JPS6247184B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 1-carbapenam-3-carboxylic acid derivative and a method for producing the same. The compound of the present invention is represented by the following general formula. (In the formula, R ₁ and R ₂ each represent lower alkyl such as methyl or ethyl, or R ₁ and R ₂ form a cyclic alkylene such as cyclopentyl or cyclohexyl. _{R 3} is hydrogen, lower alkyl, or aromatic hetero Rings are meant, for example, 2-furyl, 2-thienyl, 2-pyridyl or 2-penzothiazolyl or phenyl, lower alkyl and phenyl may be substituted by hydroxyl or amino groups. R ₄ means hydrogen or a trimethylsilyl group. _R5
is hydrogen, alkali metals such as lithium, potassium or sodium, alkaline earth metals such as calcium or magnesium, aluminum,
Groups that form salts with carboxyl groups, such as amino groups, monoalkylamino groups, dialkylamino groups, trialkylamino groups, etc. Groups that can be easily converted into carboxyl groups by catalytic reduction or hydrolysis, such as benzyl, p-methoxybenzyl, o - methoxybenzyl, etc. or pharmaceutically administrable ester residues such as phthalidyl, indanyl, pivaloyloxymethyl, etc. This compound exists in various stereoisomers, and an example of a structural formula showing the relative stereochemistry is shown below. The present invention also relates to a process for preparing compounds of formula (), which process is illustrated by the following reaction scheme. (In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as above.) That is, 4-(1,1-substituted-2-propenyl)azetidin-2-one () is converted into diethyl ether, tetrahydrofuran , dimethoxyethane, dioxane or a mixed solvent thereof, preferably a mixed solvent of diethyl ether and tetrahydrofuran at -100° to -30°C, preferably -78°C
After treatment with a strong base such as lithium diisopropylamide (LDA), lithium hexamethyldisilazide, preferably lithium hexamethyldisilazide at ~-50°C, 1.0-1.2 equivalents of bromoacetate is added to this at a low temperature, e.g. -78°C. Dropped at °C, then
When the reaction is carried out for 30 minutes to 3 hours, preferably 1 to 1.5 hours, the following compound () is produced. This material is converted into an aldehyde compound after ozone oxidation. Oxidation is carried out in a solvent such as methanol at -78° to -30°C, preferably at -
Ozone gas is passed through the reaction mixture at 60°C to -50°C, and then dimethyl sulfide is applied to convert it into an aldehyde to produce the compound of formula (2). When compound () is reacted with a Grignard reagent, a compound of formula () is produced. In the reaction, the aldehyde () is dissolved in a solvent such as methyl chloride, and the mixture is heated at -100° to -30°C, preferably at -78°C. About 1.1 equivalent of a Grignard reagent such as phenylmagnesium bromide is added dropwise at ~-50°C, and then reacted at room temperature. The resulting compound (), which may be a mixture of diastereomers, is dissolved in a solvent such as acetone and heated to -30° to 0°C, preferably -
Jones Reagent at 10° to 0°C
30 minutes to 2 hours, preferably 1 to 1.5 hours, to oxidize. The resulting ketone () or aldehyde () is reacted with a base such as lithium hexamethyldisilazide to perform intramolecular aldol condensation to produce the desired product (). The reaction is carried out in a solvent such as ether at -100° to -50°C, preferably -78° to -60°C for several tens of minutes to several hours.
Lithium hexamethyldisilazide is synthesized, for example, from a solution of hexamethyldisilazane and n-butyllithium in n-hexane. Generated compound ()
The reaction solution is neutralized with p-toluenesulfonic acid, etc., and then isolated and purified by conventional methods such as extraction, chromatography, and recrystallization. When the ester moiety is a group that can be easily induced into a carboxyl group, it can be converted into a carboxyl group by conventional methods such as catalytic reduction and hydrolysis by alkali treatment. In addition, salts of alkali metals or alkaline earth metals or salts with various nitrogen-containing bases (for example, ammonium salts, methylammonium salts, dimethylammonium salts, diethylammonium salts, trimethylammonium salts, triethylammonium salts, etc.) can also be prepared by general methods. ) or different types of esters. The method of the present invention is characterized in that a carbapenam skeleton is formed by intramolecular aldol condensation,
The novel 1-carbapenam-3-carboxylic acid derivative obtained is extremely useful and is important as a synthetic intermediate for thienamycin antibiotics, and also has antibacterial activity by itself, and is expected to be used as a medicine. Ru. Antibacterial activity is excellent even when obtained as a dl form, but it is also possible to separate the optically active form using general separation methods, such as methods using bases, and it is also possible to separate the optically active form in the middle of the manufacturing process. It is possible. Next, an example will be given and explained. All synthesis was performed under argon gas, and column chromatography was performed using a 1:1 mixture of Mallinckrodt silica gel (100 mesh) and Merck Kieselgel 60. Example 1 (a) A mixture of 17.754 g of hexamethyldisilazane and 10 ml of ether was cooled to -78°C and n-BuLi
Carefully add 67.75 ml (1.645 M hexane solution). After that, the mixture was stirred at room temperature for 1 hour, and then cooled to -78°C again. Add 50 ml of tetrahydrofuran (THF) to this to partially dissolve the lithium hexamethyldisilazide formed. Add 4 to this solution
A solution of 13.979 g of -(1,1-dimethyl-2-propenyl)azetidin-2-one dissolved in 50 ml of THF is added dropwise over 15 minutes. Immediately add 27.48 g of benzyl bromoacetate to the resulting solution.
After dropping a mixture of 20 ml of THF over 20 minutes −78
Stir at ℃ for 1 hour. After bringing the temperature of the liquid to around -5°C, add 10% citric acid aqueous solution to make it acidic. Extract with ethyl acetate 1, wash with saturated brine, dry over magnesium sulfate, and evaporate the solvent to obtain a pale yellow oil. When silica gel column chromatography (silica gel 500g, chloroform-acetone 9:1) was performed, a colorless oil was obtained.27.585
g of 2-oxo-4-(1,1-dimethyl-2
-propenyl)azetidine-1-acetic acid benzyl ester is obtained. MS m/e as C ₁₇ H ₂₁ O ₃ N Calculated value: 287.1521 (M ⁺ ) Experimental value: 287.1515 (M ⁺ ) IR spectrum ν ^CHCl3 _nax 1755, 1740, 16
40cm
^-1 NMR spectrum (CDCl ₃ ) δppm: 0.97 (s, 3H, CH ₃ ) 1.00 (s, 3H, CH ₃ ) 2.64 (dd, 1H, J=3and15Hz, H3) 2.88 (dd, 1H, J=5and15Hz, H3) 3.70 (d, 1H, J=18Hz, N-CH ₂ ) 3.73 (dd, 1H, J=3and5Hz, H4) 4.28 (d, 1H, J=18Hz, NCH ₂ ) 4.84-5.92 (m, 3H, CH=CH ₂ ) 5.12 (s, 2H, COCH ₂ ) 7.32 (s, 5H, C ₆ H ₅ ) (b) 2.874 g of the above product was dissolved in 30 ml of methanol, brought to -60°C, and ozone was passed for 1 hour.
Spots of the upper raw material disappear. After replacing the inside of the reaction vessel with argon, add 1 ml of dimethyl sulfide.
Add. After stirring at room temperature for 6 hours, the solvent was distilled off, and the resulting colorless crystalline substance was recrystallized from isopropyl ether to give colorless needle-like crystals.
Obtain 2.381g. (Compound (): _R1 = _R2 =methyl, _R5 =benzyl) Melting point 59-60°C. Elemental analysis C ₁₆ H ₁₉ O ₄ as N Calculated values C 66.42, H 6.62, N 4.84 Experimental values C 66.41, H 6.64, N 4.73 IR spectrum ν ^CHCl3 _nax 1755, 1745, 17
25cm
^-1 NMR spectrum (CDCl ₃ ) δppm: 1.07 (s, 3H, CH ₃ ) 1.12 (s, 3H, CH ₃ ) 2.72 (dd, 1H, J=3and15Hz, H3) 3.03 (dd, 1H, J=5and15Hz, H3) 3.68 (d, 1H, J=18Hz, N-CH ₂ ) 4.08 (dd, 1H, J=3and5Hz, H4) 4.24 (d, 1H, J=18Hz, NCH ₂ ) 5.13 (s, 2H, COCH ₂ ) 7.34 (s, 5H, C ₆ H ₅ ) 9.44 (s, 1H, CHO ) (c) A mixture of 1.775 g of hexamethyldisilazane and 3 ml of ether was cooled to -78°C and diluted with n
- Carefully add 6.38 ml of BuLi (1.647 Mn in hexane). Return to room temperature, stir for 1 hour, and then cool to -78°C again. A solution of 2.893 g of the aldehyde obtained in (b) dissolved in 10 ml of THF was added dropwise to this over about 15 minutes, and then further heated at the same temperature.
Stir for 30 minutes. A solution of 2.283 g of para-toluenesulfonic acid monohydrate dissolved in 5 ml of THF is added dropwise to the solution to neutralize it. After cooling to room temperature, extract with 500 ml of ethyl acetate, wash with 10% citric acid aqueous solution until the washings become acidic, then wash with saline,
Dry with magnesium sulfate. After distilling off the solvent, 2.356 g of a crystalline residue is obtained. Separation was performed using silica gel column chromatography, and in addition to 0.525 g of the raw material aldehyde, 1.1-dimethyl-
2-Hydroxy-1-carbapenam-3-carboxylic acid benzyl ester ((): (2S, 3R,
5S) and (2R, 3S, 5R), R ₁ = R ₂ = methyl, R ₃ = H, R ₄ = H, R ₅ = benzyl) 1.502
I got g. It is crystalline and spectrally pure. Recrystallization from a mixture of chloroform and isopropyl ether (5:95) gives colorless needle-shaped crystals. Melting point 149-150℃. Elemental analysis As C ₁₆ H ₁₉ O ₄ N Calculated values C 66.42, H 6.62, N 4.84 Experimental values C 66.32, H 6.50, N 4.91 IR spectrum ν ^CHCl3 _nax 1760, 1735 (sh
)cm
^-1 NMR spectrum (CDCl ₃ ) δppm: 0.84 (s, 3H, CH ₃ ) 1.16 (s, 3H, CH ₃ ) 2.66 (dd, 1H, J=2and15.5Hz, H6) 3.00 (br, 1H, OH) 3.05 (dd, 1H, J=5and15.5Hz, H6) 3.75 (dd, 1H, J=2and5Hz, 5H) 4.21 (br, d, 1H, J=4.5Hz, H2) 4.48 (d, 1H, J=4.5 Hz, H3) 5.16 (s, 1H, CO ₂ CH ₂ ) 7.32 (s, 5H, C ₆ H ₅ ) Example 2 Perform the same experiment as in Example 1 (c) to obtain the aldehyde obtained in Example 1 (b). After instilling on the body for 15 minutes, perform the following operations. That is, immediately trimethylsilyl chloride
A solution of 1.195 g dissolved in 5 ml of THF is added dropwise. −
After stirring at 78°C for 30 minutes, the temperature is reduced to -5°C, and a 5% aqueous citric acid solution is added to make an acidic solution. Extract with 500 ml of ethyl acetate, wash with saturated brine, dry over magnesium sulfate, and evaporate the solvent to obtain 3.230 g of a colorless crystalline residue. Silica gel column chromatography (silica gel 60g, chloroform-
After purification with acetone (9:1) and recrystallization from isopropyl ether, 1,1-dimethyl-2
-trimethylsilyloxy-1-carbapenam-
3-Carboxylic acid benzyl ester (():
Mixture of (2S, 3R, 5S) and (2R, 3S, 5R), R ₁
= R ₂ = methyl, R ₃ = H, R ₄ = trimethylsilyl, R ₅ = benzyl) 2.827 g are obtained. Elemental analysis C ₁₉ H ₂₇ O ₄ As NSi Calculated values C 63.13, H 7.53, N 3.87 Experimental values C 63.02, H 7.67, N 3.76 IR spectrum ν ^CHCl3 _nax 1755, 1735 (sh)
cm ^-1 NMR spectrum (CDCl ₃ ) δppm: 0.10 (s, 3H, SiMe ₃ ) 0.86 (s, 3H, CH ₃ ) 1.11 (s, 3H, CH ₃ ) 2.66 (dd, 1H, J=2and15.5Hz, H6) 3.06 (dd, 1H, J=5and15.5Hz, H6) 3.76 (dd, 1H, J=2and5Hz, H5) 4.30 (d, 1H, J=4Hz, H2) 4.47 (d, 1H, J=4Hz, H3) 5.00 (d, 1H, J=12.5Hz, COCH ₂ ) 5.28 (d, 1H, J=12.5Hz, CO ₂ CH ₂ ) 7.34 (s, 5H, C ₆ H ₅ ) Example 3 (a) Example 1 289 mg of the aldehyde obtained in step (b) was dissolved in 3 ml of methylene chloride and brought to -78°C. To this is added dropwise 0.59 ml of phenylmagnesium bromide (as a 1.87M ether solution). The reaction solution is allowed to gradually reach room temperature over a period of 1 hour, after which it is stirred for an additional 30 minutes. The reaction solution was kept at -5°C,
Add 3 ml of 10% ammonium chloride aqueous solution. Extract with 500 ml of ethyl acetate, wash with saturated brine, dry over magnesium sulfate, and evaporate the solvent to obtain 295 mg of pale yellow oil. When this was purified by silica gel column chromatography (6 g, chloroform-acetone 8:2), a crystalline compound (R ₁ = R ₂ = methyl, R ₃ = phenyl, R ₅
= benzyl) 275 mg is obtained. of this
NMR shows an approximately 2:1 mixture of diastereomers. IR (cm ^-1 ) ( _CHCl3 ), 3600
~3300 (OH, broad), 1755, 1740 (C=
0). Dissolve 275 mg of this substance in 6 ml of acetone.
Cool to ℃, stir Johns reagent 0.34 ml
was added dropwise, and then stirred at the same temperature for an additional hour. Add 1 ml of methanol to decompose excess chromic acid, and then extract with 500 ml of ethyl acetate. After washing with brine and drying over magnesium sulfate, the solvent was distilled off to obtain 280 mg of a colorless oil, which was subjected to silica gel column chromatography (6 g, chloroform-acetone 9:
Purification by 1) yields 235 mg of compound () (R ₁ =R ₂ =methyl, R ₃ = phenyl, R ₅ =benzyl). MS m/e as C ₂₂ H ₂₃ O ₄ N Calculated value: 365.1627 (M ⁺ ) Experimental value: 365.1634 (M ⁺ ) IR spectrum ν ^CHCl3 _nax 1750, 1670 cm ^-1 NMR spectrum (CDCl ₃ ) δppm: 1.34 (s, 3H, CH ₃ ) 1.41 (s, 3H, CH ₃ ) 2.72 (dd, 1H, J=3and15Hz, H3) 3.04 (dd, 1H, J=5and15Hz, H3) 3.76 (d, 1H, J=18Hz, NCH ₂ ) 4.31 (d, 1H, J=18Hz, NCH ₂ ) 4.41 (dd, 1H, J=3and5Hz, H4) 5.14 (s, 2H, CO ₂ CH ₂ ) 7.20-7.80 (m, 5H, C ₆ H ₅ ) 7.31 (s, 5H, C ₆ H ₅ ) (b) A mixture of 178 mg of hexamethyldisilazane and 2 ml of ether was cooled to -78°C and added with n-
BuLi0.64ml (as 1.647Mn-hexane solution)
Add carefully. Return to room temperature, stir for 1 hour, and then cool to -78°C again. To this (a)
A solution of 365 mg of the compound () obtained in 3 dissolved in 3 ml of THF was added dropwise, and the mixture was further stirred at the same temperature for 30 minutes. A solution of 228 mg of para-toluenesulfonic acid monohydrate dissolved in 1 ml of THF is added dropwise to this to neutralize it. Pour this into 200 ml of ethyl acetate, wash with 10% citric acid aqueous solution until the washings become acidic, then wash with brine, and dry over magnesium sulfate. When the solvent is distilled off, a crystalline residue
Get 345mg. When this is recrystallized from a mixed solvent of isopropyl alcohol and chloroform (8:2), 1,1-dimethyl-
2-hydroxy-2-phenyl-1-carbabenam-3-carboxylic acid benzyl ester ((): mixture of (2S, 3R, 5S) and (2R, 3S, 5R), R ₁ = R ₂ = methyl, R ₃ = phenyl, R ₄
=H, R ₅ =benzyl) 150 mg of crystals are obtained. Elemental analysis Calculated values as C ₂₂ H ₂₃ O ₄ N: C 72.31, H 6.34, N 3.83 Experimental values: C 72.36, H 6.37, N 3.75 193 mg of compound () exhibiting Rf0.43 was recovered from the mother liquor. IR spectrum ν ^CHCl3 _nax 1760, 1733 (sh
)cm
^-1 NMR spectrum (CDCl ₃ ) δppm: 0.60 (s, 3H, CH ₃ ) 1.04 (s, 3H, CH ₃ ) 2.72 (dd, 1H, J=2and16Hz, H6) 3.13 (dd, 1H, J=5and16Hz, H6) 3.21 (s, 1H, OH) 4.02 (dd, 1H, J=2and5Hz, H5) 5.00 (d, 1H, J=12.5Hz, CO ₂ CH ₂ ) 5.08 (s, 1H, H3) 5.15 (d, 1H, J=12.5Hz, CO ₂ CH ₂ ) 6.80-7.60 (m, 10H, 2C ₆ H ₅ ) Example 4 1,1-dimethyl-2-hydroxy-1-carbapenam-3-carboxylic acid obtained in Example 1 Benzyl ester in rabbit liver homogenate at 1000μg/
After adding the mixture to a concentration of 1 ml and reacting at 37°C for 2 hours, the same volume of ethanol was added and allowed to stand, followed by centrifugation. Prepare a 2-fold dilution series of the supernatant using dimethyl sulfoxide, and
ml was added to 9 ml of HIA medium to prepare an agar plate medium for testing. An antibacterial test was conducted according to the standard method of the Japanese Society of Chemotherapy. The results are shown in the table below. 【table】

Claims (1)

[Claims] 1 formula A compound represented by However, in the formula R ₁ and R ₂
each represents a lower alkyl group, or
R ₁ and R ₂ form a cyclic alkylene. R ₃ means hydrogen, a lower alkyl group, an aromatic heterocycle or a phenyl group, and the lower alkyl and phenyl may be substituted with a hydroxyl group or an amino group. R ₄ means hydrogen or trimethylsilyl group. R ₅ means hydrogen, an alkali metal, an alkaline earth metal, aluminum, a group that forms a salt with a carboxyl group, a group that can be easily converted into a carboxylic acid, or a pharmaceutically administrable ester residue. 2 4-(1,1-substituted-2-propenyl)azetidin-2-one is reacted with bromoacetate in the presence of a base to produce 4-(1,1-substituted-2-propenyl)-2-oxoazetidine- 1-acetic acid ester and oxidize it to form the formula An aldehyde represented by is prepared, and then treated with a Grignard reagent to form the formula A formula characterized in that a compound represented by is prepared, and this compound is further subjected to an intramolecular aldol reaction in the presence of a base to remove or convert the ester moiety as desired. A method for producing a compound represented by However, in the formula, R ₁ and R ₂ each mean a lower alkyl group, or R ₁ and R ₂ form a cyclic alkylene. R ₃ means hydrogen, a lower alkyl group, an aromatic heterocycle or a phenyl group, and the lower alkyl and phenyl may be substituted with a hydroxyl group or an amino group. R ₄ means hydrogen or trimethylsilyl group. R ₅ means hydrogen, an alkali metal, an alkaline earth metal, aluminum, a group that forms a salt with a carboxyl group, a group that can be easily converted into a carboxylic acid, or a pharmaceutically administrable ester residue.