LU81842A1 - PRODUCTION OF CEPHALOSPORINS - Google Patents

Description

D. ** · '.' 3 r

———- - G r:. \ N D -DUC HÉ DE LUXEMBOURG

Br "" K · U ...... i 0 4 J) du. 31- οΟ νΟ’ΟΓΟ ^ 1979 Minister n .. ... ί ^ ί * §> ϊ of the National Economy and the Middle Classes

Industrial Property Service

~ 7 '’LUXEMBOURG

.Φ m- w / f fv patent application request I. Request .... La - & ociâtê ..- di-ta.t ..... B3ISîûJ>: îY £ 3S ..... COIGAÎiY -r ...... M5 .... Park ..Avenue / .... .1 ........ ai ... i.YORK -, ..... ΐϊ ·, · Υ. „...... loo22, ..... United States, .d Vkriéx-icnae ..... represented ..by -Koasiau-r - J-acqu-es-de- .. tëuyssr., .... acting .. on ..... quality ..... of ... agent (2) * deposit ........ this ..... fcxenfcC ~ ôt ” Uil ..... QCtOtXG ..... 1.9GO ..... S.OiX.an.te ”diX” nouf ...... (3) i à ......... 15 ............. hours, at the Ministry of National Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for invention : ..... "Prodestio-n ···· 4a ..... cephalosporins." ........................... .................................................. ................................................

// ï ^ / pé / s ^ ÿî '/ t / 1 ^ ~ Μ ^ ΰ £ ^^ ~ ΰί ^^ 7 i ..................... .................................................. .............. (5) 2. the delegation of power, dated NEW “YQBK ..................... ...... on .3.0 P.ÇtobrG l979 3. description in language .......... english ................... .............. of the invention in two copies; 4 .............. // .......... drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office on 31 ..... Gcfcobre .... l & 79 ..................... .. ................................................ .................................................. ................. — ................................ ..........

claims for the above patent application the priority of one (or more) application (s) ......................... patent. ........................................... filed in / 1 ^ ........ ai2x .... E.fca.fcs_ ~ ïlPis ... dtABfôrigûe ............._ le ......... .... 19 ..... March ..... 1979 ........... (Sa »..... 25511) ............ .................................................. .................................................. .............................. (Sj on behalf of ....... s ..... inventors. .................................................. .................................................. .................................................. (9) v - elect domicile for him / her and, if designated, for his / her representative, in Luxembourg _________________________________ ........ 35-r ...... bld ...... Royal. ......................................... eu "._ requests the issue of an invention patent for the subject described and represented in the abovementioned appendices, - with postponement of this issue to ..... ........ fi ............................... month.

\ t *. | -r, .7.Luatàlre \ .......... t ........ 4_ l ...... \ ...... \ .. ...

-.J \ J \ J

II. Deposit Minutes

The above application for a patent for invention has been filed with the Ministry of National Economy and the Middle Classes, Industrial Property Service in Luxembourg, on: ......... Pr. the Minister at] ^ 5 am / \ of the National Economy and the Middle Classes, /; p. d.

mr \ J

^ A CS007 D.> o. 868

CLAIM OF PRIORITY

S 'mm 1 11 a * —1—! · 1'ΜΙ · »·>» · Ι · Ι1 · »··· Ι.Ι Ml I

of the patent application / d ^ / i / odéjé / çl'ytÎW /

* Eh / In THE UNITED STATES OF AMERICA

March 19, 1979 Brief Description filed in support of a request for

PATENT

at

Luxembourg

in the name of: BRISTOL-MYERS COMPANY

for: "Production of .cephalosporins".

DESCRIPTIVE MEMORY

FILED IN SUPPORT OF A REQUEST FOR

PATENT

FORMED BY

BRISTOL-MYERS COMPANY for

Cephalosporin production, f

The present invention relates to a new process for the production of antibacterial agents belonging to the class of cephalosporins or of intermediates suitable for this production.

Numerous "patents describe the production of cephalosporins by reaction of a silylated nucleus [for example of 7-aminocephalosporanic acid or of 7-aminodeaceto-xycephalosporanic acid]. With a side chain acid in the form of its chloride. acid. When this acid contains

CD. IB .GP. 6 SY-16UB

i * a free amino radical, the latter is preferably protected, for example by protonation, and is thus used to produce cephalexin, for example, 2-phenylglycyl chloride hydrochloride. The carboxyl radical in position 4- of the nucleus can be blocked by silylation or esterification. Some examples of these patents are U.S. Patents No. 3.67IW, 3-694-.4-37, 3-74-1.959, 3-957-773 3-965-098, 4-.051 -131 and English patent n ° 1.073-530. Often, the acetoxy radical in position 3 of 7 - ^^ 0-cephalosporanic acid is displaced before acylation by a heterocyclic thiol, as in the case of ceforanide (United States Patent No. 4-. 100.34-6 also describing the prior art), cefatrizine (United States patent No. 3-867-380), cefaparole (United States patent No. 3- 84-1.021), cefazolin (United States patents No. 3-518-997 and 3-819-623) I and cefazaflur (United States patent No. 3.828.037) in particular , as well as by means of other thiols mentioned in the patent of the United States of America n ° 3-928.338.

The subject of the invention is therefore a compound of formula:

0 H H

(J §! (CH ^ Si-O-C-MH-J—

V

X0-A

ï, where B represents a chlorine atom or a methoxy radical or -CHgE;

A represents a radical (CH ^^ Si- or an esterifying radical Λτ \ ™ nn η o SY-1 6llB

easily removable protector, which is preferably chosen from benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, ^ -i ^ danyl, 3 ~ phthalidyl, pivaloyloxy-methyl, acetoxymethyl and l radicals - [(ethoxycarbonyl) oxy] ethyl, and E represents a hydrogen atom or a radical. 0 ^ 0 - .. 0-, NELjC ..... · "- 0- or -SZ, where Z represents a pentagonal or hexagonal aromatic heterocycle, but preferably pentagonal, comprising two, three or four nitrogen atoms and zero or an oxygen or sulfur atom, which heterocycle optionally carries one or two substituents, but preferably a substituent * chosen from atoms, halogen and alkyl radicals, preferably methyl, C 1-6 alkoxy C ^, cyano, nitro, C ^ -C ^ cyeloalkyl, trifluoromethyl alkenyl, di (C1-Gî + alkyl) amino, phenyl, benzyl, alkoxyalkyl i up to G ^, -COOSiCCH ^) ^ and - (Cïïg ^ COOSiCCH ^) · ^, where n represents 1, 2 or 3 but preferably 1, the sulfur atom of the radical -SZ- being united to a carbon atom of the heterocycle Z and the heterocycle aromatic being preferably triazole, tetrazole, oxadiazole or thiadiazole.

Particular preferred compounds forming the subject of the invention are those in the formula of which A represents a radical (CH 2) 4 Si and E represents

0 I N-N H-S N-N

H, -OC-CH ^ * 0 ^ C KEî2> S -V '-s - ^ S> -CH5' -s “V · CEj NN HN-N NN 0, -S — Hs> or S- ^ gll- cHgb-OSifCH ^ CHgC ^ O-SitCH,) The subject of the invention is also the process for producing a compound of formula:

0 HH

He has ! q (CH ^ jSi-O-C-HH — ί- 0 L ° <

X) -A

where B represents a chlorine atom, or a methoxy radical or -CH2E; A represents a radical (CH ^) ^ Si- or an easily esterifying protective radical: -0. E represents a hydrogen atom or a radical C £ LC 0-, 3 ïïïï2C ——0 - or -SZ, where Z represents a pentagonal or hexagonal aromatic heterocycle comprising two, three or four nitrogen atoms and zero or an atom of oxygen or sulfur, which heterocycle optionally carries one or two substituents chosen from halogen atoms and alkyl and C - ^ - 0 ^ radicals, C ^ -C ^ alkoxy, cyano, nitro, C cycloalkyl ^ -C ^, Cp-G ^ alkenyl, trifluoromethyl, Gth alkylthio - ^ - C ^, di (C ^ -0 ^ ^) amino, phenyl, benzyl, alkoxyalkyl up to 0 ^, -GOOSi (CH ^) ^ and - (0Η2) η0008ΐ (σΗ2) 2, where n represents 1, 2 or 35 the sulfur atom of the radical -SZ being united to a carbon atom of the heterocycle Z, according to which dioxide is added of dry carbon to a solution of a compound of formula:

HH

Z * = (CHj) ^ SilîH — I— 0 \ °

X0-A

where B represents a chlorine atom or a methoxy radical or -CH2E; A represents a radical (CH ^) ^ Si- or an easy-to-remove protective esterifying radical which is preferably chosen from among the benzhydroxyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl radicals, indanyl, 3-phthalidyl, pivaloyloxy-methyl, acetoxymethyl and l - [(ethoxycarbonyl) oxy] ethyl, and E represents a hydrogen atom or a CH- ^ C --0-, KO2C - 0- or -SZ radical , where Z represents a pentagonal or hexagonal aromatic heterocycle, but preferably pentagonal comprising two, three or four atoms. of nitrogen and zero or an oxygen or sulfur atom, which heterocycle optionally carries one or two substituents, but preferably a substituent, chosen from halogen atoms and C 1 -C 4 alkyl radicals and preferably methyl, alkano in cyano, nitro, cycloalkyl in C ^ -C ^, alkenyl in C ^ C ^, trifluoromethyl, alkylthio in C - ^ - C ^, di (alkyl in C ^ -G ^) amino, phenyl, benzyl, alkoxyalkyl up to C ^, -COOSi (CH3) 3 and - (CHg ^ COOSiCCH ^, where n represents 1, 2 or 3j but preferably 1, the sulfur atom of the radical -SZ- being united to a carbon atom of heterocycle Z and the aromatic heterocycle preferably being triazole, tetrazole, oxadiazole or thidiazole, in =: an anhydrous inert organic solvent, which is preferably methylene chloride, at a temperature from 0 to 100 ° C, preferably from 0 to 20 ° C, until completion of the carbonylation reaction.

In particular preferred embodiments of the process, A represents a radical (CE ^ Si, B represents a chlorine atom or a methoxy radical or -CH2E and E represents, Λ ο Ο Ν-Ν Η-jN Ν -] Η, -OC-CH ^ -OC-HHg, -S -S'-ksA-cH ^, -s-kgj · ch3

N-N HN-N N-N O

-S -, - S— ^ Jn or 'S ^ gJÎ-CHgS-OSifCHj \ // H CHgC ^ O-Si (CH ^ The invention further relates to an improved process for producing a classic cephalosporin of formula :

O H H R-C-NH-— | —N

<

uh

/ "i ° where RG- represents the remainder remaining after the elimination of the hydroxyl radical of an organic carboxylic acid of 2 to 20 carbon atoms, B represents a chlorine atom or a methoxy radical or -ch2e, E represents a hydrogen atom or a radical - CH ^ C —-0-, —— 0- or -SZ, where Z represents a pentagonal or hexagonal aromatic heterocycle, but preferably pentagonal · comprising two, three or four nitrogen atoms and zero or an oxygen or sulfur atom, which heterocycle optionally carries one or two substituents, but preferably a substituent "chosen from halogen atoms and C 1 -C 4 alkyl radicals and preferably methyl, alkoxy at C - ^ - C ^, cyano, nitro, cycloalkyl at C ^ -C ^, alkenyl at C ^ -C ^, trifluoromethyl, alkylthio at C - ^ - C ^, di (alkyl at 0 ^ -Gî +) amino , phenyl, benzyl, alkoxyalkyl up to C ^, -COOSi (CH ^) ^ and - (CÏÏ2) n000Si (CH ^) ^, where n represents 1, 2 or 3 but preferably 1, the sulfur atom of radical -SZ- being united to an atom d he carbon of the Z hetero-cycle and the aromatic heterocycle preferably being triazole, tetrazole, oxadiazole or thiadiazole, according to which, in succession, acylates by means of the acid chloride derived from this carboxylic acid organic a silylated nucleus of formula: HH "" "k °

• 0-A

where A represents a radical (CH ^^ Si- or a protective esterifying radical easy to remove, preferably chosen from the radicals benzhydryi-e, benzyl, p-nitrobenzyl, p-methoxy-benzyl, trichloroethyl, phenacyl, acetonyl, methoxymé- thyle, 5 “in.danyl, l - [(ethoxycarbonyl) oxy] ethyl, 3-phthalidyl, pivaloyloxymethyl and acetoxymethyl, and B has the meaning given to it above, then the radical A is converted into an atom d hydrogen and, if desired, remove any protective radicals at A and B, characterized in that before acylation, the silylated nucleus is converted into a compound of formula: t.

0 HH

H * 5 ς

(CH ^) 3 Si-O-C-MH —S

<

X0-A

where A and B have the above meanings, addition of carbon dioxide. dry to a solution of the silylated nucleus in an anhydrous inert organic solvent, which is preferably methylene chloride, at a temperature of 0 to 100 ° C, and preferably from 0 to 20 ° C, until the reaction is complete carbonylation.

In preferred embodiments of this process, A represents a (CH ^) ^ Si radical, B represents a chlorine atom or a methoxy radical or -CEyS and E represents,

9 9 ** - Æ. Ά p N — N

H, -O-C-CH ^ j -0-c-hh2, -s —Jà, -S-Ag ^ L-CH ^ a CH ^ N-N HN-N N-N 0

“S—, ~ S ~~ 0U SAs ^^ CH2C-OSi (CHy I / H

CHgC ^ O-SifC ^) ^

A classic cephalosporin is for the purposes of the invention a cephalosporin which has already been described in patents and scientific literature, including the summaries which appear therein.

Preparation of reagents.

The specific methods below are generally applicable to the preparation of 7 “amino-3” hetero cyclo thi ome thyl c eph-3 - em-h-carb oxylic acids.

a) Acid 7 “9Jiino-3 ~ (l-carboxymethyltetrazol thiomethyl) -3-cephem- ^ f-carhoxylic O + ^ v-r ^

Nas J1— N-CH2C02Na () J-4VJ- CHj-O-Ü-CHj

0O2H

V

. h ^ nt / s1 ch2 ^ s-ü — n-ch2co2h C ° 2h 1. It is introduced into a 3-necked hallon provided with an agitator, a temperature regulator, a thermometer and a tube d admission of nitrogen, 18 g (0.066 mole) of 7-aminocephalosporanic acid (which was preferably recrystallized according to the toluenesulfonic acid method) and 300 ml of 0.1 M phosphate buffer with a pH of 6, h (20.7 g of sodium phosphate, monobasic mofiohydrate and 8.5 g of anhydrous dibasic sodium phosphate, plus water in sufficient quantity to make 2 liters).

2. While stirring the mixture described in 1, 1.5 g of sodium bisulfite and 16 g (0.078 mole) of disodium 1-carboxymethyl-5-mercaptotetrazole are added.

3. Continuing stirring, nitrogen is bubbled through the mixture for 10 minutes.

h.- While stirring and sparging with nitrogen, the suspension is heated in 20 minutes to 56 ° C. During this time, 6.5 g of sodium bicarbonate is added little by little.

K "fïVi Λ · η4 * τ> ΰ4“ ο-η 4- Ί ία σ * Α 4-ο4- * ι r \ ir \ û4 “Ίο" Ko * r "* Kr> 4-o σ * ο d ' the temperature of the solution is maintained at 60 ° C. for hours. The pH should remain at 6.2 to 6.6.

6. The reaction mixture is cooled in an ice bath to 5 ° 0- 7 · “Or add JO ml of a 1: 1 mixture of phosphoric acid and water to the mixture or else add 1 ml hydrochloric acid concentrated to pH 2.0 to 3.0.

8.- The product is collected by filtration and the filter cake is washed with 20 ml of cold water, then 200 ml of cold ethanol.

b) 1. 2.72 g of 7-amicephalosporanic acid and 1.16 g of 5_meucapto-1-methyl-1H-tetrazole are suspended in lh ml of anhydrous acetonitrile. 0.25 g of saline boron trifluoride and diethyl ether complex is then added, which is dissolved. The solution is heated at 50 ° C for 2 hours to ensure the progress of the reaction.

The reaction solution is cooled, 1 h ml of water is added thereto and the pH is adjusted to h 0 with aqueous ammonia, under cooling by means of ice. The deposited crystals are collected by filtration and washed with 5 ml of water, then 5 of acetone, after which they are dried to obtain 3.0 g (91.5% yield) of 7-amino-3 acid. - [5 “(l“ methyl-1,2,3 Λ-tetrazolyl) thiomethyl] - Δ ^-cephèm-h-carboxylic, melting at 22b - 226 ° G with decomposition.

2. The replacement of the saline complex of boron trifluoride and of diethyl ether used in 1 above with the other saline complexes of boron trifluoride below gives the following results: No. Saline complexes of trifluo- Quantity Conditions Kende -bron boron (BE- content, reaction _ __%) _ 1_ _ _ _ 1 Acid saline complex - 6.8 g 50 ° C, 2 h. 82.5% tick (approximately hO%) 2 Phenol salt complex 10.9 g 50 ° 6, 2 h. 77.5% (about 25%) 3 Saline complex of di-butyl ether (about 3H%) 6.0 g 5 ^ 0 0.2 h. 88.7% 4 Saline complex of acetic acid 2, ½ g 0-5 ° C, 8 h 90.5% 3. The replacement of acetonitrile by propio-nitrile in 1 above, brings the yield to 87.8%.

The replacement of acetonitrile by sulfo-lane in 1 brings the yield to 90.5% on condition that the reaction is continued for 10 hours at 20 ° C.

5 · “Operating as in 1, but adding 1.25 ml of 12 N hydrochloric acid to the reaction solution, continuing the stirring for 2 hours under cooling in ice and collecting the crystals by filtration. deposited and washed with 2 aliquots of 5 ml of acetone before drying, 3.20 g (88% yield) of the hydrochloride 7 “amino-3- [5 ~ (l ~ methyl- l, 2,3, ^ - tetrazolyl) -thiomethyl] - Δ ^-cephèm-h-carboxylic, melting at 18½ - 186 ° C with decomposition.

c) By operating as in b above, the 5 “mercapto-l-carboxymethyl-1,2,3 ^ -tetrazole is converted into 7-amino-3- [5“ (1 “Carboxymethyl-1,2, 3 ^ -tetrazolyl) thiomethyl] -céph-3-èm- ^ carboxylic melting at 183 ° C with decomposition.

By operating in the same way, but by replacing the above thiol with equimolar quantities of the following thiols, the respective products corresponding to the formulas indicated are obtained:

Thiol Product of formula H2NJT / ^ ch2-s-z

COOH

z = methylmercaptan methyl ethylmercaptan ethyl butylmereaptan butyl pentylmercaptan pentyl logo CNRS logo INIST. 1-chloroethylmercaptan 1-chloroethyl 2-bromo ethylmercaptan 2-bromo ethyl 2- nitroethylmercaptan 2-nitroethyl 5-nitropentylmercaptan 5 ~ nitrop entyl 3 ~ cyano-n-propylmercaptan 3-cyano-n-propyl b- (dimethylamino) -n-butyl - b- (dimethylamino) -n-butyl mercaptan 3-chloro-2-methylbutyl- .3_chloro-2-methylbutyl mercaptan benzenethiol phenyl p-chlorob enzènethi ο1 p-chlorophenyl 2, b, 5-trichlorobenzenethiol 2,4,5 “trichlorophenyl p-bromobenzenethiol p-bromophenyl 2.5 “dichlorobenzenethiol 2.5“ dichlorophenyl p-fluorobenzenethiol p-fluorophenyl m-methoxybenzeneethiol m-methoxyphenyl p-methoxybenzenethiol p-methoxyphenyl p-nitrobenzenethiol p-nitrophenyl; 3,5î6-tetrachlorophenyl benzylmercaptan benzyl p-chlorobenzylmercaptan p-chlorobenzyl phenethylmercaptan phenethyl p-nitrob enzylmercaptan p-nitrobenzyle

Tili ol Z = p-mettLOxyTienziylmercaptan p-metlioxybenzyle 1- naplitalèn.etliiol l-naphthyle 2- naphthalenetliiol 2-naplityl 4- chloro-l-naphthalenethiol 4-chloro-l-naplityl H-nitro-1-naplitalenetliiol 4-nitro -naph.tyle 2- thienylmercaptan 2-thien.yle 3- thienylmercaptan 3 “tliienyl 2- furylmercaptan 2-furyle 3- furylmercaptan 3“ ftxyl6 6-tromo-3- “Pyridazinet] iiol 6-bromopyridaziiie-3“ yle '3 ~ pyi> idazirLethiol pyridazine-3 -yle 3-methyl-l-pheiiyl - ^ - pyTazole- 3-methyl-l-phenylpyrazol -5-yle tliiol imidazole-2-thiol imidazol -2-yle 1- metdyl -;? - nitro -2-imidazole- 1-methyl - ^ - nitroimidazol - thiol 2-yl thiazole-2-tliiol thiazol -2-yle 5- methyltliiazole-2-tliiol 5 ~ methyltliiazol -2-yl oxazole-2-thiol oxazol -2- yle 5-methyloxazole-2-thiol 5 “m © thyloxazol -2-yle 2- pyridine ^ hiol 2-pyridyle M — pyridine tliiol 4-pyridyle 5-nitro-2-pyridinetliiol 5-n.itro-2-pyridyle 3- metliyl-lp] ièiiyl-5-pyrazole- 3-niétliyl-l-pliénylpyrazol - tliiol 5-yle 2-pyrazinetliiol pyrazine-2-yle H — pyrimidinetliiol pyr imidine-4-yl 4- methyl-2-pyrimidiiietliiol 4-methylpyrimid-2-yl e 3 -methyli so thiaz ol e- 5-thio 1 3-methylisotliiazole - ;? ~ yle isotliiazole - ^ - tliiol isotliiazole - ^ - yle 1,2,3,4 H ~ tliiatriazole-5 “t] iiol 1,2,3,4-thiatriazol -J-yle 5- mercapto-3“ Biétliylt] iio-l, 2,4- 3-niétliyltliio-1, 2,4-tliia-thiadiazole diazol -5-yle T-falol Z = 5-mercapto-3-metliyl3-methyl-1,2,2 ^ - thiadiazol -thiadiazole 5-yle 2-mercapto-1,3, * 1— thiadiazole 1,3, * f-thiadiazol -2-yle 5-mercapto-2-étliyl-l, 3 2-ethyl-l, 3, ^ - tliiadiazol -5-yle thiadiazole 5-mercapto-2-n-Pu. tyl-l, 3'î1 * “2-n-hutyl-l, 3, V-thiadiazol .- thiadiazole 5-yle 5-mercapto-2-trifluoromethyl- 2-trifluoromethyl-l, 3 1,3, H-thiadiazole thiadiazol -5-yle 2- mere'apto-5 “P-chlorophenyl- 5-p-ehlorophenyl-l, 3 1,3, Μ — tliiadiazole thiadiazol -2-yle 3- mercapto-l, 2, ^ - thiadiazole l ^ V-thiadiazol -3-yl 5-ïLercapto-l-hutyltetrazole 1-butyltetrazol -5-yle 5-mercapto-l-phenyltetrazole 1-pienientetrazol -5 ~ yle 1- benzyl-1H-tetrazole-5 “thiol 1-benzyl -lH-tetrazol -5- yle 5-mercapto-1H-tetrazole ll-tetrazol -5-yle 5-mercapto-l ~ p-chlorophenyl- 1-p-chlorophenyl-1H-tetrazol - ΙΗ-tetrazole 5-yle 2- mercapto-l, 3, Μ —Oxadiazole 1,3, ^ - oxadiazol -2-yle 2-mercapto-5-piienyl-l, 3 Λ “5-phenyl-1,3, H — oxadiazol; - oxadiazole 2-yle 2-mercapto-5- ' benzyl-l, 3, * + - 5-henzyl-l, 3, ^ - oxadiazol - oxadiazole 2-yle 5-mercapto-3-ph.ényl-1,2, V- 3-phenyl-l, 2, h -oxadiazol - oxadiazole 5-yl 2-mercapto-5-etliyl-1,3,1f-5-ethyl-1,3,3-oxadiazol - oxadiazole 2-yle 2-iaercapto-5-trif luoromethyl-5-trifluoromethyl-l, 3,; 1,3, ^ - oxadiazole oxadiazol -2-yl l-methyl-5-mercapto-1,2,3-l-methyl-1,2,3-triazol - = * 'triazole 5 ~ yl l-ethyl-5 -mercapto-1,2,3-l-ethyl-1,2,3-triazol - triazole 5 ~ yle 1f-metliyl-5-mer.capto-1,2,3- V-methyl-1,2,3 -triazol - triazole 5 ~ yle 1 + -allyl-3-mercapto-l, 2,1f- ^ -allyl-l ^^ - triazol - triazole 3-yle ^ -ethyl-3-mercapt 0-1,2, ^ - V-ethyl-1,2, V-triazol - triazole 3-yl

Eh-iol Z = 3-mercapto-5-methyl-1,2,4- £ -methyl-1,2 2-triazol - triazole 3-yle 3-mercapto ~ 1,2,4-triazole 1,2,4 -triazol -3-yl 4,5-diethyl-3-mercapto-1,2,4-4,7,7 “diethyl-1,2,4-triazol - triazole 3 ~ yl l-cyclopropyl-3-mercapto 1- cyclopropyl-1,2,4-triazol - 1.2.4- · triazole 3-yle 3-mercapto-5-m.ethoxymnthyl- 5-methoxymethyl -1,2,4- 1.2.4- triazole triazol -3-yle

The preferred reagents obtained in this way are those in which the radical Z has the formula:

N - N N-N N-N N-N HN-N

-U -A.JS.-XJ,

H

N-N N— "N N N

A s JL ch2cooh, -Kÿ), - H CH3

N N N —— N N —N

-AJ · -A.J "-U

CH2COOH _ ch2ch2cooh ch2ch2ch2cooh

These different products are then used to replace the 7 £ £ Cineodeacetoxycephalosporanic acid in Example 1 below and the subsequent operations.

The acid chlorides used in the examples below can be replaced by various other acid chlorides in order to obtain conventional cephalosporins. Such a reaction is not limited to the acylation of the product of Example 2, but includes the acylation of the products obtained by the methods of Examples 1 to 8 using the thiols defined above in general and cited as an example.

Thus, the acyl halide can be chosen to introduce any desired acyl radical on the amino radical at 7 as it is conventional to do, as is apparent, for example, from United States patent n ° 3-7 ^ 1-959.

It is therefore possible to introduce specific acyl radicals, in particular, but not limited to, those defined by the following general formulas: (i) H ^ C ^ Hp ^ GO-, where Bu represents an aryl radical (carbocyclic or heterocyclic) , cycloalkyl, substituted aryl, substituted cycloalkyl or heterocyclic non-aromatic or mesoionic, and n represents, 1, 2, 3 or h. Examples of such radicals are phenylacetyl, substituted phenylacetyl, such as fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methylphenylaeetyl or hydroxyphenylacetyl; H, H-bis (2-chloroethyl) aminophenylpropionyl, thiene-3-acetyl and thiene - ^ - acetyl; substituted h-isoxazolylaeetyl and If-isoxazolylae ^ tyl; pyridylacetyl; tetrazolylacetyl or sydnoneacetyl. The substituted radicalisoxazolyl can be a 3-aryl-5-methylisoxazol - ^ - yl radical in which the aryl radical is, for example, a phenyl or halophenyl radical, such as chlorophenyl or bromophenyl. An acyl radical of this kind is the radical: · 3-o-chlorophenyl-5-methylisoxazol ylacetic.

(ii) ^ η ^ 2η + 1 ^ - '° ù n represents an integer from 1 to 7 · The alkyl radical may be in a straight or "branched chain and, if desired, may be interrupted by an atom d oxygen or sulfur or carry a substituent such as a cyano radical Examples of such radicals are in particular the cyanoacetyl, hexanoyl, heptanoyl, oetanoyl and butylthioacetyl radicals.

(iii) C ^ Hp ^ -jCO-, where n represents an integer from 2 to 7 · the radical can be in a straight or branched chain and can, if desired, be interrupted by an oxygen atom or sulfur. An example of such a radical is the allylthioacetyl radical.

(iV) Rv RU0-C-CC- ‘w

Rw where has the meaning given to it under (i) and can represent, in addition, a henzyle radical, and RY and Rw, identical or different, each represent a hydrogen atom or a phenyl, henzyl, phenylethyl or lower alfcyle. Examples of such radicals are phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxy-propionyl, 2-phenoxyhutyryl, henzyloxycarbonyl, 2-methyl-2-phenoxypropionyl, p-cresoxyacetyl and p-methylthiophenoxy-acetyl.

(v) RV u 1

RuS-C-CO- • w

Rw where Ru has the meaning given to it under (i) and can have, in addition, a henzyle radical and Rv and R.W have the meanings which were given to them under (iv).

Examples of such radicals are the S-phenyl-thioacetyl, S-chlorophenylthioacetyl, S-fluorophenyl-thioacetyl, pyridylthioacetyl and S-henzylthioacetyl radicals.

(vi) RuZ (CH2) mC0-, where Ru has the meaning given to it under (i) and can represent, in addition, a henzyl radical, Z represents an oxygen or sulfur atom and m represents 2, 3> ^ or 5- An example of such a radical is the S-henzylthiopropionyl radical.

(vii) RuCO-, where Ru has the meaning given to it in (i). Examples of such radicals are, in particular, the benzoyl, substituted benzoyl (eg aminobenzoyl), * f-isoxazolylcarbonyl and isoxazolyl- radicals. substituted carbonyl, cyclopentanecarbonyl, sydnonecarbonyl, substituted napbtoyl and naphthoyl (for example 2-ethoxy-naphthoyl), substituted quinoxalinyl carbonyl and quinoxalinylcarbonyl (for example 3-carboxy-2-quinoxalinylcarbonyl.e). Other possible substituents for the benzoyl radical are in particular the alkyl, alkoxy or phenyl radicals bearing as substituent one or more carboxyl, alkylamido, cycloalkylamido, allylamido, phenyl (lower alkyl) amido, morpbolinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, tetrahydropyridino radicals ÏT-alkyl-ÏT-anilino and their derivatives, such substituents possibly occupying positions 2 or 2 and 6. Examples of such substituted benzoyl radicals are the 2,6-dimethoxybenzoyl, 2-biphenylcarbonyl, 2-methylamido-benzoyl radicals and 2-carboxybenzoyle. When represents a substituted b-isoxazolyl radical, the substituents can be as specified in (i). Examples of these b-isoxazolyl radicals are the 3 “phenyl-5-methylisoxazol -b-ylcarbonyl, 3-o-chlorophenyl-5“ ethylethylisoxazol - ^ - ylcarbonyl and 3 “(2,6-dichloropbenyl) -5-inetbylisoxazol radicals. -4-yl-carbonyl.

(viii)

Ru-CH-C0- i where Eu has the meaning given to it under (i) and Σ represents an amino, substituted amino radical (for example acylamido or a radical obtained by reaction of an amino radical and / or of or radicals of the side chain in position 7 with an aldehyde or a ketone, such as acetone, methyl ethyl ketone or ethyl acetoacetate), hydroxyl, _ -i η η η a λ r Λ · /, -i - i I / j__ _ _ Ί cyano, acyloxy (such as formyloxy or lower alkanoloxy) or etherified hydroxyl or a halogen atom. Examples of these acyl radicals are the α-amino-phenylacetyl, α-carboxyphenylacetyl'e and 2,2-dimethyl-5- “Oxo-1 + -phenyl-1-imidazolidinyl radicals.

(ix)

Rx R ^ -Ç-CO- iz where Rx and Rz, identical or different, may each represent a lower alkyl, phenyl or substituted phenyl radical. An example of such an acyl radical is the triphenyl arb onyl radical.

(*)

Y

u 11 R-NH-C- where R11 has the meaning given to it under (i) and can represent, in addition, a hydrogen atom or a lower alkyl or halogenated lower alkyl radical, and Y represents a d atom or sulfur. An example of such a radical is that of formula Cl (CB ^) 2 ^ 1300. - (xi)

X

where X has the meaning given to it under (viii) above and n represents 1, 2, 3 or 't. An example of such a radical is the 1-aminocyclohexanecarbonyl radical.

(xii) aminoacyl, for example a radical of formula R.WCÏÏ (KÏÏ2). (CH2) nC0, where n represents an integer from 1 to 10 or a radical of formula NEL.C EL Ar (CH0) CO, where m represents zero or an integer from 1 to 10 and n represents Ο, 1 or 2, Rw represents a hydrogen atom or an alkyl, aralkyl or carboxyl radical or a radical as defined with respect to E: u above and Ar represents an arylene radical, for example p-phenylene or 1, ^ - -naphthylene. Examples of such radicals are given in English Patent No. 1.05 ^ .806. One such radical is the p-amino-phenylacetyl radical. Other such acyl radicals are in particular those, for example the δ -aminoadipolyl radical, which are derived from natural amino acids and their derivatives, such as the radical D- benzoyl- <5 -aminoadipoyle.

(xiii) substituted glyoxylyl radicals of formula Ry.CO.CO-, where represents an aliphatic, araliphatic or aromatic radical, for example thienyl, phenyl or phenyl mono-, di- or tri-substituted, the substituent (s) being, for example, a or several halogen atoms (1 *, Cl, Br or I), or methyl, methoxy, amino radicals or a fused benzene ring.

When the acyl radical which is to be introduced comprises an amino radical, it may be necessary to protect the latter during the various reaction stages. The protective radical is advantageously a radical which can be eliminated by hydrolysis without influencing the rest of the molecule, especially the lactam bond and the amido bond in position 7 · The protective radical of the amine function and the esterifying radical of the carboxyl radical in position! + can be removed using the same reagent. An advanced process involves eliminating the two radicals at the last stage of the sequence of operations. Protected amine radicals are in particular the radicals urethane, arylmethylamino (for example tritylamino), arylmethyleneamino, sulféhylamino and enamine. Enamine blocking radicals are particularly useful in the case of o-amino-thylphenylacetic acid. Such radicals can, in general, be eliminated by means of one or more reagents to be chosen from dilute mineral acids, such as dilute hydrochloric acid, concentrated organic acids, such as concentrated acetic acid, trifluoroacetic acid and "hydrogen bromide liquid at very low temperature, for example at -80 ° C. An advantageous protective radical is the t-butoxycarbonyl radical which is easily removed by hydrolysis using a dilute mineral acid, such as dilute hydrochloric acid, or preferably with the aid of a concentrated organic acid, such as formic or trifluoroacetic acid, for example at a temperature of 0 to 0 ° C and preferably at room temperature (i.e. 15 to 25 ° C) Another convenient protective radical is the 2,2,2-trichloroethoxycarbonyl radical which can be eliminated using a system such as zinc with acetic acid, zinc with formic acid, zinc with a lower alcohol or zinc with pyridine.

The ÔÔL radical can also be protected in HH ^ * form by using the amino acid halide - in the form of acid addition salt under conditions in which the amino radical remains protonated.

The acid used for the formation of the acid addition salt is preferably an acid having a pE & (in water at 25 ° C) not greater than x + 1, where x is pEa (in water at 25 ° C) carboxyl radicals of the amino acid and the acid is preferably a monoprotonic acid. In practice, the acid of formula HQ (see below) generally has a pK

cl less than 3 and preferably less than 1.

The process of the invention gives particularly favorable results when the acyl halide is a salt of an amino acid halide. The amino acid halides correspond to the formula: where E1 represents a divalent organic radical and Hal represents a chlorine or bromine atom. The salts of these amino acid halides correspond to the formula: H2N ~ R1 "C0Hal [H3N-R1-COHal] V" where R- ^ and Hal have the meanings given to them above and Q represents the anion of HQ acid, the pE of which has the value defined above. The HQ acid is preferably a strong mineral acid, for example a hydrohalic acid, such as hydrochloric or hydrobromic acid. An important amino acid halide due to the antibiotics of interest in the structure of cephems which include the radical derived therefrom is DN- (a-chlorocarbonyl-a-phenyl) methyl ammonium chloride of formula D- [PhCHCUH ^) C0C1] + C1 ~, which is hereinafter called for convenience Da-phenylglycyl chloride hydrochloride.

The cephalosporins obtained by the process of the invention and comprising the acylamido radical RUCH (M2) C0IIH-, where R11 has the meaning given to it above, can be reacted with a ketone of formula popp R. R- ^ CO, where R and RJ represent lower alkyl radicals (C - ^ - C ^) for the formation of compounds comprising, it is believed, the radical of formula:

Ru-jJHCSï- HN-Ur2 3 R-3

Compounds of this type include, in particular, hetasporin and hetacephalexin.

Mention should also be made in this connection of the acyl radicals specified in columns y to 20 inclusive of "United States Patent No. ^ .013.6 ^ 8.

When the acylation according to the invention is applied to the production of cephalosporins, the final products are isolated and purified according to the usual techniques.

The preferred acyl chlorides used for the purposes of the invention for the acylation of a compound of formula:

0 HH

H! î c (CH ^ Si-O-C-HH — i — Y '^

V

X0-A

where B represents a chlorine atom or a methoxy or -C2I2E radical; A represents a radical (CH ^^ Si- or an easily esterifying protective radical, and E represents a hydrogen atom or a radical CH ^ C-0-, 0- or -SZ, where Z represents a pentagonal aromatic heteroeycle or hexagonal, comprising - 'two, three or four nitrogen atoms and zero or one oxygen or sulfur atom, which heteroeycle optionally carries one or two substituents, chosen from halogen atoms and alkyl radicals in alkoxy in cyano, nitro, C ^ -C ^ cycloalkyl, C ^ -C ^ alkenyl, trifluoromethyl, di (C ^ -C ^) alkylthio amino, phenyl, benzyl, alkoxyalkyl up to C ^, -COOSi ( CÏÏ3) 3 and - (CH ^ COOSiCCH ^, where n represents 1, 2 or 3 but preferably 1, the sulfur atom of the radical -SZ- being united to a carbon atom of the heterocycle Z , include the following: a) 0

II

A-CH2C-C1 where A represents _ ^ CH0NHR "2 ^ XXHpNHR’ .CHqNHR1

\ _y or (m) _ ° u | T ~ jL

where R represents a hydrogen atom or a hydroxyl or methoxy radical and R 'represents a hydrogen atom or a methyl radical, and the arino radical is protected, if desired, by conventional protective radicals, in particular by particularly by protonation; D) 0

B-CH-C-C1-HCl I

nh2 where B represents R2 or (0L or "where R · *" represents a hydrogen atom or a hydroxyl or acetoxy radical and R represents a hydrogen or chlorine atom or a hydroxyl radical when represents a hydroxyl p radical or else R represents a hydrogen atom when R * - represents a hydrogen atom or an acetoxy radical; c) ΓΤ ° Ks ^ -cn2c ci; d)

he

^ 0 ^ "S“ c "clî N-OCH3 e)?

OH 0 'O

-Ns. ** II

^ ^ Vc-NH-CH-C-Cl where E represents a phenyl, ^ -hydroxyphenyl, 3 ^ -dihydroxyplienyl or cyclohexa-1, * l · -diene-1-yl radical; i) 0 0} \ Su __

25 w A

where E represents a phenyl, ^ -hydroxyphenyl, 3 dihydroxyphenyl or cycloliexa-1, Μ-diene-1-yl radical; g) çy? h - "- ci’

N- 'O-C-H

0 h) ο ο ^ VC-NH-CH-C-Cl αΧ * Η where Ε represents a phenyl, 4-hydroxyplienyl, 3, ^ - dihydroxyphenyl or cyclohexadiene-1-yl radical; i) • - R2? ο o

.fL ___ L II II

* N Xr-C-NH-CH-C-Cl kXJ K1 where E ^ represents a phenyl radical, H-hydroxyphenyl, 2 3 ^ -dihydroxyphenyl or cyclohexadiene-1 -yle and E represents a hydrogen atom or a hydroxyl radical ; at)

O

II

- F3C-S-CH2C-C1; k) f = \ î ^^ - CH2C-Clj \ 1) 0

II

NC-CH2C-C1; m) / = \ ï N v / ^ - S-CH2C-C1; n) 0

Br-CH2C-Cl; o) Η2Η ^ Ν \ S; p)

O

II

N = C-CH2-S-CH2-C-C1; <Ù “VS s.

hn-U — C-C-Cl ’

H

N-OCH3 - 2?) Γ1 I — IS ”

^ 0 ^ -CH = N-N ^^ N-C-NH-ÇH-C-Cl O R

where E. represents a phenyl, h-hydroxyplienyl, 3,4-diliydroxyplienyl or cyclohexadiene-1-yl radical; s) Λ * 8

A-N N -C-NH- (j; H-C-Cl '-' R

where A represents a hydrogen atom or an alkyl radical of 1 to carbon atoms or CÏÏ ^ SO ^ -, Σ represents an oxygen or sulfur atom and R represents a phenyl radical,. H-hydroxyphenyl, 3, * f-dihydroxyphenyl or cyclohexa-1 ^ -diene-1-yl; t) / = \ _? 8 '- * CH3 where R represents a hydrogen atom or a methyl radical; / = τη3 o -C-Cl; och3 v).

'Cf-TXLl' r2 1 2 where R and R each represent a hydrogen, chlorine or fluorine atom; w) (/

rVL

och2ch3; x) ο

B-CH-Ü-C1 "HCl I

NH

C = NH

NH2 where B represents R2

R1 - ^ - or (Qj_ on (TjL

where R ^ represents a hydrogen atom or a hydroxyl or acetoxy radical and R represents a hydrogen or chlorine atom or a hydroxyl radical when R ^ represents a hydroxyl radical or else R represents a hydrogen atom when R1 represents a hydrogen atom or an acetoxy radical; y) 0% L ,: z) \\ // ° h2S ci · Ο aa) / "Vr ^ V y — ÇH-C-C1

NH

Q-s-K

0 ΤΛ)

Cl

0_J = \ S

û = <N-CH0C-C1) = 7

Cl ce) / = V '8 ^ A-CH2-C-C1 t - dd) 0

Iv ^ JJ-ch2c ci ee)

Ah? = Ο

NHH

where B represents R2

or (Qj_ o- ITjL

where R · * "represents a hydrogen atom or a hydroxyl ο or acetoxy radical and R represents a hydrogen or chlorine atom or a hydroxyl radical when R" * - represents a ο hydroxyl radical or else R represents a atom hydrogen when R1 represents a hydrogen atom or an acetoxy radical, and R represents a hydrogen radical or a cyanomethyl radical; ff)

CO

K-CH2 (! - C1 gg) s CH2 = CH-CH2-S-CH2-C-C1 hh) ΓΥ6Η5 LA-ci

II

0 ϋ) Ο B-CH-Ü-Cl

VH

0 = C-NH-Cr

Vnh2 where B represents R2 · ° u (Ql ° u Ç3- where R ^ represents a hydrogen atom or a hydroxyl or acetoxy radical and R represents a hydrogen or chlorine atom or a hydroxyl radical when R1 represents a hydroxyl radical or R represents a hydrogen atom when R1 represents a hydrogen atom or an acetoxy radical;

/ = \ S

0 kk)

Or- ~ Oo 11) ο

II

<TY * C1 \ _ / \ ra2 and the amino radical is blocked, when the thing is desired, according to a conventional technique, in particular, in particular, by protonation; mm)

Cl * CH-Ü-C1 xr ^ ci nn)

HO

Yïi "__ ^ X ^ CHC-C1 f1" ^ 83.

0 = C-CHo-NH-C-NH-C ^ v oo)

_ s HO

xx, CH-C-C1

¥ T

0 = C-ffi A / Nv

^ AJ

NOT

frn.vn. n-p.Q _ -3-5 _ sv-iAitr pp) (ch,) 9chchqch1-ci U -, - υ 0 q.q.) <Q> -çïï-l! -Cl

Nf N-CEL J 3 NH2 in the form of the hydrochloride, if desired,

• TÎTS

J

0

II

B-CH-C-C1 ¥ o y> where B represents

r1 - ^ - or [Qj_ or | TjL

where R "^ represents a hydrogen atom or a hydroxyl radical

O

or acetoxy and R represents a hydrogen or chlorine atom or a hydroxyl radical when R1 represents a hydroxyl radical or else R represents a hydrogen atom when represents a hydrogen atom or an acetoxy radical; ss)

S

B-CH-C-C1 NH RH y — v 1 N // Ht

0 = C-CH2NH-C— (J N

where B represents R2 r1O ~ 3.1 iQl or where R "*" represents a hydrogen atom or a hydroxyl or acetoxy radical and R represents a hydrogen or chlorine atom or a hydroxyl radical when R1 represents a hydroxyl radical or "well R represents a hydrogen atom when R · * · represents a hydrogen atom or an acetoxy radical; tt) 0 il B- ^ HC-C1

fn OH

N N-CHO N ^ where B represents R2 ° u (PjL or Ç3- where R ^ represents a hydrogen atom or a hydroxyl or acetoxy radical and R represents a hydrogen or η chlorine atom or a radical hydroxyl when R represents a hydroxyl radical or "else R represents a hydrogen atom when R ^ represents a hydrogen atom or an acetoxy radical; uu) ciQ ^ ci -C-Cl il il w) g -CÏÏC- C1 io - o Φ CH ^

The acid chlorides are normally prepared under vigorous conditions, for example by reaction of the acid at reflux with thionyl chloride, but in the presence of sensitive radicals, in particular sensitive protective radicals, the acid chlorides can be prepared in practically neutral medium by reaction of an acid salt with oxalyl chloride.

DIAGRAM. FROM BEAC1I0N.

Hosts: The symbols have the following meanings: 7-ADCA = acid 7 ~ sminodesacetoxycephalosporanic or aminodecephalosporanic acid TEA = triethylamine TMCS = trimethylchlorosilane.

7-ADCA + TEA + TMCS

^ in CH2C12 JS.

33 J31cH3 + TEA-HC1 C02Si (CH3) 3 (hereinafter bis-trimethylsilyl ester of 7-as ± iiodecé-phalo sporaniqpe acid)

^ C02 gas. At 20 ° C

Il _J5 - (CH3) 3Si-0-C-NH-j — Ç η o ^ U ^ Lch3 C02Si (CH3) 3 (hereinafter trimethylsilyloxy ester of trimethylsilyloxy-carhonyl-7-aniinodéphalosporanique)

/ —— y O

+ R \\ // ^ - C-Cl + propylene oxide '-' nh3 + ci “v Ί + c ° 2 '—f NH3 Cl J_Nn> s ^ LcH3 + C1CH2CHCH3 0 X2Si (CH3) 3 OSL ^) 3 , C1 + CH0-CH ^ I 2 CH OSKCH,) ^ ^ H2 ° 33

R- / VcH-C-NH — ί — r ^ S

XI1ch3 COO “” E = 3 for cephalexin E = 30- for cefadroxyl.

'FXFOTPIiE 1, -

Prénaration.de the ester trimethylsilylique acid 7 ~ amino-decéuhalosOoranique.

To a suspension of 10 g (46.48 millimoles) of 7 ~ aminodecephalosporanic acid in 100 ml of dry methylene chloride, 11.8 g (13.7 ml or 108 millimoles) of trimethylchlorosilane are added, then 10.86 g (14.4 ml or 107 millimoles) of triethylamine, drop by drop, in 30 minutes. The reaction mixture is stirred for a further 2 hours at 2 ° C. The complete silylation of the reaction mixture is then checked by examining the nuclear magnetic resonance spectrum. The nuclear magnetic resonance spectrum indicates that the ratio of the integrals of -C02Si (CH3,) 3 and of 7 “NÏÏSi (CH3) 3 is 468: 462 and that the conversion is therefore 100%.

EXAMPLE 2.-

Preparation of the trimethylsilyl ester of trimethyl-silyloxycarbonyl-7-aminodecephalosporanic acid.

Carbon dioxide is bubbled at 25 ° C for 2 hours with stirring in the reaction mixture containing the bis-trimethylsilyl ester of 7-aminodecephalosporanic acid and it is verified that the carbonylation is completed by examination of the nuclear magnetic resonance spectrum . Conversion reaches 95% · EXAMPLE 3. "

Preparation of the complex formed by dimethylformamide with 1 acid 7 (L-a-amino-p-hydroxyphenylacetamido) -3-methyl ~ 3-cephem-H— carboxylic (or cefadroxyl) starting from trimethylsilyl ester diacid trimethylsilyloxycarbonyl-7-aminodécéohaiosppranigue.

The mixture is stirred and cooled to 5 ° G, * + 6.68 millimoles of trimethylsilyl ester of trimethyl thilysilyloxycarbonyl-7-aminodecephalosporanic acid containing triethylamine hydrochloride. 3.7 ml (52.7 mmol) of propylene oxide are added dropwise to the suspension. Is added in five fractions at 5 ° C in 3 hours and with good stirring, 13.7 S 0 + 8.7 millimoles) of the solvate formed by 0.5 mole of dioxane with 1 mole of D hydrochloride chloride - (- ) -2- (V-hydroxyphenyl) glycyl. Stirring of the mixture is continued at 5 ° C for 2 hours. No amount of solid acid chloride remains in the reaction mixture. 5 ml of methanol are added to the final acylation mixture, then 60 ml of ice water. The pH is adjusted to 2.3 using triethylamine while the temperature is maintained at 5 ° 0. The aqueous phase is separated and clarified by filtration on a filter packed with a layer of diatomaceous earth (sold under the name of "Dicalite"), then the solids are washed with 1 ml of water. mixture of filtrate and washing water at pH M-, 5 using triethylamine and 100 ml of isopropanol and 220 ml of U, 2-dimé-thylformamide are added thereto. The mixture is seeded with 10 mg of complex formed by dimethylformamide and cefadroxyl and the mixture is allowed to crystallize at 25 ° C. for 7 hours with stirring, the product is collected and washed with 20 ml of dimethylformamide and twice 20 ml of acetone to obtain a quantity 11.51 g? or with a yield of 55} 96%, white crystals of the complex formed by dimethylformamide with cephadroxyl. The nuclear magnetic resonance spectrum and the infrared spectrum are identical to those of an authentic sample The nuclear magnetic resonance spectrum reveals the presence of 1.9 moles of di-methylfomamide pa r mole of cephadroxyl.

EXAMPLE acid preparation 7 ~ (f-g-amino-a-phenylacetamido) ~ 3 ~ methyl-3-cephem-1! —Carboxyliaue (cephalexin).

The mixture is stirred and cooled to 5 ° C., 6.4-8 millimoles of trimethylsilyloxycarhonyl-7-aminodecephalosporanic acid trimethylsilyl ester containing triethylamine hydrochloride. 3 * 7 ml (52.7 millimoles) of propylene oxide are added to the suspension. 10.2 g (^ 755 millimoles) of D - (-) - phenylglycyl chloride hydrochloride are added in five fractions at 5 ° 0 over 5 hours, with good stirring. Stirring of the mixture is continued for 2 hours at 5 ° C. The thin layer chromatography reveals that the acylation is incomplete. The reaction mixture is heated to 25 ° C and stirred for 1 hour. 50 ml of water are added to the final acylation mixture. The pH of the mixture is adjusted to 1.5 by stirring at 25 ° C for 20 minutes. The aqueous phase is separated and clarified by filtration on diatomaceous earth (sold under the name "Dicalite"), then the filter cake is washed with 15 ml of water. 10 ml of dimethylformamide are added to the clarified aqueous fraction containing the compound sought. The aqueous solution is then heated to 60-63 ° 0 and 11 ml of triethylamine are added thereto over 15 minutes to maintain the pH at 4.0. The suspension of crystals thus obtained is stirred for 1 hour at 5-10 ° C. The product is collected by filtration and washed with 10 ml of water and 15 ml of a 4: 1 mixture of isopropanol and water. 4.40 g of cephalexin monohydrate are thus obtained.

The nuclear magnetic resonance spectrum and the infrared spectrum are comparable to those of an authentic sample.

~ RY ~ RMPT, ~ R 5.-

The cephaloglycin is prepared as in Examples 1, 2 and 3, replacing the 7-aminodecephalosporanic acid with an equimolar amount of 7-ainincephalosporanic acid.

tXRiiPT · έ 5.-

The cephalosporin of formula is prepared: ~ 0 · 'Η' "'ΗΗ_π ^ Ί» N-f NH2 ^ L_sv ^ Lch2OC-NH2

COOH

by operating as in Examples 1, 2 and 3 and replacing the 7 “aminodecephalosporanic acid by an equimolar amount of the compound of formula:

Η2Νη — Γ ^ Ί S

J_ï ^^ J-ch2oc-nh2

COOH

• RY-RMPLE 7.-

The cephalothin is prepared by operating as in Example 5) but by replacing the 2-phenylglycyl chloride hydrochloride with an equimolar amount of 2-thienylacetyl chloride.

EXAMPLE 8.-

By operating as in the previous examples, by reacting a compound of formula:

0 HH

He | î ς

(CH ^) ^ Si-0-C-NH— | —Y * N

Jr — ® ^ sy — CE2E

o / Xo cf

xO-A

where A represents a radical (CH ^) ^ Si- or an easily esterifying protective radical, and E represents a hydrogen atom or a radical CE ^ C —-0-, ~~ —0 “or -SZ, where Z represents a pentagonal or hexagonal aromatic heterocycle comprising two, three or four nitrogen atoms and zero or one oxygen or sulfur atom, which heterocycle optionally carries one or two substituents s chosen from halogen atoms and alkyl radicals and C ^ -C ^, C - ^ - C ^ alkoxy, cyano, nitro, C ^ -C ^ cycloalkyl, trifluoromethyl alkenyl, C - ^ - C ^ alkylthio, di (C ^ -C ^ amino alkyl , phenyl, benzyl, alkoxyalkyl up to C ^, -COOSiCCïï ^) ^ and - (OHp ^ OOSiCCH ^) ^, where a represents 1, 2 or 3, the sulfur atom of the radical -SZ being united to an atom of heterocycle Z and E representing the radical suitable for the final product, with the appropriate chloride or hydrochloride of acid chloride containing, if necessary, protective radicals, then eliminating the · protective radicals optional, including the radical A, the suppression of which is desired, the following compounds are prepared: the compound BRL-16931 of formula:

C ^ -CH-CO-NH-pY8 ^ N — N

SH

Cg ^ CO-N-CH ^ C00H 5 cephaeetrile, cefaparole, cefatrizine, cefazaflur, cefazedone, ceforanide, ceftezole, cefuroxime; cephalothin, cephanone, cefaloram, cephapirin, cepliradine, cefaclor, compound ΙΈ-10612 of formula:

CH ^ SOgNH

cooh; compound HR-580 of formula: r / NV> ^ \

L] n l ^ iLcH pCONH — J N

COOH

J

1 a ce ax axre; compound PC-518 of formula: Ο-Γ ^ ΤΤ ^ Ι s-s

iNn2 —Nv ^ i ^ -CHgS —ii ^ g Ji — CHgCOOH

COOH; the compound SCE-1365 of formula: ¥ γν N -Lç-CO-NH— "(^ SVs | Ni- $ N-OCH, J — N ^ LsAnJn

0V Y I

COOH CH3; sigmaeef (ST-21); compound SQ-1W + 8 of formula:

CjJ-OH - COHH-r- | ^ S ^ N-H

0 ^ Nv ^ CH2S-lU> ï — 0 T CH, MHCH ^ CN COOH ^ y compound SQ-67590 of formula:

NC-CÎ ^ -S-CÎ ^ CONH — j N-N

O ^ Y “CH2SJ ^^ I CH, COOH ^; compound SQ-69613 of configuration L (S), of formula: ^ ç.-co'e ^ N J-j "NH —CH2b— C = 0 0 '] ij, hh2 cooh 3; the compound ¢ -1551 of formula:

HO

YJX

CH-COHH —-N | -1? 0 NH.

0 <Y ^ N / C == ° C00H CEj

VsO 5 and the compounds of the formulas:

VcHgCOHH -τ-γ B-N

COOH;

/ \ —CH-CONH — j-r ^ SN Nj-, N

^ l 0 ^ Ο- = ν-ΐΐ> I prr cooh on3;

/ N — ch - corn — j — r ^ s> if n, —iN

u XI

h <? T 2 ï 0 CH, COOH *; | N -CHgCONH —j- | ^ Svj dd N = ¥ i-N ^ —CHgOCCHj COOH and (/ ÇH-CONH— | ^ m2 ^^ J_NvJ - OCH5

COOH

The methods of the invention lend themselves to industrial applications.

Claims (8)

1. Compound of formula: O HH Il I! s (CH ^ Si-OC-NH — Tf // \ r "B X0-A where B represents a chlorine atom, or a methoxy radical or -C ^ E; A represents a radical (CH ^) ^ Si- or an easy-to-remove protective esterifying radical; .0 E represents a hydrogen atom or a CE-.C ——G- ,. NE ^ C ——0- or -SZ radical, where Z represents a pentagonal aromatic hetero ring or hexagonal comprising two, three or four nitrogen atoms and zero or one oxygen or sulfur atom, which heterocycle optionally carries one or two substituents chosen from halogen atoms and C 1 -C 4 alkyl and alkoxy radicals, cyano, nitro, cyclo C ^ -C ^ alkyl, C ^ -C ^ alkenyl, trifluoromethyl, C - ^ - C ^ alkylthio, di (C - ^ - C ^ alkyl amino, phenyl, henzyl, alkoxyalkyl up 'in C ^, -COOSi (CH ^) ^ and - (C ^^ COOSiÇCH ^) ^, where n represents 1, 2 or 3, the sulfur atom of the radical -SZ being united to a carbon atom of 1 'heterocycle Z, 2. A compound according to claim 1, of formula. : 0 HH It I! (CK ^ Si-O-C-NH — 4 — pS ^ | A — ch2e 0 I / O where A represents a radical (CH ^^ Si- and E represents a hydrogen atom. 3-- Process for the preparation of a compound of formula: 0 HH Il I i o (ch ^) 5si-o-c-ra ^ / “T B 0 \ °. X0-A where B represents a chlorine atom, or a methoxy radical or -CH2E; A represents a radical (CH ^) ^ Si- or a protective esterifying radical which is easy to remove; -0 E represents a hydrogen atom or a CH-.C —-- o-, 3 KS2C —-0-or -3-Z radical, where Z represents a pentagonal or hexagonal aromatic heterocycle comprising two, three or four atoms nitrogen and zero or an oxygen or sulfur atom, which heterocycle optionally carries one or two substituents chosen from halogen atoms and alkyl and C - ^ - C ^, C - ^ - C ^ alkoxy, cyano, nitro, C ^ -C ^ eycloalkyl, ^ 2 ~ alkenyl Gb9 Îrifluoro: aiethyl, C - ^ - C ^ alkylthio, di (C ^ -C ^ alkyl) ami.no, phenyl, henzyl, alkoxyalkyl up to C ^, -COOSi (CH ^) ^ and - (^ 2) ^ 00031 (0 ^) ^, where n represents 1, 2 or 3j the sulfur atom of the radical -SZ being united to an atom of carbon of heterocycle Z, characterized in that o adds carbon dioxide .sec to a solution of a corner wedge of formula: HH • "(CHj ^ SiMH — I — pSv- | o / Lo cf · where A and B have the meanings given to them above, in an anhydrous inert organic solvent at a temperature of 0 to 100 ° G up to completion of the reaction. 4 · .- A method according to claim 3, characterized in that A represents a radical (CH ^) ^ Si- and Έ represents a hydrogen atom. 5 · “Improved process for the preparation of a classic cephalosporin of formula: - o? ç It! H-C-NH — j — j - ^^ l J-vJ-B 0 Lo <OH where represents the remainder remaining after the elimination of the hydroxyl radical of an organic carboxylic acid of 2 to 20 carbon atoms, B represents a chlorine atom or a methoxy radical or —GE ^ n, E represents a hydrogen atom or a CH ^ C —-0-, —0- or -SZ radical, where Z represents a pentagonal or hexagonal aromatic heterocycle comprising two, three or four nitrogen atoms and zero or one oxygen atom or of sulfur, which heterocycle optionally carries one or two substituents chosen from halogen atoms and alkyl and Oj-C ^ radicals, C - ^ - C ^ alkoxy, cyano, nitro, C ^ -C ^ cycloalkyl, alkenyl ^ 2 ^ 4-5 trifluoromethyl, C-^ alkylthio - ^ - C ^, - di (C-alkyl - ^ - C ^) amino, phenyl, benzyl, alkoxyalkyl up to C ^, -COOSi (CH ^) ^ and - (CB ^^ COOSiCCïï ^) ^, where n represents 1, 2 or 3s the sulfur atom of the radical -SZ being · united to a carbon atom of the heterocycle Z, according to which, successively, we acylate, at means of the acid chloride of this acid because organic boxylic, a silylated nucleus of formula: - HH: | (CHj) 3SiNH- | —j'''8 ''! ° l / ° 0-A where A represents a radical (CH ^) ^ Si- or a protective esterifying radical which is easy to remove and B has the meaning given to it above, then the radical A is converted into an atom of hydrogen, characterized in that before acylation, this silylated nucleus is converted into a compound of formula: 0 HH H 1 1 g (CH ^ Si-OC-KH — J— o / Xo N) -a where A and B have the meanings given to them above, by adding dry carbon dioxide to a solution of the silylated nucleus in an anhydrous inert organic solvent at a temperature of 0 to 100 ° 0, until completion of the carbonylation reaction. 6. Process improved according to claim 5? for preparing a classic cephalosporin: ο Η Η II! U rc-nh -; - γ N J-nA-.ge2e </ T λ <OH Λ where R-Ci ~ - represents the remainder remaining after elimination of the hydroxyl radical of an organic carboxylic acid having 2 to 20 carbon atoms and E represents a hydrogen atom, according to which, successively, acyl at least of the acid chloride of this organic carhoxylic acid, a silylated nucleus of formula: HHZ 3 (ch ^) 3sinh! - J - 0 'i 1/0 OA where A represents (CH ^) ^ Si- and E represents a hydrogen atom, then the radical A is converted into a hydrogen atom, -characterized in that before the acylation , this silylated nucleus is converted into a compound of formula: 0 HH Il i! S (CH ^ Si ^ C-OT — j— J — s ^ -cr ° ° V X0-A where A and E have the meanings given to them above, by addition of carbon dioxide dry to a solution of this silylated nucleus in an anhydrous inert organic solvent at a temperature of 0 to 100 ° C until completion of the carbonylation reaction. 7 · - Process for the preparation of cephalexin, characterized in that the compound of formula is reacted: 0 HH,. Il M Sv (CH ^ Si-OC-HH J — K 1 i- ° I / O <> 0-Si (CH3) 3 in an anhydrous inert organic solvent with a roughly equimolar weight of D chloride chloride hydrochloride— (-) - 2-phenylglycyle. 8.- Process for the preparation of cefadrozyl, characterized in that the compound of formula is reacted: 0 HH | l = 1 q (CH ^) 5SI-0-C-HH-4 — Y ^ J — CH 3 o / Xo in an anhydrous inert organic solvent with a roughly equimolar weight of D- chloride hydrochloride (-) - 2-p-hydroxyphenylglycyl.