JPH0222254A - 2,3-diaminopropionic acid derivative - Google Patents

Abstract

NEW MATERIAL:A 2,3-diaminopropionic acid derivative expressed by formula I (R<1> is lower alkyl). EXAMPLE:Methyl (2S, 3S)-2-tritylamino-3-aminobutyrate. USE:A synthetic raw material for 3-amino-2-azetidinone derivatives expressed by formula II (R'' is H or organic residue) which is a synthetic intermediate for monobactam. PREPARATION:A compound expressed by formula III is reacted with hydrogen azide in the presence of triphenylphosphine and a dialkyl azodicarboxylate in an inert organic solvent, such as tetrahydrofuran, at -78 to +50 deg.C to form a novel azide compound expressed by formula IV, which is then reduced in the presence of 5% Pd/C, etc., in an inert organic solvent, such as ethyl acetate, at ambient temperature in H2 atmosphere to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 2,3-diaminopropionic acid derivatives.

In recent years, new basic f in β-lactam antibiotics has been developed.
Compounds with ￥ status include monocyclic β-lactam compounds,
Specifically, a group of compounds called monobactams are attracting attention. Monobactam is generally synthesized via a 3-amino-2-azetidinone derivative of the following formula, in which R7 represents the above-mentioned Δ taste (see, for example, Japanese Patent Laid-Open No. 5Et-125362).

The present inventor has discovered that 3 is an important synthetic intermediate for monobactam.
As a result of various studies on the production method of -amino-2-azetidinone derivatives, it was found that in the following formula (I), RI represents a lower alkyl group, and the 2,3-diaminopropionic acid derivative of the above formula (A)
It has been found that this is an extremely advantageous intermediate in the synthesis of 3-amino-2-azetidinone derivatives.

According to the present invention, the novel 2.3 of the formula (1)
--7 aminopropionic acid derivatives are provided.

In the compound of formula (I), the "lower alkyl group" represented by R' includes alkyl U having 4 or less carbon atoms such as methyl and ethyl groups.

The compound of the formula (I) is obtained by treating a compound of the following formula (■) in which RI has the above meaning with hydrogen azide in the presence of tri-2enylphosphine and azodicarboxylic acid dialkyl ester. It can be produced by reducing the compound in which R1 has the above-mentioned meaning.

According to the method described in -1-, the compound of formula (II) is first azidated.

This azidation can be carried out by reacting hydrogen anhydride in the presence of triphenylphosphino and azodicarboxylic acid dialkyl ester.

The ash layer is usually formed in an inert organic solvent, for example, with tetrahedron "1".
Ethers such as furano and ethyl ether.

The reaction can be carried out in aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform, preferably tetrahydrofuran and ethyl ether. Although the reaction mt+t is not critical,
The temperature is generally -78°C to 50°C, preferably 10°C to room temperature.

In the above azidation reaction, the amount of hydrogen azide used for the compound of formula (■) is generally at least 1 mol, preferably 1.5 mol, of hydrogen azide per 1 mol of the compound of formula (■).
It is advantageous to use the amount within the range of 2.5 mol, and it is preferable to use the triphenylphosphine/and azodicarboxylic acid dialkyl ester in an amount approximately equimolar to that of hydrogen azide.

Examples of the azodicarboxylic acid dialkyl ester that can be used in the above reaction include diethyl azodicarboxylate.

As a result, the azide compound of the formula (II+) is produced in a good yield, and this compound can then be converted into the compound of the formula (1) by reduction.

The reduction is usually carried out using an inert organic solvent, such as alcohols such as methanol and ethanol; esters such as ethyl acetate; ethers such as tetrahydrofuran;
Fl! fl15n: This can be carried out by reacting hydrogen in an amide such as dimethylformamide in the presence of a catalyst. Although the reaction temperature is not critical,
Room temperature is sufficient, and the pressure may be either normal pressure or increased pressure. Catalysts that can be used include common hydrogenation catalysts, such as palladium-carbon, palladium black, platinum, and rhodium shade.

In this way, the desired 2,3-diaminopropionic acid derivative of the formula (1) is produced, which can be prepared by following conventional methods.
For example, it can be separated and purified from the reaction mixture by filtration, extraction, recrystallization, chromatography, etc.

According to the method described above, if an optically active compound of the Irt family is used as the starting Irt compound, that is, N-)rityl-L(or D)-threony7-lower alkyl ester, the optically active compound of formula (1) can be obtained without causing racemization. 2,3-diami/propionic acid: *)! The J-isomer can be obtained in good yield.

The compound of formula (1) obtained according to the present invention can be treated with a silylating agent such as trimethylsilyl chloride in an inert αIB medium such as ethyl ether and then treated with a Grignard reagent such as [e"[-butylmagnesium chloride]. A ring-closing reaction is carried out by reacting with an ethyl ether solution of
-Methyl-2-azetidine 7 can be obtained in high yield. As described above, this compound is one of the essential intermediates in the synthesis of monobactams, and can be converted into known monobactams by sulfonation and acylation.

Note that the azide compound of the formula (In) produced as an intermediate in the above method is also a new compound,
It is an important intermediate when carrying out the method of the present invention.

The present invention will be further explained below with reference to Examples.

Example 1 (2 L) Under an argon atmosphere, 4.00 g of L-) leonine methyl ester hydrochloride was suspended in 150 g of methane, and 11.45 g of triphenylmethyl chloride and triethylamine 9. G-salt was added and stirred overnight at room temperature.

The reaction solution was washed with water and the solvent was distilled off under reduced pressure to obtain an oily residue.

The oily residue was subjected to silica gel column chromatography (elution solvent: dichloromethane:benzene y = 2:1), and N
-Trityl-threonine methyl ester was obtained as a viscous oil.

Yield: 8.92g.

NMR (CDC1a): 1.20 (31-1, d
, J=7Hz), 2.94 (III, m), 3
．． 14 (3H, s), 3.38 (11-1, m), 3.
70 (IH.

m), 7.30 (151L m) (b) N-trityl-L-)leonine methyl ester 4
．． 42j? and triphenylphosphine 0.72g2g
Dissolve 60 d of rubtrahydrofuran, add 3.18 N azide water (;-benzene solution 7,4 m[!, -70
Stir at ℃. To this mixture, add 25 ml of a solution of 4.1 g of diethyl azodicarboxylate in tetrahydrofuran! was slowly added dropwise, and the temperature naturally rose to 0°C. The reaction solution was further stirred under water cooling for 2 hours. The reaction solution was condensed under reduced pressure at 50° C., and the residue was subjected to silica gel column chromatography (IB solvent: dichlorometh/:n-hexane). 1:1), (2S, 3
3) -2-tritylamino-3azidobutyric acid methyl ester was obtained.

NMR (CDCl2): 1.22 (3H, d,
J=7Hz), 2.94 (III', d, J=
1011z), 3.18 (3H,s), 3.46
(IH, d, Jlollz), 3.82 (i
ll, m), 7.34 (15H, m) (c) The (23.33)-2-tritylamino-3-azidobutyric acid methyl ester obtained above was dissolved in ethyl acetate 20 m[! Dissolved in 5
% palladium on carbon at room temperature under a hydrogen atmosphere.
- Stir vigorously in the evening.

The reaction solution was filtered and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane, then dichloromethane/:methanol-20 L),
2.92 g of (2S,3S)-2-)ditylamino-3-amine acetic acid methyl ester was obtained as 11-color crystals. Melting point 89-92°C0MASS: M” 374 IR(Kl)r): 3390.3310.1730
cm-'NMR (CDC4'3): 0.98 (3
H, d, J=711z), 1.52 (2II, s),
2.84 (III, d, J=101-fz), 3.1
5 (3H, s), 3.29 (2 ratio m), 7.32
(1511, m) Reference Example Under argon atmosphere, (2S, 33)-2-) lytylamide 7-3-aminobutyric acid methyl ester 2.41 g of ethyl ether 6 solution 40 mQ, under water cooling + 1, ) rimeg lunryl chloride A solution of 838■ in ether and 1mf in ether of triethylamine 781■! i8 was added dropwise one after another. After stirring at room temperature for 1 hour, under an argon atmosphere,
The precipitated triethylamine hydrochloride was removed by IF, and the solution was stirred under water cooling. Add to this 1-butylmagnesium chloride ether solution 6,00ml! (8,30mm
o I (containing t-butylmagnesium chloride) was added dropwise to the mixture, and the mixture was stirred overnight while cooling with water. Then, 18 liquids of saturated ammonium chloride diminution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: dichloromethane:ether - 10:1) to give an oily substance of 1.41%.
I got g. Recrystallize the ether from the sun, (
3S, /Is)-3-2-azetidinone.

Melting point 170-173°C6 MASS: M+342 [α] Sweet -207,5° (C=2.03°IR(K
[lr): 3390.3350, NMR (CDCN3
): 0.38 (3111I, broads),
3.02 (III.

(III, m), 6.05 (IH, s), Cl
ICl5) 3260.1755 rya-' d, J=(311z), 2.7G (1dq, J=6
, 2Hz), 3. GO 7,32 (1511m) Obtained 29g as a white fine product.

Claims (1)

[Claims] 1. Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R^1 represents a lower alkyl group, compound.