FI59104C - SAOSOM MELLANPRODUKT VID FRAMSTAELLNING AV 3-DESACETOXI-CEFALOSPORINER ANVAENDBAR MED 3-EXOMETYLEN SUBSTITUERAD CEFALOSPORINFOERENING - Google Patents

Description

"ÖCmH ΓβΊ ANNOUNCEMENT

draTg * · * (11) UTLÄCGN I NOSSKRI FT 5 91 O 4 C M5V Patent granted 10 C6 1931 'Patent neddelat ^ (51) Kv.ik.3 / int.a.3 e 07 D 501/14 FINLAND —FINLAND ( 21) Ptt «nttlh« k «mti« —P »*« nt «n» 6k »Ur.t 763278 (22) HakumlspUvi— Aiweknlnpdag 27.10.78 (23) Alkuptlvt — GlhighMsdtg 25-02.72 (11) Tulkit JulklMktl - Bllvlt offumllg 27.10.78

Patent and raklsterihallltufl .... ............ ., _ \. ^ (44) Nihtivtl (* lp «Date and date of publication -

Petant- och raglttantyralaan Anaeka utiagd och uti »krift« n puuicand 27.02.81 (32) (33) (31) Fyydutqr utuolkeue — Buglrd priorltat 25-02.71 USA (US) 1189U1 (71) Eli Lilly and Company, 307 East McCarty Street, Indianapolis,

Indiana U6206, USA (72) Robert Raymond Chauvette, Indianapolis, Indiana, USA. (7M Oy Kolster Ab (5 ^) 3-exomethylene-substituted cephalosporin compound used as an intermediate in the preparation of Δ 2 -deacetoxy-cephalosporins The present invention relates to novel 3-exomethylene-substituted cephalosporin compounds which can be used as an intermediate in the preparation of 3 ......

δ -desacetoxy-cephalospores of the formula NH. _ / 1 \

^ 7 6f 2 I

0β-CH2 C00R1 wherein the formula has a hydrogen atom, a p-nitrobenzyl or p-methoxybenzyl group or a pharmaceutically acceptable cation.

2 591 04

According to the cephalos nomenclature system for cephalosporin antibiotics (see Morin et al. J. Am. Chem. Soc., 8i +, 3 ^ + 00 (1962)), 7-ADCA is designated 3-methyl-7-amino-4? -

O

cephem to the N-carboxylic acid, which represents the endocyclic position of the carbon-carbon double bond. 7-Aminodesacetoxycephalosporanic acid is a useful intermediate in the preparation of desacetoxycephalosporanic acid antibiotics. For example, acylation of 7-ADCA in a mixed anhydride reaction with tert-butyloxycarbonyl (t-BOC) -protected D-phenylglycine using methyl chloroformate followed by removal of the t-BOC group gives 7 - ( is called cefalexin. Other useful cephalosporin intermediates in which the carbon-carbon double bond is located at the 2-position (Δ) of the cephem ring are also known, for example, the 7-acyl-A-cephem-14-carboxylic acid esters disclosed in U.S. Patent 3,536,705 and J. Org. Chem., 35 2U29 (1970). However, the cepham-structured compounds of the invention thus having an exocyclic double bond (see Formula I) have not been previously described in the art.

"Pharmaceutically acceptable cation" means an alkali metal cation such as lithium, sodium and potassium cations and alkaline earth cations such as calcium and magnesium cations and zinc cations.

The novel compounds of formula I having a hydrogen atom may exist in amphoteric form; this form is also within the scope of the present invention.

The novel 3-exomethylene-substituted cephalosporin compounds are generally highly crystalline compounds which in many cases are more soluble in water than the correspondingly substituted 3-methyl-? In contrast to 3-methyl- [ar-cephem-U-carboxylic acids, 3-exomethylene-substituted cephalosporins do not exhibit 3 absorption in the 2β0 mp range in the ultraviolet spectrum, but, like 3-methyl-4-cephem compounds, have absorption in the infr at about 1790 cm -1, i.e., in the region typical of the β-lactam carbonyl group, the nuclear magnetic resonance spectrum of 3-methylene-substituted cephalosporins shows an allyl-type hydrogen attached to the C 1-4 carbon and two vinyl hydrogens attached to the carbon substituent on the C these properties are consistent with the structure of the 3-exomethylene-substituted cepham-1 * -carboxylic acid disclosed herein.

3,5104

The novel 3-exomethylene-substituted cephalosporins are prepared by reduction of a T-amino-N-cephem-U-carboxylic acid or ester in which the 3-carbon of the cephem core is substituted with a group -CH 2 -SR 2 -, where R 1 represents a hydrocarbon group, or with a SO 2 M + group , where M + is a metal cation.

The 3-exomethylene-substituted cephalosporins of formula I are prepared from a 3-substituted methyl cephalosporin.

The compound of formula III is reacted with hydrogen under reducing conditions by either catalytic hydrogenation or chemical reduction to give the 3-exomethylene cephalosporin of formula I. The reducing ear-response is represented by the following general equation: H- "~ j --- Oops. H-H-j .......

1-K ^ 1_CH2-S-R2.! - N J = £ H2 0 T o7 Ύ COORt C00R-,

III I

in the reaction formulas, R 1 and R 2 have the same meaning as above. The reaction is characterized herein as a reductive displacement reaction in which, under the reducing conditions used, the group S to Rg is removed by forming an exocyclic double bond at the 3-position of the cepham ring. The group SR 1 is a leaving group which is released under the reducing conditions used.

The reductive displacement reaction is carried out by introducing gaseous hydrogen into the reaction mixture in the presence of a metallic hydrogenation catalyst or with hydrogen formed by a reactive metal pair, amalgamated metal or a combination of metal and acid in the presence of dimethylformamide. The reducing substitution reaction can also be performed with +2 chromium salts.

The reductive displacement reaction is carried out under catalytic hydrogenation conditions by dissolving 3 'Substituted methylcephalosporanic acid or its ester or cationic salt in a suitable solvent and hydrogenating the solution at a hydrogen pressure between about 105 and about 3500 kPa. The hydrogenation can be performed at a temperature between about 5 and 65 ° C, and preferably at about 25-5 ° C.

Efficient hydrogenation catalysts include parent metal catalysts such as nickel and cobalt, preferably Raney-type activated catalysts such as Raney nickel and Raney cobalt, and noble metal catalysts such as platinum, palladium and rhodium. The preferred hydrogenation catalyst is Raney nickel.

11 59104

The catalytic reduction can be performed in various solvents. In general, water or any other solvent which does not react with the starting materials can be used, and preferably one which does not itself reduce can be used. For example, methanol, ethanol, isopropanol, dimethylformamide, dioxane and tetrahydrofuran, either as such or mixed with water, are suitable solvents. If the 3-substituted methylcephalosporin is used as a salt, only water can be used as the solvent.

The hydrogenation is allowed to proceed for about 2k hours in the preferred temperature range, although at somewhat higher temperatures the reaction proceeds more rapidly.

The reductive substitution reaction can also be carried out under chemical reduction conditions well known in the art, using hydrogen formed or the readily oxidizable metal salt acting as a reducing agent. Chemical reducing agents that can be used in the present process include metallic zinc in the presence of a suitable acid, aluminum amalgam, and salts of oxidizable metals, for example, chromium chloride, chromium bromide, and chromium acetate.

The chemical reduction is performed in an aqueous solution containing dimethylformamide (DMF) or dimethylacetamide (DMA), and if necessary, a water-miscible ether can be used as an additional solvent to improve the solubility of a given 3-substituted methylcephalosporin. Suitable co-solvents are, for example, tetrahydrofuran and dioxane.

The reduction is carried out with any of the above chemical reducing agents for 6-2 hours at a temperature of about 0-60 ° C. The preferred reaction temperature turns out to be between about 15 ° C and + 5 ° C.

When the amalgamated metal is used in the reductive substitution reaction, a solvent mixture containing water, an alcohol such as ethanol and dimethylformamide is used. If zinc or a metal pair is used, a suitable solvent mixture includes water, a water-miscible co-solvent such as tetrahydrofuran, dimethylformamide and an acid such as formic acid.

The preferred chemical reducing agent for the present process is zinc in the presence of an acid. Acids used with zinc include dilute aqueous solutions of mineral acids, such as 0.5 ~ 5 # hydrochloric acid and sulfuric acid solutions, or a carboxylic acid having a pKa of less than b, 0, such as formic acid, chlorinated acetic acids, such as mono-, di-, or trichloroacetic acid. . The recommended acid is formic acid.

As mentioned above, the chemical reduction is performed in the presence of dimethylformamide or dimethylacetamide. The amount of DMF or DMA used is not critical, provided that it is present in a catalytic amount corresponding to at least about one weight percent of the amount of reducing agent used. However, in some cases it is preferred to use larger amounts of DMF or DMA to improve the solubility of the starting material.

The chemical reducing agent is preferably used in excess. For example, the recommended reducing agent, zinc, is used in a 2 to 10-fold excess.

Accordingly, the acid used with the reducing agent is preferably used in excess.

The reductive displacement reaction can be performed on 3-substituted methylcephalosporin as the free acid or a salt or ester thereof. However, if the carboxylic acid protecting group is an acid labile ester or anhydride group and a preferred chemical reducing agent, zinc, is used in the presence of formic acid, the labile ester may decompose to form the 3-methylene cepham of formula I as the free acid.

If in formula III represents an ester group protecting a carboxylic acid, such as p-methoxybenzyl, and the hydrogenation is carried out with Raney nickel, the ester group remains essentially unchanged. during the reductive substitution reaction. A similar result is obtained if zinc and formic acid are used. However, if palladium is used as such or with a support as a hydrogenation catalyst, with substituted benzyl, considerable hydrogenolysis of the ester group can occur, especially when the reductive substitution reaction is carried out at elevated temperatures.

Similarly, if it is desired to prepare a 3-methylenecepham-U-carboxylate of formula I wherein R 1 is a carboxylic acid protecting group which tends to decompose in a reductive displacement reaction, an unprotected 3-methylenecepham-1-carboxylic acid carboxylic acid then the reaction product can be isolated and then protected by esterification with the desired ester group, or the mixed anhydride with acetic or propionic acid can be prepared by methods known per se. For example, 3-ethoxythionocarbonylthiomethyl-7-amino-N-cephem-N-carboxylic acid obtained by reacting 7-aminocephalosporanic acid (7ACA) with ethyl xanthate can be hydrogenated in the presence of Raney nickel to give 3-methylene-7-aminoc * primeval-1 -carboxylic acid. The cepamic acid is then esterified by known methods to give the desired ester of formula I.

Compounds of formula III in which -SO 2 M + represent a reductive displacement reaction under catalytic hydrogenation conditions, preferably in the presence of Raney nickel, to give 3-methylene cepham of formula I in satisfactory yields. However, if the reductive substitution reaction is performed under acidic reduction conditions, such as zinc in the presence of formic acid and dimethylformamide, only minor amounts of 3-methylenecepham-U-carboxylic acid or its ester are formed.

6 59104

In the preparation of β-methylene-T-aminocepham-β-carboxylic acids, esters and salts of formula I by the above reductive substitution reaction. . 3 is usually formed as by-products of the corresponding isomeric 3-methyl-7-amino-A-cephem-t-carboxylic acids, esters or salts and in some cases the corresponding 3-methyl-4i-cephem isomer.

3

The mixture of reduction products containing 3-methylene cepham and 3-methyl-A and 2 Δ-cephem acids, esters or salts can be chromatographically fractionated with a suitable absorbent to separate isomeric reduction products. Chromatographic absorbents such as silica gel and alumina can be used to separate the components. Alternatively, the reduction product mixture may be fractionated into its corresponding isomers by fractional recrystallization or preparative thin layer chromatography according to methods known per se.

The 3-methylene cephalosporins of this invention have relatively low antimicrobial activity. However, they are valuable intermediates in the preparation of deacetoxycephalosporin antibiotics with potent antimicrobial activity.

Conversion of 3-exomethylene-substituted cephalosporins to the isomerized 3-bis 3-methyl-7-amino-A-cephem-U-carboxylic acids is shown in the accompanying simplified reaction scheme.

1JH _-- N ^ HH, · -, - ------ N

2 i - ^ 2 | j M 1 = CHq J_________M —chr

/ ““ Γ 'Y

C00R ·, C00R ·, where R ^ has the same meaning as above.

The isomerization is carried out by mixing 3-methylenecepamic acid or an ester thereof prepared from a 3-substituted methylcephalosporinic acid or ester by a reductive substitution reaction with an aprotic solvent having a high dielectric constant and a strongly basic tertiary organic amine. Aprotic solvents that can be used in the isomerization process have a high dielectric constant; such as dimethyl sulfoxide, dimethylacetamide and dimethylformamide. Preferably dimethylacetamide (DMA) is used.

The amine is preferably used in excess of the amount of the 3-methylene cepham compound, but even a smaller amount is sufficient for the necessary isomerization. In several cases, the isomerization proceeds satisfactorily with the addition of a few drops of amine as a catalyst to the reaction mixture.

The isomerization is preferably carried out at room temperature and has been found to proceed rapidly in the temperature range of about 20 ° C to 35 ° C. However, the isomerization mixture is usually stirred at room temperature for about 12 hours to completely isomerize the double bond from the exo position to the endoacerase.

The compounds of formula I are valuable intermediates in the preparation of deacetoxycephalosporin antibiotics, for example cefalexin.

A particularly useful compound of formula I in the preparation of the 7-aminodesacetoxycephalosporanic acid backbone is the trimethylsilyl ester of 7-aminocepham-1 + -carboxylic acid substituted with 3-exomethylene (R.j = trimethylsilyl). In this case, a trimethylsilylating agent such as N- (trimethylsilyl) acetamide or bis-trimethylsilylacetamide is added to the suspension of 3-methylene-7-aminocepham-1 + carboxylic acid and acetonitrile with stirring to form a trimethylsilyl ester. When an ester is formed, a solution is obtained. A tertiary organic amine such as triethylamine is then added to isomerize the double bond from the exo position to the endo position to give a trimethylsilyl ester solution of 7-ADCA. The solution is diluted with water and the pH is adjusted to about 3.5 to hydrolyze the trimethylsilyl ester of 7-ADCA to form a crystalline precipitate of 7-ADCA.

7-ADCA is filtered off and can then be acylated with a desired acyl group, for example an amino-protected phenylglycine acyl group, to give cefalexin as an antibiotic.

Alternatively, the acylation can be performed on the trimethylsilyl ester of 7-ADCA in situ followed by recovery of the trimethylsilyl ester of cefalexin. The ester is hydrolyzed with water to give cefalexin. The acylation of 7-ADCA with an amino-protected phenylglycine, for example (N- (t-butyloxycarbonyl) -phenylphenylglycine, can be carried out according to methods known in the art for acylation.

The following examples further illustrate this invention (Example 2 illustrates the preparation of the final product).

Example 1 3 11 g (31 mmol) of the sodium salt of 3-ethoxythionocarbonylthiomethyl-7-amino-A-cephem-1 + -carboxylic acid were dissolved in 260 ml of 5- [mu] l of sodium bicarbonate solution, 1 + 0 ml of ethanol was added to the solution, and the solution thus formed was hydrogenated for 12 hours at room temperature under 3.2 atm of hydrogen pressure using 66 g of Raney nickel as a catalyst. The reaction mixture was filtered to separate the catalyst, and the filtrate was cooled in an ice bath and acidified to pH 8 59104 with 3.5 concentrated hydrochloric acid. The precipitated unreacted starting material (ca. 2.2 g) was filtered off and the filtrate was evaporated in vacuo to a small volume. The crude reaction product precipitated from the concentrate, which was then filtered. The crude reaction product was crystallized from water to give **, 5 g (85% yield) of pure 3-exomethylene-substituted 7-aminocepham-U-carboxylic acid.

The nuclear magnetic resonance spectrum of the product in dimethyl sulfoxide Dg had the following signals (7-values): 6. h9 {g, 2H, H 2 H), 5, k 6 (d, U 1, C 6 H), 5.07 (s, 1H, C * +, 80 (broad s, 3H, CH 2 and C 2 H) and U.13 (broad s, absent in the presence of D 6 O).

The mass spectrum peaked at 21 U m / e, corresponding to Cq H 2 qN 2 O 2 S with a calculated molecular weight of 21 U, 2.

The infrared spectrum had peaks at 5.65 (β-lactam) and 6.1 (carboxylate).

Elemental analysis for C 9 H 7 N 2 O 2 S: Theory: C i + U, 85 H U, 70 N 13.08 Found: C ** 5.12 H * +, 73 N 13.11

In a similar manner, p-methoxybenzyl 7-amino-3-exomethylenecepham - ** - carboxylate and p-nitrobenzyl 7-amino-3-exomethylene-cefam - ** - carboxylate were prepared. Both compounds were isolated and characterized as the hydrochloride disalt and the p-toluenesulfonic acid salt (tosylate salt).

Characterization of β-methoxybenzyl-7-amino-3-exomethylene cefar - ** - carboxylate hydrochloride:

Elemental analysis calculated for C 9 H 18 N 2 O 2 O 5 SO 3: Theoretical: C, 51.82; H 5.16; N 7.55 Found: C 51.65; H 5.0U; N 7.72

Melting point> 165 ° C (dec.), Crystallized from methylene chloride, ethanol and diethyl ether.

NMR (δβΟ Mc, DMSO-d 6) δ 6. ^ + 7 (s, 2H, C-2H 2), 6.23 (s, 3H, p-OC 2), 5.12 (d, 1H, C-6H ), 1 *, 9 - **, 6 (m, 6H2, C - ** H, ester CH2, C-3 CH2, and C-7H), and 2.86 (q., UH, aromatic H) p Characterization of -methoxybenzyl 7-amino-3-exomethylenecepham - * + - carboxylate p-toluenesulfonate:

Elemental analysis calculated for C 23 H 26 N 2 N 2 O 2: Theory: C 5 ** 53; H 5.17; N 5.53 Found: C 5 * +, 33; H 5.05; N. 3H, p-OCHg), 5.0 (d, 1H, C-6H), **, 85 - * +, 55 (m, 6, C - * + H, ester CH2, C-3 CH2 and C- 7H), and 3.2-2.2 (2q, 8H, aromatic H).

Characterization of 59104 p-nitrobenzyl-7-amino-3-exomethylene cepham-U-carboxylate hydrochloride:

Elemental analysis calculated for C 11 H 15 N 2 O 2 SCl: 151035 Theoretical: C, 6.69; H U, 18; N 10.89 found: C U6, U0; H U, 20; N 10.62 NMR (Δ60 Mc, DMSO-d 6) δ 6.3 U (ABq, 2H, C-2 HO), U, δ6 (d, 1H, C-6l (), h, 7-h, k ( m, 6h, C-1 + H, ester CH 2, C-3 CH 2, and C-7H), and 2.0 (q, cl, aromatic H) Melting point 160-176 ° C (dec.) »crystallized methylene chloride, ethanol and diethyl ether.

Characterization of p-nitrobenzyl 7-amino-3-exomethylene cephane-4-carboxylate p-toluenesulfonate:

Elemental analysis calculated for C 22 H 23 N 3 O 8 S 2: Theory: C, 50.66; H 14.1 + 5; N 8.06 found: C 50.1 + 1; H 1 +, 51; N 7.86 NMR (δ6θ Mc, DMSO-d 6) T 7.70 (s, 3H, p-CH 2), 6.39 (s, 2H, C-2 Hg), 1 +, 98 (d, 1H, C -6H), 1 +, 7-1 +, 3 (m, 6h, C-1 + H, ester CHn, C-3 CH2, and C-JH), and CC

2.95-1.68 (2q, 8H, aromatic H).

Melting point 11 + 5 ~ 1820 ° C (dec.), Crystallized from ethyl acetate and ethanol / diethyl ether.

Example 2

To a suspension of 1 g of 3-methylene-7-aminocepham-1 + -carboxylic acid and 20 ml of acetonitrile was added, with good stirring, 3 g of N- (trimethylsilyl) acetamide. To the resulting solution was added 3 drops of triethylamine, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water, and the pH of the solution was adjusted to 3.5 with hydrochloric acid. The reaction product, 3-methyl-7-amino-Δ8-cephem-1 + carboxylic acid (7-ADCA), formed as a crystalline precipitate from the acidic reaction solution.