FI63034C - SAOSOM MELLANPRODUKT VID FRAMSTAELLNING AV CEFALEXIN ANVAENDBAR FOERENING HETACEFALEXIN - Google Patents

Description

[B] (11) RELEASE PUBLICATION Ma L J V 'UTLÄGGNINGSSKRIFT O O U 0 4 ^ (45) ΐ'ΰ. t Li isyoiiiit- ^ ly il j4 1933 yT | fl Patent cieddelat ^ T ^ (51) K ».ik.3 / k» t.ci.3 C 07 D 501/58 FINLAND — FINLAND pi) PHwttiM ^ -riMMM ^ T92T91 * (22) 07.09.79 v 7 (23) AlkupUv · —CIM | lMtadag 13.07-71 (41) Tullut lulldtalni - MMt off «Kllg 07.09.79 MMtl. j, Nkitt ^ bdllt »(44. NjMvUulptM ·„ toMIriU »,

Patent- och r * gi * t «rstyr« lMn 'AmMcu uthgd och utUkrtftan pwMicarad 31.12.82 (32) (33) (31) Requested * tolik «u * —Mftrd priority 05.10.70 USA (US) 78165 (71) Bristol-layers Company, 3 ^ 5 Park Avenue, New York, NY, USA (72) William Joseph Gottstein, Fayetteville, New York,

Lee Cannon Cheney, Fayetteville, New York, USA (US) (7 * 0 Oy Kolster Ab (51+) Compound used as an intermediate in the manufacture of cefalexin, hetakefalexin - Säsom mellanprodukt vid framställning av Cefalexin användbar förening, hetacefalexin (62) 71 (patent 5Ö133) -Avdelad frän ansökan 1993/71 (patent 5Ö133)

The present invention relates to a compound used as an intermediate in the preparation of cefalexin, hetakefalexin, i.e. 7- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) -3-methyl-3-cephem-4-carboxylic acid of formula O — Η / ητή =,

I / J-Ns / - ^ II

\ / O I

^ c COOH

CH3 ^ ch3 and salts of this compound.

\ 63034

Cefalexin is the generic name for 7- (oE-aminophenylacetamido) -3-methyl-3-cephem-4-carboxylic acid of the formula β \

(/ y-CH - c - NH - {N

_ L 3

Wil2 O I

COOH

Cefalexin is an antibacterial agent derived from 7-deacetoxycephalosporanic acid (7-ADCA) and described, e.g., in J. Med. Chem., 12, 210-313 (1969), engl. U.S. Patent 1,174,335, South African Patent 67/1260 (Farmdoc 28,654), Japanese. in Patent 16871/66 (Farmdoc 23231), Belgian. in Patent 696,026 (Farmdoc 29494).

A method for preparing hetakefalexin is described in Finnish Patent Publication 58,133.

Conversion of the penicillin sulfoxide ester (by heating in the presence of a strong acid) to the corresponding ester of the corresponding N-acylated derivative of 7-ADCA is described in U.S. Patent 3,275,626 and J. Amer. Chem. Soc., 85, 1896 (1963) and 91 (6), 1401-1407 (1969). Variations of this method are disclosed in Dutch Patent Publications 68/06532 (Farmdoc 34,685) and 68/06533 (Farmdoc 34,686). In such patents, the side chain is usually the side chain of a fermentable penicillin, such as penicillin G or V (see column 7 in U.S. Patent 3,275,626), and the product is an ester that must be cleaved, e.g., by hydrogenation to form the active free acid of the final derivative of 7-ADCA. Example 3 of British Patent 1,174,335 illustrates the application of this "sulfoxide rearrangement" to an ester of ampicillin sulfoxide in which the QC amino group is also protected, i. 6- [N- (2,2,2-Trichloroethylcarbonyl-D-O (-amino-6-phenylacetamido) -penicillanic acid sulfoxide-2,2,2-trichloroethyl ester by heating followed by zinc and acetic acid to remove the two protecting groups and cefalexin form ..

The prior art encompasses numerous other descriptions of penicillin sulfoxy 3,63034 and their preparations, such as those described in Chow et al., J. Org. Chem, 27, 1381 (1962), Guddal et al., Tetrahedron Letters No. 9, 381 (1962), Essery et al., J. Org. Chem., 30, 4388 (1965), which also includes ampicillin sulfoxide, and U.S. Patent 3,197,466.

The reaction product of acetone with cephaloglycine but not cefalexin is described in U.S. Patent 3,303,193. The reaction of certain ring-substituted cephalexins with acetone is described generally in U.S. Patents 3,489,750, 3,489,751 and 3,489,752.

A disadvantage of these methods for the preparation of cefalexin is the need to perform a series of reactions to replace the original side chain when initiating penicillin, e.g., penicillin V is used as a starting material, and the need to first remove and then for a carboxyl group.

Thus, it has now been found that cefalexin can be prepared by A) protecting the 3-imino group of a compound of formula

O

f / \ "Cli3 \ / iB — c> - ^

\ - 1H-N2-CH3-N-COOH

ch3 °

III

by nitrosation or formylation to form an intermediate of formula

Or-l-wV ·? N- 'Z-N _ C ^ |

I ^ CH3 \ -. N - * - COOH

ch3 o

IV

4,63034 wherein Z is nitro or formyl; B) oxidizing said intermediate or a salt thereof with an intermediate sulfoxide of formula ϊ / -3 c> n-TT3

I ^ H3 J- n-L C00H

To form CH3 or a salt thereof? and, if desired, protecting the carboxylic acid group of said sulfoxide by a method known per se to form a sulfoxy di intermediate of formula / ta_ ·? ch3 \ _ / I '' n— | - | ^ S ^ ch3 vi

Z-N 2 Cl 2

| ^ CH3 i-N - COOB

ch3 σ wherein COOB is a protected carboxyl group and Z is as defined above; C) heating said sulfoxide intermediate in an inert organic solvent in the presence of an acid catalyst to form a Cephalosporin intermediate of formula

Ot ^!> -I — τ'ί N <(> vCH3 J- CH3 ° T CH3

X

5,63034 wherein Z is as defined above and X is COOH or COOB, or to form a salt thereof; and, if desired, removing the carboxyl protecting group by a method known per se; and D) cleaving off the imino protecting group to form a product of formula ch — I - * —-— ^ / 0 ^ -Ν \ ^ οη3 11

CH 2 Cl 2 CH 3 C 10 H

or a salt thereof; and E) hydrolyzing said product with a compound of formula f ~ \ 1 / S ^

(f y— CH - C -NH --p J

NH2 ^ - n - CH3

COOH

or to form a non-toxic pharmaceutically acceptable salt thereof.

Suitable salts include, for example, (1) salts of an acidic carboxylic acid group such as sodium, potassium, calcium, aluminum and ammonium salts and substituted ammonium salts of amines such as tri (lower) alkylamines, proxin, dibenzylamine, N-benzyl -beta-phenylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, dehydroabietylamine, N, N'-bis-dehydroabiethylethylenediamine, N- (lower) alkylpiperidines such as N-ethylpiperidine and other amines which used to form salts of benzyl penicillins * and (2) acid addition salts (e.g., basic nitrogen salts) such as (a) mineral acid addition salts, 63034 6 such as hydrochloride, hydrobromide, hydroiodide, sulfate, sulfamate, sulfonate, phosphate, etc. salts and b) organic acid addition salts such as maleate, citrate, tartrate, oxalate, succinate, benzoate, fumarate, malate, mandelate, ascorbate, β-naphthalenesulfonate, p-toluenesulfonate - and similar salts. Hetakefalexin is converted to cefalexin by either acidic or basic hydrolysis.

The following examples illustrate the present invention. All temperatures are in degrees Celsius. "Skellysolve B" is a petroleum ether fraction having a boiling point of 60-68 ° C and containing substantially n-hexane.

Example 1 7- (D-2,2-Dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) -3-cephem-4-carboxylic acid (hetakefalexin) to 1 g (0.0025 moles) of 7- (D -2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-1-imidazolidinyl) -3-methyl-3-cephem-4-carboxylic acid in 50 ml of dioxane (purified by passing through an alumina column), dry hydrogen chloride is added for 5 minutes at room temperature. The solution is evaporated at 30 ° C (15 mm) to a gum which is slurried with ethyl acetate and collected. The material is then dissolved in water (50 mL) and basified to pH 0.8 with aqueous sodium bicarbonate solution. The mixture is filtered and the filtrate is evaporated at 30 [deg.] C. (15 mm) to a glass which is dried by azeotropic distillation with ethyl acetate. The yield of the sodium salt is 600 mg; the product is prescribed and is the sodium salt of 7- (D-2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) -3-methyl-3-cephem-4-carboxylic acid (hetecephalexin); mp. 205 ° C with decomposition.

Analysis for C 18 H 28 N 2 O 2 SNa. 1 ^ 0:

Calculated: C, 53.39; H, 5.19; N, 9.83 Found: C, 53.63; H, 5.00; N, 9.76. 1 ^ 0, 4.30 (Karl Fischer) IR (KBr); 3600-2600 cm-1 (HO, NH, CH, CH, and CH'S) 1760 cm-1 -1 (β-lactam carbonyl), 1690 cm (amide carbonyl), 1590 cm (carboxylate carbonyl and C = C) .710 cm mono-substituted phenyl.

NMR (100 MHz) 20 mg sample in 0.4 ml D 2 O with 2 drops of 0.1 N HCl; chemical shifts in ppm from TSP; 7.52 (S, 5H's monosubstituted phenyl), 5.71 (IS, 1H, CH-N), 5.28 (AB, 2H's β-lactam CH1 S), 3.48 (AB, 2H's, S-CH2-C =) s 2.26 (S, 3H'S = C-CH3), 1.88 and 1.80 (two S's, 6 H's (CH3)).

Claims (1)

7 63034 * 7- (D, N-aminophenylacetamido) -3-methyl-3-cephem-4-carboxylic acid (cefalexin) Dissolve about 200 mg of hepathexalex sodium in as little water as possible (about 1 ml), acidify to pH 4-5 with acetic acid. and allowed to stand at 5 ° C overnight. The crystalline material is collected, washed with water and finally with acetone to give, after drying at room temperature (15 minutes), using? 2 ° 5 ^ 0 m <3 of crystalline cefalexin, m.p. At 195 ° C with decomposition, the NMR and IR spectra are identical to those of authentic cefalexin. A compound used as an intermediate in the preparation of cefalexin, hetakefalexin, i.e. 7- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) -3-methyl-3-cephem-4-carboxylic acid of formula CH-1 - N-1-f S "1/0 ^ - N \ ^ CH3 ch3 ^ C ^ ch3 cooh and its salts.