KR840000799B1 - Process for preparing penicillin compounds - Google Patents

Abstract

The title compds. I (R1 R2, R3 independently=H, lower alkyl, halo, lower alkoxy, OH, Phenylalkoxy; R4=H, lower alkyl; R5=H, OH) and their salts, useful as antibiotics, were prepd. Thus, 3.7g 6-(3,4-dimethoxyphenyl)-1,2-dihydro-2-oxonicotinic acid in 37mL anhyd. dimethylacetoamide was reacted with 4.2g amoxycillin-3H2O for 3 hrs. and adjusted to pH 2.0 with 1N-HC1. The resulting ppt. was dissolved in 15mL MeOH/dichloromethane (1:1) soln. and treated with Na 2-ethylhexane and 45mL acetone to give 5.6g Na 6-(3,4-dimethoxyphenyl)-1,2-dihydro-2-oxonicotinyl amoxycillin.

Description

Method of Preparation Penicillin Compound

The present invention relates to a process for preparing penicillin compounds of the general formula (I) and pharmaceutically acceptable salts thereof, which are effective as antibiotics.

In the above general formula

R ₁ , R ₂ and R ₃ are each hydrogen, lower alkyl group, halogen atom, lower alkoxy group, hydroxyl group or substituted or unsubstituted phenyl alkoxy group provided that R ₁ , R ₂ and R ₃ are simultaneously Cannot be hydrogen),

R ₄ is hydrogen or lower alkyl group and R ₅ is hydrogen or hydroxyl group.

Penicsilane forms of compounds exhibit antibiotic activity and many derivatives thereof have been prepared from penicillin.

Recently, research on penicillin compounds has made a lot of efforts to develop compounds that have an effective action against Gram-negative bacteria, in particular Pseudomonas aeruginosa and bacteria with lactase. However, very few penicillin compounds did not show satisfactory antibiotic activity against the bacteria which was satisfactory for the bacterium (Journal of Antibiotics, Vol. 32, No. 6, page 621 (1979)).

According to one of the methods of the present invention, a compound of formula (I) is prepared wherein R ₅ is a hydroxyl group, and according to another method, a compound of formula (I) wherein R ₃ is hydrogen or a hydroxyl group Is manufactured.

In the compound of formula (I), R ₁ , R ₂ and R ₃ may be the same or different, hydrogen; Lower alkyl groups of 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl; (lower alkoxy groups of 1 to 4 carbon atoms (e.g. methoxy, Ethoxy, propoxy and butoxy), unsubstituted or substituted phenylalkoxy groups, wherein the alkoxy moiety consists of 1 to 3 carbon atoms, and the substituents are alkyl groups of 1 to 4 carbon atoms, halogen atoms such as chlorine or bromine, Groups, formyl amino groups and lower alkoxy groups having 1 to 4 carbon atoms) [e.g., phenylmethoxy, phenylethoxy phenylpropoxy, dimethoxybenzyloxy, methoxybenzyloxy, formylaminobenzyloxy and 3-methoxy Methoxy-4-formylamino-benzyloxy]; a halogen atom (e.g., fluorine, chlorine, bromine and iodine); or a hydroxyl group, provided that R ₁ , R ₂ and R ₃ may not be hydrogen at the same time.

Examples of the substituent R ₄ include hydrogen or lower alkyl groups having 1 to 4 carbon atoms (eg, methyl, ethyl n-propyl, i-propyl, n-butyl, i-butyl and t-butyl groups).

The compound of general formula (III) mentioned later like General formula (I) compound whose R <_5> is hydroxyl group can be manufactured by the following method.

By the process according to the invention, the amoxicillin of the following structural formula (A), in which the functional group (i.e., the amino group and the carboxyl group) may or may not be protected, is substituted with a carboxylic acid of the general formula (II) or a carboxylic reactive derivative thereof (E.g., acid halides, mixed acid anhydrides, etc.), or when R ₁ , R ₂ and / or R ₃ are hydroxyl groups, reacted with hydroxyl-protected carboxylic acid derivatives or carboxylic reactive derivatives thereof. The phenylsilin compound of (III) is prepared.

In the above general formula

R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

This reaction can be carried out in a solvent, by which a COHN bond (peptide bond) is formed between the amoxicillin of formula (A) and the carboxylic acid of formula (II).

In particular, this reaction can be made under conventional reaction conditions for the production of polypeptides, penicillins or cephalosporins as described in the literature.

See Miklos Bodanszky et al., Peptide Synthesis, Interscience Publishers (1966), pp. 75-125 (ref. 1), and E. H. Flynn, Cephalosporins and Penicillins, Chemistry and Biology, Academic Press, (1972) (ref. 2)].

This reaction proceeds preferably even though the amino and carboxyl groups of amoxicillin are not protected. In this reaction, when using amoxicillin in which the amino and carboxyl groups are unprotected, organic solvents (eg esters, ethers and amides) can be used. Among them, aprotic polar organic solvents (for example, dimethylformamide and diethylformamide) are preferably used. This reaction can proceed for about 30 minutes to 24 hours at a temperature of -50 ℃ to 100 ℃.

In the reaction of the amoxicillin of formula (A) with the carboxylic acid of formula (II), amoxicillin in which one or both of the amino and the carboxyl groups is protected may also be preferably used.

The carboxyl and amino groups of amoxicillin can be protected by trialkyl silylating agents. For example, when amoxicillin must be reacted in anhydrous state, such as an organic solvent, the unprotected amoxicillin can be dissolved in an organic solvent such as an alkyl halide to form a trialkylsilylating agent (e.g. trimethyl chlorosilane or hexamethyldisilazane). Unprotected amoxicillin can be converted to tremethylsilylester or N, O-bis-trimethylsilyl derivatives.

Benzhydryl ester, benzyl ester, trichloroethyl ester, p-nitrobenzyl ester, alkoxy methyl ester, t-butyl ester and the like may be used to protect the carboxyl group of amoxicillin.

Protection of amino groups in amoxicillin is carried out according to the methods described in the literature. Cephalosporins and Penicillins, Chemistry and Biology, P. 81, Academic Press (1972). For example, amino groups are suitably protected by t-butoxycarbonyl groups, enamine-type protecting groups, or silazine-type protecting groups.

When a hydroxyl group is present in R ₁ , R ₂ and / or R _{3 in the} carboxylic acid of formula (II) or a carboxylic reactive derivative thereof, the hydroxyl group is p-nitrobenzyl ether, p- Protected with methoxybenzyl ether, methoxymethyl ether, methoxyethyl ether, pyranyl ether or phenacyl ether.

The penicillin compounds prepared by the present invention may preferably be esterified, and bioavailability (eg, oral absorption, intestinal absorption, and formulation stability) may be increased by appropriately formulating and administering the esterified product thus prepared. have. Esterification for this purpose is achieved by esterifying the final product or by reacting the esterified amoxicillin to form peptide bonds. In the latter case, there is an advantage that the amoxicillin ester can be reacted under anhydrous state because of their solubility in the organic solvent. Examples of such esters are alkanoyloxy alkyl esters (eg pivaloyloxymethyl ester and 1-acetoxy-1-ethyl ester), phthalidyl esters, phenyl esters and indanyl esters.

Reactive derivatives of the carboxyl group of the general formula (II) carboxylic acid that can be used in the present invention can be prepared by known methods [eg, References 1 and 2]. Typical examples of these compounds are acid-halides such as acid chlorides, mixed acid anhydrides prepared from several organic and inorganic acids (hemialkyl ethers of sulfuric acid, phosphoric acid and carboxylic acid), and some electrophilic alcoholic glasses. Active esters, active thioesters, active amides and similar halogenated products containing groups or phenol residues (eg acid-azides and sulfonates).

Examples of dehydrating-condensing agents that form the desired peptide bonds and provide reactive derivatives of carboxyl or amino groups include carbodiimides, alkoxyacetylenes, woodward reagents, amidephosphates, cyanide phosphates, phosphorus esters, phosphorus Anhydrides, polyphosphoric esters, Huxmeyer reagents, phosphorus ester halides and phosphorus halides.

The reaction between the reactive derivative of the carboxyl group of the carboxylic acid of formula (II) and amoxicillin is usually -50 in an organic solvent, anhydrous organic solvent or an aprotic organic solvent containing water in a molar ratio of 2: 1 to 1: 1. It is carried out for 30 minutes to 24 hours in the temperature range of ℃ to 100 ℃ or the boiling point of the solvent, the resulting peptide bonds.

Since the reaction conditions are not limited to the above ranges, they can be appropriately selected depending on the reagent to be used, the degree of activation required, the scale of the reaction, the solvent to be used, and the like.

After the reaction is completed, the product is separated by conventional methods such as solvent partition method, adsorption chromatography, ion exchange chromatography, precipitation method, recrystallization method or a mixture thereof.

If the compounds thus obtained are esters as described in Buy, do not use them directly for the purposes of the present invention. If it is necessary to recover the compound of formula (I) from the protected product, they can be deesterified to convert to the desired product.

This deesterification can be effected by hydrolysis in neutral to acidic media, by reduction such as catalytic reduction or reduction with zinc powder, or by strong acids (e.g. trifluoroacetic acid, formic acid, acetic acid) under mild conditions that do not decompose penicillin compounds. By deesterification).

The penicillin compound of general formula (I) can be manufactured by another method as described below.

That is, the protected or unprotected penicillin compound of general formula (I) and pharmaceutically acceptable salts thereof are protected with 6-amino penicsilane acid of the general formula (V) or both amino and carboxyl groups or only carboxyl groups The derivative thereof may be a compound of formula (IV) or a carboxylic reactive derivative thereof (e.g., an acid halide, mixed acid anhydride, etc.) or R ₁ , R ₂ , R ₃ and / or R ₅ is hydroxyl In the case of a group, it is reacted with a hydroxyl-protecting derivative of the general formula (IV) compound or a reactive derivative thereof.

In the above formula,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each as defined above,

R ₆ is hydrogen or an amino-protecting group,

R ₇ is hydrogen or a carboxyl-protecting group.

Carboxylic reactive derivatives of general formula (IV) can be prepared by the same method as mentioned above for the preparation of carboxyl reactive derivatives of general formula (II) compounds.

The second process according to the invention can be carried out in a similar manner as described above for the reaction of amoxicillin or its protected derivatives with carboxylic acids of general formula (II).

The type, protection purpose and method of the carboxyl and amino protecting group for the carboxyl and amino-protecting derivative represented by the general formula (V) are as described for amoxicillin.

In addition, in order to protect the hydroxyl groups present in R ₁ , R ₂ , R ₃ and / or R ₅ of the compound of formula (IV), the hydroxyl groups of the carboxylic acid of formula (II) The same hydroxyl-protecting group can be used.

The ester compound produced by this method can be de-esterified as described above to produce the desired compound as necessary.

Penicillin compounds prepared by the present invention can be converted to pharmaceutically acceptable salts by known methods described in the literature. Cephalosporins and Penicillins, Chemistry and Biology, Academic Press (1972). Examples of such salts include alkali metal salts (eg, sodium salts, potassium salts, calcium salts, and magnesium salts); Alkaline earth metal salts; Salts with organic amines such as ethylamine, benzylamine, benzatin, dimethylbenzylamine, dibenzylamine, dicyclohexylamine, 2-hydroxyethylamine, triethylamine and furokine; Salts with amino acids such as lysine, glutamic acid, aspartic acid and arginine.

The compound prepared by the present invention is a novel compound, a low-toxic compound that inhibits β-lactamase (penicillinase, sephalosporinase) and exhibits a broad spectrum of antibiotic spectrum, and is Gram-negative bacilli resistant to known synthetic penicillins. , Especially against glucose non-fermented Gram-negative bacteria. The antimicrobial test (i.e., the minimum potency concentration test) for the compound prepared by the present invention applies the method of Japanese chemotherapy, and uses apalcelin (PC-904) as a control.

The results are summarized in Table 1 below.

TABLE 1

In the following examples, the penicillin compounds of the present invention and methods for preparing these intermediates will be described in more detail.

Preparation Example 1

(1) 30 g of sodium methylate is suspended in 500 ml of isopropyl ether, and then a solution made by dissolving 90 g of 3,4-dimethoxyacetophenone in 37 g of ethyl-formate is added with stirring and ice cooling. The suspension is further stirred for 2 hours at room temperature. After isopropyl ether was removed under reduced pressure, the residue was dissolved in 500 ml of water, and then 59 g of α-cyanoacetoamide and 22 ml of piperidine-acetic acid buffer (pH 8) were added thereto.

The resulting mixture was heated at 110 ° C. for 7 hours and then the pH was adjusted to 4 by adding acetic acid with ice cooling. The precipitate thus precipitated was filtered, washed with 200 ml of water, crystallized with 300 ml of ethanol and washed with 100 ml of ether to give 41 g of 6- [3,4-dimethoxyphenyl] -3-cyano-1,2- Obtain dihydro-2-oxopyridine. Melting Point: 268 ~ 270 ℃ IR (Nusol): 2250cm ^-1 [-CN]

(2) 41 g 6- (3,4-dimethoxyphenyl) -3-cyano-1,2-dihydro-2-oxo-pyridine was suspended in 300 ml of 25% aqueous potassium hydroxide solution and then heated at 110 캜. Heat with stirring for 13 hours. When hot, the mixture is poured into 1 L of 6N aqueous hydrochloric acid and stirred with ice cooling.

The precipitate thus precipitated is filtered off, washed with 500 ml of water and then washed three times with 300 ml of acetone. This precipitate is recrystallized from dimethylformamide to give 41 g of 6- (3,4-dimethoxyphenyl) -3-cyano-1,2-dihydro-2-oxo-nicotinic acid.

Melting Point: 273 ℃

IR (nusol): 1705cm ^-1 (carboxylic acid)

1632 cm ^-1 (pyridone)

Production Example 2

Synthesis of 6- [4- (3,4-dimethoxybenzyloxy) -3-methoxyphenyl] -2-oxopyridine-3-carboxylic acid

(1) 235 g of betatrile alcohol is dissolved in 1.4 l of anhydrous methylene chloride, and then 200 g of thionyl chloride is added dropwise with ice cooling, and then the mixture is stirred at room temperature overnight. The dark brown clear solution is poured into 1 l of ice water and the pH is adjusted to 7 with sodium bicarbonate. The methylene chloride layer is separated, washed with water, dehydrated and concentrated to dryness under reduced pressure to yield 220 g of 3,4-dimethoxybenzylchloride.

Melting Point: 50 ~ 51 ℃

(2) 36 g of 60% sodium hydride solution is added to 200 ml of anhydrous dimethylformamide while stirring with ice cooling, and then a solution of 120 g of acetovanillin dissolved in 400 ml of anhydrous dimethylformamide is added dropwise. The mixture was allowed to react for 1.5 hours with stirring at room temperature, then a solution of 200 g of 3,4-dimethoxybenzyl chloride dissolved in 400 ml of anhydrous dimethylformamide was added and then heated to 110 DEG C while stirring overnight. do.

The residue obtained by removing dimethylformamide under reduced pressure was dissolved in 600 ml of methylene chloride, washed three times with 400 ml of water, dehydrated, concentrated to give a syrup, and the syrup was crystallized with ethanol to give 16.7 g of 4- [3,4-dimethoxybenzyloxy] -3-methoxyacetophenol is obtained. Melting Point 119 ~ 120 ℃

(3) 12.6 g of 60% sodium hydride is suspended in 100 ml of anhydrous tetrahydrofuran and ice cooled, followed by 50 g of 4- (3,4-dimethoxybenzyloxy) -3-methion in 700 ml of anhydrous tetrahydrofuran. A mixture of methoxy-acetophenone and 17.6 g of ethyl formate was added dropwise while stirring. The mixed solution is heated to 50 ° C. with stirring overnight. The ketrahydrofuran solution was concentrated under reduced pressure to obtain a powder, which was then dissolved in 350 ml of water, and dissolved in 20 g of α-cyanoacetoamide, 20 ml of piperidine-acetic acid, and a buffer solution (pH 8). After addition, the solution is heated to 110 ° C. with stirring overnight.

After cooling the reaction solution with ice, the pH was adjusted to 4 with acetic acid to form a precipitate, which was then filtered, washed with 300 ml of acetone, and recrystallized with dimethylformamide to give 16.7 g of 6- [4-. (3,4-dimethoxybenzyloxy) -3-methoxyphenyl] -1,2-dihydro-2-oxo-3-cyanopyridine is obtained.

Melting Point: 220 ~ 221 ℃

(4) 400 ml of 25% aqueous hydroxide of 16.7 g of 6- [4- [3,4-dimethoxybenzyloxy) -3-methoxyphenyl] -1,2-dihydro-2-oxo-cyano pyridine Suspended in potassium and heated at 110 ° C. for 42 hours while stirring, poured 600 ml of 6N aqueous HCL and ice cooled the solution to form a powdery precipitate, which was filtered and washed with water and then with methylcell Recrystallization with sol yields 10 g of 6- [4- (3,4-dimethoxybenzyloxy) -3-methoxyphenyl] -1,2-dihydro-2-oxo-nicoic acid. Melting Point: 217 ℃ 218 ℃

IR (nusol): 1710cm ^-1 (-COOH), 1640cm ^-1 (pyridone)

Preparation Example 3

8 g of 6- (3,4-dimethoxyphenyl) -1,2-dihydro-2-oxonicotinic acid are dissolved in a mixture of 48 ml of dimethylformamide and 19 ml of pyridine, followed by 10 g of p-nitro The phenyltrifluoro acetate was stirred under ice-cooling, then stirred overnight at room temperature to form a precipitate which was then filtered and washed with diethyl ether and recrystallized from dimethylsulfoxide to 7.9 g of 6- (3,4- P-nitrophenyl ester of dimethoxyphenyl-1,2-dihydro-2-oxo nicotinic acid is obtained.

IR (nusol): 1700cm ^-1 (ester)

1668 cm ^-1 (pyridone)

1525, 1350 cm ^-1 (nitro)

Production Example 4

2.75 6- (3,4-dimethoxyphenyl) -1,2-dihydro-2-oxonicotinic acid is suspended in 25 ml of dimethylformamido, followed by addition of 2 g of carbonyldiimidazole. After stirring overnight at room temperature, the crystals formed are filtered and washed with ether to give 2.8 g of imidazole amide of 6- (3,4-dimethoxyphenyl-1,2-dihydro-2-oxonnicotinic acid.

IR (nusol): 1690cm ^-1 (amide)

1642 cm ^-1 (pyridone)

Production Example 5

Suspend 55 g of 6- (3,4-dimethoxyphenyl) -1,2-dihydro-2-oxo nicotinic acid in 550 ml of methylene chloride and add 66.6 ml of triethylamine, stirring at room temperature for 1 hour. The mixture is then cooled to 5 ° C. and 38 ml of ethyl-chloroformate dropwise between 0 to 10 ° C. is added dropwise.

After stirring for 2 hours, a solution prepared by dissolving 46 g of N-hydroxysuccinimide in 78 ml of dimethylformamide was added dropwise at 5 to 10 ° C., followed by stirring overnight at room temperature. The precipitate thus formed is filtered and washed with water and a small amount of acetone. This was recrystallized from 140 ml of dimethylformamide to give 45 g of 6- (3,4-dimethoxyphenyl-1,2-dihydro-2-oxonicotinic acid succinimide-ester.

IR (nusol): 1798, 1772cm ^-1 (amide)

1730cm ^-1 (ester)

1640cm ^-1 (pyridone)

Preparation Example 6

2.0 g of D-P-hydroxyphenylglycine is turbid in 20 ml of dimethylformamide and 10 ml of water mixture, followed by 3.34 ml of triethylamine. While cooling the suspension, 39.6 g of 6- [3,4-dimethoxyphenyl] -1,2-dihydro-2-oxonicotinic acid p-nitrophenyl ester was added, and the reaction temperature was raised to room temperature. , Stir overnight. The solvent is removed under reduced pressure to form a syrup, which is then suspended in 50 ml of water and adjusted to pH 2 with 1N aqueous HCl.

The resulting precipitate is filtered off and washed with water. This is recrystallized with ethanol to give 4 g of 6- (3,4-dimethylcyphenyl) -1,2-dihydro-2-oxonicotinyl-p-hydroxyphenyl-glycine. Melting Point: 181 ~ 183 ℃ (Decomposition)

IR (nusol): 1700cm ^-1 (carboxylic acid)

1655, 1648 cm ^-1 (pyridone, amide)

Production Example 7

6 g of 6- [4- (3,4-dimethoxybenzyloxy) -3-methoxyphenyl] -1,2-dihydro-2-oxonicotinic acid was suspended in a mixture of 60 ml of dimethylformamide and 10 ml of pyridine. Thereafter, 5 g of p-nitrophenyltrifluoro acetate is added thereto with ice cooling, and then the suspension is stirred overnight at room temperature. The precipitate thus formed is filtered and washed with isopropyl ether.

This was recrystallized from dimethyl sulfoxide to give 6.2 g of 6- [4- (3,4-dimethoxybenzyloxy) -3-methoxyphenyl] -1,2-dihydro-2-oxo nicotinic acid p-nitrophenyl Obtain an ester.

IR (nusol): 1710cm ^-1 (carboxylic acid)

1650cm ^-1 (pyridone)

1515, 1345cm ^-1 (nitro)

Example 1

After 3.7 g of 6- (3,4-dimethoxyphenyl) -1,2-dihydro-2-oxonicotinic acid was suspended in 37 ml of anhydrous dimethylacetoamide, 4.2 g of Of amoxicillin trihydrate was added while stirring, and then the suspension was reacted for 2 hours with ice cooling.

The reaction suspension is poured into 140 ml of ice water and adjusted to pH 2 in aqueous IN HCl.

The precipitate thus formed is filtered off, washed with water and dried. The precipitate was dissolved in 15 ml of methanol-dichloromethane (1: 1) solvent, and the resulting crystals were filtered by adding sodium salt of 2-ethyl hexane and 45 ml of acetone to 5.6 g of 6-3,4. Sodium salt of -dimethoxyphenyl) -1,2-dihydro-2-oxonicotinyl amoxicillin is obtained.

IR (nusol): 1765cm ^-1 (β-lactam)

1655cm ^-1 (amide)

1605cm ^-1 (carboxylate)

), 5.35(m, 2H, C6-H, C5-H), 3.93(s, 1H, C3-H), 3.85, 3.80(s, 3H, -OMe), 1.55, 1.37(s, 3H, Gem-CH₃).m-r (DMSO d-6), δ = 10.55 (d, 1H, -NH), 8.95 (d, 1H, -NH), 8.29, 6.80 (d, 1H, pyridone), 7.22, 6.70 ( d, 2H, p-hydroxyphenyl) 5.78 (d, 1H,

), 5.35 (m, 2H, C6-H, C5-H), 3.93 (s, 1H, C3-H), 3.85, 3.80 (s, 3H, -OMe), 1.55, 1.37 (s, 3H, Gem- CH ₃ ).

Example 2

25 ml of 1.1 g of 6- (3,4-dimethoxyphenyl) -1,2-dihydro-2-oxonicotinyl-D-(-)-P-hydroxyphenyl glycine and 5 ml of anhydrous dimethylformamide Suspension in anhydrous tetrahydrofuran, to which 0.55 g of N-methyl-morpholine is added.

The suspension was stirred at 0 ° C. for 15 minutes and cooled to −30 ° C., and then a solution prepared by dissolving 0.59 g of ethylchloro formate in 5 ml of anhydrous tetrahydrofuran was added dropwise, and the suspension was allowed to react for 30 minutes. Let it happen. To this suspension was added dropwise a solution of 877 mg of 6-amino-phenylanic acid triethylamine salt in 10 ml of dimethylformamide, and the reaction temperature was gradually raised to room temperature, followed by stirring for 2 hours.

The solvent was removed under reduced pressure to make a syrup, which was then suspended in 100 ml of water and adjusted to pH 2 with aqueous 1N HCl with stirring and ice cooling.

The precipitated crude product is filtered off, washed with water and dissolved in aqueous sodium bicarbonate to adjust the pH to 7. This solution is washed with water and chromatographed on HP-50 resin (Daiaion HP-50, product of Mitsubushi chemical Industries Ltd.) eluted with 50% aqueous methanol to afford 350 mg of Example 1 compound.

Example 3

2.9 g of amoxicillin trihydrate was suspended in 50 ml of anhydrous dimethylformamide, followed by 0.76 ml of triethyl amine and 2.5 g of 6- [4- (3,4-dimethoxybenzyloxy) -3-methoxy P-nitrophenyl ester of phenyl] -1,2-dihydro-2-oxonicotinic acid is added with ice cooling and then stirred overnight at room temperature.

The solvent is removed under reduced pressure to make a syrup, which is then suspended in water and adjusted to pH 2 with aqueous 1N HCl. The precipitate thus precipitated is filtered, washed with water and dissolved in aqueous sodium bicarbonate to adjust the pH to 7.0. The solution was washed with water and chromatographed on HP-50 resin eluted with 80% aqueous methanol to give 2 g of 6- (4- (3,4-dimethoxybenzyloxy) -3-methoxyphenyl] -1,2- Dihydro-2-oxonicotinyl amoxicillin is prepared.

IR (nusol): 1760cm ^-1 (β-lactam)

1657cm ^-1 (amide)

1600cm ^-1 (carboxylate)

), 3.92(s, 1H, -OMe), 3.77(s, 6H, OMe), 1.56, 1.45(s, 3H, Gem-CH₃).m-r (DMSO d-6) δ = 1.68 (d, 1H, NH), 8.90 (d, 1H, NH), 8.50, 6.80 (d, 1H, pyridone), 7.25, 6.70 (d, 1H , p-hydroxy-phenyl) 7.20 (m, 6H, dimethoxyphenyl), 5.80 (d, 1H), 5.30 (m, 2H, C5-H, C ₆ -H), 5.05 (s, 2H,

), 3.92 (s, 1H, -OMe), 3.77 (s, 6H, OMe), 1.56, 1.45 (s, 3H, Gem-CH ₃ ).

[Examples 4 to 33]

In a similar manner as in the above example, the compound of formula (Ia) is synthesized.

In the general formula (Ia)

R ₅ and R ₈ represent groups as described below.

Although the invention has been described in detail herein with reference to specific embodiments, it will be appreciated by those skilled in the art that various changes and modifications can be made therein without departing from the scope of the invention.

Claims (1)

Amoxicillin or functional group-protected amoxicillin of the following structural formula (A) is reacted with a carboxylic acid or a hydroxy-protecting derivative of the following formula (II) or a reactive derivative thereof to phenyl of the general formula (III) Processes for preparing silin compounds and pharmaceutically acceptable salts thereof

In the above general formula R ₁ , R ₂ , and R ₃ are each hydrogen, lower alkyl group, halogen atom, lower alkoxy group, hydroxyl group, or substituted or unsubstituted phenylalkoxy group, Provided that R ₁ , R ₂ and R ₃ may not be hydrogen at the same time, R ₄ is hydrogen or a lower alkyl group.