KR820001453B1 - Process for preparing penicillanic acid derivatives - Google Patents

Abstract

Title compds. (I; R1 = H, lower alkyl; R2 = H, OH; R3 = OH), useful as bactericides, were prepd. by removing the protected group of II(R21 = H, OH, protected OH; R31 = OH, protected OH; Y = H, carboxyl). Thus, 1.0 g 6-[D-α-{3-(3,4-diacetoxybenzoyl)-3-methyl-1-ureido}-α-(4-hydroxyphenyl)acetamido)penicillanic acid was dissolved in 30 ml ethanol, added 0.47 ml 29 % ammonia water with cooling, and stirred at 0-5≰C for 30 min to give 6-[D(-)-α-{3-(3,4-dihydroxybenzoyl)-3-methyl-1-ureido}-α-(4-hydroxyphenyl)acetamido penicillanic acid.

Description

Preparation method of peniclanic acid derivative

The present invention relates to a method for producing a peniclanic acid derivative represented by the following general formula (I) or a salt thereof having excellent antibacterial activity.

(Wherein, R ₁ is a hydrogen atom or a lower alkyl group, R ₂ is the substitution position of a hydrogen atom or a hydroxyl group R ₃ means a 2 to 3 hydroxyl groups present in at least two contiguous. R ₃ is R ₁ is lower In case of an alkyl group, it is selected from 3 to 5 positions, and when R ₁ is a hydrogen atom, it is selected from 2 to 6 positions.)

The compound represented by the said general formula (I) has the outstanding antimicrobial activity as a novel compound of the non-patent literature. In other words, this compound exhibits a remarkable effect on Pseudomonas spp. In vitro and in animal experiments, compared with conventionally known antibacterial compounds, and also shows an excellent infection prevention effect. Moreover, the compounds are stable under neutral conditions and relatively stable under acidic conditions. Therefore, the peniclanic acid derivative represented by the above general formula is useful as an excellent antibacterial agent.

In the general formula (I), the lower alkyl group as defined by the symbol R ₁ may have 1 to 4 carbon atoms and may be branched, for example, methyl group, ethyl group, n-propyl group, isopropyl group or n-butyl. Group, isobutyl group and t-butyl group, but methyl group and ethyl group are preferable.

Since the ureido group in which the hydroxyl group exists in the 2nd or 6th position on a benzoyl nucleus becomes unstable when R <_1> is a lower alkali group, the substitution position of R <_3> is restrict | limited in such a case. That is, the substitution position of R <_3> when R <_1> is a lower alkyl group is selected from any of 3, 4, 3, 4, and 5 positions. In other cases as described above, that is, when R ₁ is a hydrogen atom, the substitution positions of R ₃ are 2, 3, 3, 4, 2, 3, 4, 3, 4, 5, 2, 4, 5 You can choose from above, 2, 3, 5, 2, 3, 6, of which 2, 3, 3, 4 or 3, 4, 5 are preferred.

Since the penicilanic acid derivative represented by the general formula (I) has a carboxyl group, salts can be formed with various basic substances in this group. All these salts fall within the scope of the object of the present invention. Examples of the salts of the penisilane acid derivatives include salts of inorganic bases, for example salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium and salts of organic bases, for example procaine or dibenzylethylene And diamine salts. These salts are prepared by treating the free carboxyl groups of the penicsilane acid derivatives with the inorganic or organic bases described above.

In the peniclanic acid derivative represented by the general formula (I), optical isomers such as DL-, D- and L- isomers exist due to the subsidiary carbon atoms in the C-acetamide group.

These are all included within the scope of the target compound of the present invention.

The present invention is characterized in that the protecting group is desorbed from the protected penicilanic acid derivative represented by the following general formula (II) as a process for preparing the penicsilane acid derivative represented by the general formula (I) or salt thereof as described above. doing

(Wherein R ₁ is the same as in formula (I), R ₂₁ is a hydrogen atom, a hydroxyl group or a protected hydroxyl group, R ₃₁ is at least two adjacent two or three hydroxyl groups or protected hydroxyl groups) The substituted position of R ₃₁ is the same as the substituted position of R ₃ in the general formula (I).

Y means a protecting group of a hydrogen atom or a carboxyl group, provided that at least one of R ₂₁ , R ₃₁ and Y includes a protecting group.)

The protecting group of the hydroxyl group contained in R ₂₁ and R ₃₁ in the general formula (II) may be a group which is easily released under mild conditions, and examples of such groups include lower alkanoyl groups. An acetyl group, propionyl group, butyloyl group, and isobutylloyl group.

The detachment of the lower alkanoyl group can be carried out by applying a means usually used for penicillins, but it is preferable to employ the means having high selectivity for detachment of the lower alkanoyl group and easy purification after the detachment reaction. In such a point, the detachment means by the action of a base is mentioned as a preferable detachment means. The base to be used may be selected from inorganic or organic bases, for example, ammonium or alkali metal salts of weakly acidic substances such as carbonic acid, acetic acid, phosphoric acid, weakly acidic ion exchange resins or inorganic bases such as ammonia, lower alkylamines of the 1st to 3rd grades, Organic bases such as alicyclic amines such as primary to tertiary amines having 1 to 3 hydroxy lower alkyl groups, piperidine, morpholine and the like.

As a form of a desorption reaction, the form which acts a base in the presence solvent of the substance which has an alcoholic hydroxyl group is mentioned. In this case, the base is an inorganic or organic base that can be dissolved in a solvent and a substance having an alcoholic hydroxyl group, preferably a base containing a nitrogen atom, for example, ammonia, propylamine, diethylamine, triethylamine , Ethanolamine, diethylaminoethanol, triethanolamine, piperidine, morpholine and the like. In addition, an aluminum type weakly acidic ion exchange resin may be used in a suspended state. Examples of the substance having an alcoholic hydroxyl group include hydroxyalkylamines such as alcoholic, such as methanol, ethanol, ethylene glycol, glycerin, diethylaminoethanol, itanolamine, and triethanolamine.

The solvent may be any one capable of dissolving salts of the protected penicillic acid derivatives and products of the peniclanic acid derivatives and the base, and include aprotic polar solvents such as dimethylformamide, nonpolar media such as dichloromethane and chloroform, and the alcoholic properties. Among the substances having a hydroxyl group, those suitable for the purpose may be used, for example, methanol or glycerin. Preferred combinations include, for example, a mixture of methanol and ammonia, a mixture of triethylaminetriethanolamine and dimethylformamide. The amount of base used is determined based on the number of lower alkanoyl groups in the protected peniclanic acid derivative represented by the general formula (III) and based on the amount of the total basic substance present in the reaction system. The release is possible in the range of 1 to 15 molar equivalents with respect to the penicilanic acid derivative, preferably in the range of 3 to 10 molar equivalents. The amount of the substance having an alcoholic hydroxyl group may be generally used in an excess amount, and may also serve as a solvent. However, when the solvent is used separately, 2 to 10 molar equivalents of the protected penicilanic acid derivative may be used. You can choose from the ranges. When using a mixture of triethylamine, triethanolamine and dimethylformamide, which is one of the preferred combinations, 0.1 to 10 molar equivalents of triethylamine, preferably 2 to 4 molar equivalents, to the protected penicilanic acid derivative 0.7 to 10 molar equivalents, preferably 3 to 5 molar equivalents, are used. In the case of using methanol and ammonia, 1.1 to 10 molar equivalents, preferably 2 to 3 molar equivalents of ammonia are used with respect to the protected penicilanic acid derivative, and methanol is used as the solvent amount.

The reaction temperature varies depending on the substance, base and solvent having an alcoholic hydroxyl group provided in the reaction, and when the substance having an alcoholic hydroxyl group also serves as a base, it is usually 10 to 40 ° C, preferably 20 to 35 ° C. When the substance having an alcoholic hydroxyl group also serves as a solvent, it is usually -30 to 40 ° C, preferably -25 to -35 ° C.

The reaction time is usually selected in the range of 30 minutes to 2 hours, preferably 1 to 10 hours.

In addition to the above-mentioned form of the elimination reaction, a form containing a nitrogen-containing salt such as ammonia or secondary amine, a peniclanic acid derivative such as group and dimethyl formamide, and a salt of a base can be used. Furthermore, inorganic bases such as ammonia, ammonium bicarbonate, ammonium carbonate, alkali bicarbonate metal salts, alkali metal carbonate salts or ethylamine, diethylamine, triethylamine, pyridine, piperi in the presence of water or a hydrophilic aprotic solvent containing water A form in which an organic base such as dine or morpholine is applied may be used.

In addition, in general formula (II), R <_21> may contain the hydroxyl group protected by the benzyl group. Benzyl groups can be released by catalytic reduction using a catalyst such as palladium-carbon.

As an example of the protecting group contained in Y, the group which can comprise an ester with respect to carboxyl groups, such as a trimethylsilyl group, is mentioned first. The trimethylsilyl group can be easily detached by treating with water or alcohol.

Other examples of the protecting group included in Y include inorganic or organic salts capable of forming salts in 3-carboxyl groups, for example alkali metals, alkaline earth metals, triethylamine, N-methylpiperidine, Tertiary organic bases such as pyridine. Desorption of these bases is effected by treatment with acid.

The protected penicilanic acid derivative represented by formula (II) can be prepared by various methods. For example, the following general formula

(Wherein, each symbol is the same as in General Formula (II) above) and a reactive derivative and a general formula of substituted ureidophenyl acetate

In the formula, Y is prepared by reacting with 6-aminophenic silane acid or a reactive derivative thereof represented by General Formula (II). Here, an acid anhydride, an active ester, and an active amide are mentioned as a reactive derivative of substituted ureido phenylacetic acid represented by general formula (II).

As another manufacturing method of the protected penicilanic acid derivative represented by general formula (II), General formula

Wherein R ₂₁ and Y are the same as in the general formula (II) described above, and the α-amino group of the α-aminobenzylphenicillin derivative represented by the general formula

Wherein R ₃₃ means 2 to 3 protected hydroxyl groups in which at least two are present adjacent to each other, provided that the substitution position is selected from the 2 to 6 positions;

(Wherein, R ₃₃ is the same and, X represents a halogen atom, and R ₁₁ means a lower alkyl group. Further, the substitution position of R ₃₃ is selected from above 3 to 5 described above) N- benzoyl represented by The method of making a carbamic acid halide react is also mentioned.

In addition, as another manufacturing method, a general formula

(Wherein R ₁ and Y are as defined above) a general formula for α-ureidobenzylphenylsilanes or reactive derivatives thereof

And a method of reacting the benzoyl halides represented by (wherein, R 33 and X are the same as described above).

The preparation of an optically active compound [D- or L-isomer], which is one of the objective compounds of the present invention represented by general formula (I), uses a protected penicylic acid derivative having the corresponding optical activity [General formula (II) Is implemented. And the optically active substance of the compound represented by general formula (II) is implemented using the substituted ureidophenyl acetate [general formula (III)] which has the corresponding optical activity. Thus, substituted ureidophenyl acetate having optical activity is conventional optical cleavage technique in the step of α-aminophenyl acetate or the substituted ureidophenyl acetate, for example J.P. Greenstein, M. Winitz, "Chemistry of the Amino Acids" Vol. 1, pp. 715 to 760, obtained by applying the technique described in John Wiley & Sons, N.Y. (1961).

In addition, the optically active substance of the compound represented by general formula (II) is manufactured by using the compound represented by general formula (V) or (iii) which has the corresponding optical activity.

The compound of interest of the present invention can be prescribed in a form suitable for various administration methods as in the case of other penicillin-based compounds. Accordingly, embodiments of the present invention include various pharmaceutical compositions suitable for human or animal medicinal use. These compositions are provided by conventional methods using the required pharmaceutical carriers or excipients. That is, when provided as an injectable composition, formulations such as suspensions, solutions and emulsions in oily or aqueous excipients can be taken.

It can also be suppository. That is, a normal suppository base such as cocoa fat or other glycerides can be used.

These compositions may contain 0.1% or more, for example 5 to 99%, preferably 10 to 60% of active substance, depending on the mode of administration.

Doses for humans are usually selected in the range of 100 to 3000 mg for adults. For example, a dosage of 500 to 2000 mg per day, depending on the route of administration, the number of times or the weight, age and symptoms, is preferred.

Regarding some of the target compounds of the present invention, the minimum growth concentration (MIC) of various bacteria is shown in comparison with carbenicillin.

(1) 6- [D (-)-α- {3- (2,3-dihydroxybenzoyl) 1-ureido} -α-phenylacetamido] phenicylic acid

(2) 6- [D (-)-α- {3- (3,4-dihydroxybenzoyl) 1-ureido} -α-phenylacetamido] phenicylic acid

(3) 6- [D (-)-α- {3- (3,4-dihydroxybenzoyl) 1-ureido} -α-hydroxyphenyl) acetamide] phenicylic acid

(4) 5- [D (-)-α- {3- (3,4,5-trihydroxy benzoyl) -1-ureido} -α-phenylacetamido] phenicylic acid

(5) 6- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -1-ureido} -α- (4-hydroxyphenyl) acetamide] phenisilane acid

(6) 6- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -1-ureido} -α-phenyl) acetamido] phenicylic acid

(7) 6- [D (-)-α- {3- (3,4-trihydroxy benzoyl) -3-ethyl-1-ureido} -α-phenylacetamido] phenicylic acid

(8) 6- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-ethyl-1-ureido} -α-phenylacetamido] phenicylic acid

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1

(1) To a 40 ml solution of 4.0 g of 1,2-dichloroethane of 4.0 g of 3,4-diacetoxybenzamide, 5.1 g of oxaryl chloride was added under cooling and stirring. The mixture is then slowly heated to reflux and reacted for 13 hours. Solvent and excess oxaryl chloride in the reaction mixture are distilled off under reduced pressure to give 3,4-diacetoxybenzoyl isocyanate. This was dissolved in 30 ml of anhydrous cichloromethane and provided to the reaction described later.

(2) To 70 ml of anhydrous dichloromethane of 10.00 g of amoxicillin trihydrate, 11.8 ml of N, O-bis (trimethylsilyl) acetamide was added at 15 to 20 ° C, stirred until uniform, and the preparation was carried out in (1). 30 ml of anhydrous dichloromethane solution was added dropwise. The mixture was stirred for 1.5 hours, evaporated to dryness at room temperature under reduced pressure, ethanol anhydride was added to the residue, and evaporated to solidity under reduced pressure. After 200 ml of ethyl acetate and cold 1N hydrochloric acid were added to the residue, the organic layer was separated. The organic layer was washed with 200 ml of cold saturated brine, and then extracted three times with 300 ml of cold saturated aqueous sodium hydrogen carbonate solution.

The aqueous layer is separated and washed twice with 150 ml of ethyl acetate each time. The pH is adjusted to about 2.5 with cold 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with cold saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was treated with 50 ml of n-hexane to give 6- [D-α- {3- (3,4-diacetoxybenzoyl) -3- A white powder of methyl-1-ureido] -α- (4-hydroxyphenyl) acetamido] phenylanic acid is obtained.

Rf: 0.40, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1700, 1720∼1620, 1510IR

3700-2300, 1700, 1720-1620, 1510

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.45 (3H, s), 1.57 (3H, s), 2.28 (6H, s), 4.23 (1Hs), 5.3 to 5.8 (3H, m), 6.6 ~ 7.8 (7H, m)

(3) 1.0 g of the white powder obtained above was dissolved in 30 ml of ethanol, and 0.47 ml of 29% aqueous ammonia was added dropwise under ice-water cooling. After stirring for 30 minutes at 0 ° to 5 ° C and injected into 50 ml of cold 1N hydrochloric acid and extracted with 100 ml of acetic acid. After the ethyl acetate layer was washed with water, 50 ml of cold saturated aqueous sodium hydrogen carbonate solution was added and the aqueous layer was adjusted to pH 8.5. The aqueous layer was separated, washed with 50 ml of ethyl acetate, the pH was adjusted to about 2.5 with cold 2N hydrochloric acid, and extracted with 100 ml of ethyl acetate. The organic layer is washed with cold saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was treated with 50 ml of n-hexane to give 6- [D-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4 To obtain an off-white amorphous solid of -higeshiphenyl) acetamido] phenicylanic acid.

Rf: 0.38, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1770, 1750∼1620IR

3700-2300, 1770, 1750-1620

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.42 (3H, s), 1.55 (3H, s), 3.10 (3H, s), 4.20 (1H, s), 5.3 to 5.7 (3H, m) , 6.5 to 7.4 (7H, m)

UV: (C ₂ H ₅ OH) λmax (mμ) 275, 280 (Shoulder), 290 (Shoulder)

Ferric chloride color reaction: positive (dark green)

Example 2

(1) In Example 1 (2), the same treatment was carried out using 9.64 g of ampicillin trihydrate instead of 10.00 g of amoxicillin trihydrate, to give 6- [D (-)-α- {3- (3,4-diacene. A white powder of oxy benzoyl) -3-methyl-1-ureido} -α-phenyl acetamido] phenicylanic acid is obtained.

Rf: 0.44, Carrier: Silica gel 60F ₂₅₄ <Pre-coated plate made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼1200, 1780, 1720∼1620, 1510IR

3700-1200, 1780, 1720-1620, 1510

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.48 (6H, s), 2.27 (6H, s), 3.18 (3H, s), 4.34 (1H, s), 5.35 to 5.75 (3H, m) , 7.1 to 7.6 (8H, s)

(2) 6 g of 6- [D-(-)-α- {3- (3,4-diacetoxy benzoyl) -3-methyl-1-ureido} -α-phenyl acet amido] peniclanic acid 1.0 g Was dissolved in 5 ml of methanol, and 3 ml of methanolic ammonia (0.075 g / cc) was added dropwise under stirring while maintaining the temperature at -15 to -10 DEG C, and then stirred at the same temperature for 20 minutes. This reaction solution is then added to a mixture of 20 ml of 5% hydrochloric acid and 20 ml of ethyl acetate with ice-water cooling and stirring. The ethyl acetate layer was separated, the aqueous layer was extracted again with 20 ml of ethyl acetate, combined with the first ethyl acetate layer and washed with water. The organic layer was extracted with 100 ml of cold saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was washed with ethyl acetate. The aqueous layer is separated, adjusted to pH 2.5 with cold 2N hydrochloric acid, and extracted with 30 ml of ethyl acetate. The ethyl acetate layer is washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was treated with 50 ml of n-hexane to give 6- [D (-)-α- {3- (3,4-dihydroxy benzoyl) -3-methyl-1-ureido} -α -Phenyl acetamido] To obtain an off-white amorphous solid of peniclanic acid.

R _f : 0.39, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1775, 1740∼1620IR

3700-2300, 1775, 1740-1620

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.41 (3H, s), 1.54 (3H, s), 3.10 (H, s), 4.20 (1H, s), 5.3 to 5.8 (3H, m) , 6.6 to 7.5 (8H, m)

UV: (C ₂ H ₅ OH) λ max (mμ) 207, 295

Ferric chloride color reaction: positive (dark green)

Example 3

(1) To an 80 ml solution of 7.5 g of 3,4-diacetoxybenzamide 7.5 g of 1,2-dichloroethane, 10.1 g of oxaryl chloride was added under cold stirring. Subsequently, the mixed solution is gradually heated to reflux and reacted for 13 hours. The solvent and excess oxaryl chloride are distilled off under reduced pressure from the reaction mixture to obtain 3,4-diacetoxybenzoyl isocyanate. This is dissolved in 40 ml of anhydrous dichloromethane and provided to the reaction described later.

(2) 12.8 g of ampicillin trihydrate is suspended in 100 ml of anhydrous dichloromethane, and 40 ml of N, O-bis (trimethylsilyl) acetami is added dropwise at room temperature and stirred uniformly. The total amount of the dichloromethane solution prepared in (1) was added dropwise while maintaining the mixed solution at 5 to 10 ° C and stirred at the same temperature for 2 hours. Subsequently, the mixture is evaporated to dryness at room temperature under reduced pressure, followed by addition of anhydrous methanolol and evaporated to dryness under reduced pressure. 300 ml of ethyl acetate and 100 ml of cold 2N hydrochloric acid were added to the residue, and the organic layer was separated. The organic layer was extracted three times with 200 ml of cold saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer was washed with 200 ml of ethyl acetate, and the pH value was adjusted to about 2.5 with 2N cold hydrochloric acid and extracted with 150 ml of enyl acetate. The organic layer is washed with cold saturated brine and dried over anhydrous sodium sulfate. Subsequently, activated carbon treatment was concentrated at room temperature under reduced pressure, and the residue was treated with 80 ml of n-hexane to give 6- [D (-)-α- {3- (3,4-diacetoxybenzoyl-1-ureido} -α. -Phenylacetamido] 8.0 g of peniclanic acid is obtained as an off-white amorphous solid.

R _f : 0.43, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2200, 1770, 1770∼1620, 1525, 14590IR

3700-2200, 1770, 1770-1620, 1525, 14590

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.42 (3H, s), 1.54 (3H, s), 2.28 (6H, s), 4.2 (1H, s), 5.3 to 6.1 (3H, m) , 7.0-8.0 (8H, m)

(3) 2.0 g of 6- [D (-)-α- {3 (3,4-diacetoxy benzoyl) -1-ureido} -α-phenylacet amido] phenylanic acid was dissolved in 30 ml of methanol; 3.7 ml of methanolic ammonia (0.07 g / cc) is added dropwise with stirring while maintaining at −15 to −10 ° C. The reaction was terminated by stirring for 75 minutes while gradually raising the reaction temperature to around 0 ° C.

Subsequently, this reaction solution is added to a mixture of 150 ml of 5% hydrochloric acid and 150 ml of ethyl acetate while stirring under ice water cooling.

The organic layer was extracted with 100 ml of cold saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was washed with ethyl acetate. The aqueous layer was separated, adjusted to pH 2.5 with cold 2N hydrochloric acid, and extracted with 100 ml of ethyl acetate.

The ethyl acetate layer was washed with cold saturated brine and dried over anhydrous magnesium sulfate. Concentrate the solvent at room temperature under reduced pressure and treat the residue with 80 ml of n-hexane to give 6- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -1-ureido} -α-phenyl 1.2 g of acetamido] phenic acid was obtained as an off-white amorphous solid.

R _f : 0.399, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1770,1740, 1690∼1620, 1550∼1480IR

3700-2300, 1770,1740, 1690-1620, 1550-1480

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.41 (3H, s), 1.53 (3H, s), 5.3 to 6.0 (3H, m), 6.6 to 7.7 (8H, m)

UV: (C ₂ H ₅ OH) λmax (mμ) 260, 295

Ferric chloride color reaction: positive (dark green)

Example 4

(1) In Example 3 (2), the following treatment was carried out using 13.1 g of amoxicillin trihydrate instead of 12.8 g of ampicillin trihydrate. 9.0 g of cethoxy benzoyl) -1-ureido} -α- (4-hydroxyphenyl acetamido] phenylanic acid is obtained as an off-white amorphous solid.

R _f : 0.40, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1770, 1710∼1630, 1550∼1450IR

3700-2300, 1770, 1710-1630, 1550-1450

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.47 (3H, s), 1.56 (3H, s), 2.28 (6H, s), 4.24 (1H, s), 5.3 to 6.0 (3H, m) , 6.6 to 8.2 (8H, m)

(2) 6- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -1-ureido} α- (4-hydroxyphenyl) acetamido obtained in (1). 6- [D (-)-α- {3- (3,4-dihydroxy benzoyl) -1-ureido} -α with the same treatment as in Example 3 (3) using 2.0 g of peniclanic acid 1.1 g of-(4-hydroxyphenyl) acetamido] phenic acid was obtained as an off-white amorphous solid.

R _f : 0.35, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1770, 1740∼1630, 1560∼1480IR

3700-2300, 1770, 1740-1630, 1560-1480

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.43 (3H, s), 1.57 (3H, s), 4.22 (1H, s), 5.3 to 5.9 (3H, m), 6.5 to 7.6 (7H, m)

UV: (C ₂ H ₅ OH) λ max (mμ) 266, 295

Ferric chloride color reaction: positive (dark green)

Example 5

(1) Example 3 In the same manner as in (1), instead of 7.5 g of 3,4-diacetoxybenzamide, 8.0 g of 3,4,5-triacetoxybenzamide and 8.6 g of oxalyl chloride were used in the same manner as in the following. Treatment gives 3,4,5-triacetoxybenzoyl isocyanate.

(2) 6- [D (-)-α- {3- (3,4,5-triacetoxybenzoyl) by treating ampicillin trihydrate with the isocyanate obtained above in the same manner as in Example 3 (4) -1-ureido} -α-phenylacetamido] 5.0 g of peniclanic acid is obtained as a light brown amorphous solid.

R _f : 0.35, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1775, 1700∼1600, 1520∼1485IR

: 3700-2300, 1775, 1700-1600, 1520-1485

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.46 (3H, s), 1.55 (3H, s), 2.30 (9H, s), 4.26 (1H, s), 5.3 to 6.1 (3H, m) , 7.2 to 7.7 (5H, m), 7.83 (2H, s)

(3) 30 ml of 6- [D (-)-α- {3- (3,4,5-triacetoxybenzoyl) -1-ureido} -α-phenylacetamido] phenic acid 2.2 g methanol 3.7 ml of methanolic ammonia (0.075 g / cc) is added dropwise under stirring while maintaining the solution at -15 to -13 ° C. The reaction is terminated by stirring for 40 minutes while slowly raising the reaction temperature to -9 to -8 ° C. 6- [D (-)-α- {3- (3,4,5-trihydroxybenzoyl) -1-ureido} -α when the treatment after the reaction was performed in the same manner as in Example 3 (3) below. 1.0 g of -phenylacetamido] phenic acid is obtained as an off-white amorphous solid.

R _f : 0.34, Carrier: silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1770, 1750∼1630, 1560∼1470IR

: 3700-2300, 1770, 1750-1630, 1560-1470

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.42 (3H, s), 1.53 (3H, s), 4.23 (1H, s), 5.3 to 6.0 (3H, m), 6.8 to 7.7 (7H, m)

UV: (C ₂ H ₅ OH) λmax (mμ) 268

Ferric chloride color reaction: positive (black-blue)

Example 6

(1) 20 ml of anhydrous dichloromethane solution containing 8.04 g of triethylamine in 70 ml of anhydrous dichloromethane solution containing 20.0 g of N-methyl-3,4-diacetoxybenzamide and 8.65g of trimethylsilyl chloride at room temperature Add it down. The mixture is heated to reflux for 20 minutes, and then 82 ml of anhydrous dichloromethane solution containing 56 ml of phosgene at -5 to 5 ° C under cooling is added. The solution temperature is gradually raised to room temperature, and then depressurized to distill and solidify excess phosgene and solvent to obtain crude N- (3,4-diacetoxybenzoyl) -N-methylcarbamine chloride. This is dissolved in 50 ml of cooled anhydrous dichloromethane, and the insolubles are filtered off and used for the reaction described later.

(2) To a 150 ml suspension of 18.7 g of D (-)-pheniglycine anhydrous dichloromethane, 44.3 ml of N, O-bis (trimethylsilyl) acetamide was added at 5 to 10 ° C. under stirring, and the N- obtained in (1) above was stirred. Anhydrous dichloromethane solution of (3,4-diacetoxybenzoyl) -N-methylcarbamic acid chloride is added dropwise. After 1.5 hours of stirring at 5 to 10 ° C., the mixture was evaporated to solidity at room temperature under reduced pressure, anhydrous methanol was added to the residue, and dried again under reduced pressure.

500 ml of ethyl acetate and cold 1N hydrochloric acid were added to the residue, and the organic layer was separated. The organic layer was washed with 500 mlfh of cold saturated saline, and then extracted three times with 700 ml of cold saturated aqueous sodium carbonate solution. The separated aqueous layer was adjusted to about 2.5 with cold 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with cold brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and then D (-)-α- [3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido ] 2.0 g of an off-white powder of] -α-phenylacetic acid is obtained.

R _f : 0.52, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2400, 1775, 17440, 1700, 1510IR

3700-2400, 1775, 17440, 1700, 1510

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm): 2.29, 3.12 to 5.35, 7.2 to 7.6, 9.65

(3) 20.0 g of D (-)-α- [3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido] -α-phenylacetic acid obtained in the above (2) was diluted with dichloromethane. Dissolve in 50 ml, add 5.8 g of pivalic acid chloride with cooling and stirring below -15 ° C, and add 6.6 ml of triethylamine dropwise at the same temperature. After continuing stirring for 1 hour, the dichloromethane solution of 6-aminophenicylate triethylamine salt made from 12.8 g of 6-aminophenic silane acid was added dropwise by stirring at -15 ° C or lower. After stirring for 1 hour, the reaction solution was poured into 100 ml of chilled brine containing 15 ml of concentrated thermal acid, and the dichloromethane layer was washed several times with cold brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and n-hexane was added to the residue to obtain powder. 26.7 g of 6- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] phenylanic acid was obtained. Lose.

(4) 6- [D (-)-α- {3- (3,4-diacetoxybenzoyl) 3-methyl-1-ureido} -α-phenylacetamido] phenic silane 26.7 obtained above g is dissolved in 52 ml of dimethylformamide and 26 ml of triethanolamine and 18 ml of triethylamine are added under cooling, followed by stirring at room temperature to 35 ° C for about 2 hours. After completion of the reaction, the reaction solution was poured into a mixture of 300 ml of ice water, 39 ml of concentrated hydrochloric acid, and 140 ml of ethyl acetate, and the ethyl acetate layer was washed with water. The organic layer is extracted with saturated sodium bicarbonate solution under cooling and the aqueous layer is washed with ethyl acetate. The aqueous layer is aliquoted and poured into 100 ml of ice water and ethyl acetate and adjusted to pH 3 by dropwise addition of 6N hydrochloric acid under stirring. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The crude product (16 g) obtained by treating the residue with n-hexane was diluted with dichloromethane-acetone (1: 1 v / v) as a developing solvent. 480 g of Sephadex LH-20 (manufactured by Fine Chemicls, dextran crosslinked polymer) Purified by column chromatography packed with 6- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α-phenyl Acetamido] 11.2 g of peniclanic acid is obtained. This product is the same as the target compound obtained in Example 2 (2) in each spectrum, Rf value, and ferric chloride color reaction of IR, NMR and UV.

Example 7

(1) In Example 6 (1), the reaction treatment was carried out in the same manner using N-3,4-methyldiacetoxybenzamide instead of N-methyl-3,4-diacetoxybenzamide to give N- (3 , 4-Diacetoxybenzoyl) -N-ethylcarbamic acid chloride was prepared and reacted with D (-)-phenylglycine in the same manner as in Example 6 (2) to treat D (-)-α- [3- (3,4-Diacetoxybenzoyl) -3-ethyl-1-ureido] -α-phenylacetic acid is obtained.

R _f : 0.54, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1775, 1750, 1770, 1510IR

3700-2300, 1775, 1750, 1770, 1510

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 1.10 (3H, t, J = 7 Hz), 2.28 (6H, s), 3.75 (2H, q, J = 7 Hz), 5.53 (1H, d, J = 67.5 Hz), 7.2 to 7.5 (8H, m), 9.70 (1H, d, J = 6.5 Hz)

(2) Example 6 of 21.0 g of D (-)-α- [3- (3,4-diacetoxybenzoyl} -3-ethyl-1-ureido] -α-phenylacetic acid obtained in the above (1) When reacted with 6-aminophenic silane in the same manner as in (3), 6- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-ethyl-1-ureido}- 26.5g of (alpha)-phenylacetamido] peniclanic acid is obtained.

Reaction treatment as in Example 6 (4) gave 6- [D (-)-α- {3- (3,4-dihydroxybenzoyl) 3-ethyl-1-ureido} -α-phenylacetami To obtain a white amorphous solid of peniclanic acid.

R _f : 0.42, Carrier: silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1775, 1750∼1620, 1515IR

3700-2300, 1775, 1750-1620, 1515

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm): 0.8 to 1.3 (3H, m), 1.43 (3H, s), 1.57 (1H, s), 3.4 to 4.0 (2H, m), 4.23 (1H) s) 5.3 to 5.8 (3H, m), 6.7 to 7.5 (8H, m)

UV: (C ₂ H ₅ OH) λ max (mμ) 265 (shoulder), 292

Ferric chloride color reaction: positive (dark green)

Example 8

(1) In Example 6 (1), instead of 20.0 g of N-methyl-3,4-diacetoxybenzamide, 4.5 g of N-methyl-3,4,5-triacetoxybenzamide was used in the same manner. The reaction is carried out to obtain N- (3,4,5-triacetoxybenzoyl) -N-methylcarbamic acid chloride.

When this was reacted with 4.5 g of D (-)-phenylglycine in the same manner as in Example 6 (2), D (-)-α- [3- (3,4,5-triacetoxybenzoyl) -3 was treated. 3.0 g of light red powders of -methyl-1-ureido] -α-phenylacetic acid are obtained.

R _f : 0.51, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1780, 1750∼1570, 1510IR

3700-2300, 1780, 1750-1570, 1510

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm): 2.21 (9H, s), 3.14 (3H, s), 5.49 (1H, d, J = 6.5 Hz), 7.1 to 7.5 (7H, m), 9.88 (1H, doublet, J = 6.5 Hz)

(2) Example 6 (3) or less 1.1 g of D (-)-α- [3- (3,4,5-triacetoxybenzoyl) -3-methyl-1-ureido] -α-phenylacetic acid 6- [D (-)-α- {3- (3,4,5-trihydroxybenzoyl) -3-methyl-1-ureido} -α-phenylacetic acid by reaction treatment in the same manner as in (4). Amido] phenicsilane acid 0.4 g (light brown amorphous replacement) is obtained.

R _f : 0.35, Carrier: Silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2200, 1770, 1740∼1620, 1515IR

3700-2200, 1770, 1740-1620, 1515

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm): 1.42 (3H, s), 1.56 (3H, s), 3.10 (1H, s), 4.20 (1H, s), 5.2 to 5.8 (3H, m ), 6.5 (2H, s), 7.1 to 7.5 (5H, s)

UV: (C ₂ H ₅ OH) λmax (mμ) 260 (Shoulder), 270 (Shoulder), 285

Ferric chloride color reaction: positive (black-blue)

Example 9

(1) To a 540 ml solution of 1,2-dichloroethane of 4.0 g of 2,3-diacetoxybenzamide, 5.3 g of oxachloride is added under cooling and stirring. The mixture is then slowly heated to reflux and allowed to react for 10 hours. Solvent and excess oxaryl chloride in the reaction mixture are distilled off to give 2,3-diacetoxybenzoyl isocyanate. This was dissolved in 40 ml of anhydrous dichloromethane and provided to the reaction described later.

(2) 5.3 g of D (-)-phenylglycine is suspended in 100 ml of anhydrous dichloromethane, and 19 ml of N, O-bis (trimethylsilyl) acetamide is added dropwise at room temperature, followed by stirring until uniform. Subsequently, anhydrous dichloromethane solution of 2,3-diacetoxybenzoyl isocyanate obtained in the above (1) was added dropwise at 5 to 10 ° C under stirring. After stirring at the same temperature for 1.5 hours, the mixture was evaporated to dryness at room temperature under reduced pressure, anhydrous methanol was added to the residue, and the resultant was evaporated to dryness under reduced pressure. 200 ml of cold hydrochloric acid is added to the residue, and the mixture is stirred for 5 to 10 minutes. The obtained white precipitate is filtered off and then dissolved in 250 ml of cold saturated aqueous sodium hydrogen carbonate solution to filter insoluble matter. The aqueous layer was washed with 250 ml of ethyl acetate, and the precipitated white precipitate was filtered by adjusting the pH value to about 2.5 with cold 2N hydrochloric acid. After washing with water and then ether, it is air dried to obtain 4.5 g of a white powder of D (-)-α- {3- (2,3-dihydroxybenzoyl) -1-ureido] -α-phenylacetic acid. . Melting Point: 2000-201 ℃ (Decomposition)

(3) Treating the white powder in the same manner as in Example 6 (3) and reacting with 6-aminophenicylanic acid to give 6- [D (-)-α- {3- (2,3-dihydroxybenzoyl) 1.0 g of -1-ureido} -α-phenylacetamido] phenylanic acid is obtained as a white amorphous solid.

R _f : 0.37, Carrier: silica gel 60F ₂₅₄

<Preparatory coating made by Merck Co., Ltd.>

Developing solvent: ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)

: 3700∼2300, 1770, 1745∼1625, 12560, 1450.IR

: 3700-2300, 1770, 1745-1625, 12560, 1450.

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm): 1.41 (3H, s), 1.56 (3H, s), 4.23 (1H, s), 5.3 to 6.0 (3H, m), 6.6 to 7.7 (8H , m)

UV: (C ₂ H ₅ OH) λ max (mμ) 254, 322

Ferric chloride color reaction: positive (dark green)

Claims (1)

A method for producing a penicilanic acid derivative represented by formula (I) or a salt thereof, characterized in that the protecting group is separated from the protected penicsilane acid derivative represented by the following formula (II):

Food, R ₁ is a hydrogen atom or a lower alkyl group, R ₂ means a hydrogen atom or a hydroxyl group, R ₃ means at least two hydroxyl groups adjacent to each other, Substitution position of the R ₃ group is the same as R ₃₁ , R ₂₁ represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group, R ₃₁ means 2 to 3 hydroxyl groups or protected hydroxyl groups at least two of which are present adjacent to each other, Substituent positions for R ₃₁ are selected from 3 to 5 positions when R ₁ is a lower alkyl group and 2 to 6 positions when R ₁ is a hydrogen atom. Y means a hydrogen atom or a carboxyl group provided that at least one of R ₂₁ , R ₃₁ and Y contains a protecting group.