KR930001114B1 - Cephalosporin derivatives - Google Patents

Abstract

7- Acylamino-3-(5- methoxythiazolin-2-yl) thiomethyl-3-cephem carboxylic acid derivs. of formula(I) are new. In (I), R=H, 2- (2aminothiazol-4-yl)-2(syn)- methoxyiminoacetyl, 2-(2- aminothiazol - 4-yl)-2-(2-t- butoxycarbonyl-2- propyloxyimino) acetyl, 2- (2aminothiazol-4-yl)-2-(2-carboxy-2-propyloxyimino)acetyl or D(-) alpha-(4- ethyl-2,3- dioxo-1- piperazine carboxyamido)-alpha- (4hydroxyphenyl)acetyl; R'=H or paramethoxybenzyl (PMB). Also claimed is the prepn. of (I) which comprises cyclizing dithiocarbamate of formula (II) in acidic condition and acylating the obtd. intermediate with an acetate deriv.

Description

Cephalosporin derivatives and preparation methods thereof

The present invention is a novel 7-acylamino-3- (5-methoxythiazolin-2-yl) thiomethyl-3-cepemcarboxylic acid derivative represented by general formula (I) (hereinafter referred to as cephalosporin derivative). And a method for producing the same. The cephalosporin derivative of general formula (I) is weak in activity against Pseudomonas strain but shows strong activity against gram positive and gram negative bacteria, and thus can be used as an antibacterial agent and intermediate.

In formula (I), R is hydrogen, 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetyl, 2- (2-aminothiazol-4-yl)- 2- (2-t-butoxycarbonyl-2-propyloxyimino) acetyl, 2- (2-aminothiazol-4-yl) -2- (2-carboxy-2-propyloxyimino) acetyl or D (-)-Alpha- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -alpha- (4-hydroxyphenyl) acetyl, where R is hydrogen, paramethoxybenzyl PMB), sodium or potassium.

The cephalosporin derivative represented by the general formula (I) of the present invention is a novel compound, which cannot be found in any literature, but US Pat. No. 3,992,377 discloses cephalo substituted with a heterocyclic thiol compound in the 3-position acetoxyl group. Sporin antibiotics are known, and in particular in the magazine (J. Antibiotics 29, 1987), the structure-activity correlation of aminothiazolyl cephalosporin derivatives of general formula (II) with thiazole at the 3 position is reported. have. Wherein R ₁ is hydrogen, methyl and R ₂ and R ₃ are hydrogen, methyl, carboxyl, carboxymethyl or their alkylesters.

In addition, the magazine (J.Med. Chum. 8, 174, 1965) discloses a compound of the general formula (III) substituted with a xanthate or dithiocarbamate group of the 3-position acetoxyl group of the cephalosporin derivative. It is described. Here, R ₄ represents an alkoxy, alkylamino or dialkylamino group.

The present inventors have developed a tea novel cephalosporin derivative of the general formula (I), which has been constantly studied to synthesize cephalosporin derivatives showing a broad antimicrobial spectrum. That is, the present invention was found that dithiocarbamate having an acetal group of general formula (IV) is easily converted into a novel cephalosporin intermediate of general formula (I) by causing an intramolecular cyclization reaction in the presence of Lewis acid. .

In more detail describing the preparation method of the present invention, the dithiocarbamate of general formula (IV) used as a starting material is amino of general formula (V) as in Korean Patent Application No. 90-10721 (1990.7.14). Acetals may be reacted with triethylamine and carbon disulfide in a tetrahydrofuran solvent to prepare dithiocarbamate triethylamine salts of formula (VI). When this is stirred with a 3-chloromethyl cefem compound of general formula (15) at 15 ± 5 ℃, dithiocarbamate of general formula (IV) is obtained in high yield (92%). The cyclization reaction with Lewis acid at 10 ± 5 ° C. in the presence of a solvent yields a high yield (97%) of the cephalosporin intermediate of formula (I) ′ wherein R is hydrogen and R ′ is PMB. As the Lewis acid, trifluoroborane and magnesium bromide anhydride are effective. Dichloromethane, dichloroethane, chloroform and the like can be used as the reaction solvent.

Meanwhile, when the cephalosporin intermediate of Formula (I ') and the acetate derivative are acylated in the presence of an organic solvent such as dichloromethane, the cephalosporin derivative protected by PMB of Formula (VII) can be prepared. Acetate derivatives refer to 2- (2-aminothiazol-4-yl) -2 (syn) -methoxyiminothiophenylacetate

, 2-(2-아미노티아졸-4-일)-2-(2-t-부톡시카르보닐-2-프로필옥시이미노)티오벤즈티아졸일 아세테이트

, 2- (2-aminothiazol-4-yl) -2- (2-t-butoxycarbonyl-2-propyloxyimino) thiobenzthiazolyl acetate

, 2-(2-아미노티아졸-4-일)-2-(2-카르복시-2-프로필옥시이미노)티오벤즈티아졸일 아세테이트

, 2- (2-aminothiazol-4-yl) -2- (2-carboxy-2-propyloxyimino) thiobenzthiazolyl acetate

, D(-2)α-(4-에틸-2,3-디옥소-1-피페라진카르복시아미도)-α-(4-히드록시페닐)아세틸클로라이드

를 말하는데, 일반식(Ⅰ)에 있어서 원하는 R에 따라 아세테이트 유도체를 선택할 수 있다.

, D (-2) α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -α- (4-hydroxyphenyl) acetylchloride

In the formula (I), an acetate derivative may be selected according to the desired R.

R in general formula (i) is the same as R of general formula (I).

Finally, in order to reach the cephalosporin derivative of the general formula (I), the protecting group of the carboxyl group can be removed by using trifluoroacetic acid and anisole which are known methods. Thus, the present invention is a novel cephalo of general formula (I) via 3-thiomethylbathemic compound of general formula (IV) from 3-chloromethylcefem compound of general formula (X) which is a readily available basic raw material. It is an easy way to obtain a sporin derivative.

In order to help the understanding of the present invention, the manufacturing process from the starting material to the final material is shown in the following picture.

The present invention is explained in more detail with reference to the following examples. However, it should be understood that modifications and variations by those skilled in the art are not limited to the embodiments of the present invention but within the protection scope of the present invention.

Example 1

Preparation of 7-amino-3- (dimethoxyethylaminothiocarbonyl) thiomethyl-3-cepem-4-carboxylic acid paramethoxybenzyl ester (IV)

5.26 g of aminoacetaldehyde dimethylacetyl was dissolved in 200 ml of tetrahydrofuran, 10.1 g of triethylamine was added thereto, and 3 ml of carbon disulfide was added dropwise, followed by stirring at 15 ± 5 ° C. for 30 minutes. V) 20.3 g is added and stirred for an additional 30 minutes at the same temperature. The triethylamine hydrochloride precipitated in the reaction solution was filtered off and the filtrate was removed under reduced pressure (30 mmHg) to give a foamy solid, which was crystallized with dichloromethane and ether to give 23.6 g (92% yield) of the pure desired product. Get

Melting Point: 50-51 ℃

¹ H-NMRδ (CDCl ₃ ): 1.81 (br s, 2H), 3.41 (s, 6H), 3.58 (br s, 2H), 3.80 (s, 3H), 3.91 (dd, J = 6.2, J = 5 , 3,2H), 4.34,4.44 (2d, ABq, J = 13.9, 2H), 4.57 (t, J = 5.3, 1H), 4.72 (d, J = 5.0, 1H), 4.90 (d, J = 5.0 , 1H), 5.18, 5.26 (2d, ABq, J = 11.9, 2H), 6.88 (d, J = 8.7, 2H), 7.34 (d, J = 8.7, 2H), 7.70 (t, J = 5.3, 1H )

Elemental analysis _{(C 21 H 27 N 3 S} 3 O 6)

Calculated Value: C; 49.11, H; 5.30, N; 8.18

Found: C; 48.92, H; 5.37, N; 7.89

Example 2

7-amino-3- (5-methoxythiazolin-2-yl) thiomethyl-3-cepem-4-carboxylic acid paramethoxybenzyl ester (I ', R = hydrogen, R' = paramethoxybenzyl Manufacturing

1) How to use BF ₃

5.13 g of 7-amino-3- (dimethoxyethylaminothiocarbonyl) thiomethyl-3-cepem-4-carboxylic acid paramethoxy ester (IV) obtained by the method of Example 1 was dissolved in 50 ml of dichloromethane. Thereafter, 3.1 ml of trifluoroborane ether was added dropwise at 10 ± 5 ° C. and stirred at the same temperature for 30 minutes. The reaction solution was neutralized with aqueous sodium hydrogen carbonate solution, adjusted to pH 8-9, extracted three times with 50 ml of dichloromethane, dried over anhydrous forget-me-not, the solvent was removed under reduced pressure (30 mmHg), and dichloromethane and ether were added to the residue, followed by crystallization. 4.67 g (97% yield) of pure desired product are obtained.

Melting Point: 53-54 ℃

¹ H-NMRδ (CDCl ₃ ): 1.86 (br s, 2H), 3.27 (s, 3H), 3.53, 3.66 (2d, ABq, J = 20,2H), 3.80 (s, 3H), 4.06 (dd, J = 17.9, J = 5.2,1H), 4.41 (d, J = 17.9, 1H), 4.41,4.55 (dd, ABq, J = 13.5, 2H), 4.70 (d, J = 5.0, 1H), 4.88 ( d, J = 5.0, 1H), 5.22, 5.23 (2s, 2H), 5.61 (d, J = 5.2,1H), 6.88 (d, J = 8.5,2H), 7.35 (d, J = 8.5,2H)

Elemental Analysis (C ₂₀ H ₂₃ N ₃ O ₅ S ₃ )

Calculated Value: C; 49.88, H; 4.81, N; 8.73

Found: C; 49.90, H; 4.80, N; 8.48

2) How to use MgBr ₂

5.13 g of Compound (IV) obtained by the method of Example 1 was dissolved in 50 ml of dichloromethane, and 6.45 g of anhydrous magnesium bromide ether was added at 10 ± 5 ° C., stirred at the same temperature for 30 minutes, and then treated in the same manner as in 1). To obtain 4.52 g (94% yield) of the desired product.

Example 3

7- [2- (2-aminothiazol-4-yl) -2- (syn)-(methoxyimino) acetamido] -3- (5-methoxythiazolin-2-yl) thiomethyl- Preparation of 3-cefem-4-carboxylic acid paramethoxybenzyl ester [VII, R = 2- (2-aminothiazol-4-yl) -2- (syn)-(methoxyimino) acetyl]

Example 2-1) 0.96 g of cephalosporin intermediate (I) 'obtained by the method was dissolved in 10 ml of dichloromethane, and then 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino 0.59 g of thiophenyl acetate was added and stirred at 20 ± 5 ° C. for 1 hour, and then the solvent was removed under reduced pressure (30 mmHg). The residue was chromatographed on 50 g of silica gel using ethyl acetate and separated to give 1.21 g (91) of the desired product. % Yield).

Melting Point: 107-112 ℃

¹ H-NMRδ (CDCl ₃ ): 3.26 (s, 3H), 3.56, 3.67 (2d, ABq, J = 18.5,2H), 3.80 (s, 3H), 4.02 (s, 3H), 3.96-4.62 (m , 4H), 5.03 (d, J = 4.9, 1H), 5.21 (s, 2H), 5.60 (d, J = 5.3, 1H), 5.68 (br s, 2H), 6.00 (dd, J = 8.9, J = 4.9,1H), 6.73 (s, 1H), 6.89 (d, J = 8.6,2H), 7.34 (d, J = 8.6,2H), 7.99 (d, J = 8.9,1H)

Example 4

7- [2- (2-aminothiazol-4-yl) -2- (syn)-(methoxyimino) acetamido] -3- (5-methoxythiazolin-2-yl) thiomethyl- Preparation of 3-cepem-4-carboxylic acid [I, R = 2- (2-aminothiazol-4-yl) -2- (syn)-(methoxyiminoacetyl, R '= hydrogen]

0.50 g of the compound (VII) obtained in Example 3 was dissolved in 5 ml of dichloromethane, 2 ml of anisole and 2 ml of trifluoroacetic acid were added thereto, stirred at 20 ± 5 ° C for 1 hour, and then the solvent was removed under reduced pressure (30 mmHg). 20 ml of isopropyl ether was added to the residue and stirred to precipitate crystals. The precipitate was filtered and washed with ether and dichloromethane to obtain 0.33 g (82% yield) of the desired product.

Melting Point: 195-200 ℃

¹ H-NMRδ (DMSO-d ⁶ ): 3.20 (s, 2H), 3.84 (s, 3H), 3.21-4.39 (m, 6H), 5.04 (d, J = 4.6,1H), 5.63 (dd, J = 8.0, J = 4.6, 1H), 5.82 (d, J = 4.9, 1H), 6.73 (s, 1H), 7.24 (br s, 2H), 9.56 (d, J = 8.0, 1H)

Example 5

7- [2- (2-aminothiazol-4-yl) -2- (2-t-butoxycarbonyl-2-propyloxyimino) acetamido] -3- (5-methoxythiazoline- 2-yl) thiomethyl-3-cepem-4-carboxylic acid paramethoxybenzyl ester [VII, R = 2- (2-aminothiazol-4-yl) -2- (2-t-butoxycar Carbonyl-2-propyloxyimino) acetyl]

Dissolve 0.96 g of cephalosporin intermediate (I) 'in 10 ml of dichloromethane and then 2- (2-aminothiazol-4-yl) -2- (2-t-butoxycarbonyl-2-propyloxyimino) thio 0.96 g of benzthiazolyl acetate was added and stirred at 20 ± 5 ° C. for 3 hours, and then the solvent was removed under reduced pressure (30 mmHg). The residue was purified by 50 g of silica gel using ethyl acetate-hexane (2: 1, v / v). Chromatographic phase and separation affords 1.34 g (85% yield) of the desired product.

Melting Point: 95-97 ℃

¹ H-NMRδ (CDCl ₃ ): 1.42 (s, 9H), 1.57 (s, 3H), 1.59 (s, 3H), 3.27 (s, 3H), 3.55, 3.68 (2d, ABq, J = 19.0,2H ), 3.73 (s, 3H), 3.79-4.62 (m, 4H), 5.02 (d, J = 5.0, 1H), 5.18,5.27 (2d, ABq, J = 11.9, 2H), 5.61 (d, J = 5.3, 1H), 5.96 (dd, J = 8.9, J = 5.0, 1H), 6.73 (br s, 2H), 6.86 (s, 1H), 6.89 (d, J = 8.6,2H), 7.35 (d, J = 8.6,2H), 7.58 (d, J = 8.9,1H)

Example 6

7- [2- (2-aminothiazol-4-yl) -2- (2-t-butoxycarbonyl-2-propyloxy imino) acetamido] -3- (5-methoxythiazoline -2-yl) thiomethyl-3-cepem-4-carboxylic acid [I, R = 2- (2-aminothiazol-4-yl-2- (2-carboxy-2-propyloxyimino) acetyl, R '= hydrogen]

0.49 g of the compound (VII) obtained in Example 5 was dissolved in 5 ml of dichloromethane, 2 ml of anisole and 5 ml of trifluoroacetic acid were added thereto, stirred for 3 hours at 20 ± 5 ° C., and the solvent was removed under reduced pressure (30 mmHg). 20 ml of isopropyl ether was added to the residue and stirred to precipitate crystals. The precipitate was filtered and washed with ether and dichloromethane to obtain 0.32 g (84% yield) of the desired product.

Melting Point: 115 ℃ (Decomposition)

¹ H-NMRδ (DMSO-d ⁶ ): 1.46 (s, 3H), 1.47 (s, 3H), 3.19 (s, 3H), 3.33-4.49 (m, 6H), 5.17 (d, J = 4.9,1H ), 5.75 (d, J = 4.9, 1H), 5.83 (dd, J = 8.0, J = 4.8, 1H), 6.80 (s, 1H), 9.48 (d, J = 8.0, 1H)

Example 7

7- [D (-)-alpha- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -alpha- (4-hydroxyphenyl) acetamido] -3- (5- Methoxythiazolin-2-yl) thiomethyl-3-cepem-4-carboxylic acid paramethoxybenzyl ester [VII, R = D (-)-alpha- (4-ethyl-2,3-dioxo- 1-piperazincarboxamido) -alpha- (4-hydroxyphenyl) acetyl]

1.85 g of D (-)-alpha (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -alpha- (4-hydroxyphenyl) acetic acid in 30 ml of dried N, N-dimethylacetamide After dissolving and cooling to -20 ° C, 0.58 ml of POCl ₃ was slowly added and stirred at the same temperature for 1 hour. In another flask, 3.3 g of N- (trimethylsilyl) acetamide and 2.4 g of cephalosporin intermediate (I) 'were dissolved in 30 ml of dichloromethane, and slowly added dropwise at -20 ° C to the solution prepared above, followed by stirring for 2 hours, followed by reaction solution. 100 ml of water was added to the mixture, followed by stirring to precipitate crystals. It was filtered, the solid was dissolved in chloroform, dried over anhydrous forget-me-not, chromatographed on 100 g of silica gel using chloroform-methanol (10: 1, v / v) and separated to give 2.75 g (69% yield) of the desired product. Get

Melting Point: 99-103 ℃

¹ H-NMRδ (CDCl ₃ ): 1.19 (t, J = 6.8, 3H), 3.23 (s, 3H), 3.78 (s, 3H), 3.35-4.45 (m, 12H), 4.77 (d, J = 4.6 , 1H), 5.17 (br s, 2H), 5.58 (d, J = 5.0, 1H), 5.67 (d, J = 7.0, 1H), 5.79 (dd, J = 8.9, J = 4.7, 1H), 6.71 (d, J = 8.1,2H), 6.86 (d, J = 8.4,2H), 7.19 (d, J = 8.1,2H), 7.35 (d, J = 8.4,2H), 7.79 (d, J = 8.9 , 1H), 10.04 (d, J = 7.0,1H)

Example 8

7- [D (-)-alpha- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -alpha- (4-hydroxyphenyl) acetamido] -3- (5- Methoxythiazolin-2-yl) thiomethyl-3-cepem-4-carboxylic acid [I, R = [D (-)-alpha- (4-ethyl-2,3-dioxo-1-piperazine Carboxamido) -alpha- (4-hydroxyphenyl) acetyl, R '= hydrogen]

0.79 g of the compound (VII) obtained in Example 7 was dissolved in 5 ml of dichloromethane, 2 ml of anisole and 2 ml of trifluoroacetic acid were added thereto, stirred at 20 ± 5 ° C. for 1 hour, and the solvent was removed under reduced pressure (30 mmHg). 20 ml of isopropyl ether was added to the residue, followed by stirring to precipitate crystals. The precipitate was filtered and washed with ether and dichloromethane to obtain 0.58 g (86% yield) of the desired product.

Melting Point: 170 ℃ (Decomposition)

¹ H-NMRδ (DMSO-d ⁶ ): 1.08 (t, J = 7.1d 3H), 3.19 (s, 3H), 3.32-4.43 (m, 12H), 5.01 (d, J = 4.8,1H), 5.47 (d, J = 7.2, 1H), 5.72 (dd, J = 8.5, J = 4.8, 1H), 5.83 (d, J = 8.5, 2H), 6.72 (d, J = 8.5, 2H) 7.21 (d, J = 8.5, 2H), 9.33 (d, J = 8.5, 1H), 9.71 (d, J = 7.2, 1H)

Claims (6)

Novel cephalosporin derivatives represented by general formula (I)

In formula (I), R is hydrogen, 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetyl, 2- (2-aminothiazol-4-yl)- 2- (2-t-butoxycarbonyl-2-propyloxyimino) acetyl, 2- (2-aminothiazol-4-yl) -2- (2-carboxy-2-propyloxyimino) acetyl and D (-)-Alpha- (4-ethyl-2,3, -dioxo-1-piperazinecarboxamido) -alpha- (4-hydroxyphenyl) acetyl group, and R 'represents hydrogen or paramethoxy Benzyl (PMB). The first step of preparing a cephalosporin intermediate of general formula (I ') by cyclization of dithiocarbamate of general formula (IV) under acidic conditions, and the intermediate and acetate derivative of general formula (I)' A process for producing the cephalosporin derivative of the general formula (I), comprising a second step of producing a cephalosporin derivative of the general formula (I).

In formula (I), R is hydrogen, 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetyl, 2- (2-aminothiazol-4-yl)- 2- (2-t-butoxycarbonyl-2-propyloxyimino) acetyl, 2- (2-aminothiazol-4-yl) -2- (2-carboxy-2-propyloxyimino) acetyl and D (-)-Alpha- (4-ethyl-2,3, -dioxo-1-piperazinecarboxamido) -alpha- (4-hydroxyphenyl) acetyl group, and R 'represents hydrogen or paramethoxy Benzyl group (PMB) is indicated. The process for producing cephalosporin derivatives of the general formula (I) according to claim 2, wherein the acid of the first step is selected from tribroroboran and anhydrous magnesium bromide. The method for producing a cephalosporin derivative according to claim 2, wherein the solvent is selected from dichloromethane, dichloroethane and chloroform as the solvent in the first step. The method for producing a cephalosporin derivative according to claim 2, wherein the reaction is carried out at 10 ± 5 ° C. by the cyclization reaction of the first step. The method of claim 2, wherein the acetate derivative of the second step is 2- (2-aminothiazol-4-yl) -2 (syn) -methoxyiminothiophenylacetate,

2- (2-aminothiazol-4-yl) -2- (2-t-butoxycarbonyl-2-propyloxyimino) thiobenzthiazolyl acetate,

2- (2-aminothiazol-4-yl) -2- (2-carboxy-2-propyloxyimino) thiobenzthiazolyl acetate,

D- (2) -α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -α- (4-hydroxyphenyl) acetyl chloride

Method for producing a cephalosporin derivative of the general formula (I), characterized in that the reaction.