KR860001086B1 - Process for preparing penicillanic acid derivatives and cephalosporanic acid derivatives - Google Patents

Abstract

Penicillin and cephalosporanic derivs. of formula (I) [R1 = Ph, 4- hydroxyphenyl, 3,4-dihydroxyphenyl, 1-hydroxyethyl ; R2 = H or MeO; A = (CH3)2CH(COOH) or CH2C(CH2R3) = (COOH); R3 = 5-membened bicyclic contg. two or more than N and one S, or substd. with lower alkyl! was prepd. Thus, a soln. of 3.02g D(-)-α-(4-ethyl2,3-dioxo-1- piperazinylcarbonylamino) phenylacetate and 0.8 ml pyridine in 32 ml N,N-dimethylformamide was acylated with 2.96g 1,1'-(carbonyldioxy) dibenzotriazole at room temp. for 1h and later reacted with 2.27g 6- aminopenicillanic acid for 2h at room temp. The reaction mixt. was diluted with 1l H2O and adjusted to pH 2.0 with 2N HCl soln. to give 4.43g(I) H2O [R1 = phenyl, R2 = H, A = (CH3)2CH(COOH) .

Description

Method for preparing penicillin and cephalosporin derivatives

The present invention relates to a novel process for the preparation of penicillin and cephalosporin derivatives represented by the following general formula (I) useful as antibiotics.

Wherein R ₁ is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 1-hydroxyethyl group, R ₂ is hydrogen or methoxy, and A is -C (CH ₃ ) 2-CH ( COOH)-or CH ₂ C (CH ₂ R ₃ ) = C (COOH), wherein R ₃ is a five-membered heterocyclic group containing one or two or more nitrogens or one sulfur atom and which may be substituted with a lower alkyl group ).

The compound represented by the general formula (I) exhibits strong antimicrobial activity against Gram-negative and Gram-positive bacteria, and particularly has a strong antibacterial activity against bacteria belonging to the genus Streptococcus, Pseudmonas and Entero Bacter. Known known compounds and methods for their preparation are, for example, Belgian Patent No. 828692, German Patent No. 2519400, and Japanese Patent Application Laid-open No. 52-106883, which react 1-ethyl-2,3-dioxopiperazine with phosgene. To obtain 4-ethyl-2,3-dioxopiperazinocarbonylchloride, which is prepared by reacting with Ampicillin or Amoxicillin or D-(-)-phenylglycine with 4-ethyl-2,3 Dioxopiperazinocarbonyl chloride was reacted to prepare D (-)-α- (4-alkyl-2,3-dioxopiperazinocarbonyl) -phenyl lysine, which was then reacted with ethylchlorocarbonate to give an acid anhydride. Gaining anhydrides and 6-ah Although it was prepared by reacting minophenicyl carbonate or 7-aminoseparophosphanoic acid, these preparation methods are similarly prepared by preparing 4-ethyl-2,3-dioxopiperazinocarbonyl chloride and recrystallization to separate it into a pure compound. It is very demanding, and carbonyl chloride itself is unstable in water, and has the disadvantage of easily converting into carboxylic acid, and has the disadvantage of reacting at a low temperature of about -25 ° C. In the arc, D (+)-α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -β-[(S) -hydroxy] butanoic acid was silylated and then trichloro Reaction with methylchlorocarbonate to give carbonyl chloride, which is a hydrochloride of 7-β-amino-3- [5- (1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylic acid The target product was prepared by acylating in an organic solvent. The method also uses a compound that is toxic to the human body, has difficulties in operation such as reacting at a low temperature of -20 ° C, and has a low yield.

The present inventors have completed the present invention by studying a new method without the above drawbacks. That is, the present invention, unlike the known methods, is safe and easy to handle, using an acylating agent that is readily available at room temperature, and the present invention in a new and economic way that can be easily separated in a high yield. In more detail, in the present invention, by reacting the organic acid represented by the general formula (II) with the acylating agent represented by the general formula (III) in the presence of an organic base, to prepare a reactive ester represented by the general formula (IV) Phenitanic acid derivatives and Sepharo represented by general formula (I) by reacting with 6-aminophenicylanic acid derivatives or 7-aminocephalosporanic acid derivatives represented by general formula (V) continuously without separation in the reaction mixture. The method for preparing a spotanic acid derivative is as follows.

Wherein R ₁ , R ₂ , R ₃ and A are as described above, R ₄ is a benzotriazole group, and n is 1 or 2.

These reactions are preferably carried out in a solvent, and as the solvent, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dichloromethane, 1,2-dichloroethane, chloroform, Acetonitrile, tetrahydrobutane, dioxane and the like are used, of which N, N-dimethylformamide and N, N-dimethylacetamide are suitable. As the acylating agent, it is preferable to use the same number of moles as for the organic acid and the organic base, and pyridine, triethylamine, N, N-dimethylaminopyridine, diisopropylamine, etc. are used as the organic base. The reaction temperature is usually carried out at room temperature, and reactive esters are quantitatively produced in 1 to 2 hours. A general (V) compound is added thereto and reacted at room temperature for 1 to 3 hours.

The acylation process of the present invention is characterized by being easier to handle than a known acylation process, using a stable acylating agent, carrying out the reaction at room temperature, and eliminating the need for making silylated amine salts. The object can be separated simply by adding the liquid to water.

When the acylation reaction is completed, the reaction mixture is poured into water at once, and the pH is adjusted appropriately to obtain the compound of formula (I) as a precipitate. At this time, the amount of water is suitably 20 to 30 times the amount of the solvent used, and the pH is preferably in the range of 1.5 to 2.5.

The following examples illustrate the method of the present invention in more detail.

Reference Example 1.

82 g of 1-hydroxytriazole was suspended in 400 ml of toluene, 36 ml of trichloromethylchloroformate was added, the mixture was heated to reflux for 2.5 hours, and then the precipitate was filtered off, washed with 150 ml of toluene and dried, and then 71 g of 1,1- ( Carbonyldioxy) dibenzotriazole is obtained.

Yield: 80%

Melting Point: 150 ℃ (Decomposition)

I, R, (KBr, cm ^-1 ): 1,800

Reference Example 2.

27.3 g of 1-hydroxybenzotriazole was suspended in 300 ml of toluene, 8.6 ml of oxalyl chloride was added thereto, heated to reflux for 3 hours, cooled with ice bath, and the precipitate was filtered off. Then, 1,1'-dibenzotriazole was filtered. 21.7 g of oxalate are obtained.

Yield: 67%

Melting Point: 158-160 ° (Decomposition)

I, R. (KBr, cm ^-1 ): 1725

Reference Example 3.

20 ml of phosgene (2.5 M toluene solution) is added to 80 ml of anhydrous methylene chloride, and a mixture of 9.5 g of 2-hydroxypyridine and 220 ml of methylene chloride of 12.1 g of triethylamine is added to the solution at 0 ° C. and stirred at the same temperature for 1 hour. . The phosphorus reaction mixture was washed with 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in that order, dried over magnesium sulfate and concentrated to give 9.94 g (92%) of di-2-pyridyl carbonate crude crystal. This crude crystal was recrystallized from a methylene chloride-petroleum ether system to obtain 8.11 g of pure di-2-pyridylcarbonate.

Yield: 75%

Melting Point: 84 ~ 86.5 ℃

I, R (KBr, cm ^-1 ): 1770

Example 1

3.02 g of D-(-)-α- (4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino) finylacetic acid and 0.8 ml of pyridine were dissolved in 32 ml of N, N-dimethylformamide. 2.96 g of 1,1 '-(carbonyldioxy) dibenzotriazole is added to this solution, and the mixture is stirred at room temperature for 1 hour. 2.27 g of 6-aminophenicylanic acid hydrochloride was added again to the solution, stirred at room temperature for 2 hours, and then the reaction mixture was poured into 1 L of water, the pH of the solution was adjusted to 2N-Hcl, 2.0, and stirred at room temperature for 1 hour, After standing in the refrigerator overnight, the resultant precipitate was filtered to give 6-[[[((4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] -3,3 4.43 g of -dimethyl-7-oxo-4-thia-1-azabicyclo [3 · 2 · 0] heptane-2-carboxylic acid monohydrate is obtained.

Yield: 92%

Melting Point: 153 ~ 155 ℃ (Decomposition)

I, R. (KBr, cm ^-1 ): 1775, 1735, 1705, 1680, 1660

NMR (DMSO-d ₆ , δ): 1.09 (s, 2-CH ₃ ), 1.56 (s, 2-CH ₃ ), 3.38 (q, J = 8Hz, CH ₃ -CH ₂ ), 3.51 (m, piperazinering 6-CH ₂ ), 4.17 (s, 3-H), 5.36 (d, J = 4 Hz 5-CH) 5.47 (q, J-4 Hz and 7 Hz, 6-H), 5.68 (a, J = 7 Hz, α -H) 7.31 (s, C ₆ H ₅ ), 9.24 (d, J = 7 Hz, NH), 9.80 (d, J = 7 Hz, NH)

Example 2

In Example 1, when 35 ml of N, N-dimethyl acetamide was used instead of N, N-dimethylformamide, the desired compound 6-[[[(4-ethyl-2,3-dioxo-1-piperazinyl 4.39 g of carbonyl] amino] phenylacetyl] amino] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid monohydrate is obtained.

Corn yield: 91% mp152-154 ° C. (decomposition)

Example 3

In Example 1, when 37 ml of N-methyl-2-pyrrolidone was used instead of N, N-dimethylformamide, the desired compound 6-[[[[(4-ethyl-2,3-dioxo-1-pi 4.38 g of ferrazinyl) carbonyl] amino] phenylacetyl] amino] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid monohydrate is obtained.

Yield: 91% mp153-155 DEG C (decomposition)

Example 4

3.02 g of D (-)-α- (4-ethyl-2,3-dioxo-1-pyrephazinylcarbonylamino) phenylacetic acid and 0.8 ml of pyridine were dissolved in 40 ml of N, N-dimethylacetamide. 3.24 g of 1,1'-dibenzotriazolooxalate is added to the solution and stirred at room temperature for 1.5 hours. 2.27 g of 6-aminophenicylanic acid hydrochloride was added to the solution and stirred at room temperature for 3.5 hours, the reaction mixture was poured into 1.2 l of water, the pH of the solution was adjusted to 2.0 with 2N-Hcl, and stirred at room temperature for 1 hour, After standing in the refrigerator overnight, the resultant precipitate was filtered to give 6-[[[((4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] -3,3 4.29 g of -dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid monohydrate is obtained.

Yield: 89% mp153-155 DEG C (decomposition)

Example 5

In Example 4, 38 ml of N, N-dimethylformamide instead of N, N-dimethylacetamide was used to prepare the desired compound 6-[[[(4-ethyl-2,3-dioxo-1-piperazinyl 4.22 g of) carbonyl] amino] phenylacetyl] amino] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid monohydrate is obtained.

Yield: 87.5% mp152-154 ° C (decomposition)

Example 6

In 35 ml of N, N-dimethylformamide, 3.02 g of D (-)-α- (4-ethyl-2,3-dioxo-1-pyrephazinylcarbonylamino) phenylacetic acid and 0.8 ml of pyridine were dissolved. 2.38 g of di-2-pyridylcarbonate was added to the mixture, and the mixture was stirred at room temperature for 4.5 hours. 2.02 g of 6-aminophenicylate hydrochloride was added to the solution, stirred at room temperature for 6 hours, poured into 1 l of water, the pH of the solution was adjusted to 2.0 with 2N-HCl, stirred at room temperature for 1 hour, and left in the refrigerator overnight. The resulting precipitate was filtered to give 6-[[[(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] -3,3-dimethyl-7-oxo 3.30 g of 4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid monohydrate are obtained.

Yield: 77% mp153∼155 ℃ (decomposition)

Example 7

3.18 g of D (-)-α- (4-ethyl-2,3-dioxo-1-pyrephazinylcarbonylamino) -p-hydroxyphenylacetic acid and 0.8 ml of pyridine were mixed with 35 m of N, N-dimethylacetate. It is dissolved in amide, 2.96 g of 1,1 '-(carbonyldioxy) dibenzotriazole is added and stirred at room temperature for 1.5 hours. 3.30 g of a hydrochloride of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid was added to this solution, followed by stirring at room temperature for 2 hours. The mixture was poured into 1 l of water, the pH of the solution was adjusted to 2.0 with 2N-HCl, stirred at room temperature for 1 hour, and left in the refrigerator overnight. The resulting precipitate was filtered, and 7- [D (-)-α- (4-ethyl- 2,3-dioxo-1-piperazinecarboxamido) -α- (hydroxyphenyl) acetamido] -3- [5- (1-methyl-1H-tetrazol-5-yl) thiomethyl] 5.52 g of 3-cefe-4-carboxylic acid dihydrate are obtained.

Yield: 90%

Melting Point: 188 ~ 190 ℃ (Decomposition)

I, R. (KBr, cm ^-1 ): 1775, 1705, 1680, 1670

Example 8

In Example 7, 37 ml of N, N-dimethylformamide in place of N, N-dimethylacetamide was used to obtain the desired compound 7- [D-(-(-(-α- (4-ethyl-2,3-dioxo-). 1-pyrephazincarboxamido) -α- (p-hydroxyphenyl) acetamido] -3- [5- (1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem- 5.40 g of 4-carboxylic acid dihydrate are obtained.

Yield: 88% mp 188 ~ 191 ℃ (decomposition)

Example 9

3.18 g of D (-)-α- (4-ethyl-2,3-dioxo-1-pyrefazinylcarbonylamino) -α-hydroxyphenylacetic acid and 0.8 ml of pyridine were added to 40 ml of N, N-dimethylacetate. Dissolve in amide, add 3.24 g of oxalate with 1,1'-dibenzotriazole, and stir at room temperature for 2.5 hours. To this solution was added 3.30 g of a hydrochloride of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid and stirred at room temperature for 3 hours, followed by 1.2 l of water. Pour the reaction mixture, adjust the pH of the solution with 2N-HCl, stir at room temperature for 1 hour, leave in the refrigerator overnight, and filter the resulting precipitate to obtain the desired compound 7- [D (-) α- (4-ethyl- 2,3-dioxo-1-pyrepazincarboxamido) -α- (hydroxyphenyl) acetamido-3- [5- (1-methyl-1H-tetrazol-5-yl) thiomethyl]- 5.28 g of 3-cefem-4-carboxylic acid dihydrate are obtained.

Yield: 86% mp 188 ~ 190 ℃ (decomposition)

Example 10

42 ml of N, N-dimethylformamide in place of N, N-dimethylacetamide in Example 9 provided the desired compound 7- [D (-)-(4-methyl-2,3-dioxo-1-pyre. Pazincarboxamido) -α- (p-hydroxyphenyl) acetamido] -3-] 5- (1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylic acid 5.21 g of dihydrate are obtained.

Yield: 85% mp 189-191 ° C (decomposition)

Example 11

To 45 ml of N, N-dimethylacetamide, 3.18 g of D (-)-α- (4-ethyl-2,3-dioxo-1-pyrefazinylcarbonylamino) -p-hydroxyphenylacetic acid and 0.8 ml of pyridine After dissolving, 2.38 g of di-2-pyridylcarbonate was added to this solution, followed by stirring at room temperature for 5 hours. To the solution was added 2.73 g of a hydrochloride of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid and stirred at room temperature for 6 hours, followed by water 1.3 Pour into l, adjust the pH of the solution to 2.0 with 2N-HCl, stir at room temperature for 1 hour, and leave in the refrigerator overnight to filter the resulting precipitate, and then filter 7- [D (-)-α- (4-ethyl-2, 3-dioxo-1-piperazinecarboxamido-α- (p-hydroxyphenyl) acetamido] -3- [5- (1-methyl-1H-tetrazol-5-yl) thiomethyl]- 3.38 g of 3-cefem-4-carboxylic acid dihydrate are obtained.

Yield: 75% mp 188 ~ 191 ℃ (decomposition)

Example 12

2.87 g of D (+)-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido-3-hydroxybutynoic acid and 0.8 ml of pyridine were added to 32 m of N, N-dimethylformamide. After dissolving, 2.96 g of 1,1 '-(carbonyldioxy) dibenzotriazole was added to the solution, which was stirred for 1.5 hours at room temperature to 7β-amino-α-methoxy-3- (1-methyl-1H). 3.56 g hydrochloride of -tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid was added thereto, stirred at room temperature for 3 hours, and then the reaction mixture was poured into 1 l of water and the pH of the solution was adjusted to 2.0 with 2N-HCl. After aligning, the mixture was stirred at room temperature for 1 hour, left in the refrigerator overnight, and the resulting precipitate was filtered and 7β- [D (+)-α- (4-ethyl-2,3-dioxo-1-pyrepazincarboxamido) 5.25 g of -β-hydroxybutaneamido-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cef-4-carboxylic acid are obtained.

Yield: 93%

Melting Point: 175 ~ 175 ℃ (Decomposition)

I, R. (KBr, cm ^-1 ): 1775, 1710, 1675, 1660

Example 13

In Example 12, using 35 ml of N, N-dimethylacetamide instead of N, N-dimethylformamide, 7β- [D (+)-α- (4-ethyl-2,3-dioxo-1-pyrephazine 5.14 g of carboxamido) -β-hydroxybutanamide-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cef-4-carboxylic acid are obtained .

Yield: 91%

mp 173-175 ° C (decomposition)

Example 14

2.87 g of D (+)-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido-3-hydroxybutanoic acid and 0.8 ml of pyridine were added to 38 ml of N, N-dimethylformamide. After dissolving, 3.24 g of 1,1'-dibenzotriazole oxalate was added to the solution, followed by stirring for 2 hours at room temperature, again to 7β-amino-α-methoxy-3- (1-methyl-1H-tetra). 3.56 g of hydrochloride of sol-5-yl) thiomethyl-3-cepem-4-carboxylic acid were added and stirred at room temperature for 3 hours. The reaction mixture was poured into 1.2 l of water and the pH of the solution was adjusted to 2.0 with 2N-HCl. After stirring for 1 hour at room temperature, and left in the refrigerator overnight, the resulting precipitate is filtered and 7β- [D (+)-α- (4-ethyl-2,3-dioxo-1-pyrepazincarboxamido)- 5.08 g of β-hydroxybutaneamido-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cef-4-carboxylic acid are obtained.

Yield: 90%

mp 172-174 캜 (decomposition)

Example 15

In Example 14, using 45 ml of N-methyl-2-pyrrolidone instead of N, N-dimethylformamide, 7β-[(+)-α- (4-ethyl-2,3-dioxo-1-pyre was used. Fazin carboxamido) -β-hydroxybutaneamido] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cefe-4-carboxylic acid 4.97 g Is obtained.

Yield: 88%

mp 173-175 ° C (decomposition)

Example 16

2.87 g of D (+)-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3-hydroxybutanoic acid and 0.8 ml of pyridine were added to 40m of N, N + -dimethylformamide. After dissolving, 2.38 g of di-2-pyridylcarbonate were added to this solution, and the mixture was stirred at room temperature for 5 hours. To this solution was added 2.96 g of a hydrochloride salt of 7β-amino-α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid and 6 hours at room temperature. After stirring, the reaction mixture was poured into 1.2 l of water, the pH of the solution was adjusted to 2.0 with 2N-HCl, stirred at room temperature for 1 hour, allowed to stand overnight in a refrigerator, and the resulting precipitate was filtered to obtain 7β- [D (+)-α. -(4-ethyl-2,3-dioxo-1-pyrepazincarboxamido) -α-hydroxybutanamido] -7α-methoxy-3-[(1-methyl-1H-tetrazol-5 -Yl) thiomethyl] -3-cepem-4-carboxylic acid is obtained.

Yield: 74%

173-175 ° C (decomposition)

Claims (3)

A reactive ester obtained by reacting an organic acid of general formula (II) with an acylating agent of general formula (III) in an organic solvent in the presence of an organic base is used as a 6-aminophenicyl carbonate derivative or general formula (V). A process for preparing penicillin and cephalosporin derivatives of general formula (I) by reacting with a hydrochloride salt of a sportanic acid derivative. Wherein R ₁ is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 1-hydroxyethyl group, R ₂ is hydrogen or hydroxy group, A is-(CH ₃ ) ₂ -CH (COOH )-Or -CH ₂ C (CH ₂ R ₃ ) = C (COOH)-group. (Wherein R ₃ is a five-membered heterocyclic group which contains one or more nitrogens or one sulfur atom and may be substituted with a lower alkyl group)

C) R is a benzotriazolyl group and n is 1 or 2. The process according to claim 1, wherein the organic solvent is selected from N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidone. The process according to claim 1, wherein the acylation reaction is carried out at room temperature in a range of 2 to 5 hours.