JPS59148762A - Azetidinone derivative - Google Patents

Abstract

NEW MATERIAL:An azatidinone derivative shown by the formula I (R1 is H, or amino-protecting group; X is H, alkyloxy, aralkyloxy, aryloxy, OH, OSO3H, or SO3H). EXAMPLE:3-t-Butoxycarboxamido-1-benzyloxy-4-trifluoromethyl-2-azetidin one. USE:Useful as a parent nucleus for beta-lactam antibiotic having high activity. PREPARATION:For example, a compound shown by the formula II is reacted with titanium trichloride in water or an aqueous solution to give a compound shown by the formula I where R<1> is amino-protecting group and X is H. This compound is reacted with sulfuric anhydride or its reactive derivative to give a compound where X of the formula I is a salt of SO3H (group shown by the formula III, n-Bu4N<+>, K<+>, Na<+>, etc.).

Description

Detailed Description of the Invention The present invention relates to the following general formula (1) (where RI is a hydrogen atom or an amino protecting group, X is a hydrogen atom, alkyloxy, aralkyloxy, aryloxy, OH, -0303M 1- 5o, '-M+. M+ is H+ or H"0, n-Bu4N",
K+, Na+, and other cadecations. ), which is novel and useful as a base for highly active β-lactam antibiotics.
- Trifluoromethylazetidinone derivatives (including their salt forms).

Examples of highly active β-lactam antibiotics containing the present compound as a core include compounds represented by the following formula.

Examples of the amino protecting group in R□ include aromatic acyl groups such as phthaloyl, p-nido-benzoyl, p-tert-benzoyl, p-ttrt-71, and methylbenzenesulfonyl, formyl, acetyl, and propionyl. , monochloroacetyl, dichloroacetyl,
Esterified aliphatic anol groups such as trichloroacetyl, methoxycarbonyl, ethquincarbonyl, t-phytoxycarbonyl, impropoxycarbonyl, benzyloxycarbonyl, p-benzyloxinecarbonyl, p-methoxybe/zyloxycarbonyl, etc. Examples include a carboxyl group, a trityl group, and a 2-nitrophenylthio group.

In X, the alkyl group of alkyloxy is, for example, lower alkyl such as methyl, ethyl, butyl, etc., and the 7ralkyl group of aralkyloxy is, for example, hahenzyl,
Phenethyl, p-2)a benzyl as the aryl group of aryloxy.

(The series can include evaphenyl, p-nitrophenyl.

Do you produce derivatives of the present invention? For example, there are the following methods:

(1) When a compound represented by the general formula is reacted with titanium trichloride in water or an aqueous solution.

general formula An azetidinone derivative represented by is obtained. R.

has the same meaning as above except for the hydrogen atom.

When the derivative obtained here is reacted with sulfuric anhydride or a reactive derivative thereof, an azetidinone derivative represented by the general formula is obtained. R1 represents the above amino protecting group.

M■ means the same cation as above.

(2) When a compound represented by the general formula is reacted with sulfuric anhydride or a reactive derivative thereof, an azetidinone derivative represented by the general formula is obtained. R8 and M■ have the same meanings as above.

The compound represented by the general formula is, for example, 2-amino-3-hydroxy-4,4,4-trifluorobutanoic acid (Journal
of American Chemical 5oc
ieLy+80.187-192 (1958)) and condensing it with O-alkyl or O-arafurekylhydroxylamines using carbodiimide as a condensation agent. , carrying out a dehydration ring-closing reaction using ethyl azonecarboxylate.
It can be manufactured in a hassle-free manner. Of course, R1 and R2 have the same meaning as above.

Specific examples of amino-protecting groups used to protect free amino groups in the present invention include groups that form a urethane group together with the amino group (eg, t-butoxycarbonyl, ncrobe/thyloquinocarbonyl, 2.2. Common amino-protecting groups such as trityl (2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrohe/leroxycarbonyl, lephenylmethoxycarbonyl, etc.) are included, and t-butoquinocarbonyl is particularly preferred. The condensation of the amino group-protected compound represented by the following formula with 0-alkyl or 0-aralkylhydroxylamines can be carried out in a mixed solvent of tetrahydrofuran (THF) and water or dimethylformamide (DMF) and water. The reaction temperature is -5 to 40°C, preferably θ to 2°C. The condensing agent is carbodiimide,
Particularly preferred is l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide. The hydroxylamine used for the starting material tit is 1 to 2.0 times the mole, preferably 1 to 1.5 times the mole, and the carbodiimide is also 1 to 2.0 times the mole.
It is about 2.0 times the mole, preferably about 1 to 1.5 times the mole.

The dehydration ring closure reaction of the compound track can be carried out in an ether-based inert solvent such as tetrahydrofuran, diethyl ether, dioxane, etc. Tetrahydrofuran is especially preferred. The amount of triphenylphosphine to be used for compound (2) is 1 to 3 times mol, preferably 1-L, 5 times mol, and even if diethyl azodicarboxylate is used, it is 1 to 3 times mol, preferably 1 to 1.5 mol. It is twice the mole. The reaction temperature is from -30C to refluxing the solvent, preferably from -10C to 25C. The reaction time is 1 to 30 hours, preferably 15 hours.
~20 hours. Compound (II) is a compound (II) in which R2 is be/zyl or p-nitrobenzyl in a solvent such as ethyl acetate, dioxane, tetrahydrofuran, methanol, or ethanol. 10%Pd/c, '30%Pd/
25r from OC in the presence of a hydrogenation catalyst such as BaCO3
It can be produced by subjecting it to a hydrogenation reaction under hydrogen pressure of 1 to 10 atm for 5 minutes to 2 hours.

Compound @) is compound (It) prepared using titanium trichloride in a mixed solvent of alcohol and water under neutral conditions? This can be reduced. The reaction temperature is θ~30C, preferably θ~IO
c. Reaction time is 1-2 hours.

Compound axis and (b) are compounds (It) or (a)
It can be produced by reacting, for example, sulfuric anhydride or a reactive derivative of sulfuric anhydride.

It can be produced by reacting the above-mentioned reactive derivatives of sulfuric anhydride. Examples of the above-mentioned reactive derivatives of sulfuric anhydride include adducts of sulfuric anhydride-pyridine, sulfuric anhydride-dimethylformamide, sulfuric anhydride-reoxane, chlorsulfonic acid-pyridine, and chlorsulfonic acid-α-picolinato. The reaction is with compound (II) 1
For each mol of I', about 1 to about 5 moles, more preferably about 1 to about 2 moles of sulfuric anhydride or a reactive derivative of sulfuric anhydride is added. The reaction temperature is -10~8
0C1, more preferably 0 to 30C. Reaction solvents include ethers such as dioxane, THF diethyl ether, esters such as ethyl acetate and ethyl formate, chloroform, methylene chloride, etc., logenated hydrocarbons,
−'+Hydrocarbons such as nzene and n-hexane 174,
Chylformamide, dimethylacetamide, etc. are used alone or in combination. After the completion of the reaction, the reaction mixture can be obtained in any purity by known purification and separation means such as solvent extraction, recrystallization, and phosphorography.

The cationic moiety of the azetidinone derivatives and (b) sulfonate salts can be obtained from either organic or inorganic bases.

Such cationic moieties include, but are not limited to, the ions shown below. Such ions include substituted ammonium such as ammonium, alkylammonium (e.g., tetra-n-butylammonium), alkali metals such as lithium, sodium, potassium, alkaline earth metals such as calcium, magnesium, pyridinium, dichlorohexylammonium, etc. can be mentioned.

Furthermore, there are optical isomers of the derivative 1 of the present invention,
In this case, each of these isomers and mixtures thereof are also included in the present invention. It was confirmed by elemental analysis, infrared absorption spectrum, nuclear magnetic resonance spectrum 0, etc. that the compound of the present invention has the chemical structure described above.

In the production of the derivatives of the present invention, the method for protecting the amino group or the method for removing the protecting group is a method commonly used in peptide synthetic chemistry, for example, in Protein Chemistry 1 Amino Acids and Peptides, co-edited by Tokohori, Kaneko, and Narita, Kyoritsu Shuppan, 1968.
The method described in 2006 may be used.

Hereinafter, the present invention will be explained in detail with reference to Examples.

Example 1 Production of 3-t-butoxycarboxamide-1-benzyloxy-4-triple-omethyl-2-7zetidinone (a) 2-t-butoxycarboxamide-3-hydroxy-4,4,4-)refluoro Production of butanoic acid: 2-amino-3-hydroxy-4,4,4-trifluorobutanoic acid (29111, 6mM) was dissolved in THFIOm
A mixed solvent of 1V and 20ml of water? This was dissolved.

This is triethylamine (1.62 ml, + 1
．． ) and di-t-butyl dicarponate (3,2
F.

14.7mM) was added and stirred at room temperature for 15 hours.

After the reaction was completed, THF was distilled off under reduced pressure, and the pH was adjusted to 2.5 with IN hydrochloric acid under water cooling. This aqueous solution was extracted three times with 30 ml of ethyl acetate, and these organic layers were combined for 40 ml of ethyl acetate.
After washing with 1 ml of water, it was washed with 30 ml of saturated saline.

After drying this with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude title compound was obtained by reprecipitation with n-hexane (2.2f, yield 70%).

KBr-1 1R, max('m:330011730116
45t1520.1258.1160゜l 14 O NMR (DMSO-d6ppm) + 1.40 (S
, 9H).

4.20 (m, 28) (b) Production of 0-benzyl-2-t-butoxycarboxamide-3-hydroxy-4,4,4-)lifluorobutanohydroxamate 2-[-butquincarboxamide- 3-hydroxy-4
,4,4-)lifluorobutanoic acid(+,!It Ov,
6.96mM) to THFI5+! +/ and water l511
Ie and then O-benzylhydroxylamine hydrochloride (1,3a y).

8.36mM) was added. After adjusting the pH of this solution to 4.0 to 5.0 with saturated deuterated water, l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (water-soluble carbodiimide) ( +, 46
An aqueous solution of 7.64 mM) was added dropwise. The pH of the solution during the addition and reaction was adjusted to 4.0-5.0 with 1N HCl. After reacting for 20 minutes under water cooling and 30 minutes at room temperature, THF was distilled off under reduced pressure and extracted three times with 40M ethyl acetate.

All the organic layers were combined and washed with 0.5M citric acid aqueous solution, then washed with 5 ml of sodium chloride water, and further washed with saturated brine. After drying this with anhydrous sodium sulfate, ethyl acetate was distilled off to give 1.84% of the crude title compound.
f, obtained in 70% yield.

KBr-1 1R, m8xcm: 3400, 3300, 3200
゜1680, +660.1520゜1300, +260i1160゜1120.740.69O NMR (DMSO-d6 ppm), 41 (S, 9
H).

4.20 (m, 2H), 4.82 (S.

2 H), 6.40 (broad S.

IH), 7.35 (S, 5H) (c) 3-
t-Butoxycarboxamide-1-benzyloxy-4
-Preparation of trifluoromethyl-2-7zetidinone 0-benzyl-2-t-butquincarboxamide-3-hydroquino-4,4°4-trifluorobutanohydroxamate (0,70f, 1. 8'5mM
) and triphenylphosphine (0,589,2,21
) was dissolved in 15+ml/l of dry THF. This is t
Diethyl azonecarboxylate (,0,35f, 2.03
3mM) dissolved in 1ON1 dry THF and cooled with water.
It was dropped in 0 minutes. The 30-minute diameter sample was brought back to room temperature and stirred for 20 hours. After distilling off the solvent, the residue was subjected to silica gel chromatography. Elution with ethyl acetate-n-hexane (1:3) yielded 0.219 3-t-butoxycarboxamide-1-benzyl-leoxy-4-trifleomethyl-2-7zetidinone.
Obtained as crystals with a yield of 0%.

IRKBr Sen-”:'3320,1805.+698
゜νmax +523.1285, 116.0゜114 O NMR (DMSO-d6ppm): 1.40 (S
, 9H).

4.80 (m, IH), 4.94 (S.

2H), 5.15 (m, IH)+ 7.40 (S, 5H), 8.00 (d.

17H) Example 2 3-[-butoquinocarboxamide-1-hydroxy/-4
-) Production of trifluoromethyl-2-azetidinone quin-4-trifluoromethyl-2-7zetidinone (7
0mg, O, 19mM) was dissolved in methanol IOme, 10T Pd/C (20μ) was added, and the mixture was stirred for 45 minutes under a hydrogen stream at normal pressure and room temperature. The catalyst was filtered and the solvent was distilled off under reduced pressure to obtain the title compound in a yield of 38'R9,72q.

JR, maxCm: 33101178011752
11690.1517.1290°-1160,940,87O NMR (CDCl2.ppm): 1.42 (S,
9H), 4.33(rrzt+-+)'+s,z(d,
+H) The obtained compound can be converted to the free form by treatment with trifluoroacetic acid.

Patent applicant: Ajinomoto Co., Inc.

Claims (1)

[Claims] 1. General formula (in the formula, R8 represents a hydrogen atom or an amino protecting group, and X represents a hydrogen atom, alkyloxy, aralkyloxy, aryloxy, OH, 0508H or 5OIIH, respectively. 2. The derivative according to claim 1, which is in the form of a salt when X in the general formula represents O20, H or 5o3H.