KR850001130B1 - Process for preparing methlene-bis-amino acid - Google Patents

Abstract

Methylene-bis-amino acids of formula (I) are prepd. by reacting two equivs. of amino acids of formula (II) with one equiv. of formaldehyde of formula (III). In the formulas, a is phenyl, hydroxy phenyl, or methoxy phenyl, end R is Na+, K+, or any other alkali metal. (I) are used to synthesize penicillin or cephalosphorin antibiotics.

Description

Method for preparing methylene-bis-amino acid

The present invention relates to a method for preparing methylene-bis-amino acid of the formula (I) below.

Wherein A is hydrogen, lower alkyl having 1-6 carbon atoms, cyclohexyl, cyclohexadienyl, thiazolyl and phenyl, hydroxyphenyl, methoxy phenyl group and R is hydrogen or inorganic metal such as sodium, potassium or triethylamine And quaternary salts of tertiary bases such as trimethylamine and aromatic bases such as pyridine.

The compound of formula (I) of the present invention is a synthetic intermediate of amino acid derivatives protected with a novel compound, which is a novel compound, and is particularly used for the synthesis of penicillin or cephalosporin antibiotics. The method of protecting amino groups in peptide synthesis should firstly be easy in the protection process, high in yield, secondly in the reaction, less in side reactions, thirdly, the protection groups should be easily removed, and fourthly, low cost molecular weight protective agents.

Looking at the protection example of the amino group in the synthesis of peptides already known in the literature, firstly, a method of protecting the amino group by forming a salt by reacting the amino group with an acid, and the protecting agent used is hydrochloric acid, phosphorus trichloride, etc. Is protected by enamined with alkylaceto acetate or alkylaceto acetone, and the protecting agent used is methylacetoacetate, ethylacetoacetate, methylacetoketone, benzyl acetoketone, and the like. It is a method of protecting by Schiff base reaction by reacting, and the protecting agent used here is benzaldehyde, parinitro benzaldehyde, etc. are used.

In addition, a substance used as an amino group protecting agent is a urethane-based protecting agent such as benzyloxycarbonyl, t-butoxycarbonyl, diphenyl methoxy carbonyl βββ-trichloroethoxy carbonyl, and arylmethyl-0-nitrophenyl Protective agents of small phenyl series such as phenyl and paranitro sulfenyl, and aryl methylene series protective agents such as 5-chlorosalicyl aldehyde, 2-hydroxy-1-naphthaaldehyde and 3-hydroxypyridine are used. Silver is relatively expensive and has a high molecular weight as well as its removal method is not easy to use.

The inventors have completed the present invention, the most inexpensive, low molecular weight, low side reaction, economical method that can easily eliminate this drawback.

When the content of the present invention is described in detail, the amino acid of the following structural formula (II) is dissolved in an organic or inorganic base in a polar solvent, and then reacted with 1/2 equivalent of formaldehyde of the following structural formula (III) to remove water. It relates to a method of obtaining the methylene-bis-amino acid of the structural formula (I) below.

In the above structural formula A and R are as described above.

The compound of formula (II) is reacted in polar solvents such as water, methanol, ethanol and isopropanol, and the base used at this time is an inorganic base such as caustic soda or caustic, a tertiary base such as trietheramine, or an aromatic base such as pyridine. Is used.

In addition, formalin of formula (III) is reacted with 1/2 equivalent of amino acid.

In the reaction scheme, a dehydrating agent is used to shift the right equilibrium, and anhydrides of hygroscopic inorganic salts such as anhydrous magnesium sulfate anhydrous sodium sulfate may be used as the dehydrating agent, and a solvent which forms an azeotrope with water may be used.

For example, benzene, toluene, dichloromethane, ethyl acetate, hexane and the like are used, most preferably hexane.

The compound of formula (I) thus obtained was confirmed by ultraviolet absorption spectroscopy, elemental analysis, or the like.

The table below shows the results of comparing the analysis values of the Schiff base and bispecies compounds, which are phenylglycine derivatives.

Example 1 Preparation of N. N'-Methylene-bis-alpha-amino Phenylglycine Potassium Salt

Dissolve 6.6 grams of Potassium Hydroxide (85%) in 50 ml of methyl alcohol, add 15.1 grams (0.1 mol) of phenylglycine, add 4.3 grams (0.05 mol) of 35% formalin aqueous solution, and react at room temperature for 4 hours. Normal-hexane-200 milliliters were added to reflux to remove water and methyl alcohol, and then dispersed in 200 milliliters of ether to obtain 19 grams of yellow-white crystals (97.3%).

MP: -159 ~ 160 ℃

U. V: 248 nm (λ max)

Elemental analysis

Elemental calculated value

C: 52.3% 52.2%

H: 4. 13% 4. 1%

N: 7.17% 7.1%

Example 2 Preparation of N, N'-Methylene-bis-Alpha-Amino-Parahydroxy Phenylglycine Potassium Salt

After dissolving potassium hydroxyside (85%) and 6.6 grams in 50 ml of methyl alcohol, parahydroxy phenylglycine was dissolved in 16.7 grams (0.1 mole), followed by 4.3 grams (0.05 mole) of 35% formalin aqueous solution. While stirring at room temperature, 200 ml of normal-hexane was added to reflux to remove water and methyl alcohol, and then dispersed in 200 ml of ether to give 20.5 grams of yellow-white crystals (97%).

M. P: -173 ° C (decomposition)

U.V: -250 nm (λ max)

Elemental analysis

C: 48.3% 48.2%

H: 3.8% 3.7%

N: 6.63% 6.6%

Claims (1)

A method of preparing a compound of formula (I) by reacting 2 equivalents of amino acid of formula (II) with 1 equivalent of formaldehyde of formula (III)

Wherein A is a phenyl, hydroxy phenyl, methoxy phenyl group and R is an alkali metal such as Na ⁺ , K ⁺ .