JPH0470315B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to intermediates useful in the preparation of novel penicillanic acid ester derivatives. The novel penicillate ester derivatives prepared from the compounds of the present invention exhibit particularly strong activity against β-lactamase producing bacteria. The derivatives are useful as antibiotics in human or animal therapy and include compounds represented by the following formula [']. [wherein R ₁ is phenyl, 4-hydroxyphenyl, 1,4-cyclohexadienyl or 3-thienyl; R ₂ is primary amino or carboxy;
R ₃ represents hydrogen or lower alkyl; A represents one of the groups represented by the following formula [], [] or []. (In the formula, R ₄ is hydrogen or halogen; R ₅ is hydrogen,
It represents an amino group or 2,6-dimethoxybenzamide, and at least one of R ₄ and R ₅ is hydrogen. R ₆ represents halogen. )]. Generally, lower alkyl represents a straight chain or branched alkyl group having 1 to 6 carbon atoms. The * mark on the side chain and the + mark on the ester residue when R ₃ is not hydrogen indicate an asymmetric center that gives rise to a diastereomeric form in the compound [']. The present invention includes all these diastereomers and mixtures thereof. The novel compound ['] and its salts formed with pharmacologically acceptable non-toxic acids or bases, depending on whether R ₂ is carboxy or a primary amine, are particularly suitable for enteral administration and for ingestion. Shows strong antibacterial properties in vivo. Compound ['] contains highly antibacterially active penicillin residues and effective β-
Since it also contains residues of lactamase inhibitors, it exerts an advantageous effect on β-lactamase producing bacteria. In the clinical treatment of bacterial infections, the increasing frequency of β-lactamase producing bacteria is a significant problem. This enzyme inactivates many penicillins and cephalosporins. It is also known that β-lactamases produced by both Gram-positive and Gram-negative bacteria are highly involved in bacterial resistance to β-lactam antibiotics. Several naturally occurring β-lactamase inhibitors are known, including clavulanic acid and olivanic acid. Recently, a number of semi-synthetic β-lactam compounds have been developed, such as penicillanic acid 1,1-dioxide, 6α-chloropenicillanic acid 1,1-dioxide, a series of clavulanic acid derivatives, 6β-bromopenicillanic acid, methicillin sulfone and quinacylin sulfone. were found to have similar biological properties. With few exceptions, these compounds exhibit only weak antibacterial activity against many Gram-positive and Gram-negative bacteria, but are potent inhibitors of a wide range of β-lactamases. These compounds exhibit synergistic effects against various β-lactamase producing bacteria in conjunction with selected penicillins and cephalosporins. This is because these compounds protect penicillins and cephalosporins from inactivation. As mentioned above, the present invention provides a novel intermediate useful for producing compound [']. In one aspect, the present invention provides the formula: [wherein X halogen; R ₃ represents hydrogen or lower alkyl; A represents (a)] (In the formula, R ₄ represents hydrogen or halogen; R ₅ represents hydrogen or 2,6-dimethoxybenzamide, and at least one of R ₄ and R ₅ is hydrogen.) (b) Formula: (In the formula, R ₆ represents halogen.) and (c) formula: is a group selected from the group consisting of the groups shown in Another aspect of the present invention is a method for producing a compound [] of the formula: A-M [wherein A has the same meaning as above; M is a cation, such as Na ⁺ , K ⁺ , ammonium ion, tri- Or it represents a tetra-alkylammonium ion (tetrabutylammonium ion, etc.). ] A compound represented by the formula: By reacting with a compound represented by the formula in a solvent, the formula: Provides a method for producing a compound represented by [wherein R ₃ and It is the basis. ]. This reaction is carried out in a suitable solvent (e.g. dimethylformamide, ethyl acetate, dichloromethane, acetone or hexamethylphosphoric triamide).
It is usually carried out at 0 to 60°C. Compound [], which is a starting material, is a known compound or can be prepared by a method similar to a method for producing similar known compounds. Many of the starting materials A-M or the corresponding acids are known compounds. Acids and salts corresponding to A in which R ₅ is a group [] representing 2,6-dimethoxybenzamide are new compounds. The latter compounds are penicillin sulfones, which are prepared by known methods. Compound [] is purified and isolated by conventional methods. The compounds may be obtained as diastereomeric mixtures, which can be separated, if desired, by known methods such as chromatography. Compound [ ] is, for example, penicillanic acid halomethyl or 1-haloethyl ester 1,1-
Dioxide, clavulanic acid halomethyl ester or 6β-bromo- or 6β-iodopenicillanic acid halomethyl ester. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples. Preparations 1 and 2 illustrate the preparation of novel starting materials used in some of the examples. Production example 1 Production of 6α-bromopenicillanic acid 1,1-dioxide: - Potassium permanganate 1.90 g (12 mmol) water 35
1.91 g (6 mmol) of potassium 6α-bromopenicillanate in a solution of 1.36 ml (24 mmol) of acetic acid and 25 ml of water with stirring and ice-cooled to 0-5°C.
Add solution dropwise. After the addition is complete (approximately 15 minutes), the mixture is stirred for a further 20 minutes, also at low temperature. Remove the cold bath and add 1.25 g of solid sodium pyrosulfite to the mixture.
(8 mmol) is added to reduce excess oxidant.
The precipitated manganese oxide is filtered off and 20 g of solid sodium chloride and 50 ml of ethyl acetate are added to about 60 ml of the filtrate. The pH of the mixture is adjusted to 1.5 by adding 4N hydrochloric acid with stirring and the organic phase is separated. The aqueous phase is re-extracted with 25 ml of ethyl acetate and the combined organic extracts are washed with saturated sodium chloride solution, dried and then evaporated under reduced pressure. The obtained amorphous residue was evaporated with ether.
Crystallization from diisopropyl ether gave 6α-bromopenicillanic acid 1,1-dioxide. Melting point 124-127°C The crystalline potassium salt of the above compound was added to a solution of 0.94 g (3 mmol) of 6α-bromopenicillanic acid 1,1-dioxide in 12 ml of acetone with stirring.
Potassium ethylhexanoate 1M acetone solution 3.6
ml was added. NMR spectrum (CD ₃ OD) of 6α-potassium bromopenicillanate 1,1-dioxide: δ=
1.48 (s, 3H; 2-C H ₃ ), 1.59 (s, 3H; 2-
CH3 ), 4.48 (s, 1H; 3 _- H ), 5.10 (d, J=
2Hz, 1H; 6- H ) and 5.35(d, J=2Hz,
1H; 5- H ) ppm. Tetramethylsilane was used as an internal standard. Production Example 2 Production of 6α-chloropenicillanic acid 1,1-dioxide: - In Production Example 1, 6α-chloropenicillanic acid 1,1- Dioxide was obtained. Crystallization from diisopropyl ether melting point 134-137°C. NMR spectrum (CDCl ₃ ): δ=1.50 (s,
3H; 2-C H ₃ ), 1.64 (s, 3H; 2C H ₃ ), 4.46
(s, 1H; 3- H ), 4.70 (d, J=1.5Hz, 1H;
6- H ) and 5.18 (d, J=1.5Hz, 1H; 5-
H) ppm. Tetramethylsilane was used as an internal standard. The crystalline potassium salt of the above compound was obtained by adding a 0.8 M solution of potassium 2-ethylhexanoate in acetone to a solution of 6α-chloropenicillanic acid 1,1-dioxide in acetone with stirring. Example 1 Preparation of penicillanic acid chloromethyl ester 1,1-dioxide: - A solution of 1.17 g (5 mmol) of penicillanic acid 1,1-dioxide in 7.5 ml of dimethylformamide with 0.98 ml (7 mmol) of triethylamine and 2.18 ml of chloroiodomethane. (30 mmol) is added and the mixture is stirred at room temperature for 4 hours. After dilution with 30 ml of ethyl acetate, the mixture was washed with water (3 x 10 ml), then with a saturated aqueous solution of sodium chloride (5 ml), dried and evaporated under reduced pressure to give the desired compound as a yellow oil. This was crystallized from ether-petroleum ether. Melting point 94-96℃. NMR spectrum (CDCl ₃ ): δ = 1.47 (s,
3H; 2- CH3 ) _, 1.66(s, 3H; ₂ - CH3 ),
3.53 (d, J = 3Hz, 2H; 6α- H and 6β- H ),
4.46 (s, 1H; 3- H ), 4.68 (t, J=3Hz,
1H; 5- H ) and 5.85 (ABq, J=6Hz,
2H; _OCH2Cl )ppm. Tetramethylsilane was used as an internal standard. Example 2 Penicillanic acid 1-chloroethyl ester 1,1
- Preparation of dioxide: - The same procedure as in Example 1 was repeated except that 1-chloro-1-iodoethane was used instead of chloroiodomethane and the reaction time was extended to 16 hours to produce 1-chloroethyl penicillanate as a yellow oil. A crude ester 1,1-dioxide was obtained. This was purified by dry column chromatography on silica gel (eluent ethyl acetate-petroleum ether 7:3). Example 3 Preparation of 6α-bromopenicillanic acid chloromethyl ester 1,1-dioxide: - In Example 1, 6α-bromopenicillanic acid 1,1-dioxide was replaced with 6α-bromopenicillanic acid 1,1-dioxide.
The same procedure was repeated except that 6α-bromopenicillanic acid chloromethyl ester 1,1-dioxide was obtained as a yellow oil. NMR spectrum (CDCl ₃ ): δ = 1.48 (s,
3H; 2- CH3 ) _, 1.64(s, 3H; ₂ - CH3 ),
4.46 (s, 1H; 3- H ), 4.71 (d, J=1.5Hz,
1H; 6- H ), 5.17 (d, J = 1.5Hz, 1H; 5-
H) and 5.80 (ABq, J=6Hz, 2H; OCH ₂ Cl)
ppm. Tetramethylsilane was used as an internal standard. Example 4 Preparation of 6β-bromopenicillanic acid chloromethyl ester: - The same procedure as in Example 1 was repeated using potassium 6β-bromopenicillanate in place of penicillanic acid 1,1-dioxide and trimethylamine to produce viscous oily 6β-bromopenicillanic acid. Chloromethyl ester was obtained. Example 5 Production of clavulanic acid chloromethyl ester:- The same procedure as in Example 1 was repeated using sodium clavulanate in place of penicillanic acid 1,1-dioxide and triethylamine to obtain clavulanic acid chloromethyl ester. . Example 6 Preparation of penicillanic acid chloromethyl ester 1,1-dioxide: - Potassium penicillanic acid 1,1-dioxide 1.08
1.6 g of bis-chloromethyl sulfuric acid was added to 12 ml of dimethylformamide suspension, and the mixture was heated to 45 g at room temperature.
Stir for a minute. After dilution with 50 ml of ethyl acetate, the mixture was washed with water and then with aqueous sodium bicarbonate solution, dried and evaporated under reduced pressure to give an oil. This was purified by chromatography on silica gel to obtain the desired compound, which is identical to the compound of Example 1. Example 7 Preparation of 6α-chloropenicillanic acid chloromethyl ester 1,1-dioxide: - In Example 1, 6α-chloropenicillanic acid 1,1- was substituted for penicillanic acid 1,1-dioxide.
The same procedure was repeated using carbon dioxide to obtain 6α-chloropenicillanic acid chloromethyl ester 1,1-dioxide in the form of a viscous oil. NMR spectrum (CDCl ₃ ): δ = 1.48 (s,
3H; 2- CH3 ) _, 1.64(s, 3H; ₂ - CH3 ),
4.47 (s, 1H; 3- H ), 4.68 (d, J = 1.5Hz,
1H; 6- H ), 5.17 (d, J = 1.5Hz, 1H; 5-
H) and 5.81 (ABq, J=6Hz, 2H; OC H
_2Cl ) ppm. Tetramethylsilane was used as an internal standard. Example 8 Preparation of penicillanic acid iodomethyl ester 1,1-dioxide:- To a solution of 5.6 g (20 mmol) of penicillanic acid chloromethyl ester 1,1-dioxide in 45 ml of acetone was added 9 g of sodium iodide, and the mixture was stirred at room temperature for 16 Stir for an hour. Precipitated sodium chloride 1.15
g is collected by filtration, the solvent is distilled off under reduced pressure, and the resulting residue is treated with ethyl acetate (1:1).
6 g of undissolved sodium iodide are filtered off and the filtrate is evaporated under reduced pressure. The oily residue was purified by column chromatography on silica gel (eluent ethyl acetate-n-hexane 4:6) and crystallized from ether to give the title compound as colorless crystals. Melting point 101-102℃. Example 9 Production of 1,1-dioxopenicillanic acid chloromethyl ester: - 2.7 g of potassium 1,1-dioxopenicillanate
(10 mmol), potassium hydrogen carbonate 6.0 g (60 mmol), tetrabutylammonium hydrogen sulfate 0.34
g (1 mmol), 10 ml of water and dichloromethane
1.5 ml of chloromethyl chlorosulfate to 15 ml of mixture
Add. After stirring for 1 hour at 30° C., the mixture is filtered, the organic phase is separated and dried over sodium sulfate. After dilution with 25 ml of 2-propanol, the solution is concentrated under reduced pressure to about 10 ml and left at 5°C for 1 hour. The crystals were collected by filtration, washed with cold 2-propanol, and dried under reduced pressure to give colorless crystals of the title compound. Melting point 94-96℃. Example 10 Production of 1,1-dioxopenicillanic acid 1-chloroethyl ester: - 40.7 g of potassium 1,1-dioxopenicillanate
(0.15 mol), silver nitrate 25.5g (0.15 mol), silver oxide
Add 42 ml of 1-chloro-1-iodoethane to a mixture of 7.5 g and 750 ml of acetonitrile. After stirring for 48 hours at room temperature, the silver salt is filtered off and the filtrate is dried under reduced pressure. The residue is dissolved in 200 ml of ethyl acetate, the solution is washed with saturated aqueous sodium chloride solution, filtered, dried and evaporated under reduced pressure. The residue was chromatographed on silica gel (eluent hexane-ethyl acetate 3:2) to give the title compound as a crystalline mixture of two diastereomers. Melting point 130~
132℃. Example 11 Preparation of 1,1-dioxopenicillanic acid 1-iodoethyl ester: - 30 g of sodium iodide in a solution of 30 g (about 0.1 mol) of 1,1-dioxopenicillanic acid 1-chloroethyl ester in 100 ml of acetone. (0.2 mol) and
The mixture is stirred at room temperature for 3 days. Add aqueous sodium thiosulfate solution and remove acetone under reduced pressure. The separated oil is dissolved in ethyl acetate, the solution is washed with water, dried and evaporated under reduced pressure. The residual oil was chromatographed on silica gel (eluent hexane-ethyl acetate 3:1) to give a diastereomeric crystalline mixture of 1-iodoethyl and 1-chloroethyl esters. Melting point 134-136
℃. The mixture contained 40% iodine compounds according to iodine trace analysis. Example 12 Preparation of 6β-bromopenicillanic acid chloromethyl ester: - To a solution of 0.96 g (3 mmol) of potassium 6β-bromopenicillanate and 1.80 g (18 mmol) of potassium bicarbonate in 9 ml of water and 9 ml of ethyl acetate was added tetrahydrogen sulfate with stirring. Butylammonium 0.10
g (0.3 mmol) and then 0.45 ml (4.5 mmol) of chloromethyl chlorosulfate are added and the mixture is stirred at room temperature for 1.5 hours. The organic phase is separated and the aqueous phase is re-extracted with 9 ml of ethyl acetate. Combine the organic phases;
Wash with water (2 x 5 ml), dry and concentrate under reduced pressure to approximately 5 ml. The concentrated solution was subjected to dry column chromatography on silica gel (eluent: petroleum ether).
Pure 6β-bromopenicillanic acid chloromethyl ester was obtained as an almost colorless oil. NMR spectrum (CDCl ₃ ): δ = 1.54 (s,
3H; 2- CH3 ) _, 1.70(s, 3H; ₂ - CH3 ),
4.54 (s, 1H; 3- H ), 5.35 and 5.59 (2d, J
=4Hz, 2H; 5- H and 6- H ) and 5.77
(ABq, J=5Hz, 2H; OC H ₂ Cl) ppm. Tetramethylsilane was used as an internal standard. Example 13 Preparation of 6β-bromopenicillanic acid iodomethyl ester: - To a solution of 0.82 g (2.5 mmol) of 6β-bromopenicillanic acid chloromethyl ester in 5 ml of acetone, add 0.75 g (5.0 mmol) of sodium iodide,
After blocking the light, the mixture is stirred at room temperature for 24 hours. The precipitated sodium chloride is filtered off, washed with acetone (2 x 1 ml) and the filtrate is evaporated under reduced pressure to give an oily residue. This is dissolved in 20 ml of ethyl acetate, the resulting solution is washed with water (2 x 10 ml), dried over magnesium sulfate and concentrated under reduced pressure to about 5 ml. Next, it was subjected to silica gel column chromatography using petroleum ether-ethyl acetate (9:
Elute with 1). Fractions shown by thin layer chromatography to contain pure title compound were combined and evaporated under reduced pressure to give 6β-bromopenicillanic acid iodomethyl ester as a slightly yellow oil. NMR spectrum: δ = 1.55 (s, 3H; 2-C
H ₃ ), 1.69 (s, 3H; 2-C H ₃ ), 4.50 (s,
1H; 3- H ), 5.34 and 5.57 (2d, J=4Hz,
2H; 5- H and 6- H ) and 5.97 (ABq, J
= 5 Hz, 2H; OC H ₂ I) ppm. Tetramethylsilane was used as an internal standard. Example 14 Preparation of 1,1-dioxo-6β-(2,6-dimethoxybenzamide)penicillanic acid chloromethyl ester:- 1,1-dioxo-6β-(2,6-dimethoxybenzamide)penicillanic acid (methicillin sulfone) 6.2 g (15 mmol), potassium bicarbonate 8.7
1.8 ml (18 mmol) of chloromethyl chlorosulfate are added to a mixture of g (87 mmol), 0.51 g (1.5 mmol) of tetrabutylammonium hydrogen sulfate, 15 ml of water and 15 ml of dichloromethane at room temperature over a period of 20 minutes. After stirring for a further 15 minutes, the organic phase is separated, dried and evaporated under reduced pressure to give an oil. This was crystallized from 96% ethanol to obtain colorless crystals. Melting point 142-143°C (decomposition). A pure product was obtained by recrystallization twice from acetone-water. Melting point 154-155℃
(Disassembly). [α] ²⁰ _D = +195° (c = 1, CHCl ₃ ). Example 15 Preparation of 1,1-dioxo-6β-(2,6-dimethoxybenzamide)penicillanic acid iodomethyl ester:-1,1-dioxo-6β-(2,6-dimethoxybenzamide)penicillanic acid chloromethyl ester 2.31 3 g (20 mmol) of sodium iodide are added to a solution of g (5 mmol) in 10 ml of acetone and the mixture is stirred at room temperature overnight. The title compound is precipitated as crystals by addition of water, filtered off and dried under reduced pressure. Melting point 153-156°C (decomposition). The product is dissolved in a mixture of acetone and 96% ethanol, the acetone is removed under reduced pressure, and the desired compound is crystallized. Repeat this step to determine the melting point
The compound was obtained at 169-170°C (decomposition). [α] ²⁰ _D =+
197° (c=1, CHCl ₃ ). Example 16 Production of 1,1-dioxo-6α-chloropenicillanic acid chloromethyl ester: - Same procedure as in Example 12 using potassium 1,1-dioxo-6α-chloropenicillanate instead of potassium 6β-bromopenicillanate. The procedure was repeated and crystallized from ether-diisopropyl ether to give the title compound as colorless crystals. Melting point 111~
113℃. [α] ²⁰ _D = +210° (c = 0.5, CHCl ₃ ). Example 17 Preparation of 1,1-dioxo-6α-chloropenicillanic acid iodomethyl ester:- In Example 13, 1,1-dioxo-6β-bromopenicillanic acid chloromethyl ester was replaced with
A similar procedure was repeated using 6α-chloropenicillanic acid chloromethyl ester to give the title compound as a colorless foam. NMR spectrum (CDCl ₃ ): δ = 1.49 (s,
3H; 2- CH3 ) _, 1.62(s, 3H; ₂ - CH3 ),
4.41 (s, 1H; 3- H ), 4.66 and 5.16 (2d, J
= 1.5Hz, 2H; 5- H and 6- H ) and 6.01
(ABq, J=5Hz, 2H; _OC H2I ) ppm. Tetramethylsilane was used as an internal standard. Example 18 Preparation of 1,1-dioxo-6α-bromopenicillanic acid chloromethyl ester: - Repeat the same procedure as in Example 12 using potassium 1,1-dioxo-6α-bromopenicillanate instead of potassium 6β-bromopenicillanate. , crystallized from ether-diisopropyl ether to give colorless crystals of the title compound. Melting point 92~93
℃. [α] ²⁰ _D = +185° (c = 0.5, CHCl ₃ ). Example 19 Preparation of 1,1-dioxo-6α-bromopenicillanic acid iodomethyl ester:- In Example 13, 1,1-dioxo-6β-bromopenicillanic acid chloromethyl ester was replaced with
A similar procedure was repeated using 6α-bromopenicillanic acid chloromethyl ester to obtain the title compound. The compound was a colorless foam and did not crystallize. NMR spectrum (CDCl ₃ ): δ = 1.49 (s,
3H; 2- _CH3 ), 1.63(s, 3H; ₂ - CH3 ),
4.41 (s, 1H; 3- H ), 4.70 and 5.16 (2d, J
= 1.5Hz, 2H; 5- H and 6- H ) and 6.01
(ABq, J=5Hz, 2H; _OC H2I ) ppm. Tetramethylsilane was used as an internal standard. Example 20 Preparation of 6β-iodopenicillanic acid chloromethyl ester: - The same procedure as in Example 12 was repeated using potassium 6β-iodopenicillanate in place of potassium 6β-bromopenicillanate to obtain the title compound as a slightly yellow oil. NMR spectrum (CDCl ₃ ): δ=1.52 (s,
3H; 2- CH3 ) _, 1.71(s, 3H; ₂ - CH3 ),
4.55 (s, 1H; 3- H ), 5.40 and 5.63 (2d, J
=3.5Hz, 2H; 5- H and 6- H ) and 5.78
(ABq, J=5.5Hz, 2H; OC H ₂ Cl) ppm. Tetramethylsilane was used as an internal standard. Example 21 Preparation of 6β-iodopenicillanic acid iodomethyl ester: - The same procedure as in Example 13 was repeated using 6β-iodopenicillanic acid chloromethyl ester in place of 6β-bromopenicillanic acid chloromethyl ester to obtain the title compound as a yellow oil. Ta. NMR spectrum (CDCl ₃ ): δ = 1.53 (s,
3H; 2- CH3 ) _, 1.70(s, 3H; ₂ - CH3 ),
4.53 (s, 1H; 3- H ), 5.39 and 5.61 (2d, J
=3.5Hz, 2H; 5- H and 6- H ) and 6.00
(ABq, J=5.5Hz, 2H; OC H ₂ I) ppm. Tetramethylsilane was used as an internal standard. Example 22 Preparation of 6β-chloropenicillanic acid chloromethyl ester: - The same procedure as in Example 12 was repeated using potassium 6β-chloropenicillanate instead of potassium 6β-bromopenicillanate to obtain the title compound as a colorless oil. . NMR spectrum (CDCl ₃ ): δ = 1.53 (s,
3H; 2- CH3 ) _, 1.69(s, 3H; ₂ - CH3 ),
4.54 (s, 1H; 3- H ), 5.24 and 5.62 (2d, J
=4Hz, 2H; 5- H and 6- H ) and 5.80
(ABq, J=5Hz, 2H; OC H ₂ Cl) ppm. Tetramethylsilane was used as an internal standard. Example 23 Production of 6β-chloropenicillanic acid iodomethyl ester: - The same procedure as in Example 13 was repeated using 6β-chloropenicillanic acid chloromethyl ester instead of 6β-bromopenicillanic acid chloromethyl ester to produce a slightly yellow color. The title compound was obtained as an oil. NMR spectrum (CDCl ₃ ): δ=1.52 (s,
3H; 2- CH3 ) _, 1.69(s, 3H; ₂ - CH3 ),
4.52 (s, 1H; 3- H ), 5.22 and 5.58 (2d, J
=4Hz, 2H; 5- H and 6- H ) and 5.99
(ABq, J=5Hz, 2H; _OC H2I ) ppm. Tetramethylsilane was used as an internal standard. Example 24 Production of 6β-bromopenicillanic acid chloromethyl ester: - A Production of 6.6-dibromopenicillanic acid chloromethyl ester: - In Example 12, potassium 6,6-dibromopenicillanate was substituted for 6β-bromopenicillanic acid potassium. A similar procedure was repeated to obtain a slightly yellow oil, which was crystallized from ether-diisopropyl ether. Melting point 105~107
℃. [α] ²⁰ _D = +206° (c = 0.5, CHCl ₃ ). NMR spectrum (CDCl ₃ ): δ = 1.54 (s,
3H; 2- CH3 ) _, 1.66(s, 3H; ₂ - CH3 ),
4.60 (s, 1H; 3- H ), 5.80 (ABq, J=5
Hz, 2H; OC H ₂ Cl) and 5.83 (s, 1H; 5-
H) ppm. Tetramethylsilane was used as an internal standard. B Preparation of 6β-bromopenicillanic acid chloromethyl ester: - 1.63 g (4 mmol) of 6,6-dibromopenicillanic acid chloromethyl ester in dry benzene
1.16 (4 mmol) of tri-n-butyltin hydride are added to the 40 ml solution at 0° C. in a nitrogen atmosphere while stirring. After stirring for 18 hours at room temperature, the mixture is evaporated under reduced pressure. The oily residue was purified by dry column chromatography on silica gel (eluent petroleum ether-ethyl acetate 85:15) to yield pure chloromethylethyl 6β-bromopenicillanate as a slightly yellow oil. The NMR spectrum was identical to that of the compound obtained in Example 12. Example 25 Preparation of 1,1-dioxopenicillanic acid bromomethyl ester: - In a solution of 1.0 g of sodium bromide in 10 ml of N,N-dimethylformamide, 0.28 g of 1,1-dioxopenicillanic acid chloromethyl ester (1 mmol) and the mixture is stirred at room temperature for 20 hours. After diluting with 50 ml of ethyl acetate, the mixture was washed with water (4 x 10 ml).
After drying, evaporate under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound as a yellow oil. NMR spectrum (CDCl ₃ ): δ = 1.49 (s,
3H; 2- CH3 ) _, 1.64(s, 3H; ₂ - CH3 ),
3.52 (m, 2H; 6- H ), 4.47 (s, 1H; 3- H ),
4.75 (m, 1H; 5- H ) and 5.98 (ABq, J=
4.5Hz, 2H; OC H ₂ Br) ppm. Tetramethylsilane was used as an internal standard. Next, the production of a novel penicillanic acid ester derivative will be explained as an application example. Application example 1 Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride:-A 6-(D-α-azido-α- Production of 1,1-dioxopenicillanoyloxymethyl ester of penicillanic acid (phenylacetamide): -6-(D-α-azido-α-phenylacetamido)penicillanic acid chloromethyl ester
2.54 g (6 mmol) dimethylformamide
1.63 g (6 mmol) of potassium penicillanate 1,1-dioxide are added dropwise to the 35 ml solution and the mixture is stirred at room temperature for 20 hours. After dilution with 140 ml of ethyl acetate, the mixture is washed with water (4 x 35 ml) and then with 20 ml of saturated aqueous sodium chloride solution, and the organic phase is dried and evaporated under reduced pressure. The resulting yellow oily residue was purified by dry column chromatography on silica gel (eluent cyclohexane-ethyl acetate 1:1) to give the title compound as a yellow oil. NMR spectrum (CDCl ₃ ): δ = 1.43 (s,
3H; 2- CH ₃ ), 1.52 (s, 3H, 2- CH ₃ ),
1.59 (s, 3H; 2-C H ₃ ), 1.66 (s, 3H; 2
-CH3 ), _3.48 (d, J=3Hz, 2H; 6α- H and 6β- H ), 4.44 (s, 1H; 3- H ), 4.51
(s, 1H; 3- H ), 4.63 (t, J=3Hz,
1H; 5- H ), 5.13 (s, _1H ; CHN3 ), 5.65
(m, 2H; 5- H and 6-H), 5.92 (s,
2H; OC H ₂ O) and 7.48 (s, 5H; aromatic C
H) ppm. Tetramethylsilane was used as an internal standard. B Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride:
- A solution of 1.77 g (2.85 mmol) of 6-(D-α-azido-α-phenylacetamide) penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester in 25 ml of ethyl acetate was introduced into the gas/
Charge to a three-necked flask equipped with an evacuation tube, a glass-calomel electrode, and a bottle controlled by an automatic titrator. Add 20 ml of water and 1.77 g of 10% palladium/carbon catalyst and fill the system with nitrogen.
The suspension is then bubbled with hydrogen while stirring.
During this time, add 0.5N hydrochloric acid using an automatic titrator to maintain the pH of the aqueous phase at 2.5. When acid consumption is complete, the flask is purged with nitrogen until all hydrogen has been removed and the catalyst is then removed. The aqueous phase was separated and lyophilized to give the title compound as a colorless foam. NMR spectrum (D ₂ O): δ = 1.38 (s,
6H _; 2- CH3 ) _, 1.46(s, 3H; 2- CH3 ),
1.58 (s, 3H; 2-C H ₃ ), 3.56 (m, 2H; 6α
-H and 6β- H ), 4.60 (s, 1H; 3- H ),
4.63 (s, 1H; 3- H ), 5.03 (m, 1H; 5-
H), 5.27 (s, 1H; C H -NH ₂ ), 5.53 (s,
2H; 5- H and 6- H ), 5.97 (bs, 1H; OC
H ₂ O) and 7.53 (s, 5H; aromatic C H )
ppm. Tetramethylsilane was used as an external standard. Application example 2 6-(D-α-amino-α-(p-hydroxyphenyl)acetamide) penicillanic acid 1,1-
Production of dioxopenicilanoyloxymethyl ester hydrochloride:-A 6-[N-(benzyloxycarbonyl)-D
-α-amino-α-(p-hydroxyphenyl)
Production of penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester:
- Penicillanic acid chloromethyl ester 1,1-
6-[N-(benzyloxycarbonyl)-
D-α-amino-α-(p-hydroxyphenyl)acetamide]potassium penicillanate 2.46
g (5 mmol) is added and the mixture is stirred at room temperature for 18 hours. After diluting with 100ml of ethyl acetate,
The mixture is washed with water (4 x 25 ml), dried and evaporated under reduced pressure. The oily residue was purified by dry column chromatography on silica gel (eluent ethyl acetate-petroleum ether 8:2) to give the title compound as a yellow oil. B 6-[D-α-amino-α-(p-hydroxyphenyl)acetamide]penicillanic acid 1,1
-Production of dioxopenicilanoyloxymethyl ester hydrochloride: -The benzyloxycarbonyl protecting group of the compound obtained in A above is removed by hydrogenation at normal pressure by the method described in Application Example 1B to form a colorless amorphous title. The compound was obtained. Application Example 3 A Preparation of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1-(1,1-dioxopenicilanoyloxy)ethyl ester hydrochloride: - In Application Example 1A, the corresponding chloro 6-(D-α-azido-α-phenylacetamide) was obtained by repeating the same procedure using 6-(D-α-azido-α-phenylacetamide) penicillanic acid α-chloroethyl ester instead of the methyl ester. Penicillanic acid 1-(1,1-dioxopenicilanoyloxy)ethyl ester was obtained. B In Application Example 1B, 6-(D-α-azido-α
-phenylacetamide) penicillanic acid 1,1
-6-(D-α-azido-α-phenylacetamido)penicillanic acid 1-(1,1-
Amorphous 6-(D-α-amino-α-
phenylacetamide) penicillanic acid 1-(1,
1-Dioxopenicilanoyloxy)ethyl ester hydrochloride was obtained. Application example 4 Production of 6-(D,L-α-carboxy-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester sodium salt:-A 6-(D,L-α- Production of benzyloxycarbonyl-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester:- In Application Example 2A, 6-[N-benzyloxycarbonyl-D-α-amino-α-( The title compound was obtained by repeating the same procedure using sodium 6-(D,L-α-benzyloxycarbonyl-α-phenylacetamido)penicillanate in place of potassium hydroxyphenyl)acetamido]penicillanate. B 6-(D,L-α-carboxy-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester sodium salt production: -6-(D,L-α-benzyloxycarbonyl -α-phenylacetamide) penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester 1.43 g (2 mmol) in ethanol 20
Add 10% palladium/carbon catalyst to the ml solution and hydrogenate the mixture at normal pressure until hydrogen consumption stops. The catalyst is removed, washed with ethanol and the liquid is evaporated under reduced pressure. The oily residue obtained is dissolved in 15 ml of ethyl acetate and 15 ml of water are added. While stirring, add 0.2N aqueous sodium hydroxide solution to adjust the apparent pH of the aqueous phase to 7.0. The aqueous phase was separated and lyophilized to give the title compound as a yellow foam. Application example 5 Production of 6-(D-α-amino-α-phenylacetamide) penicillanic acid clavulanoyloxymethyl ester hydrochloride: - In application example 1A, potassium penicillanate 1,
A yellow oily 6-(D
-α-azido-α-phenylacetamide) penicillanic acid clavulanoyloxymethyl ester was obtained. This intermediate was catalytically hydrogenated by the method of Application Example 1B to obtain the title compound in the form of an amorphous powder. Application example 6 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxo-6α-
Production of chloropenicillanoyloxymethyl ester hydrochloride: - In Application Example 2A, 6α-chloropenicillanic acid chloromethyl ester 1,1-dioxide was substituted for penicillanic acid chloromethyl ester 1,1-dioxide, and 6-[N -(benzyloxycarbonyl)-D-α-amino-α-(p-hydroxyphenyl)acetamide] 6-[N-(1-N,N-dimethylaminocarbonylpropen-2-yl) instead of potassium penicillanate )-D-α-amino-
α-phenylacetamide] Repeat the same procedure using triethylammonium penicillanate to obtain 6-(N-(1-N,N-dimethylaminocarbonylpropen-2-yl)-D-α-amino-α-
[phenylacetamide] penicillanic acid 1,1-dioxo-6α-chloropenicilanoyloxymethyl ester was obtained. The protecting group of this intermediate was hydrolyzed in an ethyl acetate-water mixture (1:1) with acid catalyst (PH ca. 3), the aqueous phase was separated and lyophilized to give the amorphous title compound. Application Example 7 Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 6β-bromopenicilanoyloxymethyl ester hydrochloride:- In Application Example 2A, the production of penicillanic acid chloromethyl ester 1,1-dioxide Instead, 6β-bromopenicillanic acid chloromethyl ester, 6-
[N-(benzyloxycarbonyl)-D-α-amino-α-(p-hydroxyphenyl)acetamide] 6-[N-
(1-N,N-dimethylaminocarbonylpropen-2-yl)-D-α-amino-α-phenylacetamide] By repeating the same procedure using triethylammonium penicillanate, 6-[N-(1
-N,N-dimethylaminocarbonylpropene-
2-yl)-D-α-amino-α-phenylacetamide]penicillanic acid 6β-bromopenicilanoyloxymethyl ester was obtained. This intermediate was acid-catalyzed (PH ca. 3) hydrolyzed to remove the protecting groups in an ethyl acetate-water mixture (1:1), and the aqueous phase was separated and lyophilized to yield the amorphous title compound. Application example 8 Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride:-A 6-(D-α-amino-α- Preparation of tetrabutylammonium penicillanate (phenylacetamido): - 8.08 g of 6-(D-α-amino-α-phenylacetamide) penicillanic acid trihydrate, 6.9 g of tetrabutylammonium hydrogen sulfate, 20 ml of water and 40 ml of dichloromethane. Cool the mixture to 5°C and add 2N aqueous sodium hydroxide solution while stirring.
Add ml. The organic phase is separated and the aqueous phase is extracted with 20 ml of dichloromethane. The dichloromethane phases are combined, dried over magnesium sulphate and then evaporated under reduced pressure to give a viscous oil. This oil is dissolved in 100 ml of ethyl acetate and residual dichloromethane is removed under reduced pressure. After leaving it at 5℃ overnight,
The precipitated crystals were collected, washed with ethyl acetate, and then dried under reduced pressure to obtain the title compound as colorless, slightly hygroscopic crystals. Melting point 125-130℃ (decomposition). B Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride:
- 1.9 g of iodomethyl 1,1-dioxopenicillanate was added to a suspension of 2.95 g of natrabutylammonium 6-(D-α-amino-α-phenylacetamide) penicillanate in 20 ml of ethyl acetate and 5 ml of dichloromethane with stirring. Ethyl acetate
Add 10ml solution. After a few minutes an almost clear solution is obtained. Dichloromethane was distilled off under reduced pressure.
The precipitated tetrabutylammonium iodide is removed. Transfer the title compound from the solution to an aqueous phase (25 ml, PH 3.0, 5°C) containing 1N hydrochloric acid, and then transfer from the aqueous phase to an organic phase (25 ml of ethyl acetate, PH 7.0, 5°C) containing a 0.5 M aqueous sodium bicarbonate solution. ). The organic phase is washed with water and the title compound is transferred back to the aqueous phase using the procedure described above. N-butanol was added to the aqueous phase, and the mixture was azeotropically distilled under reduced pressure to obtain colorless crystals of the title compound. Melting point 175-177°C (decomposition). [α] ²⁰ _D =
+201° (c=1, water). Application example 9 Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester: 0.631 g of the compound obtained in Application example 8 cooled to -5°C.
Add 10 ml of ethyl acetate to a 10 ml solution of water, and adjust the pH of the mixture to 7.0 by adding 0.5 M aqueous sodium bicarbonate solution with stirring. The organic phase was separated, washed with water, dried over magnesium sulphate and then evaporated under reduced pressure to give the title compound as a colorless solid. IR spectrum (KBr) is 1780 and 1690 cm ^- ₁
showed strong absorption. Application example 10 6-[D-α-amino-α-(p-hydroxyphenyl)acetamide] penicillanic acid 1,1-
Production of dioxopenicilanoyloxymethyl ester hydrochloride: - A 6-[D-α-amino-α-(p-hydroxyphenyl)acetamide] Production of tetrabutylammonium penicillanate: - Tetrabutylammonium hydrogen sulfate 3.57 g
(10.5 mmol) in 10 ml of water was cooled to 5°C, and while stirring, 20 ml of dichloromethane-n-butanol mixture (9:1) was added, followed by addition of 2N aqueous sodium hydroxide solution to bring the pH to about 3.
Amoxicillin (6-[D-α-amino-α-
Add 4.2 g (10 mmol) of (p-hydroxyphenyl)acetamido]penicillanic acid) trihydrate, and add 2N aqueous sodium hydroxide solution to adjust the pH.
Adjust to 9. The organic phase is separated and the aqueous phase is extracted twice with 10 ml of dichloromethane-n-butanol (9:1). The extracts are combined and concentrated under reduced pressure to give a viscous oil. The residue was dissolved in 50 ml of ethyl acetate and crystallized by scratching.
After standing at ℃ for 2 hours, the crystals were collected, washed,
Drying gave the title compound. Melting point 148-151℃
(Disassembly). B 6-[D-α-amino-α-(p-hydroxyphenyl]acetamide]penicillanic acid 1,1
-Production of dioxopenicilanoyloxymethyl ester hydrochloride: - 6-[D-α-amino-α-(p-hydroxyphenyl)acetamide] 0.606 g (1 mmol) of tetrabutylammonium penicillanate in 5 ml acetonitrile solution 0.373 g of 1,1-dioxopenicillanic acid was cooled to 5°C and stirred.
(1 mmol) in 2 ml of acetonitrile is added. After stirring for 10 minutes at 5°C, ethyl acetate 50
ml and the solvent is removed under reduced pressure. The residue is dissolved in 20 ml of ethyl acetate and the crystallized tetrabutylammonium iodide is removed. liquid to water 10
ml and adjust the pH to 3 with 1N hydrochloric acid. The aqueous phase was separated and lyophilized to give the title compound as a colorless powder. NMR spectrum [(CD ₃ ) ₂ SO]: δ=1.37
(s, 6H; 2-C H ₃ ), 1.50 (s, 6H; 2-C
_H3 ), 3.46 (m, 2H; 6α- H and 6β- H ),
4.46 (s, 1H; 3- H ), 4.57 (s, 1H; 3-H)
H), 5.04 (bs, 1H; C H NH ₂ ), 5.27 (m,
1H; 5- H ), 5.58 (m, 2H; 5- H and 6
−H ) _, 5.96 (bs, 2H; OC H2O ), 6.87 and
7.37 (2d, J=8.5Hz, 4H; aromatic CH ) ppm.
Tetramethylsilane was used as an internal standard. Application example 11 Production of 6-(D-α-amino-αphenylacetamido)penicillanic acid 1-(1,1-dioxopenicilanoyloxy)ethyl ester hydrochloride: - 6-(D-α-amino- α-phenylacetamido)tetrabutylammonium penicillanate
10.55 g of 1,1-dioxopenicilane 1-iodoethyl ester (purity 40
%, corresponding to 4.22 g (10.9 mmol)) in 30 ml of ethyl acetate. Seed crystals of tetrabutylammonium iodide are immediately added to the clear solution, and the dichloromethane is distilled off under reduced pressure to remove the separated tetrabutylammonium iodide. From the solution, transfer the title compound to 50 ml of an aqueous phase containing 1N hydrochloric acid (PH3.0, 5
℃), and then the organic phase containing sodium hydrogen carbonate from the aqueous phase (50 ml of ethyl acetate, PH7.0, 5℃).
Return to. The organic phase is washed with water and the title compound is transferred back to the aqueous phase using the procedure described above. The aqueous phase was lyophilized to give the title compound as a colorless powder. NMR spectrum (D ₂ O): δ = 1.38 (s, 6H;
2- CH3 ) _, 1.43 (s, 3H; 2- CH3 ) _, 1.55
(s, 3H; 2- CH ₃ ), 1.56 (d, 3H; CHC H
₃ ), 3.50 (m, 2H; 6α- H and 6β- H ), 4.53
(s, 1H; 3- H ), 4.55 and 4.56 (2s, 1H; 3
-H ), 4.96 (m, 1H; 5- H ), 5.26 (s, 1H;
C H NH ₂ ), 5.51 (s, 2H; 5- H and 6-
H), 6.95 (m, 1H; C H CH ₃ ) and 7.51 (s,
5H; aromatic C H ) ppm. Application example 12 Production of 6-(D-α-amino-α-phenylacetamide)penicillanic acid 6β-bromopenicilanoyloxymethyl ester hydrochloride:- 6-(D-α-amino-α-phenylacetamide) Tetrabutylammonium penicillanate
Add 0.82 g (1.4 mmol) to a mixture of 2.8 ml of ethyl acetate and 1.4 ml of dichloromethane with stirring.
Iodomethyl 6β-bromopenicillanate 0.60g
Add a 5.6 ml solution of (1.4 mmol) in ethyl acetate.
After stirring for a few minutes at room temperature, crystals of tetrabutylammonium iodide begin to precipitate. Dichloromethane was distilled off from the reaction mixture under reduced pressure to remove the crystals,
Wash with ethyl acetate (2 x 2.5 ml). After washing the liquid with 5 ml of water and adding 10 ml of distilled water to the organic phase,
Adjust the pH of the aqueous phase to 3.1 by adding 1N hydrochloric acid with stirring. The aqueous phase was separated and lyophilized to give the title compound as a colorless foam. NMR spectrum (D ₂ O): δ = 1.34 (s, 3H;
2- CH3 ) _, 1.36 (s, 3H; 2- CH3 ) _, 1.43
(s, 3H; 2- CH ₃ ), 1.58 (s, 3H; 2- CH
₃ ), 4.54 (s, 1H; 3- H ), 4.75 (s, 1H; 3-
H), 5.24 (s, 1H; C H NH ₂ ), 5.46-5.62 (m,
4H; 5- H and 6- H ), 5.88 (bs, 2H; OC H
_2O ) and 7.47 (s, 5H; aromatic CH ) ppm. Application example 13 6-[D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxo-6α-
Production of chloropenicilanoyloxymethyl ester hydrochloride: - In Application Example 12, 1,1-dioxo- in place of 6β-bromopenicillanic acid iodomethyl ester
A similar procedure was repeated using 6α-chloropenicillanic acid iodomethyl ester to give the title compound as a colorless foam. NMR spectrum (D ₂ O): δ = 1.35 (s, 6H;
2- CH3 ) _, 1.41 (s, 3H; 2- CH3 ) _, 1.53
(s, 3H; 2- CH3 ), 4.57 (s _, 1H; 3- H ),
4.73 (s, 1H; 3- H ), 5.08 (s, 1H; 5- H or 6- H ), 5.26 (s, _1H ; CHNH2 ), 5.34
(s, 1H; 5- H or 6- H ), 5.49(s,
2H; 5- H and 6- H ), 5.94(b, 2H; OC H
_2O ) and 7.49 (s, 5H; aromatic CH ) ppm. Application example 14 Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride:-A 6-(D-α-amino-α- (phenylacetamide) penicillanic acid 1,1-dioxo-6α
- Production of bromopenicillanoyloxymethyl ester hydrochloride: - Repeat the same procedure in Application Example 12 using 1,1-dioxo-6α-bromopenicillanic acid iodomethyl ester instead of 6β-bromopenicillanic acid iodomethyl ester to obtain a colorless product. A foamy title compound was obtained. NMR spectrum (D ₂ O): δ = 1.36 (s,
6H _; 2- CH3 ) _, 1.41(s, 3H; 2- CH3 ),
1.54 (s, 3H; 2-C H ₃ ), 4.57 (s, 1H; 3
- H ), 4.71 (s, 1H; 3- H ), 5.09 (s,
1H; 5- H or 6- H ), 5.27(s, 1H; C
_HNH2 ), 5.35(s, 1H; 5- H or 6-
H), 5.50 (s, 2H; 5- H and 6- H ),
5.95 (b, 2H; OC H ₂ O) and 7.50 (s, 5H;
Aromatic C H ) ppm. Production of B 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride:
- 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxo-6α
- To a solution of bromopenidylanoyloxymethyl ester (free from 1.36 g of the corresponding hydrochloride) in 50 ml of ethyl acetate are added 25 ml of water and 0.7 g of 10% palladium/carbon catalyst and the mixture is stirred in an atmosphere of hydrogen.
Shake for 40 minutes. After removing the catalyst, adjust the pH of the aqueous phase to 2.5 by adding 1N hydrochloric acid. The title compound was transferred from the solution to an organic phase containing an aqueous potassium hydrogen carbonate solution (25 ml of ethyl acetate, pH 7.0, 5°C), and then a fresh aqueous phase containing 1N hydrochloric acid (PH 2.7).
Return to. The aqueous phase was lyophilized to give the title compound as a colorless powder. The NMR spectrum was identical to that of the compound obtained in Application Example 1. Application example 15 Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 6β-iodopenicillanoyloxymethyl ester hydrochloride: - In application example 12, 6β-bromopenicillanic acid iodomethyl ester was replaced with 6β -Iodopenicillanic acid iodomethyl ester gave the title compound as a colorless foam. NMR spectrum (D ₂ O): δ = 1.38 (s, 3H;
2- CH3 ) _, 1.38 (s, 3H; 2- CH3 ) _, 1.45
(s, 3H; 2- CH ₃ ), 1.60 (s, 3H; 2- CH
₃ ), 4.56 (s, 1H; 3- H ), 4.74 (s, 1H; 3-
H)), 5.22 (s, 1H; C H NH ₂ ), 5.3-5.7 (m,
4H; 5- H and 6- H ), 5.92 (bs, 2H; OC H
_2O ) and 7.49 (s, 5H; aromatic CH ) ppm. Application example 16 Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 6β-chloropenicillanoyloxymethyl ester hydrochloride: - In application example 12, 6β-bromopenicillanic acid iodomethyl ester was replaced with 6β A similar procedure was repeated using -chloropenicillanic acid iodomethyl ester to give the title compound as a colorless foam. The IR spectrum showed strong absorption at 1790-1770 and 1690 cm ^-1 . Application example 17 Production of 6-(D-α-amino-α-phenylacetamide)penicillanic acid clavulanoyloxymethyl ester hydrochloride:-A 6-(D-α-azido-α-phenylacetamide)penicillanic acid Production of iodomethyl ester: -6-(D-α-azido-α-phenylacetamido)penicillanic acid chloromethyl ester
Add 1.80 g (12 mmol) of sodium iodide to a solution of 1.32 g (3 mmol) in 25 ml of acetone,
The mixture is stirred at room temperature for 18 hours. The precipitate is removed and the liquid is evaporated under reduced pressure. The residue was extracted with 25 ml of ethyl acetate, the extract was concentrated to about 3 ml, and then subjected to column chromatography on silica gel, eluting with hexane-ethyl acetate (1:1). Fractions containing the desired compound were combined and evaporated under reduced pressure to give the title compound as a yellow oil. NMR spectrum (CDCl ₃ ): δ=1.58 (s,
3H; 2- CH3 ) _, 1.67(s, 3H; ₂ - CH3 ),
4.47 (s, 1H; 3- H ), 5.13 (s, 1H; C H
_N3 ), 5.52-5.82 (m, 2H; 5- H and 6-
H), 6.00 (ABq, 2H; OC H ₂ I), 7.4 (s,
5H; aromatic C H ) and 7.0-7.4 (m, 1H;
CONH )ppm. Tetramethylsilane was used as an internal standard. B Production of 6-(D-α-azido-α-phenylacetamide) penicillanic acid clavulanoyloxymethyl ester: - 6-(D-α-azido-α-phenylacetamide) penicillanic acid iodomethyl ester
To a solution of 0.378 g (0.73 mmol) in hexamethyltriamide phosphate in 3.8 ml is added 0.09 g (0.44 mmol) of lithium clavulanate and the mixture is stirred at room temperature for 1 hour. Mixture with ethyl acetate 90ml
diluted with water, washed with water (3 x 20 ml) and then with saturated aqueous sodium chloride solution (10 ml), dried and evaporated under reduced pressure. The resulting yellow oily residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:4) to give the title compound as a slightly yellow foam. NMR spectrum (CDCl ₃ ): δ=1.51 (s,
3H; 2- CH3 ) _, 1.64(s, 3H; ₂ - CH3 ),
3.11 (d, J = 17Hz, 1H; 6- H ), 3.51 (dd,
J ₁ = 17Hz, J ₂ = 3Hz, 1H; 6- H ), 4.25(d,
J=7Hz, _2H ; CH2OH ), 4.51(s, 1H; 3
- H ), 4.92 (m, 1H; = C H -), 5.13 (s,
1H; 5- H ), 5.13 (s, 1H; 3- H ), 5.5~
5.8 (m, 3H; 5 _- H , 6- H and CHN3 ),
5.89 (ABq, 2H; OC H ₂ O), 7.16 (d, J = 8.5
Hz, 1H; CONH ) and 7.41 (m, 5H; aromatic CH ) ppm. Tetramethylsilane was used as an internal standard. Production of C 6-(D-α-amino-α-phenylacetamido)penicillanic acid clavulanoyloxymethyl ester hydrochloride:-6-(D-α-azido-α-phenylacetamidoclavulanoyl penicillanate A solution of 0.13 g (0.22 mmol) of oxymethyl ester in 20 ml of ethyl acetate is charged to a three-necked flask equipped with a gas inlet/outlet, a glass-calomel electrode and a bottle. 20 ml of water and 0.13 g of 10% palladium/carbon catalyst are added. Fill the system with nitrogen.
Pass hydrogen through the mixture with stirring and at the same time
Add 0.1N hydrochloric acid to maintain pH at 2.5. Once the acid has been consumed, the flask is filled with nitrogen and the catalyst is removed. The aqueous phase was separated, stripped and lyophilized to give the title compound as a colorless powder. NMR spectrum [(CD ₃ ) ₂ SO]: δ=1.30
(s, 3H; 2-C H ₃ ), 1.44 (s, 3H; 2-C
_H3 ), 3.12 (d, J=17Hz, 1H; 6- H ), 3.65
(dd- _J1 = 17Hz, _J2 = 3Hz, 1H; 6- H ),
4.00 (m, 2H; CH ₂ OH), 4.42 (s, 1H; 3-
H), 4.75 (m, 1H; -C H =), 5.15 (bs,
1H; 3- H ), 5.40-5.75 (m, 3H; 5- H ,
6- H and CHNH2 ), 5.85 ( _ABq , 2H; OC
H ₂ O), 7.50 (m, 5H; aromatic C H ) and
9.45 (d, J = 7 Hz, 1H; CON H ) ppm. Tetramethylsilane was used as an internal standard. Application example 18 Production of 6-[D-α-amino-α-(p-hydroxyphenyl)acetamide] penicillanic acid clavulanoyloxymethyl ester hydrochloride: - A 6-[N-benzyloxycarbonyl-D-
α-amino-α-(p-hydroxyphenyl)
Production of acetamide] penicillanic acid chloromethyl ester: -6-[N-benzyloxycarbonyl-D-
α-amino-α-(p-hydroxyphenyl)
Acetamide] Potassium penicillanate 2.46g
(5 mmol) in 25 ml of N,N-dimethylformamide and 2.18 ml of chloroiodomethane (30
mmol) and the mixture is stirred at room temperature for 3 hours. After dilution with 100 ml of ethyl acetate, the mixture is washed with water (4 x 25 ml), dried and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate-hexane (1:
Elution with 1) gave the title compound as a yellow oil. Production of B 6-[D-α-amino-α-(p-hydroxyphenyl)acetamide] penicillanic acid clavulanoyloxymethyl ester hydrochloride:
- In application examples 17A, 17B and 17C, 6-(D
-α-azido-α-phenylacetamide) 6- instead of penicillanic acid chloromethyl ester
The same procedure was repeated using [N-benzyloxycarbonyl-D-α-amino-α-(p-hydroxyphenyl)acetamide] penicillanic acid chloromethyl ester and freeze-dried to obtain the title compound in the form of a colorless powder. IR spectrum (KBr) is 1775 and 1690cm
^-1 showed strong absorption. Application example 19 Production of 6-(D,L-α-carboxy-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester sodium salt:-A 6-(D,L-α- Production of benzyloxycarbonyl-α-phenylacetamide) penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester: - Sodium 6-(D,L-α-benzyloxycarbonyl-α-phenylacetamide) penicillanate 0.75 g of penicillanic acid iodomethyl ester 1,1-dioxide in a solution of 0.98 g (2 mmol) in 10 ml of N,N-dimethylformamide
(2 mmol is added and the mixture is stirred at room temperature for 30 min. 50 ml of ethyl acetate is added and the mixture is extracted with saturated aqueous calcium chloride solution (3 x 12 ml).
After drying, evaporate under reduced pressure. The oily residue was purified by column chromatography on silica gel (eluent hexane-ethyl acetate 1:1) to give the title compound as a yellow oil. NMR spectrum ( _CDCl3 ): δ=1.4-1.6
(m, 12H; 2- CH ₃ ), 3.46 (m, 2H; 6-
H), 4.4-4.5 (m, 2H; 3- H and CH
CO), 4.56-4.65 (m, 2H; 3- H and 5-
H) _, 5.19 (s, 2H; PhC H2O ), 5.4-5.75 (m,
2H; 5- H and 6- H ), 5.9 (ABq, 2H;
OC H ₂ O), 7.3 (s, 5H; aromatic C H ), 7.35
(s, 5H; aromatic C H ) and 7.5-7.95 (m,
1H; CONH )ppm. Tetramethylsilane was used as an internal standard. B 6-(D,L-α-carboxy-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester sodium salt production: -6-(D,L-α-benzyloxycarbonyl 1.0 g (1.4 mmol) of ethyl acetate 25
ml solution, add 25 ml of water and 1.0 g of 10% palladium/carbon catalyst and adjust the PH of the mixture to 7.0.
of the mixture by passing hydrogen through the mixture with stirring.
Adjust the pH to 7.0 by adding 0.1N sodium hydroxide. Once consumption of the base had ceased (after about 1 hour), the catalyst was removed, and the aqueous phase was separated, dried, and lyophilized to give the title compound as a colorless powder. NMR-spectrum (D ₂ O): δ = 1.47 (s,
3H; 2- CH3 ) _, 1.53(s, 3H; ₂ - CH3 ),
1.63 (s, 6H; 2-C H ₃ ), 3.55 (m, 2H; 6
- H ), 4.12 (s, 1H; 3- H ), 4.17 (s,
1H; 3- H ), 4.70 (s, 1H; CHCO ), 5.00
(m, 1H; 5- H ), 5.4-5.7 (m, 2H; 5- H
and 6- H ), 6.00 (bs, 2H; _OC H2O ), 7.42
(s, 5H; aromatic C H ) ppm. Tetramethylsilane was used as an external standard. Application example 20 Production of 6β-aminopenicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride: - A Production of tetrabutylammonium 6β-aminopenicillanic acid: - 4.32 g of 6β-aminopenicillanic acid ( 20 mmol), 6.8 g of tetrabutylammonium hydrogen sulfate
(20 mmol), dichloromethane 50 ml and water 20
ml of the ice-cooled mixture while slowly adding a solution of 1.60 g (40 mmol) of sodium hydroxide in 3.5 ml of water with stirring. The organic phase is separated and the aqueous phase is extracted with dichloromethane (2 x 25 ml). The organic phases were combined, dried and evaporated under reduced pressure to give the title compound as a viscous oil. IR spectrum ( _CHCl3 ) is 1760 and 1610
It showed a strong absorption band at cm ^-1 . Production of B6β-aminopenicillanic acid 1,1-dioxopenicilanoyl methyl ester hydrochloride:
- Tetrabutylammonium 6β-aminopenicillanate 5.1 g (11 mmol) of ethyl acetate 25
ml solution of 3.73 g (10 mmol) of penicillanic acid mode methyl ester 1,1-dioxide in 25 ml of ethyl acetate. 15 at room temperature
After stirring for a minute, the precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue was subjected to column chromatography on Sephadex (trademark) LH20 and chloroform-hexane (65:
35) for purification. Purified product with ethyl acetate
Dissolve in 25ml and add 25ml of water to adjust the PH of the mixture.
Adjust to 2.0 by adding 2N hydrochloric acid. The aqueous phase was separated and lyophilized to give the title compound as a colorless powder. NMR spectrum (D ₂ O): δ = 1.52 (s,
2H _; 2- CH3 ) _, 1.60(s, 3H; 2- CH3 ),
1.65 (s, 3H; 2-C H ₃ ), 1.76 (s, 3H; 2
-CH3 ), 3.52-3.8 (s, 2H; 6 _- H ), 4.78
(s, 1H; 3- H ), 4.90 (s, 1H; 3- H ),
5.05-5.25 (m, 1H; 5- H ), 5.20 (d, J=
4Hz, 1H; 6- H ), 5.78(d, J=4Hz,
1H; 5- H ) and 6.08 (bs, 2H; _OC H2O )
ppm. Tetramethylsilane was used as an internal standard. Application example 21 Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride: - D-α-phenylglycyl chloride hydrochloride 1.98
g (10 mmol) in 25 ml of dichloromethane with stirring at 0°C.
(20 mmol) and then 3.98 g (8 mmol) of 6-aminopenicillanic acid 1,1-dioxopenicilanoyloxymethyl ester. at 0℃
After stirring vigorously for 1.5 hours, the mixture is evaporated under reduced pressure. The residue is dissolved in an ice-cold mixture of 25 ml of ethyl acetate and 25 ml of saturated aqueous sodium bicarbonate solution. Separate the organic phase, add 20ml of water and adjust the PH of the mixture.
is adjusted to 2.5 by adding 2N hydrochloric acid. The aqueous phase is separated and lyophilized to obtain an amorphous powder. Application example 8 by crystallizing this from ethanol-butanone-2
A compound identical to that obtained in . Application example 22 Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride:-A 6-[N-(1-dimethylaminocarbonyl Preparation of potassium penicillanate (propen-2-yl)-D-α-amino-α-phenylacetamide: -6-[N-(1-dimethylaminocarbonylpropen-2-yl)-D-α-amino -α-phenylacetamide] triethylammonium penicillanate 27.3 g (48 mmol) in acetone
49 ml of a 2M solution of potassium 2-ethylxanoate in acetone is added dropwise to the 1000 ml solution. After stirring at room temperature for 2 hours, the precipitate was collected and recrystallized from methanol-isopropanol to give the title compound. Melting point 201-203°C (decomposition). [α] ²⁰ _D = +174° (c = 1, water). B Production of 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxopenicilanoyloxymethyl ester hydrochloride:
- 6-[N-(1-dimethylaminocarbonylpron-2-yl)-D-α-amino-α-phenylacetamide] potassium penicillanate
3.73 g (10 mmol) of penicillanic acid iodomethyl ester 1,1-dioxide are added to a solution of 5.49 g (11 mmol) in 25 ml of ice-cold N,N-dimethylformamide and the mixture is stirred at 5 DEG C. for 30 minutes. Dilute with 100 ml of ethyl acetate and mix the mixture with water (4 x 25 ml) and saturated aqueous sodium chloride solution.
Extract with 25ml. The organic phase is dried and evaporated under reduced pressure to half its initial volume. Add 25ml of water,
While stirring, add 2N hydrochloric acid and check the appearance of the mixture.
Adjust pH to 2.5. During hydrolysis, this pH value is maintained by further adding hydrochloric acid. Once acid consumption has stopped (after about 30 minutes), the aqueous phase is separated and lyophilized to obtain the product. When this was crystallized from ethanol-butanone-2, it was found to be the same as the compound obtained in Application Example 8. Application example 23 6-(D-α-amino-α-phenylacetamido)penicillanic acid 1,1-dioxo-6β-
Preparation of (2,6-dimethoxybenzamide) penicillanoyloxymethyl ester hydrochloride: - 1,1-dioxo-6β-(2,6-dimethoxybenzamide) penicillanic acid iodomethyl ester 1.11 g (2 mmol) in dimethylformamide
Sodium 6-(D-α-amino-α-phenylacetamido)penicillanate 0.75 in 10ml ice-cold solution
g (2 mmol). The resulting solution is kept in an ice bath for 30 minutes, diluted with 40 ml of ethyl acetate and washed with water (4 x 40 ml). Stir together the organic phase and water, and keep the pH at 2.5 by adding hydrochloric acid during this time. The aqueous phase was separated and lyophilized to give the title compound as a colorless powder. NMR _spectrum ( _CD3OD , internal reference tetramethylsilane): δ = 1.47 (s, 3H; 2- CH3 ),
1.50 (s, 6H; 2-C H ₃ ), 1.58 (s, 3H; 2-
C H ₃ ), 3.83 (s, 6H; OC H ₃ ), 4.50 (s, 1H;
3- H ), 4.69 (s, 1H; 3- H ), 5.18 (s,
1H; CHNH ₂ ), 5.21 (d, J=4Hz, 1H; 5-
H), 5.4-5.8 (m, 2H; 5- H and 6- H ),
6.00 (m, 2H; OC H ₂ O), 6.27 (d, J = 4Hz,
1H; 6- H ), 6.73 (d, 2H; aromatic 3- H and 5- H ), 7.43 (t, 1H; aromatic 4- H ) and 7.58 (s, 5H; aromatic CH ) ppm. Application example 24 6. [D-α-amino-α-(p-hydroxyphenyl)acetamide] penicillanic acid 1-(1,
Production of 1-dioxopenicillanoyloxyethyl ester hydrochloride: - In Application Example 10B, 1,1-dioxopenicillanic acid 1-iodoethyl ester was used instead of 1,1-dioxopenicillanic acid iodomethyl ester. The same procedure was repeated to obtain the title compound as a colorless powder. IR spectrum (KBr) is 1785, 1690 and
It showed a strong absorption band at 1655 cm ^-1 . Application Example 25 Production of 6-[D-α-amino-α-(p-hydroxyphenyl)acetamide]penicillanic acid 6β-bromopenicilanoyloxymethyl ester hydrochloride:- In Application Example 10B, 1,1-dioxo The same procedure was repeated using 6β-bromopenicillanic acid iodomethyl ester in place of penicillanic acid iodomethyl ester to obtain the title compound as a yellow powder. IR spectrum (KBr) is 1790, 1775 and
It showed strong absorption at 1690cm ^-1 . Application Example 26 Preparation of 6-[D-α-amino-α-(p-hydroxyphenyl)acetamide]penicillanic acid 6β-iodopenicilanoyloxymethyl ester hydrochloride:- In Application Example 10B, 1,1-dioxo The same procedure was repeated using 6β-iodopenicillanic acid iodomethyl ester instead of penicillanic acid iodomethyl ester to obtain the title compound in the form of an amorphous powder. IR spectrum (KBr) is 1790, 1775 and
It showed a strong absorption band at 1685 cm ^-1 .

Claims (1)

[Claims] 1 A compound represented by the formula: [Formula] [wherein, X is halogen; R ₃ represents hydrogen or lower alkyl; A is (a); (In the formula, R ₄ represents hydrogen or halogen; R ₅ represents hydrogen or 2,6-dimethoxybenzamide, and at least one of R ₄ and R ₅ is hydrogen.) (b) Formula: (In the formula, R ₆ represents halogen.) and (c) formula: is a group selected from the group consisting of the groups shown in 2. The compound according to item 1, wherein R ₃ is hydrogen or a methyl group. 3. The compound according to item 1, which is penicillanic acid halomethyl ester 1,1-dioxide. 4 Penicillanic acid 1-haloethyl ester 1,1
- The compound according to item 1, which is a carbon dioxide. 5 The second clavulanic acid halomethyl ester
Compounds described in Section. 6. The compound according to item 1, which is 6β-bromopenicillanic acid halomethyl ester. 7. The compound according to item 1, which is 6β-iodopenicillanic acid halomethyl ester. 8. The compound according to item 1, wherein X is iodine. 9 Formula: A-M [wherein A is (a) Formula: (In the formula, R ₄ represents hydrogen or halogen; R ₅ represents hydrogen or 2,6-dimethoxybenzamide, and at least one of R ₄ and R ₅ is hydrogen.) (b) Formula: (In the formula, R ₆ represents halogen.) and (c) formula: A group selected from the group consisting of the groups represented by; M represents a cation. ] A compound represented by the formula: [Wherein, X is halogen; R ₃ represents hydrogen or lower alkyl; Y is bromine or iodine,
It represents a chlorosulfonyloxy or α-haloalkyloxysulfonyloxy group, and is a group that is more easily eliminated than X. ] wherein X, R ₃ and A have the same meanings as above. ] A method for producing a compound represented by. 10. The method according to item 9, wherein the reaction is carried out at a temperature of 0 to 60°C.