JPH038357B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 6-aminopenicillanic acid esters and a method for producing the same, and more specifically, the present invention relates to novel 6-aminopenicillanic acid esters and a method for producing the same, and more specifically, (In the formula, R represents a methyl group or a phenyl group.) The present invention relates to a novel 6-aminopenicillanic acid ester or an acid addition salt thereof, and a method for producing the same. The compound represented by the above general formula () and its acid addition salt are both new compounds that have not been described in literature.Specifically, the compound represented by the formula () is 6-aminopenicillanic acid (5-methyl-2 -oxo-1,
3-dioxolen-4-yl) methyl ester and 6-aminopenicillanic acid (2-oxo-5-phenyl-1,3-dioxolen-4-yl) methyl ester, and as their acid addition salts, hydrochloric acid,
Salts with inorganic acids such as hydrobromic acid and sulfuric acid, or p-
There are salts with organic acids such as toluenesulfonic acid, citric acid, and oxalic acid. When the 6-position amino group of these compounds of the present invention is acylated, they give the corresponding new ester derivatives of 6-acylaminopenicillanic acid, and the 6-acylaminopenicillanic acid esters obtained here, such as amino The ester of benzylpenicillin (ampicillin) exhibits superior oral absorption not only to ampicillin itself but also to known easily absorbable ampicillin esters, such as ampicillin phthalidyl ester. It has been revealed that the concentration in the blood increases (see Test Example 1 below). The novel ampicillin ester also has extremely low toxicity (see Test Example 2). Accordingly, the present invention provides useful intermediates for producing novel 6-acylaminopenicillanic acid esters particularly suitable for use as oral penicillins. Compounds represented by the general formula () and acid addition salts thereof are represented by the general formula (In the formula, A represents an amino group or a protected amino group) 6-aminopenicillanic acid or its 6-position protected derivative, or a salt thereof at the carboxyl group has the general formula (In the formula, R is the same as above. X represents a halogen atom.) When A is a protected amino group, it is converted to an amino group. It can be produced by further converting it into an acid addition salt. As the protecting group for the protected amino group (A) in general formula (), those known as protecting groups for amino groups in the field of synthetic penicillins are used. As the protecting group for the amino group, for example, a trityl group, a benzylcarbonyl group, a phenoxymethylcarbonyl group, etc. are preferably used. The compound of formula () is a new substance and has the known general formula (In the formula, R is the same as above) Compound (Tetrahedron Letters, 1972,
(see pages 1701-1704 and Liebitz His Annalen der Hemy, Vol. 764, pp. 116-124, 1972).
It can be obtained by reacting with a halogenating agent. In the case of producing a compound in which X is a chlorine atom or a bromine atom in formula (), the above halogenation reaction is performed using an equimolar amount to an excess molar amount of a chlorinating agent or Brominating agents such as chlorine, bromine, N-bromophthalimide, N-
This is carried out by reacting bromosuccinimide, N-chlorophthalimide, N-chlorosuccinimide, etc. in an inert organic solvent such as methylene chloride, chloroform, carbon tetrachloride, benzene, etc., preferably under radical-generating conditions. It will be done. In addition, the compound in which X is an iodine atom in formula () can be produced by substituting the chlorinated or brominated product obtained above with halogen using, for example, potassium iodide according to a conventional method. Can be done. The reaction for obtaining the compound () of the present invention from the compound () and a salt of the above compound () or a salt of the carboxyl group with a metal salt such as a sodium salt, or a tertiary organic base such as a triethylamine salt is as follows. , preferably in an inert organic solvent, preferably in the presence of a base. Examples of inert organic solvents include ethyl acetate,
Aprotic inert organic solvents such as tetrahydrofuran, dioxane, acetone, dimethylformamide, dimethyl sulfoxide are preferably used. As the base, preferably used are, for example, trialkylamines such as triethylamine, alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and alkali carbonates such as sodium carbonate and potassium carbonate. Since a base generally acts as a scavenger for the acid produced by the reaction, it is not necessary to use it when using a salt at the carboxyl group of the compound (). In the reaction of the present invention, approximately equimolar to excess molar amount of the compound (), particularly the compound () in which X is a chlorine atom or a bromine atom, is used, It is carried out by acting under ice cooling or around room temperature. In this reaction, when a compound () in which A is an amino group is used as a starting material, the compound obtained here is the target compound of formula (), but when A is a protected amino group, the product is The A group of the obtained compound is further converted to an amino group to obtain a compound of formula (). This conversion to an amino group is carried out according to a conventional method. For example, when the A group is a protected amino group such as a benzylcarbonylamino group or a phenoxymethylcarbonylamino group, under cooling with dry ice-acetone, The reaction product may be reacted with phosphorus pentachloride and a lower alcohol in the presence of a base such as trialkylamine or quinoline to form an iminoether compound, and then water may be allowed to react with the reaction product for hydrolysis. In addition, when the A group is a protected amino group such as a tritylamino group, it is sufficient to simply react the reaction product with an acid, and therefore, this reaction is a step of converting the compound of formula () into an acid addition salt. You can also do this all at once. The compound of formula () produced in the above reaction is preferably isolated as its acid addition salt, but such acid addition salt can be obtained by adding the corresponding inorganic acid or This can be easily achieved by treatment with organic acids. Furthermore, when a compound in which the A group is a benzylcarbonylamino group in the formula () is used and the deacylation is carried out under the conditions described above, when the reaction is completed, the formula ()
Since the compound is obtained as its hydrochloride, it can be isolated as it is. By introducing various acyl groups into the 6-position amino group of the compound of the present invention obtained as described above, a novel 6-acylaminopenicillanic acid ester useful as an oral penicillin can be obtained. However, examples of acyl groups that are effective when applied to the compounds of the present invention include α-aminobenzylcarbonyl group, α-amino-p-hydroxybenzylcarbonyl group, α-
Carboxybenzylcarbonyl group, 5-methyl-
There are 3-phenyl-4-isoxazolylcarbonyl groups, and when these groups are introduced, new ester derivatives such as ampicillin, amoxicillin, carbenicillin, and oxacillin are obtained. In the case of an ester of ampicillin, it can be further reacted with acetone to form an ester of hetacillin. Below, the usefulness of the compound of the present invention will be clarified by citing the results of pharmacological tests using, as an example, ampicillin ester obtained by introducing an α-aminobenzylcarbonyl group into the compound of the present invention. Test Example 1 Blood concentration upon oral administration (1) Test compound A Ampicillin (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyl ester hydrochloride [Ampicillin ester derived from the compound of the present invention in which R is a methyl group in formula (). See Production Example 1 below] B Ampicillin (2-oxo-5-phenyl-
1,3-Dioxolen-4-yl) methyl ester hydrochloride [Ampicillin ester derived from the compound of the present invention in which R is a phenyl group in formula (). See Production Example 2 below] C Ampicillin phthalidyl ester hydrochloride [known ampicillin ester] D Ampicillin trihydrate [control compound] (2) Test method 4-week-old mice fasted overnight (ddY strain, body weight approx. 20
The test compound (dissolved or suspended in water or 0.5% CMC solution at a concentration of 5 mg/ml in terms of ampicillin) was orally administered to 50 mg/kg of ampicillin (5 animals/group), and Blood was collected and the serum ampicillin concentration was measured by a bioassay method, and the serum ampicillin concentration ratio was determined using the following formula. Ampicillin concentration ratio = Blood ampicillin concentration at the time of administration of test compound A, B, C or D/Blood ampicillin concentration at the time of administration of test compound D (3) Results [Table] Test Example 2 Acute Toxicity Test Example 1 Using test compounds A and B, ddY
Acute toxicity to the mouse strain (same as Test Example 1) was measured. The results are shown in Table 2. [Table] From the above results, it is clear that the novel 6-acylaminopenicillanic acid ester derived from the compound of the present invention exhibits better oral absorption than conventionally known similar penicillin esters, has low toxicity, and is effective as an oral penicillin ester. It is clear that the compounds of the present invention are useful as a compound of the present invention, and therefore have sufficient utility in this sense. Hereinafter, the present invention will be explained in more detail with reference to Examples and Production Examples. Example 1 6-aminopenicillanic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester p-toluenesulfonate [In formula (), R is a methyl group p- of the compound
Synthesis of toluene sulfonate]. (1) Synthesis of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one [a compound in which R is a methyl group and X is a bromine atom] 4,5-dimethyl-1, 3-dioxolene-2
-On (Tetrahedron Letters, 1972,
1701-1704) was dissolved in 150 ml of carbon tetrachloride, 5.34 g of N-bromosuccinimide and a catalytic amount of α,α'-azobisisobutyronitrile were added, and 15 The mixture was heated under reflux for a minute.
After concentrating the reaction solution to half its volume and removing insoluble materials,
The liquid was concentrated. The syrup-like residue was distilled under reduced pressure and a fraction with a boiling point of 115-120°C/5 mm was collected to obtain 4.2 g of the title compound as a colorless liquid (yield 73%). Elemental analysis (molecular formula C ₅ H ₅ BrO ₃ ): Theoretical value (%) C, 31.12; H, 2.61; Br, 41.40 Actual value (%) C, 31.30; H, 2.49; Br, 41.31 IR (neat, νcm ^{- 1} ): around 1825 (carbonyl) NMR (CCl ₄ , δppm): 2.10 (-CH ₃ , s), 4.10
(-CH ₂ Br, s) (2) 6-aminopenicillanic acid (5-methyl-2-
Synthesis of oxo-1,3-dioxolen-4-yl) methyl ester/p-toluenesulfonate 6β-tritylaminopenicillanic acid [J.Am.Chem.Soc. ), Vol. 84, p. 2983 (1963)] was dissolved in 100 ml of dimethylformamide, and heated at 0 to 5°C.
After cooling to , 3 g of potassium hydrogen carbonate and 6 g of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one were added, and the mixture was stirred at the same temperature for 3 hours. After the reaction was completed, the reaction solution was poured into ice water, the precipitated solid was extracted with ethyl acetate, the ethyl acetate layer was washed several times with saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to form a yellow syrup. I got it. This syrup was dissolved in 80 ml of ethyl acetate, 5.2 g of p-toluenesulfonic acid was added under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling to precipitate a colorless solid. This was taken and thoroughly washed with a mixture of ethyl acetate and ether (1:1) to obtain 8.3 g of a colorless solid compound exhibiting the following physical properties (yield: 60
%). Melting point: 130-138℃ (decomposition) Elemental analysis (molecular formula C ₁₃ H ₁₆ N ₂ O ₆ S・
CH ₃ C ₆ H ₄ SO ₃ H): Theoretical value (%) C, 47.99; H, 4.83; N, 5.60 Actual value (%) C, 47.31; H, 4.82; N, 6.00 IR (KBr, νcm ^-1 ): 1820 (cyclic carbonate),
1780 (β-lactam) 1760 (ester), NMR (DMSO-d ₆ , δppm): 1.40, 1.59 (6H, 2
position methyl, s), 2.12 (3H,
[Formula] s), 4.46 (1H, proton at 3rd position, s), 4.90-5.10 (3H, proton at 6th position and [formula] m), 5.41 (1H, proton at 5th position, d), 2.24 (3H,
[Formula] s), 6.97, 7.38 (4H, [Formula] d) The solid obtained from the above physical property values was identified as the target compound. Example 2 6-aminopenicillanic acid (2-oxo-5-phenyl-1,3-dioxolen-4-yl) methyl ester p-toluenesulfonate [In the formula (), R is a phenyl group compound p
-Toluenesulfonate] synthesis. (1) 4-bromomethyl-5-phenyl-1,3-
Synthesis of dioxolen-2-one [a compound in which R is a phenyl group and X is a bromine atom]. 2.4 g of 4-methyl-5-phenyl-1,3-dioxolen-2-one (synthesized according to Liebitzsch Annalen der Chemie, Vol. 764, pp. 116-124, 1972) was dissolved in 150 ml of carbon tetrachloride. 2.9 g of N-bromosuccinimide and a catalytic amount of α,α'-azobisisobutyronitrile were added thereto, and the mixture was heated under reflux for 90 minutes. The reaction solution was concentrated to half its volume, the insoluble portion was separated, the solution was concentrated, and the residue was recrystallized from a mixture of benzene and cyclohexane to obtain 2.3 g of the title compound as colorless needle crystals (yield 66%). Melting point: 90.5-91.5°C Elemental analysis (molecular formula C ₁₀ H ₇ BrO ₃ ): Theoretical value (%) C, 47.09; H, 2.77; Br, 31.33, Actual value (%) C, 47.22; H, 2.64; Br, 31.29, IR (KBr, νcm ^-1 ): around 1825 (carbonyl), NMR (CCl ₄ , δppm): 4.35 (-CH ₂ Br, s) 7.40
(benzene ring, s) (2) 6-aminopenicillanic acid (2-oxo-5-
phenyl-1,3-dioxolen-4-yl)
Synthesis of methyl ester/p-toluenesulfonate Using 1 g of 6-tritylaminopenicillanic acid and 0.55 g of 4-bromomethyl-5-phenyl-1,3-dioxolen-2-one, the procedure was carried out using (2) of Example 1. Similarly, 0.50 g of a compound exhibiting the following physical properties was obtained as a colorless solid (yield 41%). Melting _point : 130-135℃ (decomposition) Elemental analysis ( _{C18H18N2O6S ・}CH3C6H4SO3H) _: Theoretical value (%) _C , _53.37 ; H, _4.66 ; N, _4.98 , Actual value (%) C, 53.37; H, 4.60; N, 5.48, IR (KBr, νcm ^-1 ): 1835 (cyclic carbonate),
1790 (β-lactam), 1755 (ester), NMR (DMSO-d ₆ , δppm): 1.49, 1.64 (6H, 2
Methyl at position, s), 4.64 (1H, proton at 3rd position,
s), 5.15 (1H, 6th proton, d), 5.37
(2H, [Formula] s), 5.56 (1H, 5th proton, d), 7.4-7.7 (7H,
[Formula] [Formula] m), 7.13 (2H, [Formula] d), 2.32 (3H, [Formula] s) From the above physical property values, the obtained solid was identified as the target compound. Example 3 6-aminopenicillanic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester hydrochloride [hydrochloride of a compound in which R is a methyl group in formula ()] synthesis of. (1) Synthesis of benzylpenicillin (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester. 10 g of benzylpenicillin potassium salt was dispersed in 50 ml of dimethylformamide, and under ice cooling, 520 mg of potassium bicarbonate and 5.2 g of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one were added, and the mixture was heated at 0°C for 4 hours. The mixture was stirred and reacted. After the reaction was completed, the reaction solution was poured into ice water to remove the precipitated solid. This solid was dissolved in ethyl acetate, washed with diluted sodium chloride water, and repeatedly washed with ice water. The ethyl acetate layer was dried, and the solvent was distilled off under reduced pressure to obtain 12.5 g of the title compound, a pale yellow amorphous form. Obtained as a solid (97% yield). IR (KBr, νcm ^-1 ): 1825 (cyclic carbonate),
1785 (β-lactam), 1750 (ester),
1670 (amide) NMR (CDCl ₃ , δppm): 1.37, 1.42 (6H, 2-position methyl, s), 2.13 (3H,
[Formula] s), 3.72 (2H, -C H ₂ -C ₆ H ₅ , s), 4.29 (1H, proton at 3rd position, s), 4.80 (2H,
[Formula] s), 5.3-5.6 (2H, protons at 5th and 6th positions, m), 6.16 (1H,
NH, d), 7.14 (5H, benzene ring proton, s). (2) 6-aminopenicillanic acid (5-methyl-2-
Synthesis of oxo-1,3-dioxolen-4-yl) methyl ester hydrochloride. Dissolve 5.9 g of phosphorus pentachloride in 30 ml of dry methylene chloride, add 6.3 ml of quinoline, and heat to -30°C with dry ice-acetone. Cooled. While vigorously stirring this solution, a solution of 11 g of benzylpenicillin (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester dissolved in 10 ml of dry methylene chloride was gradually added dropwise to the above solution. After stirring for 35 minutes at temperature, propyl alcohol
20 ml was added dropwise over 5 minutes, and the mixture was further stirred for 30 minutes. Next, 20 ml of saturated saline was added dropwise while stirring vigorously, and stirring was continued for about 1 hour. After the stirring was completed, the separated methylene chloride layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and the methylene chloride was distilled off under reduced pressure to obtain a gum-like product.
This gum-like material was thoroughly washed with n-hexane and further washed with ethyl acetate to produce a compound that showed the following physical properties.
Obtained 6.6 g as a pale yellow amorphous solid (yield 72
%). Melting point: 115-120℃ (decomposition) Elemental analysis (C ₁₃ H ₁₆ N ₂ O ₆ S・HCl・1/2H ₂ O): Theoretical value (%) C, 41.77; H, 4.85; N, 7.49, actual value (%) C, 41.91; H, 4.77; N, 7.67, IR (KBr, νcm ^-1 ): 1825 (cyclic carbonate),
1790 (β-lactam), 1750 (ester), NMR (DMSO-d ₆ , δppm): 1.45, 1.66 (6H, 2
position methyl, s), 2.22 (3H,
[Formula] s), 4.57 (1H, 3rd position proton, s), 5.0-5.2 (3H, 6th position proton and [Formula] m), 5.56 (1H, 5th position proton, d) Obtained from the above physical property values. The resulting solid was identified as the compound of interest. Example 4 6-aminopenicillanic acid (2-oxo-5-phenyl-1,3-dioxolen-4-yl) methyl ester hydrochloride [hydrochloride of a compound in which R is a phenyl group in formula ()] Synthesis: From 10 g of benzylpenicillin potassium salt and 7 g of 4-bromomethyl-5-phenyl-1,3-dioxolen-2-one, 8.6 g of a compound exhibiting the following physical properties was obtained as a yellow amorphous solid in the same manner as in Example 3. (yield 74%). Melting point: 105-110℃ (decomposition) Elemental analysis ( _C18H18N2O6S・_HCl・₁ / _2H2O ): Theoretical value (%) C, _49.60 ; H, 4.62; N, 6.42, actual value (%) C, 49.58; H, 4.56; N, 6.65, IR (KBr, νcm ^-1 ): 1830 (cyclic carbonate),
1790 (β-lactam), 1755 (ester), NMR (DMSO-d ₆ , δppm): 1.46, 1.63 (6H, 2
Methyl at position, s), 4.55 (1H, proton at 3rd position,
s), 4.95 (1H, 6th proton, d), 5.36
(2H, [Formula] s), 5.53 (1H, 5th position proton, s), 7.45-7.75
(5H, [Formula] m) The solid obtained from the above physical property values was identified as the target compound. Production example 1 Ampicillin (5-methyl-2-oxo-1,
Synthesis of 3-dioxolen-4-yl) methyl ester. (1) Add 10 g of D-(-)-2-phenylglycine to 250 ml of methylene chloride, cool to 0°C, pass hydrochloric acid gas to make hydrochloride, and add 20 g of phosphorus pentachloride to this.
was added and stirred at 0 to 5°C for 4 hours. The precipitated solid was collected and washed repeatedly with methylene chloride. 13.1 g of D-(-)-phenylglycyl chloride hydrochloride as a colorless amorphous solid (yield 90%)
I got it. (2) 200 mg of 6-aminopenicillanic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester hydrochloride obtained in Example 3
was dispersed in 10 ml of methylene chloride, 50 mg of potassium hydrogen carbonate was added, and the mixture was stirred at 0°C for 15 minutes. To this, 110 mg of the acid chloride obtained in (1) above was added and stirred for 2 hours, and the mixture was stirred at room temperature. The mixture was further stirred for 2 hours. After stopping the reaction, the solid was separated and the liquid was concentrated under reduced pressure. The resulting syrup was dissolved in water and washed with ethyl acetate. The aqueous layer was saturated with sodium chloride.
The precipitated oil was extracted with methylene chloride and washed with saturated brine. Methylene chloride was concentrated to half its volume, and isopropyl alcohol was added to precipitate a colorless solid. This was taken and washed successively with isopropyl alcohol and ether to obtain 132 mg of the title compound as an amorphous solid (yield 54%). Melting point: 145℃ (decomposed), elemental analysis (molecular formula C ₂₁ H ₂₃ N ₃ O ₇ S・HCl・H ₂ O): Theoretical value (%) C, 48.88; H, 5.08; N, 8.14; S, 6.21, Actual value (%) C, 48.51; H, 5.15; N, 8.02; S, 6.44, IR (KBr, νcm ^-1 ): 1825 (cyclic carbonate),
1785 (β-lactam), 1750 (ester),
1690 (amide), NMR (DMSO-d ₆ , δppm): 1.33, 1.48 (6H, 2
position methyl, s), 2.19 (3H,
[Formula] s), 4.43 (1H, 3rd proton, s), 5.11 (2H,
[Formula] s), 5.16 (1H, benzyl proton, s), 5.43−5.65
(2H, 5th and 6th protons, m), 7.3−
7.6 (5H, benzene ring proton, m), 8.95
(3H, -N H ₃ ), 9.4 (1H, CONH-, d) Production example 2 Ampicillin (2-oxo-5-phenyl-
Synthesis of 1,3-dioxolen-4-yl)methyl ester hydrochloride. 200 mg of 6-aminopenicillanic acid (2-oxo-5-phenyl-1,3-dioxolen-4-yl) methyl ester hydrochloride obtained in Example 4 and D-(-)-phenylglycyl chloride hydrochloride salt 95
148 mg of the title compound in the same manner as in Production Example 1.
was obtained as a colorless amorphous solid (yield 56%). Melting point: 140℃ (decomposition) Elemental analysis (molecular formula C ₂₆ H ₂₅ N ₃ O ₇ S・HCl・2H ₂ O): Theoretical value (%) C, 52.39; H, 5.07; N, 7.05; S, 5.38 Actual value (%) C, 52.17; H, 4.83; N, 7.31; S, 5.64 IR (KBr, νcm ^-1 ): 1830 (cyclic carbonate),
1785 (β-lactam), 1760 (ester),
1690 (amide) NMR (DMSO-d ₆ , δppm): 1.32, 1.45 (6H, 2
Methyl at position, s), 4.44 (1H, proton at 3rd position,
s), 5.12 (1H, benzyl proton, s),
5.31 (2H, [Formula] s), 5.4-5.6 (2H, 5- and 6-position protons, m), 7.3-7.6 (10H, benzene ring proton, m), 8.8 (3H, -N H ₃ ), 9.3 (1H,
-CONH-, d). Reference example 1 Hydrolyzability in acidic and basic media (a) Hydrolyzability in acidic media (1) Test compound A, B and C of Test Example 1 (2) Test method Acidic medium (artificial Equivalent to gastric juice; salt 2.0
g, 24 ml of 10% hydrochloric acid, 3.2 g of pepsin and water.
1000ml. The test compound was dissolved at a constant concentration in pH 1.2), sampled over time while shaking at 37°C, and subjected to high performance liquid chromatography using a reversed phase distribution column. The hydrolysis rate of each test compound was determined from the decrease in peak height. (3) Results [Table] (b) Hydrolyzability in basic medium (1) Test compound A, B and C of Test Example 1 (2) Test method Basic medium (artificial intestinal fluid) was used instead of acidic medium. Equivalent to; 35.8 g of disodium phosphate, 6.0 g of 10% hydrochloric acid
ml, 2.8g of pancreatin and water added to make 1000ml. PH7.50. ) except for using (a)-(2) above.
I did the same thing. (3) Results [Table] As is clear from the above results, the ampicillin ester derived from the compound of the present invention has superior stability in acidic and basic media compared to the conventionally known ampicillin phthalidyl ester. ing. Reference example 2 Hydrolyzability in mouse serum (1) Test compound A and B of Test Example 1 (2) Test method Test compound was dissolved in 40% mouse serum (0.1M phosphate buffer solution) at 37°C. After incubating for 10 minutes, a portion of the solution was subjected to thin layer chromatography followed by bioautography to identify the compounds in the solution. (3) Results For both test compounds A and B, only ampicillin spots were observed, and no spots of the test compound itself were observed. It is therefore concluded that ampicillin esters derived from compounds of the invention are completely converted to ampicillin within 10 minutes at 37° C. in 40% mouse serum.

Claims (1)

[Claims] 1 General formula () (In the formula, R represents a methyl group or a phenyl group.) A novel 6-aminopenicillanic acid ester or an acid addition salt thereof. 2. The compound according to claim 1, wherein the acid addition salt is a hydrochloride or a para-toluenesulfonate. 3 General formula () (In the formula, A represents an amino group or a protected amino group) 6-aminopenicillanic acid or its 6-position protected derivative, or a salt thereof at the carboxyl group, with the general formula () (In the formula, R is a methyl group or a phenyl group, and
represents a halogen atom), and when A is a protected amino group, converting it into an amino group, and if necessary, further converting the resulting compound into an acid addition salt. A general formula (), characterized by (In the formula, the definition of R is the same as above.) A method for producing a novel 6-aminopenicillanic acid ester or an acid addition salt thereof. 4. The method according to claim 3, wherein the reaction of the compound of formula () or a salt of its carboxyl group with the compound of formula () is carried out in the presence of an inert organic solvent. 5. The method according to claim 3 or 4, wherein the reaction of the compound of formula () or a salt of its carboxyl group with the compound of formula () is carried out in the presence of a base.