JPH0240670B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 2-oxo-carbapenam derivatives, more specifically, In the formula, R ¹ and R ² each independently represent an acyl group or together represent an imide-forming residue, and R ³ represents a substituted or unsubstituted benzyl group. - Regarding carbapenam derivatives. The following formula 7-oxo-1-azabicyclo [3.
2.0] Antibiotics with hept-2-ene-2-carboxylic acid cores (hereinafter referred to as carbapenem antibiotics) generally have high antibacterial activity and β-lactamase inhibitory activity, and have traditionally been processed using fermentation methods. Various derivatives have been produced by , semi-synthetic methods, and total synthetic methods [for example, Thienamycin (Journal of Antibiotics, Vol. 32 (1979), 1-
p. 12, PS-5 (ibid., vol. 32 (1979), 262-286
page), derivatives having a wide range of substituents at the 3- and 4-positions (for example, JP-A-56-5478, etc.)]. In addition, the following formula is used as an important intermediate for producing these antibiotics. 2-oxo-azetidine derivatives represented by the following formula, where R represents a hydrogen atom or a methyl group [see Tetrahedron Letters No. 40 (1979), pp. 3867-3870 or JP-A-56-131565] are known, but all of these are 6 of the carbapenem bone nucleus.
It is provided for the purpose of producing carbapenem antibiotics that have no substituent or a carbon-carbon bond at the position. On the other hand, US Pat. No. 4,218,459 discloses carbapenem antibiotics having an amino group protected by an acyl group at the 6-position and a method for producing them. However, this production method requires the isolation of the target antibacterial active substance from the mixture of stereoisomers generated, and a method for producing the target substance in a higher yield has been desired. The present inventors conducted research to develop a selective synthesis of carbapenem antibiotics having the desired three-dimensional structure having an amino group at the 6-position.
By subjecting the oxo-azetidine derivative to a known ozonolysis while keeping the amino group at the 3-position in the imide form, the double bond of the crotyl group substituted at the 4-position can be oxidatively cleaved to lead to an aldehyde; Furthermore, by performing a cyclization reaction known per se, the aldehyde body can be converted to 2 represented by the formula ().
-Oxo-carbapenam derivatives can be obtained, and the present invention has been completed. It should be noted that regarding the above ozonolysis, biologically active type [2-oxo-azetidine used in the present invention, 3
(S), 4(R)], the configuration of the substituents at the 3- and 4-positions of the 2-oxo-azetidine ring is cis, and 3
When the positional substituent is an amide group, what is produced by ozonolysis is not the desired aldehyde, but a ring-closed formula of the hydrogen atom of the amide group and the aldehyde. In the formula, R ¹ represents the above-mentioned meaning, and R represents an ester residue. Since the compound represented by the following is mainly produced, the object of the present invention cannot be achieved. According to the invention, R ¹ and
Examples of the acyl group for R ² include acetyl, propionyl, butyroyl, benzoyl, phenylacetyl, trichloroacetyl,
Examples include monochloroacetyl or dichloroacetyl groups, or phthalyl groups when expressed at the same time, but in order to obtain a carbapenem antibiotic having an amino group protected with an acyl group at the 6-position, R ¹ and R ² The acyl groups are groups with different electronegativities, for example, when R ¹ is a phenylacetyl group, R ² is a trichloroacetyl group,
A monochloroacetyl group or a dichloroacetyl group is preferably selected. In addition, examples of the substituted or unsubstituted benzyl group for R ³ include benzyl, p-nitrobenzyl,
Examples include p-methoxybenzyl, p-bromobenzyl, benzhydryl, trityl, phenacyl, or phthalidyl groups, and preferred examples include p-nitrobenzyl or benzhydryl groups, which can be easily removed if necessary. can. These compounds include, for example, tetrahedron.
The following reaction scheme was prepared according to the method described in Letters, Volume 21 (1980), pages 4221-4224. (However, in the formula, R ¹ , R ² and R ³ have the above-mentioned meanings, and R ⁴ represents various organic groups.) It is useful as a synthetic intermediate that can lead to carbapenem antibiotics, which are known per se and have an s-substituent at the 3-position. According to the invention, the compound of formula () may be, for example:
Said Tetrahedron Letters, No. 40 (1979),
According to the method described on pages 3867-3870, the following reaction scheme was obtained from penicillin G. (In the formula, Pc represents penicillin and Tr represents a trityl group.) The natural form represented by formula (a) obtained through each step,
It can be synthesized using a 2-oxo-azetidine (3(S), 4(R)) derivative as a starting material, for example, by a synthetic route shown in the reaction formula below. (However, in the reaction formula, R ¹ , R ² and R ³ have the above meanings.) The unit reactions at each stage shown in the above reaction formula are known per se, and can be carried out by known methods. However, a brief explanation of each step of the reaction is as follows. (a)→(1) When R ¹ or R ² each represents an independent group in the reaction of this step, for example, the ² -oxo-azetidine derivative of ^formula (a) is After obtaining an amide compound by reacting it with a reactive derivative of an acid (for example, a halide such as chlorobrome of the carboxylic acid, an active ester of an isopropenyl group, or an acid anhydride), the above-mentioned compound selected depending on the purpose is further obtained. This can be carried out by reacting a reactive derivative in the presence of a reaction accelerator such as a basic, acidic or salt catalyst if necessary (see, for example, Japanese Patent Publication No. 33919/1983). In addition, when R ¹ or R ² together represent an imide residue, for example, by reacting the compound of formula (a) with an N-alkyloxycarbonylimide compound, the 3-position of formula (1) can be It can be converted into a 2-oxo-azetidine (hereinafter also referred to as azetidinone) derivative in which the amino group is protected by an imide residue. This reaction can be carried out using a known imidization reaction of an amino group. (1)→(2) In this step, the crotyl group at the 4-position of azetidinone can be changed to a formylmethyl group by ozonolysis of the compound of formula (1). This reaction can also be carried out by a conventional olefin oxidative decomposition reaction. (2)→(3) In this step, the aldehyde derivative of formula (2) is subjected to an oxidation reaction to convert it into the compound (3) in which the aldehyde group is oxidized to a carboxyl group. This reaction can be carried out using a normal oxidation reaction, but preferably using chromic acid, for example,
This can be done by Jones oxidation or the like. (3)→(4) In this step, the compound of formula (3) is converted into a ketoester form of formula (4) by a carbon-carbon bond forming reaction known per se.
It can be converted into a compound of For example, the compound of formula (4) can be obtained by reacting the imidazolide obtained by treating the compound of formula (3) with N,N'-carbonyldiimidazole and magnesium-mono-p-nitrobenzylmalonate. can. (4)→(5) In this step, the ketoester of formula (4) obtained as described above is ozonolyzed and further methanolyzed to obtain the 1-position side chain (methyl-
3-methylbutenoate-2-yl) is converted into the compound of formula (5). (5)→(6) In this step, the compound of formula (5) is treated with tosyl azide to convert it into a diazoketoester represented by formula (6). (6)→() In this step, the ring is closed by a carbene insertion reaction, and it can be converted into a 2-oxo-carbapenam derivative of the bicyclyl formula (). For example, this can be carried out by treating the diazoketoester of formula (6) obtained as described above with a rhodium or copper catalyst, or by generating a carbene by irradiation with light. In each of the above reactions, if necessary, it is preferable to purify the product obtained in each reaction step by a separation means known per se, and to preserve the configuration of the compound obtained in each step. This can lead to the target compound of the present invention represented by the formula (). As mentioned above, the compound of formula () thus obtained has a suitable configuration for exhibiting biological activity, and is converted into a carbapenem derivative having an amino group at the 6-position by a known 3-position conversion method. Useful as a stereoselective synthetic intermediate. The present invention will be explained in more detail with reference to production examples below. Example 1 Method for producing 5(R),6(S)-3.7-dioxo-6-phthalimido-1-azabicyclo[3.2.0]heptane-2-carboxylic acid paranitrobenzyl ester Aminoazetidinone (a) ~297 mg (1.185 mmol) was dissolved in 3 ml of acetone, and 99.4 mg (1.183 mmol) of anhydrous NaHCO ₃ dissolved in 3 ml of water was added.
Add N-carboethoxyphthalimide to this mixture.
260 mg (1.183 mmol) was added and stirred overnight at room temperature. The reaction solution was diluted with methylene chloride (hereinafter abbreviated as CH ₂ Cl ₂ ), washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent, a silica gel column (benzene:acetone=
20:1) to obtain 340 mg (75.2%) of the desired product. NMR (CDCl ₃ ) δ1.35 (3H, m, = CH−C H3 ),
2.25, 2.27 (3H, s, [formula] respectively), 2.35 (2H, m, -CH ₂ -CH=), 3.75 (3H, s,
OCH ₃ ), 4.24 (1H, m, C-4H), 5.18 (2H,
m, -C H , =C H -), 5.42 (1H, d, J = 5
Hz, C-3H), 7.60-7.85 (4H, m, ArH) IR (CHCl ₃ ) 1780 (sh), 1765, 1725, 1395cm ^-1 β-phthalimide-β-crotylazetidinone
(b) ~100 mg (0.262 mmol) was dissolved in 20 ml _{of CH2Cl2} ,
It was cooled to −78° C. and ozone was passed through it for 5 minutes. Excess ozone was removed with _N2 gas. Excess dimethyl sulfide was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting oil was applied to a BioBead (Bio-Rad) column, and 82.8mg
(85.4%) of the target objects were obtained. NMR (CDCl ₃ ) δ 2.17, 2.20 (3H, s, respectively
[Formula]), 2.66-3.10 (2H, m, -CH ₂ CHO), 3.77 (3H, s, OCH ₃ ), 4.73 (1H, m,
C-4H, 5.50 (1H, d, J=5Hz, C-3H),
7.62-7.86 (4H, m, ArH), 9.57 (1H, s, C
HO) IR (CHCl ₃ ) 1780 (sh), 1760, 1740 (sh),
1725, 1390cm ^-1 Dissolve ~73.2 mg (0.204 mmol) of aldehyde (c) in 20 ml of acetone, and add 30.6 mg of chromic anhydride under ice cooling.
(0.306 mmol) and 1-2 drops of concentrated sulfuric acid were added and reacted for 20 minutes. The reaction was diluted with CH ₂ Cl ₂ and poured onto crushed ice. The organic layer was washed with saturated brine, dried, and then the solvent was distilled off and purified using a biobead column (benzene) to obtain 63 mg (79.9%) of the desired product. NMR (CDCl ₃ ) δ 2.20, 2.23 (3H, s, respectively
[Formula]), 2.57 (1H, dd, J = 7, 18Hz, - C H HCOOH), 2.84 (1H, dd, J = 7, 18Hz,
-CH H COOH), 3.75 (3H, s, CCH ₃ ), 4.56
(1H, dt, J=5.7Hz, C-4H), 5.50 (1H,
d, J=5Hz, C-3H), 5.6~6.3(1H, m,
COO H ), 7.63-7.85 (4H, m, ArH) IR (CHCl ₃ ) 1780 (sh), 1760, 1720, 1385 cm ^-1 Phthalimidocarboxylic acid (d) ~432.8mg
(1.121 mmol) was dissolved in 30 ml THF, and 200 mg (1.233 mmol) of N,N'-carbonyldiimidazole was dissolved in 4 ml of tetrahydrofuran (hereinafter abbreviated as THF).
solution was added. The reaction was carried out at room temperature under nitrogen for 6 hours. 8.6 ml of 618.8 mg (1.233 mmol) of magnesium mono-p-nitrobenzyl malonate was added to the reaction solution.
A THF solution was added and the mixture was reacted under nitrogen at room temperature for 16 hours.
The reaction solution was diluted with 150 ml of CH ₂ Cl ₂ , washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using a silica gel column (chloroform) to obtain 285.9 mg (45.3%) of the desired product. NMR (CDCl ₃ ) δ 2.17, 2.23 (3H, s, respectively
[Formula]), 2.90 (1H, dd, J = 7, 18Hz, - C H HCO -), 3.14 (1H, dd, J = 7, 18Hz,
-CH H CO-), 3.36 (2H, s, -COC H ₂ -
COO−), 3.79 (3H, s, OCH ₃ ), 4.72 (1H,
q, J = 5,7 Hz, C-4H), 5.05 (2H, s,
CH ₂ Ar), 5.56 (1H, d, J = 5Hz, C-3H),
7.46 (2H, d, J=9Hz, ArH), 7.30~7.53
(4H, m, ArH), 8.15 (2H, d, J=9Hz,
ArH) IR ( _CHCl3 ) 1780 (sh), 1760, 1720, 1525,
1385, 1350cm ^-1 Mass (m/z) 563 (M ⁺ ) Keto ester (e) ~204 mg (0.362 mmol) in 30 ml
After dissolving in CH ₂ Cl ₂ and cooling to −78° C., ozone was bubbled through for 10 minutes. Two drops of dimethyl sulfide were added at the same temperature, and after raising the temperature to room temperature (reaction for 30 minutes), the solvent was distilled off under reduced pressure. Dissolve the residue in 2 ml of THF, add 15 ml of methanol and 3 ml of water, and heat under reflux for 10 minutes.
The solvent was removed under reduced pressure and the residue was dissolved in CH ₂ Cl ₂ .
After washing with water and drying (anhydrous sodium sulfate), the solvent was distilled off under reduced pressure to obtain 152 mg (93.1%) of a colorless oil. NMR (CDCl ₃ ) δ 2.83 (1H, dd, J = 7, 18
Hz, -CH H -CO-), 3.30 (1H, dd, J=8,
18Hz, -CH H CO-), 3.48 (2H, s, -CO-C
H ₂ −COO−), 4.30 (1H, m, J = 5, 7, 8
Hz, C-4H), 5.12 (2H, s, CH ₃ Ar), 5.43
(1H, d, J=5Hz, C-3H), 7.42 (2H, d,
J = 9Hz, ArH), 7.66-7.88 (4H, m,
ArH), 8.13 (2H, d, J = 9Hz, ArH) IR (KBr) 1780, 1765, 1715, 1520, 1385cm ^-1 Mass (m/z) 452 (M ⁺ +1) ~310 mg (0.687 mmol) of ketoester (f) was dissolved in 1.0 ml of dimethylformamide and 9.0 ml of acetonitrile was added. Tosylazide 271mg
(1.375mmol) and triethylamine 103mg
(1.018 mmol) was added and stirred at room temperature for 3 hours.
The reaction solution was diluted with chloroform and washed with water. Dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify with a silica gel column (CHCl ₃ ) to give 300 mg (91.5
%) of the target product was obtained. NMR (CDCl ₃ ) δ 3.10 (1H, dd, J = 6, 18
Hz, -CH HCO- ), 3.37 (1H, dd, J=8,
18Hz, -CH H CO-), 4.37 (1H, m, J=5,
6,8Hz,C-4H),5.23(2H,s,-C H ₂
Ar), 5.46 (1H, d, J=5Hz, C-3H),
6.58 (1H, s, NH), 7.38 (2H, d, J=8
Hz, ArH), 7.67-7.87 (4H, m, ArH), 8.10
(2H, d, J=8Hz, ArH) IR (CHCl ₃ ) 2140, 1780, 1765, 1720, 1525,
1390cm ^-1 ~380 mg (0.797 mmol) of diazoketo ester (f) was dissolved in 150 ml of dry benzene and 10 mg of rhodium acetate was added. Degas the solvent and incubate at 50°C for 20
It reacted for minutes. After cooling the reaction liquid and separating and washing the catalyst, the liquid and washing liquid were distilled off under reduced pressure to obtain 196.8 mg.
(55%) of the target objects were obtained. TLC Rf value: 0.76 (Silica gel TLC Merck) Benzene:acetone 3:1 (v/v) Example 2 5(R),6(S)3-(2-hydroxyethyl)
Thio-7-oxo-6-phthalimido-1-azabicyclo[3.2.0]hept-2-ene-
Method for producing 2-carboxylic acid sodium salt 196.8 mg of bicycloketoester was added to 100 ml of acetonitrile, and 257 mg (0.957 mmol) of diphenylchlorophosphate and 124 mg (0.961 mmol) of diisopropylethylamine were added at 0°C, and the mixture was reacted for 30 minutes. Thereafter, 74.7 mg (0.957 mmol) of 2-hydroxyethyl mercaptan and 124 mg (0.961 mmol) of diisopropylethylamine were added, and the mixture was reacted at 5°C overnight. The reaction solution was diluted with CH ₂ Cl ₂ and washed with water.
After drying, it was separated and purified using a silica gel column (benzene: acetone = 5:1 (v/v)) to give 162.2 mg (70
%) was obtained. NMR (CDCl ₃ ) δ 2.93 (2H, t, J=6Hz, -
SC H ₂ CH ₂ OH), 2.97 (1H, dd, J = 10, 18Hz,
C-4Hα), 3.32 (1H, dd, J=8, 18Hz, C
-4Hβ), 3.42 (2H, t, J=6Hz, -SCH ₂ C
H ₂ OH), 4.53 (1H, m, J = 6, 8, 10Hz,
C-5H), 5.23 (1H, d, J = 14Hz, C H
HAr), 5.50 (1H, d, J=14Hz, CH H Ar),
5.74 (1H, d, J=6Hz, C-6H), 7.60 (2H,
d, J=9Hz, ArH), 7.36-7.87 (4H, m,
ArH), 8.15 (2H, d, J=9Hz, ArH) IR (CHCl ₃ ) 1795, 1780, 1725, 1700 (sh),
1525, 1385cm ^-1 High mass (m/z) 509.0866 (calculated value
C ₂₄ H ₁₉ N ₃ O ₈ S ₁ 509.0890) [α] ²² _D = −108.3° (c1.0, CHCl ₃ ) UV 323, 306, 271 (nm) 21 mg of paranitrobenzyl ester was dissolved in 2 ml of dioxane and an additional 2 ml of water was added. 20 mg of platinum oxide was added to this solution and reacted for 2 hours under 4.5 Kg/cm ² of hydrogen. Separate the catalyst and drain the liquid.
Apply to QAE Sephadex column, 0-1.0M
Elution was performed by concentration gradient gradient method using saline. The active fraction was applied to a Sephadex HP20AG column and eluted with 20% acetone water. The active fraction was detected by high performance liquid chromatography and freeze-dried to obtain 5.3 mg of the target product. (1) Physical and chemical properties NMR (D ₂ O) δ 3.00 (2H, t, J=6Hz, -
SC H ₂ CH ₂ OH), 3.13 (2H, d, J = 10Hz,
C-4H), 3.80 (2H, t, J=6Hz, -
SCH ₂ C H ₂ OH), 4.70 (1H, m, C-5H, overlap with heavy water), 5.93 (1H, d, J = 6Hz,
C-6H), 7.95 (4H, m, ArH) UV λ ^H2O _nax = 300.5nm (ε11900) (2) Antibacterial activity of the antibiotic (minimum inhibitory concentration against various pathogenic test bacteria) For example, test bacteria MIC (μg/ml) Bacillus subtilis ATCC6633 1.56 Staphylococcus aureus 209P 0.39 Proteus retogeri P-7 6.26

Claims (1)

[Claims] 1 formula A compound represented by the following formula, wherein R ¹ and R ² each independently represent an acyl group or together represent an imide-forming residue, and R ³ represents a substituted or unsubstituted benzyl group. 2 Claims in which R ¹ and R ² each independently represent an acetyl, propionyl, butyroyl, benzoyl, phenylacetyl, trifluoroacetyl, monochloroacetyl, or dichloroacetyl group, or together represent a phthalyl group A compound according to item 1. 3. The compound according to claim 1, wherein R ¹ and R ² together represent a phthalyl group.