JPS60252460A - Azetidinone derivative - Google Patents

Abstract

NEW MATERIAL:An azetidinone derivative shown by the formula I (R1 is acyl, H, or amino-protecting group; X is H, alkyloxy, aralkyloxy, aryloxy, OH, OSO3H, or SO3H). EXAMPLE:3-[ D(-)-alpha-( 4-Ethyl-2,3-dioxo-1-piperazinecarboxamido )-alpha-phenylacetamido]-4-trifluoromethyl-2-azetidinone-1-sulfonic acid. USE:Useful as a beta-lactam antibiotic or its intermediate. Showing a wide antibacterial spectrum against Gram-negative bacteria including Pseudomonas aeruginosa, and Gram-positive bacteria. PREPARATION:For example, a compound shown by the formula II is reacted with titanium dichloride in a mixed solvent of water and an alcohol or in an aqueous solution, to give an azatidinone derivative shown by the formula IIIamong the compound shown by the formula I. This compound is reacted with sulfuric anhydride to give a compound shown by the formula IV (M<+> is cation).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound useful as an antibiotic or a novel compound thereof, more specifically, the following general formula (1) (wherein R5 is an acyl group, a hydrogen atom, or an amino acid group). group, X is a hydrogen atom, alkyloxy, aran-Bu
4N''-, K+, Na, etc.) and is a novel and useful 4-trifluoromethylazetidinone dosing derivative (its salts) as a highly active β-lactam antibiotic or as an intermediate thereof. (Including the form P2J x)
Regarding. That is, in the above formula, the derivative in which R4 represents an acyl group has been found to have a wide range of antibacterial properties against Gram-negative bacteria including Pseudomonas aeruginosa and Gram-positive bacteria, and is expected to be used as an antibiotic. - Derivatives representing all the hydrogen atoms or amine protecting groups are expected as intermediates for their production.In R1, the acyl group is substituted, for example, at the 6-position of a conventional hydrogen atom conductor or at the 7-position of a cephalosporin conductor. For example, the following acyl groups are mentioned.

(1) Formula R2Co - [wherein R2 represents lower alkyl, a phenyl group which may have an Fi substituent, a heterocyclic group, or a benzoyl which may have an 11L substituent. ].

(2) Formula R, NT(CHCO- (in the formula, R3 is hydrogen, an optionally substituted amino acid residue, a holding group for an amine group, 2R4-
(0M2) nl-Co (wherein R4 is a heterocyclic group which may have a substituent, phenyl which may have a substituent, lower alkyl which may have a substituent, a substituent phenylthio or lower alkylthio foundation that may be contained, n represents 0 or an integer from 1 to 4;
The -(CH2)nl- group has a substituent [wherein 4' and 4] are the same or different and are hydrogen, lower alkyl, lower alkylcarbamoyl, phenylcarbonyl which may have a substituent, or R4/ R/ represents a cyclic hydrocarbon which may be bonded to a heteroatom such as nitrogen or oxygen; in this case, the carbon atom or nitrogen atom may have a substituent. or sulfonic acid. ], or 2R4# -802-C In the formula, R4 represents a lower alkyl which may have a substituent. ], R5 is hydrogen, lower alkyl which may contain a substituent, phenyl which may contain a substituent, '6L ring which may contain a substituent, cycloalkenylene,
A group represented by ), which represents a complex cartenylamino which may contain a substituent or may have an alkylene lead association.

More specifically, the group of type C is particularly preferably represented by the following formula (,).

a carbocyclic aromatic hydrocarbon such as a halodane group, a cyan group, a nitro group, an amino group or a mercapto group;
．． 2. Substituted or unsubstituted 5°6 or 7 & heteroaromatics containing 3 or 4 nitrogen, oxygen or sulfur atoms.

] and R15 are alkyl, substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amine or mercapto groups), arylmethyleneamino (i.e. - N=
CH-R161, where R161 means all of the substituents listed above as representing R6.

), arylcal i? nylamino (i.e. -NHCR4
/ , where R16 means any of the substituent groups described above as representing R16. ) ν or alkylcar is nylamino. ] (4-substituted-2,3-dioxy-1-piperazinecarboxamide)
-arylacetyl group.

Preferred examples include derivatives in which R15 is ethyl and R46 is phenyl or p-hydroxyphenyl. (3) Formula X' is an oxygen or sulfur atom, R8 is a heterocycle which may have a substituent, or phenyl which may have a substituent; R2 is hydrogen; phenyl which may have a substituent; or lower alkenylene, R
4 represents carboxyl, its ester or a heterocyclic group. ) are represented respectively. ) represents a group represented by R7 alkyl, phenyl which may contain a substituent, or a heterocyclic group which may contain a substituent (I7), respectively. ] A more specific example of this type of group is the following (b)
'y' Ki 9% type is particularly preferable ~"-4-Ly
-+1"-□-Shame-□-Tableゎ-1,-□member-;!;4y
=-C2znimo 7-r, 7'-Y-7Z Pumo'i3--4-4-z-)2-ten t'i=Photograph side number...reharuka, [in the ceremony"19 and R20 are the same or different, and each is a 01-C4 alkyl group or R20 is
19 and R20 represent those which together with the carbon atoms to which they are bonded form a C6-C7 cycloalkylidene group. ] A 2-(2-aminothiazol-4-yl)-(2)-2-i-substituted oxyiminoacetyl group.

Is R1 preferable? and R20 is methyl.

(4) Formula droxysulfonyloxy, carboxyl, substituted end (sulfamoyl, sulfonic acid, benzyloxycarzanyl, formyloxy, acid or halodane atom which may have one), R14 is hydrogen, lower alkyl, halogen, A group represented by -] representing acid, nitro or hydroxyl.

In the above, lower alkyl means alkyl having 1 to 4 carbon atoms.

Examples of the amino-linking group in R1 include aromatic acyl groups such as phthaloyl, p-nitrobenzoyl, p-tert-bunalpensoyl, p-t@rt-butylbenzenesulfonyl, formyl, acetyl, propionyl,
Monochloroacetyl, dichloroacetyl, trichloroacetyl fatty acyl group, methoxycarvinyl, ethoxycarbinyl, 1-butoxycarbonyl, ingropoquin carbonyl/L/% benzyloxycarbonyl, p-
Examples include esterified carboxyl groups such as nitrobenzyloxycarbinyl and p-methoxybenzyloxycarbonyl, trityl groups, and 2-nitrophenylthio groups.

In X, the alkyl group of alkyloxy is, for example, lower alkyl such as methyl, ethyl, butyl, etc.; the aralkyl group of aralkyloxy is, for example, benzyl, phenethyl, p-nitrobenzyl; For example, phenyl and p-nitrophenyl may be cited. The following methods can be used to produce the derivatives of the present invention.

A derivative in which R1 is an amino protecting group is produced as follows.

(1) When the compound represented by the general formula is reacted with water, an alcohol mixed medium, or titanium trichloride in an aqueous solution, an azetidinone derivative represented by the general formula is obtained.

The derivative prepared here is treated with sulfuric anhydride or its reaction
When reacted with a conductor, an azetidinone derivative represented by the general formula is obtained. Cation means the same cation as above.

(2) When the compound represented by the general formula is reacted with sulfuric anhydride or a reactive derivative thereof, the a→non g4 compound represented by the general formula is obtained.Mo has the same meaning as above.

The compound represented by the general formula (herein, R21t; i represents an alkyl, aralkyl, or aryl group) is ψ1j, for example, 2-amino-3-hydroxy-4,4,4-trifluorobutanoic acid (Journal of Amerlean Chem
ical 5ociety.

80.187 to 192 (1958)), and this is combined with O-alkyl or O-aralkylhydroxylamines using shiimide as a condensing agent, as shown by the general formula The compound can be produced by performing a dehydration ring closure reaction using triphenylphosphine and diethyl azodicarboxylate.Of course, R4 and R21 have the same meanings as above.

Specific examples of amine-holding groups used to protect free amine groups in the present invention include groups that form urethane groups together with amino groups (e.g., t-butoxycarcanyl, cyclopentyloxycarbonyl, 2.2. !J Kurokoethoxy7cargenyl, penzyloxycarbonyl, p-
Nitrobenzyloxycarbonyl, diphenylmethoxy7
Cal? Common amino protecting groups such as the trityl group (such as t-butoxycarbonyl group) are included, and the t-butoxycarbonyl group is particularly preferred.

The condensation of compound (X)υ with a protected amine group represented by the following formula and O-alkyl or O-aralkylhydroxylamines is 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 0 to 20°C. Carbodiimide is used as the condensing agent,
Especially 1-ethyl-3-(3-(tumethylamine) f
o building) Carbodiimide is H4. Hydroxyamines used in comparison with the starting material are 1 to 2.0 times the mole, preferably 1 to 1.5 times the mole, and carbodiimide is also 1 to 2 times the mole.
．． The amount is 0 times the mole, preferably about 1 to 1.5 times the mole.

The dehydration ring closure reaction of compound (■) is performed using tetrahydrofuran,
The reaction can be carried out in an x-thyl inert solvent such as diethyl ether or dioxane, and tetrahydrofuran is particularly preferred. The amount of triphenylphosphine used for compound (■) is 1 to 3 times the mole, preferably 1 to 1.5 times the mole,
The amount of diethyl azodicarboxylate is also 1 to 3 times the mole, preferably 1 to 1.5 times the mole. The reaction temperature is -30℃
The reaction is carried out under refluxing of the bath medium at a temperature of 10°C to 25°C.

The reaction time is 1 to 30 hours, preferably 15 to 2 hours.
It is 0 hours. Compound (n) is a compound (■) in which R21 is benol, and a p-nitropenzyl compound is mixed with platinum metal, its oxides, or 10chi Pd/c.

It can be produced by carrying out a hydrogenation reaction 11 in the presence of a hydrogenation catalyst such as 30% Pd/B a CO at 0° C. to 25° C. for 5 minutes to 2 hours under hydrogen pressure of 1 to 10 atm. Compound (In) can be reduced by reducing compound (II) under neutral conditions using titanium trichloride in a mixed bath of alcohol and water. The reaction temperature is 0 to 30℃, preferably 0
-10°C, reaction time is 1-2 hours.

Compounds (■) and (Vl) are obtained by reacting 1 g of compound (II) or qll) with, for example, sulfuric anhydride or dihydrous sulfuric acid,
By reacting with derivatives! A can be built.

It can be produced by reacting the above-mentioned sulfuric anhydride with a reactive conductor. Examples of the above-mentioned reactive derivatives of sulfuric anhydride include sulfuric anhydride-bilicin, sulfuric anhydride-bilicin,
%-α-picoline, anhydrous Cv-dimethylformamide, anhydrous sulfuric acid-dioxane, chlorsulfonic acid-bilinone, chlorsulfone 1g-α-picoline, and the like are used. The reaction is carried out by adding about 1 to about 5 moles, more preferably about 1 to about 2 moles, of a reactive derivative of sulfuric anhydride or ff1it acid anhydride to 1 mole of compound (n) or (a). The reaction temperature is -10 to 80°C, more preferably 0 to 30°C. Anti-technical 6 bath IN is dioxane, TH
Ethers such as F-danyl ether, esters such as ethyl acetate and ethyl formate, chloroform, methic chloride!
Halodanized hydrocarbons such as /N, hydrocarbons such as benzene and n-hexane, dimethylformamide, dimethylacetamide, etc. are used singly or in combination. After the completion of the reaction, the reaction mixture can be obtained at any purity by conventional purification methods such as medium extraction, recrystallization, and chromatographies.

The cationic moiety of the sulfonate of azenacnone derivative (IV) and (■) can be derived from either organic or inorganic bases. Including, but not limited to, ions.

Such ions include substituted ammonium such as ammonium and argylammonium (e.g., tetra-n-butylammonium), alkali metals such as lithium, sodium, and potassium, alkaline earth metals such as calcium and magnesium, pyridinium, and diammonium. Cyclohegysylammonium nato is mentioned.

A compound in which R1 is hydrogen (X has the same meaning as in qll) can be obtained by removing the protection group of the amine group in the general formula (R1 represents an amino protecting group). 6E is a method commonly used in peptide synthetic chemistry, such as Akahori, Kaneko,
The method described in ``Narita co-edited Tansu] Chemistry 1 Amino Acid 4 Petide Kyoritsu Shuppan H (Shiwa 44) may be used.

The compound (M) in which KX is So, H, 080, H is important as the core of a new highly active β-lactam antibiotic.

In the case where R4 is an acyl group, the production method is to synthesize the compound (3) in which R1 is H, and then acylate it, or
There are two methods: (■) where 4 is an acyl group, or (2) in which a ring-closing reaction is performed after synthesizing the VO compound's proboscis.The acylating agent is an acid. Includes chloride or bromide. Such an acylating agent can be prepared by reacting an acid or its salt with a nologonating agent such as phosphorus trichloride, thionyl chloride, or sulfur chloride.

Acylation using r9 halides is carried out in aqueous and non-aqueous reaction media at temperatures of -50 to 50°C, preferably -30 to 20°C.
It is carried out in the presence of an acid binder at a temperature of °C. Suitable reaction solvents include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as DMF', nitriles such as acetonitrile, ethers such as THF, Mixtures of two or more of certain such solvents are included.

Suitable acid binders include tertiary amines (e.g. triethylamine, dimethylaniline, diisopropylethylamine), inorganic salts (e.g. sodium bicarbonate, calcium carbonate), and those capable of binding hydrogen halide liberated during the acylation reaction. and 2-alkylene oxides (e.g., ethylene oxide or zolobylene oxide).

Kaldev rice itself is also used as an acylating agent. Acylation using carboxylic acids is a condensing agent example, 7ijN, N
'-Dicyclohexylcarbodiimide, 1-enal-3
-(3-(dimethylamino)globulin is a caldecimide such as diimide, a carbonyl compound such as carbonyldiimidazole, or It is carried out in the presence of isoxazolium chloride.

Acylation is also carried out by reacting other carboxylic groups with reactive g-conductors. Examples of the A-form include acid anhydrides, mixed acid anhydrides, active esters, acid azides, inverse ratios to Vilsmeier's reagent, and 2H-forms. Examples of the mixed acid anhydride include mixed acid anhydrides with carbonic acid monoalkyl esters such as carbonic acid monoethyl ester and carbonic acid monoybutyl ester; Examples include mixed acid anhydrides with alkanes and mixed acid anhydrides with argylsulfonic acids such as methanesulfonic acid and ethanesulfonic acid.

Examples of active esters include substituted phenyl esters, benztriazole esters, and succinimide esters. In addition, derivatives reactive with the Vilsmeier reagent include acid amides such as N,N-dimethylformamide and N,N-dimethylacetamide, phosgene, thionyl chloride, phosphorus trichloride, phosphorus oxychloride, and trichloromethylchloroformate. Induction of reactivity with the Vilsmeier reagent obtained by the action of an acid halogenating agent (4) is mentioned. Suitable I# media used in reactions with these reactive derivatives include diethyl ether, T
) (Ethers such as those in Table F, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene and toluene, ketones such as acetone, or mixtures of two or more of such solvents are used.

Additionally, the reaction can be carried out in the presence of a base, including tertiary amines such as triethylamine, dimethylaniline, diisopropylethylamine, and the like. The reaction temperature and reaction time are not particularly limited;
It is preferable to carry out the reaction at a temperature of .degree. C. to 30.degree. C., and the reaction is usually completed within several hours. Frozen The above acylation reaction can be carried out in the presence of a beneficent agent such as 4-dimethylaminopyridine.

Further, the g-conductor of the present invention has optical isomers, and 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, etc. that the compound of the present invention has the chemical structure described above.

Among the compounds of the present invention represented by the above general formula, R1
Derivatives in which is an acyl group are Gram-negative species including Pseudomonas aeruginosa,
It has been shown to have a wide range of antibacterial activity against Gjim-positive bacteria, and is expected to be used as an antibiotic.

The compound of the present invention refers to the above-mentioned toshifun form, and the in-situ formed cations include those known in the art, such as alkaline range ions such as lithium, sodium, and potassium; Magnesium is an alkaline earth metal ion such as calcium, ammonium, tetra-n-butylammonium, bilinonium, and fc is R such as dicyclohexylammonium.
, and ammonium ions which may be P-type.

Hereinafter, the present invention will be explained in detail based on Example 9.

Example 1 Production of 3-t-butoxylupoxamide-1-penzyloxy-4-trifluoromethyl-2-azetidinone (a) 2-t-! Production of toxiccarboxamide 3-hydroxy-4,C4-trifluorobutanoic acid: 2-amino-3-hydroxy-4,4,4-trifluorobutanoic acid (21,11,6mM) was mixed with 10 ml of THF and 20 ml of water.
It was bathed in a mixed solvent of alcohol. This is added to triethylamine (
1,62''s 11-6 mM) and so-t-butyl dicarbonate (3,2,9° 14.7 mPA) were 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 3 Qmf of ethyl acetate, and these organic extracts were combined to give 4
After washing with 0 vagina water, it was washed with 3ON saturated saline. After drying this with anhydrous sodium sulfate, the solution was distilled off under reduced pressure and reprecipitated with n-hexano.
(2.21 yield 70%).

KRr　-1.

IR,m,,rm,3300,1730,164.5
,1520°1258.1160.114O NMR (DMSO-d6ppm): 1.40 (
8,9)T).

4.20 (m, 2H) (b) 0-benzyl-2-t-poxycard? Preparation of 2-t-butoxycardexamide 3-hydroxy-4,4,4-trifluorobutanohuman 90xamate 2-tert-butoxycardexamide 3-hydroxy-4
,4,4-trifluorobutanoic acid (1,90,G',
6.96 mM) in 15 ml of THF, and 15 ml of water.
1, and then O-benzylhydroxylamine acid salt (1,3:M, 8.36 mM) was added. The − of this bath solution was adjusted to 4.0 to 5.0 with saturated heavy water, stripped, and then added to 1-ethyl-3-(3-(tumethylamine)globil)carbodiimide hydrochloride (water-bath carbidiimide) under water cooling. (1,461i%7,64mM
) was added dropwise. p1 of bath liquid during dropping and reaction
4 was adjusted to 4.0-5.0 with lN HC/-. 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 40% ethyl acetate. All the Ariiso layers were combined and washed with a 0.5M citric raw aqueous solution, then washed with 5-6 times soybean water, and further washed with saturated saline. After drying this with anhydrous sodium sulfate, ethyl acetate was distilled off to obtain compound ffl fG at 1.84,9
, 70 cm @ KBr −”: 3400, 3300, 3200°XR,
m,,Xcnt 1680.1660. ]520°1300.1260.1160°1.120,740,69O NMR (DMSO-d6ppm): 1. , 41 (
s, 9H) e4.20 (m, 28), 4.82
(g, 2H) *6.40 (broad *, I
H).

7.35 (s, 5H) (c) Production of 3-t-butoxycardexamide-1-benzyloxy-4-trifluoromethyl-2-azetidinone 0-benzyl-2-t-butodo- Caldexano-3-hydroxy-4,4,4-trifludon rogtanohydroxamate (0.70 g, 1.85 mM
) and triphenylphosphine (0,58,9',2,2
1 mM) in completely dry THF 15N. To this, diethyl apalponate (0,35,F, 2,03 m
M) f dry THF ] otnr to Fr 'tr>
The solution was added dropwise over 30 minutes while cooling with water. After 30 minutes, the mixture was returned to room temperature and left to stand for 20 hours. After distilling off the solvent, the residue was subjected to silica del chromatography. Elution with ethyl acetate-rohegisan (1:3) yielded 3-t-ptoxycarbixamide-1-benzyloxy-4-1-17fluoromethyl-2-azetidinone 0
．． It was obtained as crystals in a yield of 214.30.

IRKBr −1°1/maxrTq. 3320.1805, 1698° 1523.1285, 1160° 14O NMR (DMSO-d6ppm): 1.40 (s
, 9H).

4.80 (m, IH), 4.94 (s.

2I (), 5.15 (m, IH).

7.40 (s, 5B), 8.00 (d.

IH) Example 2 3-t-butoxylupoxamide 1-hydroxy-4
-Production of trifluoromethyl-2-azetidinone 3-t-butoxycarboxamide-1-benzyloxy-4-trifluoromethyl-2-azetidinone (70'
910.19 mM) was dissolved in 10 ml of methanol-k, 10% Pd/C (20~) was added, and the mixture was stirred for 45 minutes under a hydrogen stream at normal pressure and room temperature. By filtering and distilling off the solvent under reduced pressure, the compound described above was obtained. The yield was 72 cm.

KBr -1.

IR,, Tlaxm, 3310s1780t1752
゜1690.1517,1290゜1160.940,87O NMR (CDCl s, ppm): 1-42
(s * 9 H) + 4-33 (m, 18)
, 5.11 (dd, IH) Example 3 Production of 3-t-butoxycardexamide-4-trifluoromethyl-2-azetidinone. Fluoromethyl-2-azena dione (140In210.
52 mM) f in a mixed solvent of 8 ml of methanol and 12 ml of water and cooled on ice. Add to this 0.0% sodium acetate.
After adding 6 F'e and dissolving, add 10% sodium hydroxide under water cooling while maintaining pi-1 at 7.5 to 6.0.
1.8 ml of 0% titanium trichloride water bath solution was added dropwise. 0-5
After reacting at ℃ for 30 minutes, the mixture was further reacted for 30 minutes in a trap chamber vortex.

After the reaction was completed, the mixture was extracted three times with 20 m6 of ethyl Daigo, and the organic layers were combined and washed with 30 m1 of a 0.5M citric acid water bath. Furthermore, it was washed with 5% NaHCOs water and then with saturated saline. After drying this with anhydrous sulfuric acid and distilling off the ethyl acetate, 110% of the crude title compound (yield: 83%) was obtained.

IR pear cm-': 3300. 1780.1690
．． 1520°1280.1150,1070.85O
NMR (DMSO-d6ppmC1,39(s,9H)
, 4.38 (m, IH) 5.20 (d, d, 11 (),
7.92 (d, IH).

8.87 (a, IH) Example 4 3-t-Ptoxycargoxamide 4-Trifluoromethyl-2-azetidinone-1-sulfone Bite Preparation of Tetrabutylammonium 3-t-Ptoxy under a nitrogen stream Carmexamide 4-trifluoromethyl-2-azetidinone (1001F'9
, 0.39 mM) was dissolved in 20 d of dry methylene, to which α-picoline sulfuric anhydride complex 0
．． 30 g was added and allowed to react at room temperature for 3 days. Reaction metallization 0.
It was added to 5M KH2PO4 aqueous solution 201 and extracted into the aqueous layer. The methylene chloride layer was further diluted with 0.5 M IG (10
After extracting with 2 Qml of water and combining the aqueous layers, 0.13.9-ml of tetrabutylammonium hydrogen oxide was added and extracted with 40ml of methylene chloride. Add 4Q methylene chloride to the aqueous layer.
The organic layers were combined, dried over anhydrous sodium sulfate, and then methylene chloride was distilled off to obtain an oily crude compound of 130 da (yield: 60%). 3300-2950-2850
r1790.

1720, 1280. 1250. 1160°11
40, 1045 NMR (1045N, ppm): 1.00 (m-12
)t), 1.45 (m, 17K).

1.65 (m, 8B), 3.25 (m, 8H), 4.
55 (mtlH), 5.08 (d, IH), 5.35
(d, d.

IH) Typical Example 5 Production of 3-amino-4-triple olomethane-2-azetidinone-1-sulfonic acid n -Bu a N Under nitrogen atmosphere, 3-t-butoxycarboxamide-4-
Trifluoromethyl-2-azetidinone-1-sulfone tetrazoderammonium tJ (100~, 0.
18 mM) was dissolved in dry methylene chloride 3d. This was reacted with 0.5 ynl of anisole and 1 M of trifluoroacetic acid at 0 to 5° C. for 40 minutes under water cooling.

After distilling off methylene and trifluoroacetic acid, diethyl ether was added to precipitate the product, resulting in a zwitterionic adduct of the indicated compound (yield: 23+7+y).
65%).

IRI("cm-' :34.OO,3000,18
00,1320°11m111x 1300, 1270. 1200. 115ONMR
(D20.ppm): 5.05 (m, IH), 5
．． 15(d,1)I) Example 6 3-t-butoxycar? Production of 4-trifluoromethyl-2-azetidinone-1-oxysulfonic acid tetrabutylammonium container under nitrogen stream 3-L-butoxycardexamide-1-hydroxy-4-trifluoromethyl-2-azetizonone (100 dap 0.37
(IJM) in 201 d of dry methylene chloride. To this was added 0.30 J of α-picoline sulfuric anhydride complex.
It was added and allowed to react at room temperature for 1 day. 0.5 of the reaction solution
M was added to 20v of KH2PO4 water bath solution and extracted into the aqueous layer. The methylene chloride layer was diluted with K 0.5 M Kl (2
The mixture was extracted with 20 ml of PO4 water, the water droplets were combined, 0.13 g of tetrabutylammonium hydrogen sulfate was added, and the mixture was extracted with 40 ml of methylene chloride. The aqueous layer was further extracted with 4Qd of methylene chloride, the organic layers were combined and dried over diluted sulfur and sodium, and the methylene chloride was distilled off to obtain 1,571. Ta.

n@at -1゜I Rl'mAX Confucian 13300 # 2950 *
2850 r 1800 r1710, 1280.
1150. 105ONl'ilR(CDCt51Pm
): 1100 (, 12H), 1.45 (m, 17M) 1
．． 65 (me 8H) + 3.25 (me 8f
() e5.00(m, 2K)-5,30(d-d-I
H) Example 7 3-CD(→-α-(4-ethyl-2,3-dioxo-
D(-)-α-(ethyl-2, 3-dioxo-1-biperanonecalgexamide) phenylacetic acid (9
5mp l 0.28 mM) was dissolved in dry methylene chloride, and oxalic loride gold 76 ~ and DM were dissolved under water cooling.
F-ft@f was added and reacted at room temperature for 1 hour. The solvent was distilled off under reduced pressure and dry Tl (P4rrLt) was added to obtain an acid chloride solution. Separately, 3-amino-
4-Trifluoromethyl-2-azetidino/-1-sulfone f12 (30m?, 0.15 mM) and 4-
Dimetera constant noviridine (No. S, O, 04mM) was dissolved in dry DMF and diisoglobylethylamine (6jIn9-0.5tnM) was added to the same solution.

This solution was cooled to -10 to -5°C, and the previously obtained THF Q solution of acid chloride was added dropwise. 3 at -10~-5℃
After reacting for 0 minutes, the reaction was further continued for 1 hour at room temperature. After the reaction is complete, pour into 10 d of ice water to pH 4 = 6.5 to 7-O.
After adjusting with K NaHCOs water, KTI (F) was distilled off under reduced pressure and washed with 10 ml of ethyl acetate.The -1 of the aqueous layer was adjusted to 2.5 with 5% hydrochloric acid, and then the -1 of the aqueous layer was adjusted to 2.5 with 10-ethyl acetate. The aqueous layer was adjusted to pi (g 6.5-7.0), then 50 da of tetragutylammonium hydrogen sulfate was added and extracted three times with 15 d of methylene chloride. The methylene chloride layers were combined and washed with IQ ml of water. After drying with sulfuric acid), the solvent was distilled off. Diethyl ether was added to the residue to precipitate the product, thereby obtaining an oily crude compound t-63 (yield: 55%).

IR""crn-': 33oo# 2950t 28
50. 179L max 1670, 1250p1150. 1035NMR(
CDCL3e1035N: 1.00 (m, 12H),
1.20 (te3H).

1.45 (m, 8H), 1.65 (m, 8H), 3.
25(m18f()+3.55('1-2H), 3.
60-4.20 (m-4H), 4.65 (m, IH) *
5.57 (d, IH), 5.70 (d, d, II ()
, 7.30~7.40 (m = 5H) -7,5
9(d a I H)nfW=-me;==to;ruZ:
3 me: 11th grade! -2-7-i Binikotsu Keijiden Signi-Funiy' Double Defective Example i' Production of 3-amino-4-trifluoromethyl-2-azetidinone trifluoroacetate 3-t- under nitrogen'AH Butoxycargexamide-4-
Trifluoromethyl-2-azetidinone (80~, 0.
(31 mM) was dissolved in 0.5 mA of anisole, and 1 tnl of trifluoroacetic acid was added thereto under water cooling.

After reacting at 0 to 5°C for 1 hour, trifluoroacetic acid was distilled off under reduced pressure at 25°C or lower, and diethyl ether and n-
By adding hexane to precipitate the product, 56 kg of the compound (yield: 66%) was obtained.

IRcm, 3200.3000~2900.1800
．． 1780.1650°νmax 1200.116O NMR (D20.ppm): 4.70 (rn, IH
), 5.00 (d, IH) Example 7F 3-[(Zl-2-(2-diphenylmethoxycarbonylprop 2-oximino)-2-(2-tritylaminothiazol-4-yl)-acetamide]- Preparation of 4-trifluoromethyl-2-azetidinone (Z+-2-(2-diphenylmethoxycarbonylgulog-2-oximino)-2-(2-tritylaminothiazol-4-yl)acetic acid (1121Q,
0.16mM) was dissolved in dry methylene chloride 4H, -
At 35°C, 511n9 phosphorus oxychloride and 121ny dimethylformamide were added, and the mixture was reacted at -15 to -10°C for 2 hours. A mixed solution of 3-amino-4-trifluoromethyl-2-azetidinone trifluoroacetate (407112, 0.15 mM), 31 g of dry methylene chloride, and 130 μl of diisopropylethylamine was added dropwise to this reaction solution at -45°C. After reacting at −10° C. for 1 hour, the reaction was further carried out in a room for 1 hour. After the reaction is completed, the mixture is poured into 20 ml of ice water, and methylene chloride xornl is added to extract the organic layer. The methylene chloride layer was washed with 5 IQm of NaHCO3 water, dried over IJ sulfuric acid, and the solvent was distilled off. The residue was subjected to silica dal chromatography and eluted with ethyl acetate-n-hexane (1:2), yielding 58~. Obtained with a yield of 48%.

1285.115O NMR (CDCt5.Ppm): 1.65 (8,3
H), 1.70 (s, 3FI), 4.2
5 (m, IH), 5.80 (d, d, IH), 6.20
(a;If(), 6.55(a, IH), 6.85(s
.

IH), 6.93 (s, IH), 7.20-7.35 (
m.

25H), 7.50 (d, IH) Example rows 1,11 3-[■l-2-(2-diphenylmethoxycarbonylglog-2-oximino) 2-(2-tritylaminothiazol-4-yl)- 3-[(2))-2-(
2-diphenylmethoxycarbonyl grog-2-oximino]-2-(2-)cutylaminothiazole-4-
yl)-acetamido)-4-)lifluoromethyl-2
-Azetidinone (115mp, 0.14mM) was dissolved in 5ml of dry methylene chloride. This and 2M DMF
So3 core f V, Kusuno DMF solution 400
ttll was added dropwise under ice-cooling and heated at 15:00 at 15-20°C. 1. Add the reaction solution to 0.5M KH2PO4 water. O
Add an additional 60 m7 of am hydrogen tetrabutylammonium. Add 5 ml of methylene chloride to this and extract the organic layer. Add 1 mL of methylene chloride to the aqueous layer.
The extract was extracted with 0a and the seven layers were combined and dried with anhydrous sulfuric acid. After drying with IJum, an oil was obtained by distilling off the methylene chloride. Diethyl ether was added thereto to precipitate the product, and the solvent was removed to give a foamy crude compound of 120~ (yield: 7cm).

1270.1146, 1045.702NMR (CDC
43, ppm): 1.00 (m, 12H),
1.43 (m, 8H), 1.65 (m,
14H), 3.25(m, 8H), 4.
62 (m.

IH) 15.70 (d, d, IH), 6.53 (s+I
H).

6.89 (s, IH), 7.1.5-7.40
(m, 27H) Example 1/I 3-[ri)-2-(2-carboxyglof-2-oximino)-2-(2-aminothiazol-4-yl)-
Production of lifluorocomethyl-2-azetidinone-1-sulfonic acid.
-tritylaminothiazol-4-yl)-acetamido)-4-)lifluoromethyl-2-azetidinone-1
-tetrabutylammonium sulfonate i (110■,
0.1 mM)'fr: Dissolved in 0.5d of anisole. Add 1.5 m/ml of trifluoroacetic acid under water cooling and O~5C.
After reacting for 1 hour at 25C or lower, trifluoroacetic acid was distilled off under reduced pressure.

Diethyl ether was added thereto, the product was filtered, and the product was further washed thoroughly with methylene chloride to obtain 28 mg (yield: 57%) of the title compound.

IRKBr cm-”: 3300-2800.179
0,1680.1640°νmax 1280.1185,1150,1053,644NM
R (DiO+ppm): L50 (s r 6H)
+ 5.00 (m, IH), 5.85 (d, IH),
7.00 (S, IH) [Antibacterial activity test] The target compound obtained by the present invention has antibacterial activity against a wide range of Gram-negative bacteria including Pseudomonas aeruginosa and Durum-positive bacteria.

MIC (μri/ynl) MTC measurement was performed using the Japanese Society of Chemotherapy standard method.

Claims (1)

[Claims] 1. General formula (wherein R1 is an acyl group, a hydrogen atom or an amine protecting group, and X is a hydrogen atom, alkyloxy, aralkyloxy, aryloxy, 0H10805H or 5o3H)
Q, respectively. ) Azetidinone derivatives. 2. In the general formula, X is 0803H or 80. ) 1, patent l in the form of salt! 1. The derivative according to item 1. 3. The acyl group has the formula: R2Co- [wherein R2 is lower alkyl or a phenyl group which may have an additional substituent,
The derivative according to claim 1, which is a group represented by the following formula: a heterocyclic group or a benzoyl group which may have a substituent. 95 Element, amino acid residue which may have an additional substituent, amino group preserving group, formula R4-(CH2)nl-CoC, where R
4 is a heterocyclic group which may have a substituent, phenyl which may have a substituent, lower alkyl which may have a substituent, phenylthio or lower which may have a substituent The alkylthio group represents n1 O or an integer from 1 to 4, and the -(CH2)nl- group may be a substituted group. ], hydrogen, lower alkyl, lower alkylcarbamoyl, phenylcarginyl which may have a substituent, or R4 and R/ are bonded and contain a hetero atom such as nitrogen or oxygen. Represents ring-shaped carbonized limescale. In this case, the carbon atom and nitrogen atom may have a substituent or represent sulfonic acid. ]
or a group represented by the formula R//I~5O2- (wherein %R
4/I represents lower alkyl which may be substituted. ], R5 is hydrogen, lower alkyl which may have a substituent, phenyl which may have a substituent, heterocycle which may have a substituent, microalkenylene, substituent Each represents a heterocyclic car♂ylamino which may have or may have an alkylene interposed therebetween. ) The derivative according to claim 1, wherein H'F is a group represented by: 5. The acyl group has the formula: R6-R,CO-[: where, R
6 is, R8 is an optionally substituted heterocycle or phenyl optionally has a substituent, R7 is hydrogen,
Phenyl, lower acyl, and acetate which may have substituents
t7m't or the formula "jO-RNC" In the formula, "10" represents lower alkylene or lower alkenylene, and 'R1, represents carboxyl, its ester, or a heterocyclic group t, respectively. ) are represented respectively. ), R7 represents a simple bond or phenyl which may have a bond or a heterocyclic group which may have a substituent. ) are represented respectively. ] The derivative according to claim 1, which is a group represented by the following. is hydroxyl, hydroxysulfonyloxy, cal7
rxyl, moyoisulfamoyl having a substituent,
The derivative according to claim 1, which is a group represented by sulfonic acid, benzyloxycarbonyl, formyloxy, azide, or halodane, and R14 represents hydrogen, lower alkyl, halodane, azido-nitro, or hydroxyl. 7, 34D←]-α-(4-ethyl-2,3-dioxy-1-biirazine-rubikyamide)-α-phenylacetamide-]-4-trifluoromethyl-2-azetidinone-1-sulfonic acid salt A derivative according to claim 1 which is a salt of trifluoromethyl-2-azetidinone-1-sulfonic acid.