Boc-D-Ser or Boc-D-Ser
Add an aqueous solution of alkali metal hydroxide to a system where oc -L -Ser and benzyl halide exist, or add benzyl halide and alkali metal hydroxide to a system where Boc -D -5er or Boc -L -Ser exists. BoC-0-B characterized by simultaneously adding and reacting with an aqueous solution of
zl -D -Ser or Boc -0-Bzl -
L-Ser c7) Production method Theal.

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

In the present invention, BoC-D-3e used as a raw material
R BOC -L -SER + i -I can also use it in a way that can be used in a small way, and may be a commercially available product.

Examples of the benzyl halide used in the present invention include benzyl bromide and benzyl chloride. The amount used is usually Boc-D-5er or Boc-
0.9 to 6 times mole relative to L-Ser, preferably 1
~4 times the mole.

Examples of the alkali metal hydroxide used in the present invention include lithium hydroxide, potassium hydroxide, and sodium hydroxide. The alkali metal hydroxide is added as an aqueous solution, and its concentration is usually 10-50%, preferably 30-45%. The amount used is usually 0.9 to 11 times the mole of benzyl halide, preferably an equimolar amount.

In the present invention, it is important to add and react these raw materials, benzyl halide and alkali metal hydroxide in the following procedure.

i.e. Boc-D-Ser or Boc-L
An aqueous solution of an alkali metal hydroxide is added to a system in which -8er topenzyl halide is present, or
-D-SerAlso 1, tBoc-L-3erc7) Benzyl halide and an aqueous solution of alkali metal hydroxide are simultaneously added to the existing system and reacted.

The former addition procedure, for example, involves adding BoC-D-Ser or Boc-L to a small amount of organic solvent in advance.
-Ser and benzyl halide are dissolved, and an aqueous solution of an alkali metal hydroxide is added to the system at a rate that suppresses hydrolysis of benzyl halide.

Here, if the addition rate of the aqueous alkali metal hydroxide solution is too fast, the temperature of the alkali metal hydroxide in the reaction system will rise,
The raw material benzyl halide tends to be hydrolyzed and the reaction does not proceed properly.

The latter addition procedure is, for example, specifically adding a small amount of organic solvent and Boc-D-Ser or Boc-L-5e.
This is carried out by continuously adding equimolar amounts of benzyl halide and an aqueous solution of alkali metal hydroxide to a solution of r. The benzyl halide and the alkali metal hydroxide must be added in such a way that the molar ratio of the alkali metal hydroxide to the benzyl halide is below Ll.

When the molar ratio of alkali metal hydroxide to benzyl halide is higher than Ll, benzyl halide tends to be hydrolyzed.

In these addition procedures, dimethylformamide, tetrahydrofuran, etc. are preferably used as the organic solvent used in the reaction.

Its usage is usually Boc-D-Ser or BoC
The weight may be equal to or greater than the weight of -L-Ser, but it is preferably 1 to 5 times the weight in order to obtain the target product from the reaction solution in good yield.

The reaction proceeds suitably at 0 to 3 fJ°C and is completed in about 0.5 to 3 hours.

The target compound thus produced can be isolated, for example, by the following method.

First, the reaction solution is diluted with water, and then extracted with a water-insoluble organic solvent such as ethyl acetate, benzene, carbon tetrachloride, etc. to remove unreacted benzyl halide and the like. This method is advantageous in practice since it is not necessary to remove the organic solvent used in the reaction in advance. After adjusting the pH of the raffinate aqueous layer with a mineral acid such as hydrochloric acid or sulfuric acid, it is treated with a water-insoluble organic solvent such as ethyl acetate,
Extract again with chloroform etc. If the obtained organic solvent layer is concentrated, Boc-0-Bzl-D-3er or i!
Boc-0-Bzl-L-Ser is obtained in high yield.

〔Example〕

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

Example 1 A mixture of 3.08 f Boc-L-Ser (15 mmol), 7.701 C45 mmol of benzyl bromide) and 10 g of dimethylformamide was stirred in a water bath. 4896 sodium hydroxide aqueous solution 3 to the above solution
．． After adding 75y (45 mmol) over 30 minutes, stirring was continued for an additional 2 hours.

After the reaction was completed, the reaction solution was diluted with 35 ml of water and washed twice with 31 J ml of benzene. The separated aqueous layer was adjusted to pH 3.0 with a 10% aqueous hydrochloric acid solution, and then
Extracted three times with 3 Q zl of ethyl acetate.

After washing the extract three times with 30 ml of water, the solvent was distilled off under reduced pressure.
An oil containing 5.08 F was obtained. The yield was 74%.

The entire amount of the above oil was dissolved in 40 ml of ethyl acetate, and cyclohexylamine LIF was added. Stir at room temperature,
The precipitated crystals were collected as Boc-O-Bzl -L
-Ser cyclohexylamine salt 3.98F was obtained.

Melting point 150-152°C [α: l'6 +29.88 (C = 1. methanol) Example 2 Boc-L-3er 6.16 f (30 mmol) was dissolved in 201 It of dimethylformamide and stirred in a water bath. did. To this solution was added 7.5 g of 48% sodium hydroxide aqueous solution (9 tJ E remol) and 1 ml of benzyl bromide.
5.4f (90 mmol) was continuously added in equimolar portions over 30 minutes, and stirring was continued for an additional 2 hours.

After the reaction was completed, the reaction solution was treated in the same manner as in Example 1.
Oil containing c-0-Bzl-L-5er 10, 36
I got r. The yield was 76%.

Comparative Example 1 Boc-L-3er 3.08 f (15 mmol)
, benzyl bromide 7.70 f (45 mmol), powdered sodium hydroxide 18F (45 mmol) and dimethylformamide 5 Q liter/ml was stirred at room temperature for 3 hours.

After the reaction was completed, the reaction solution was neutralized by adding 1% hydrochloric acid, and the solvent was distilled off at 40°C under reduced pressure. The resulting residue was dissolved in 50 zl of saturated sodium bicarbonate solution, and ether 5 m
After washing with l for 3 times, add 10% hydrochloric acid to pH 3! I made this adjustment. This solution was extracted three times with 5 tj me of ethyl acetate, the extract was washed twice with 50 g of water, and the solvent was distilled off to obtain 5.05F of an oil containing Boc-0-Bzl-L-Ser. Ta.

The yield was 71%.

Comparative Example 2 A mixed solution of 3.08f (15 mmol) of Boc-L-Ser, 3.75r (45 mmol) of a 48% aqueous sodium hydroxide solution, and 1xl of dimethylformamide was stirred in a water bath. 7. Add benzyl bromide to this solution.
After adding 70f (45 mmol) over 30 minutes,
Stirring was continued for an additional 2 hours.

After the reaction was completed, the reaction solution was treated in the same manner as in Example 1 to obtain Bo.
Oil containing c-0-Bzl-L-Ser 2, 2
I got 9t. The yield was 28%.

〔Effect of the invention〕

According to the invention, Boc-D-Ser or BOC
The O-benzylation of -L-Set proceeds with good yield even in the presence of water, and in the isolation operation of the target product from the reaction solution, B
oc-0-Bzl-D-5ermar: l! Boc
-0-Bzl-L-Ser can be obtained in high yield.

Furthermore, since the alkali metal hydroxide has a high solubility in an aqueous solvent, a large amount of solvent is not required. Moreover, solvent recovery is easy, and the alkali metal hydroxide can be used in the form of an aqueous solution.

Claims (1)

[Claims] An aqueous solution of an alkali metal hydroxide is added to a system in which D- or L-Nt-butoxycarbonylserine and benzyl halide are present, or D- or L-Nt-
1. A method for producing D- or L-Nt-butoxycarbonyl-O-benzylserine, which comprises simultaneously adding benzyl halide and an aqueous solution of an alkali metal hydroxide to a system in which butoxycarbonylserine is present and reacting the same.