JPS58194856A - Novel 2-azetidinone derivative - Google Patents

Abstract

NEW MATERIAL:A 2-azetidinone derivative of formula I (R1 is pyrrolidinyl, pyrrolyl, piperidyl, pyridyl, each of which may bear hydroxyl and/or lower alkyl; R2 is H, hydroxyl; R3, R4 are lower alkyl; M is H, cation). EXAMPLE:Potassium (3S, 4S)-3-[D-alpha-(4-hydroxy-6-methylnicotinamide)-p-hydroxyphenylacetami de]-4-metyl-2-azetidinone-1-oxysulfonate. USE:Antibacterial with markedly improved antibacterial activity. PREPARATION:A compound of formula II (R5 is protecting group for NH2) is sulfonated into a compound of formula III, Then, its protecting groups are removed to give a compound of formula IV, further the product is made to react with a compound of formula V or its reactive derivative in the carboxyl to give the compound of formula I .

Description

[Detailed description of the invention] The present invention is.

General formula (in the formula, IR, is pyrrolidinyl-, which may have a hydroxyl group and/or a lower alkyl group).

Pi01J Rou, piperidyl- or pyridyl-group I
R2 represents a hydrogen atom or a hydroxyl group, R3 and R1 are the same or different and represent a hydrogen atom or a lower alkyl group, and 1M represents a hydrogen atom or a cation. ) The present invention relates to a 2-azetidinone derivative represented by:

The lower alkyl group in the definitions of R, R3 and Uma above means a branched or straight-chain alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an isopropyl group, and a butyl group.

Examples include tert-butyl group, pen/tyl group, and hequinyl group. Cations in the definition of M include alkali metal ions such as sodium and potassium; alkaline earth metal ions such as calcium and magnesium; alkylammonium ions such as triethylammonium ion;
; Examples include pyridinium ion, synchhexylammonium ion, and the like.

The compound (1) of the present invention is a novel compound useful as an antibacterial agent, and is a compound at the N position of azetidine, K -080, M
It has a chemical structure characteristic in that it has a group.

Conventionally, a compound having a -503M group at the N-position of azetidine has been known as a 2-azetidinone-induced θ ■ conductor having antibacterial activity.
etc.) 3 This is the result of intensive research by the inventors.

e ■ e ■ It was found that the antibacterial activity was dramatically increased by converting the -803M group at the N-position of azetidine to the -0803M group (1) and the present invention was completed.

Compound (1) of the present invention can be produced by various methods, for example, by the method shown in the following scheme.

In the above scheme, R,, R2, R3 and H have the above meanings, and R represents a protecting group for an amino group.

In this method, Compound (II) is sulfonated (first step) to obtain Compound (1), and secondly, the protecting group of the amine group of Compound (Ill) is removed at °C (second step) to form Compound (IV). )
and finally reacting compound (rV) with compound (V) or its carboxylic acid-reactive derivative (third step).

Examples of the carboxylic acid-reactive derivative of compound (V) in this method include acid bromides, acid chlorides, and other acid-rides;
Acid anhydrides; mixed acid anhydrides with alkyl carbonates, etc.; active esters such as N-hydroxybenzimidazole, N-hydroxysuccinimide, p-nitrophenyl + 2,4-dinitrophenyl; combinations with pyrazole, imidazole, benzotriazole, etc. Examples include activated amides.

Suitable protecting groups for the amino group represented by R5 in compounds (n) and (II) include acetyl, propyl, ethoxycarbonyl, t-butoxycarbonyl, benozoyl, benzyloxycarbonyl, and the like.

Next, each step of this method will be explained.

(1) First step (sulfonation) Sulfonation of compound (II) can be carried out in an organic solvent using SO, gas, sulfuric acid, chlorosulfonate, sulfur trioxide complex, etc., usually at room temperature. Suitable organic solvents include dimethylformamide, dimethylacetamide, dioxano, tetrahydrofurano, methylene chloride, chloroform, benzene, toluene, and appropriate mixed solvents thereof. As a sulfur trioxide complex.

Pyridino-sulfur trioxide, lutidino-sulfur trioxide.

Dimethylformamide-sulfur trioxide, etc. can be used.

(2) Second step (deprotecting group) The protecting group for the amine group of compound (1) can be removed in an organic solvent using an acid such as hydrochloric acid, sulfuric acid, or trifluoroacetic acid, or by using an acid such as baradium carbon or platinum oxide. , catalytic reduction using a metal catalyst such as Raney nickel. As the organic solvent, the solvents exemplified in the first step and alcohols such as methanol and ethanol are suitable.

(3) Third step (acylation) The reaction between compound (IV) and compound (V) or its carboxylic acid-reactive derivative is carried out in an organic solvent under cooling or at room temperature, preferably in the presence of a base.

Suitable organic solvents include acetonate, tetrahydrofuran, acetonitrile, methylene chloride, chloroform, dimethylformamide, dimethylsulfoquinide, and appropriate mixed solvents thereof, and triethylamine, pyridine, and the like are suitable bases. Compound(
When V) is used as a free acid, N.

The reaction can be easily carried out using a condensing agent such as N'-synchrohexylcarbodiimide or N,N'-carbonylimidazole.

The product obtained as a free oxysulfonic acid or a salt thereof by the reactions in the first to third steps above can be converted into other oxysulfonic acid salts by conventional means, if desired. Compound (1) thus obtained can be filtered,
It is isolated and purified by conventional operations such as recrystallization, extraction, and Calano chromatography.

The compound (IT) used as a starting material in this method is:
Journal of American Chemical Science ((J
, Am, Chem, Soc, ) 102 volumes C/1g
23) Method of 7026-7032 (1980),
Alternatively, it can be produced by hydrolyzing a compound obtained by a similar method.

Note that the side chain at position 3 of the compound (I) of the present invention can have either an α-8β-configuration.

The compound (I) of the present invention can be prepared as a powder, granule, capsule, or pill using conventional pharmaceutical additives.

It is possible to prepare preparations such as injections and suppositories and administer them orally or parenterally.

Next, the compound of the present invention and its production will be explained in more detail by way of Examples.

Example 1 (1) First step (3S, 48)-1-hydroxy-3-t-butoxycarbonylamino-4-methyl-2-azetidine/10g
1. Dissolve Om in dry dimethylformamide, add 294 g of pyridino-sulfur trioxide complex, and react overnight at room temperature. Pour the reaction solution into 80 ml of ether, dissolve the oily substance that separates in 15 ml of ice water, and adjust to T7 with cold hydrogen carbonate solution. The aqueous layer was washed three times with 5 ml of methylene chloride, and then subjected to column chromatography [Diaion Column (HP-20) (trade name,
(manufactured by Mitsubishi Chemical Corporation), (3S, 48)-3-
t-Butoxycarbonylamino-4-methyl-2-azetidinone-1-oxysulfonic acid sodium salt t24g
(yield 84%).

(1) Infrared absorption spectrum vKB"am-': 3350, 1775, 1685
, 1520, 1280, 1250°160 (11) Nuclear magnetic resonance spectrum (Da DMSOD2
0) δ: 1.36 (3H, d, J-7Hz
, C4CH3)1.38 (9H,'s, (C
H3>s C) 3.90 (11(, d of q, J=7
．． 2.5Hz, C4-)()4.06 (IH,d
, J=2.51(z) (2) Second step 318 mg of the above product is dissolved in dimethylformamide and 5 ml of methylene chloride and cooled below OC.

After adding 4 ml of anisole, add 8 ml of trifluoroacetic acid.
ml dropwise and reacted at 0-5C for 45 minutes. The reaction solution was concentrated, 60 ml of ether was added to remove the precipitate, and the precipitate was washed with ether at °C.

4S)-3-amino-4-methyl-2-azetidino/-
250 mg of 1-oxysulfo/acid are obtained.

(1) Infrared absorption subek) le v KBram': 3350 (pu0-)'),
■775,1670,1290°1260.120
0 (11) Nuclear magnetic resonance spectrum (D6-DMSO-D2
0') δ: 1.39 (3T(,d, J=7
Hz, C4CT-13)4.05 (H(,d,
J=2.5) (z, C3-H)4.14 (LH
, d of q, J=7.2.5H7,C4H) (3)
Third and fourth steps 1 g of the above product 2401T was dissolved in dimethylformamide 2
ml and 3 ml of methylene chloride, and add 14 ml of triethylamine O. Add D-α-(4
-Hydroxy-6-methylnicotinamide)-p-hydroxyphenylglycide 7302 qj in dimethylformamide (3 ml) was added, and N-hydroxybe/
Add Citriazole 1351T1g and dicyclohexylcarbodiimide 2061Ttg and stir at room temperature for 2 hours. After removing the generated urea, the P solution was concentrated under reduced pressure, and 60 ml of ether was added to the residue to make a powder.
Remove and wash with ether. Column chromatography was performed using 40 g of silica gel, and chloroform-methanol (
3:1) Repeat the elution operation twice with the mixture (3S.

48) -3-CI) -α-(4-Hydroxy 〇-methylnicotinamide)-p-hydroxyphenylacetamide]-4-methyl-2-acetidino-1-oxysulfonic acid triethylamine salt (254 mg) is obtained. Dissolve 106 mg of the product in 1 ml of methanol, add 2 ml of acetonate solution containing 68 mg of potassium perfluorobuta/sulfonate, and further add 10 m7 of acetonate to obtain 65111 g of potassium salt as a crystalline powder.

(i) Infrared absorption spectrum νmax (:In: 3000-3450,1765
,1650,1630°1510.1280.1240 (11) Nuclear magnetic resonance spectrum (D, -DMSO-D
20) δ: 1.30 (3H, d, J=6
H7, C4CH3) 3.68 (IH, d of q,
J-6,2Hz, C4H)4.26 (IH,d,
J=2Hz, C3-H) Example 2 0■ (38)-1-Hydroquine-3-t-butoxycarbonylamino-2-azetidinone obtained by treating in the same manner as in the first and second steps of Example 1. (3S)-3-amino-2-azetidinone-1-oxysulfonic acid 1581T
Dissolve 1 g in 1 ml of dimethylformamide and 2 ml of methylene chloride, and add 70 μl of triethylamine. Add D-α-(4-hydroxy-6-methylnicote/amide)-p-hydroxyphenyldi9fufu1 to the solution.
Add 67.5 mg of 51-hydroxybenzotriazole and 1103rI1 of dicyclohexylcarbodiimide and stir at room temperature for 2 hours. After removing the resulting urea.

Concentrate the P solution under reduced pressure, add 30 ml of ether to the residue, make it powder, remove the P, and wash with ether. Column chromatography was performed using 50 g of silica gel (.

Chloroform-methanol (12:1) mixture
1 g of (38)-3-[D-α-(4-hydroxy-6-7+tilnicotinamide)-p-hydroxyphenylacetamide]-2-acetedino-1-oxysulfofic acid triethylamine salt 1901T is obtained. The product was dissolved in 4 ml of methanol (acetic acid containing 114 mg of potassium perfluorobutanosulfonate):
/ 10 ml solution was added, and 15 ml of acetonate was added to obtain 56 ml of potassium salt, which is a crystalline powder. Get mg.

1) Infrared absorption spectrum νm□”, 3300 (broad), 1765,1
650,1.5], 0°1280-1240.1053 11) Nuclear magnetic resonance spectrum (Da DMSOH2O
)3.5~4.2 (2H, m, C4-H)4.8
3 (IH, dd, J-2, 6Hz, Cs
H) 15- Patent applicant Akira Sasaki, Yamanouchi Pharmaceutical Co., Ltd. agent - 161

Claims (1)

[Claims] General formula (in the formula I
2 represents a hydrogen atom or a hydroxyl group + R3 and R4 are the same or different and represent a hydrogen atom or a lower alkyl group; 2M represents a hydrogen atom or a cation; ) A 2-azetidinone derivative represented by: