LU81432A1 - PENICILLIN PRODUCTION - Google Patents

Description

DESCRIPTIVE MEMORY

FILED IN SUPPORT OF A REQUEST FOR

PATENT

FORMED BY

BRISTOL-MYERS ^ CQMPAM for

Production of penicillins.

<< * The present invention relates to a new process for the production of antibacterial agents belonging to the class of so-called semi-synthetic penicillins and, preferably, to the subclass of penicillins carrying an α-amino radical on the side acyl chain. in position 6, as in ampicillin and amoxicillin.

The first commercial penicillin comprising an α-amino radical on the lateral 6-acylamido chain was

CD.MdC.GP.6 SY-1611C

cillin or 6- (D-a-amino-a-phenylacetamido) penicillanic acid (see United States Patent No. 2,985-648).

Amoxicillin is an antibacterial agent used in human medicine and sold as a free acid trihydrate (i.e., zwitterion). This compound is described, for example, in English Patent No. 978.17¾ in J. Chem. Soc. (London), pages 1.920 to 1.922 (1971) and in Antimicro-bial Agents and Chemotherapy - 1970, pages 407 to 430 (1971).

This compound is 6- [D-a-amino-a- (p-hydroxyphenyl) aceto-midojpenicillanic acid.

The use of amino acid hydrochloride hydrochlorides for the preparation of these penicillins has been described in various patents, for example English patents Nos. 938,321 and 959,853 for the conduct of operations in anhydrous medium (according to the second patent, the carboxyl radical 6-aminopenicillanic acid is protected by a silyl radical during acylation, as also described in English Patent No. 1,008,468 and United States Patent No. 3-249,622) and the English Patent No. 962.719 for the conduct of operations in cold aqueous acetone. These penicillins are amphoteric amino acids, the isolation of which has therefore been carried out (for example as described in US Pat. Nos. 3,157 * 640 and 3-271,389) by means of certain non-aliphatic secondary amines. symmetrical branched (often called liquid resinous amines), which had already been used for the isolation of 6-aminopenicillanic acid which is also an amphoteric amino acid (see United States Patent No. 3,008,956). Various improved processes for the isolation and purification of these penicillins have been described, for example in United States patent No. 3,180,862, in which β-naphthalenesulfonates are used, and in the United States patent -

United States of America No. 3 * 198.804, according to which the heta-cillin is isolated as an intermediate compound, then the latter is easily hydrolyzed.

The use of a silyl radical to protect the carboxyl radical of a natural penicillin during the chemical decomposition into 6-aminopenicillanic acid has been described in the patent of the United States of America No. 3 * 499 * 909 * The use of silylated 6-aminopenicillanic acid during acylation in an anhydrous medium by means of amino acid hydrochlorides has been described in numerous "patents, for example" US Pat. Nos. 3,479. 018, 3-595-855, 3-654.266, 3-479-338 and 3.487.073. Some of these "patents also describe the use of liquid resinous amines. Reference may also be made in this connection to" United States patents 3,912,719, 3,980,637 and 4,128,547.

"English Patent No. 1,339-605 includes various specific and detailed examples of the preparation of amoxicillin by reacting a silylated derivative of 6-aminopenicillanic acid with a reactive derivative (in particular the hydrochloride of chloride) of the D - (-) - a-amino-p-hydroxyphenyl-acetic acid whose amino radical is protected, then by elimination of the silyl radical (s) during hydrolysis or alcoholysis and then, when possible , by collecting amoxicillin, usually in the form of the crystalline trihydrate. Thus, the crystalline amoxicillin is obtained in Example 1 by precipitation at isoelectric pH from an aqueous solution, for example at pH 4, 7 * It should be assumed that the purification is carried out in this example by dissolving the crude product (before precipitation with isoelectric pIï) in water with a pH of the acid domain, for example 1.0, ( for example in aqueous hydrochloric acid) (TTL ΜΗΠ CP A _ X _ cv ί τ n in presence nce of an organic solvent immiscible with water such as methyl isobutyl ketone. The process applied in the. U.S. Patent No. 3 * 674,776 is for the most part the same.

The subject of the present invention is a process for the production of a known penicillin, according to which a compound of formula is reacted:

0 S

He X \ ^ CH

(CH,), Si-0-C-KH-0H-GH G - ητΡ

33 || | CHJ

X1 — T

COB

II

o where B represents an easy-to-remove protective esterifying radical chosen from trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1- [(ethoxycarbonyl ) oxy] ethyl, pivaloyloxymethyl and acetoxy-methyl in an anhydrous inert organic solvent and preferably in methylene chloride, preferably in the presence of a weak base, which is preferably propylene oxide, and preferably to a temperature above -10 ° C, which is preferably from -8 to + 20 ° C, more advantageously from 0 to 20 ° C i and most advantageously from approximately 20 ° C, with an approximately equimolar weight of an acid chloride or acid chloride hydrochloride, the latter preferably being added little by little to the solution of the first, then, if necessary, the radical B is replaced by a hydrogen atom.

A known penicillin as defined above is a penicillin which has already been described in patents and scientific literature, including the summaries which are published therein.

The invention further relates to a method of pro-

1 -1¾. J

duction of the compound of formula:

0 S

,, He / \ / CH,

(CH *) * Si-0-C-NH-CH-CH C ^ T nxP

33 | , | ^ -CH5

1-H-CH

cf I

. COB

II

o where B represents an easy-to-remove protective esterifying radical chosen from the trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, l - [(ethoxyearbonyl) radicals ) oxy] ethyl, pivaloyloxymethyl and acetoxy-methyl, according to which dry carbon dioxide is added in the gaseous state to a solution of a compound of formula:

yS

/ X ^ ch * (CH *) * Si-M-CH-CH C c nn 33 || | CHj

J-H-CH

0 ^ I

COB

II

0 where B has the meaning given to it above, in an anhydrous inert organic solvent, preferably in methylene chloride, at room temperature or at a temperature of 0 to 100 ° C until completion of the reaction.

According to a preferred embodiment, the invention relates to a process for the production of a 6-oc-aminoarylacetamidopenicillanic acid, which is preferably ampicillin or amoxicillin, according to which the compound of formula is reacted:

0 .S

, Λ II / \ z ^ CH * (CH *) * Si-0-C-HH-CH-CH CCT 0 * * It! CH * JN-Cïï 0 C-0-Si (CH *) * il 3 3 * in an anhydrous inert organic solvent and preferably in methylene chloride, preferably in the presence of a weak base, which is preferably 1 propylene oxide, and preferably at a temperature above -10 ° C, which is preferably from -8 to + 20 ° C, more advantageously from 0 to 20 ° C and most advantageously from approximately 20 ° C, with an approximately equimolar weight of a D - (-) - a-amino-arylacetyl chloride hydrochloride, which is preferably D - (-) - 2-phenylglycyl chloride hydrochloride or hydrochloride hydrochloride D - (-) - 2-p-hydroxyphenylglycyl, respectively, the latter reagent being preferably added little by little to a solution of the former.

One of the surprising features of the new process is the stability of the anhydrous acylation solution. It can be stored for a long time, even at room temperature, without significant decomposition of the penicillin. This contrasts with the behavior of the acylation solutions used in the processes already described. This advantage offered by the stability makes it possible to carry out the acylation reaction at much higher temperatures (the Applicant operating at ambient temperature) than those normally chosen for the production of ampicillin, which are usually less than 0 ° C and typically around -10 ° C.

According to a preferred embodiment, the invention also relates to a process for producing the compound of formula:

0 ^ S

,, Il / \ (CHx) xSi-0-C-EH-CH-CH cC ^ mr 3 3 | I I 0H3

X-H-CH

r / y I

u O-O-SiCCH *),

It follows that dry carbon dioxide is added in the gaseous state to a solution of trimethylsilyl 6-trimethylsilylaminopenicillate in an anhydrous inert organic solvent and preferably in methylene chloride, at room temperature or at a temperature of 0 to 100 ° C until completion of the reaction.

According to one embodiment, the invention relates to a compound of formula:

0 H H S

It f! / \ (CH ^ Si-O-C-HH — j-Y] <CÏÏ -H-1 3 o- ^ \ .0

^ 0-B

where B represents an easy-to-remove esterifying radical which is preferably chosen from the trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichlo-roethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl radicals - [(ethoxycarbonyl) oxy] ethyl, pivaloyloxymethyl and acetoxymethyl.

According to another preferred embodiment, the invention has for object the compound of formula:

0 .S

,, Il / \ (0Hx) * Si-0-C-HH-CH-OH C - ητ / 3 3 II | CH3

J-H-CH

0 ^ I

O-O-SiCOH,) *

It 5 3 ο hereinafter also called bis-silylated carbamate of 6-aminopenicillanic acid or trimethylsilyl ester of 6-trimethyl s ilyl oxyc ar b onylp eni cillanic acid.

The very existence of this compound is surprising since it is known that the reaction of 6-aminopenicillani- ___ -i _ t · _ i_ _i / j acid. · I_ π "_ ♦" t · y · * - "lanique with formation of 8-hydroxypénicillanique acid, as described, for example, in the patent of the United States of America n ° 3.225.Ο33.

The decisive operation for obtaining a quantitative yield of trimethylsilyl ester of 6-trimethylsilyl-oxycarbonylaminopenicillanic acid is the completion of the production of the precursor 6-aminopenicillanic acid bis-trimethylsilylated. The operation is carried out by reaction of 6-aminopenicillanic acid with hexamethyldisi-lazane, as illustrated below.

1 mole of 6-aminopenicillanic acid + 6-8 hours of 100% silylation ~ heating of the carboxyl radical 1.1 moles of hexa- s. - ^ and at approximately hO at methyldisilazane at rej> q · ^. 65% of the radical in position 6 _ 3-5 moles% of imidazole (catalyst)

+ 5 moles% TMSUH S

trimethylchloro- ^ f

silane and heating I I I

at reflux until Λ — U- \ next day υ 'oo2tms (6-aminopenicillanic acid bis-trimethylsilylated) The completion of bis-trimethylsilylation can be easily monitored by nuclear magnetic resonance spectroscopy. Indeed, the trimethylsilyloxycarbonyl radical in position 3 leads to a singlet dd to the methylsilyl radical at 0.31 pp (with respect to tetramethylsilane = 0), while the "*, dical methylsilyl radical at 0.09 ppm.

Trimethylsilylation of 6-aminopenicillinic acid has so far only been carried out in methylene chloride. However, other solvents are also suitable, for example acetonitrile, dimethylformamide or hexamé-thyldisilazane itself.

The conversion of the trimethylsilylamino radical to the trimethylsilyloxycarhonylamino radical is easily carried out by "bubbling dry carbon dioxide into the reaction solution. The conversion is easily followed by nuclear magnetic resonance spectroscopy because the singlet due to the trimethylsilylamino radical at 0.09 ppm s weakens, while a new singlet due to the trimethylsilyloxycarbonylamino radical appears at 0.27 ppm.

When the process of the invention is applied to the production of ampicillin, anhydrous ampicillin, ampicillin trihydrate, amoxicillin or amoxicillin trihydrate, the final products are isolated and purified in a conventional manner. , as described in the patents of the United States of America n ° 3-912-7195 3-980.637 and 4.128.547 and those mentioned in quotation.

The acid chlorides used in the examples below can be replaced by other acid chlorides for the production of known penicillins.

Thus, the acyl halide can be chosen so as to fix any desired acyl radical on the amino radical in position 6, as is conventional to do, for example as described in the patent of United States of America n ° 3-741.959- It is therefore possible to introduce specific acyl radicals including, without limitation, those of the following general formulas: (i) ΚΧ, Η ^ ΟΟ- where Ru represents an aryl radical (carbocyclic or heterocyclic), cycloalkyl , substituted aryl, substituted cycloalkyl, or non-aromatic or mesoionic heterocyclic and n represents an integer from 1 to 4. Examples of such radicals are phenylacetyl radicals; (substituted phenyl) acetyl, such as fluorophenylacetyl, nitrophenylacetyl, amino-phenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methylphenylacetyl or hydroxyphenylacetyl; U, U-bis- (2-chloro-ethyl) aminophenylpropionyl; thiene-2-acetyl and thiene-3-acetyl 4-isoxazolyl and (4-isoxazolyl substituted) acetyl; py-ridylacetyl; tetrazolylacetyl or sydnoneacetyl. The substituted 4-isoxazolyl radical may be a 3-aryl-5-methyl-isoxazol-4-yl radical in which the aryl radical is, for example, a phenyl or halophenyl radical such as chlorophenyl or bromophenyl. One such acyl radical is the 3- o-chlorophenyl-3-methylis oxazο1-4-ylac ethyl radical.

(ii) G H0 -.CO- 'n 2n + l where 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 or sulfur or carry a substituent, such as a cyano radical. Examples of such radicals are the cyanoacetyl, hexa-nucleus, heptanoyl, octanoyl and butylthioacetyl radicals.

(iii) V ^ -i00- where n represents an integer from 2 to 7- This radical can be in a straight or branched chain and, if desired, can be interrupted by an oxygen or sulfur atom. An example J I _____ j · __n__i_ "i ___ J · __η __- I _! _ Ί_ · ___ 'Λ ___ η ^ (iv) Bv

u I

B. ô-C-CO-Rw where BU has the meaning given to it under (i) and can also represent a henzyle radical and Rv and Rw, identical or different, each represent a hydrogen atom or a radical phenyl, henzyl, phenylethyl or lower alkyl. Examples of such radicals are phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybuty-ryle, benzyloxycarbonyl, 2-methyl-2-phenoxypropionyl, p-cre-soxyacetyl and p-methylthiophenoxyacetyl.

(y) u 1 ES-C-GO-

Rw where fiu has the meaning given to it under (i) and can also represent a henzyle radical and Rv and Rw have the meanings which were given to them under (iv). Examples of such radicals are the S-phenylthioacetyl, S-chlo-rophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthio-acetyl and S-benzylthioacetyl radicals.

(vi) E ^ ZCCHp ^ CO- where R11 has the meaning given to it under (i) and can also represent a henzyl radical, Z represents an oxygen or sulfur atom and m represents an integer of 2 to 5 · U11 example of such a radical is the radical S-henzylthopropopropyl.

(vii) BuC0-

\ -r-vU _. . _. ,. · -, · , /-NOT

examples of such radicals are benzoyl, substituted benzoyl (like aminobenzoyl), 4-isoxazolylcarbonyl and (substituted 4-isoxazolyl) carbonyl, cyclopentanecarbonyl, syd-nonecarbonyl, naphthoyl and substituted naphthoyl (like 2-eth.o-xynylcarbyl) and substituted quinoxalinylcarbonyl (such as 3-carboxy-2-quinoxalinylcarbonyl). Other possible substituents for the benzoyl radical are in particular the alkyl, alkoxy, phenyl and substituted phenyl radicals carrying carboxyl, alkylamido, cycloalkylamido, allyl-amido, phenyl (lower alkyl) amido, morpholinocarbonyl, pyrolidinocarbonyl, piperidinocarbonyl, tetrahydropyridino radicals , fur-furylamido or N-alkyl-N-anilino and the radicals derived therefrom, which can occupy positions 2 or 2 and 6. Examples of these substituted benzoyl radicals are the 2,6-dimé-thoxybenzoyl radicals, 2- biphenylcarbonyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. When the radical R11 is a substituted 4-isoxazolyl radical, the substituents can be as indicated under (i). Examples of such 4-isoxa-zolyl radicals are 3-phenyl-5-methylisoxazol-4-ylcarbo-nyle, 3-o-chlorophenyl-5-methylisoxazol-4-ylcarbonyl and 3- (2,6-di chloroph radicals) enyl) -3-methyli s oxazol-4-ylc arb onyl.

(viii) RU-GH-CO-! where Ru has the meaning given to it under (i) and X represents an amino, substituted amino radical (for example acyl-amido or a radical resulting from the reaction of the amino radical and / oi of one or more radicals of the side chain in position 7 with an aldehyde or a ketone, such as acetone, methyl ethyl ketone or ethyl acetoacetate), hydroxyl, carboxyl, esterified carboxyl, triazolyl, tetrazolyl, cyano, acyloxy (such as for-myloxy or lower alkanoyloxy ) or ether hydroxyl or a

CD.MdC; GP.9 - 12 - SY-1611C

halogen atom. Examples of such acyl radicals are the α-aminophenylacetyl, α-carboxyphenylacetyl and 2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl radicals.

(ix) -EX

r7-c-co- lz

RZ

where Rx, R ^ and Rz, identical or different, each represent a lower alkyl, phenyl or substituted phenyl radical. An example of such an acyl radical is the triphenylcarbonyl radical.

Y

(x) R -DH-C- where R has the meaning given to it under (i) and can also represent a hydrogen atom or a lower alkyl or lower haloalkyl radical and Y represents an oxygen atom or sulfur. An example of such a radical is that of formula ClCCH ^ g ^ ŒKX).

(xi) <GE2> n ^ C-00-

ÖE2 X

where X has the meaning given to it under (viii) and n represents an integer from 1 to 4. An example of such an acyl radical is the 1-aminoeyclohexanecarbonyl radical.

(xii) Aminoacyl, for example R ^ HCDIL ·,). (CI ^^ CO-, where n represents an integer from 1 to 10, or else ira2.C ^ Hp ^ Ar (CHp) mC0- "where m represents 0 or an integer from 1 to 10, n represents 0, 1 or 2, Rw represents a hydrogen atom or an alkyl, aralkyl or carboxyl radical or else a radical R11 as defined above and Ar represents an arylene radical, for example p-phenylene ηπ 1 M — nnnVltvl pnp _ Tlaa ovorrml οα ri o -hole r * cri -i non-v an-nh given in "English patent n ° 1.054-.806. A radical of this kind is the p-aminophenylacetyl radical. Other acyl radicals of this kind are in particular those which, like the δ-aminoadipoyl radical, derive from natural amino acids and the radicals which derive therefrom, like the ÏT-benzoyl-8 '-aminoadipoyl radical.

(xiii) 00.00-

which are substituted glyoxylyl radicals, in the formula des-Y

which R represents an aliphatic, araliphatic or aromatic radical, for example a thienyl, phenyl or phenyl mono-, di- or trisubstituted radical whose substituents are, for example, one or more halogen atoms (R, Cl, Br or I ) or methoxy, methyl or amino radicals or a benzene ring-condensed.

When the acyl radical which is introduced contains an amino radical, it may be necessary to protect the latter during the various stages of the reaction. The protective radical is advantageously a radical which can be eliminated by hydrolysis without influence on the rest of the molecule and especially on the lactam and 7-amid.o bonds. The radical protecting the amino function and the radical esterifying the carboxyl radical in position 4 can be removed using the same reagent. An advantageous procedure consists in eliminating the two radicals at the last stage of the sequence. Protected amino radicals are in particular the radicals of the urea-thane, arylmethylamino (for example tritylamino), arylmethylene- • amino, sulphenylamino or enamine type. The enamine block radicals are especially useful in the case of o-amino-methylphenylacetic acid. Such radicals can, in general, be eliminated by means of one or more reagents chosen from dilute mineral acids, such as hydrochloric acid di- "I 1Ί ό Iaq π rl ac> rvr * a * an π ηηοσ Γ · ηη η οττΗ-ηάσ η rnnma 1> αρ-ί λΙω πιίο concentrated, or trifluoroacetic acid and hydrogen bromide liquid at very low temperature, for example -80 ° G. 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 using a strong organic acid, such as formic or trifluoroacetic acid, for example at a temperature from 0 to 40 ° C. and preferably at room temperature (15 to 25 ° C.) Another advantageous protective radical is the 2,2,2-trichlo-roethoxycarbonyl radical which can be removed using a system such as zinc / acetic acid, zinc / formic acid, zinc / lower alcohol or zinc / pyridine.

The HEU radical can also be protected in the form of the UH ^ + radical by using the amino acid halide in the form of an acid addition salt under conditions in which the amino radical remains protonated.

The acid used for the formation of the acid addition salt preferably has a pK (in water at 25 ° C) not greater than X + 1, where X is pKa (in water at 25 ° C) of the carboxyl radical of the amino acid and the acid is preferably monoprotonic. In practice, HQ acid (see below) generally has a pK of less than 3 and preferably less than 1.

3.

* The process of the invention has been found to offer particular advantages when the acyl halide is a salt of an amino acid halide. Amino acid halides have the formula:

HoU-R1-C0Hal • d.

where E1 represents a divalent organic radical and Hal represents a chlorine or bromine atom. The salts of these amino acid halides are of the formula: [H3U-E1-00Hal] + Q "where T? · * · And Hal have the sienifications yes they have been given below

above and Q “represents the anion of the acid, HQ having pK

If defined above. The HQ acid is preferably a strong mineral acid, such as a hydrohalic acid such as hydrochloric or hydrochloric acid. An important amino acid halide due to the interesting antibiotic penicillins which contain the radical derived therefrom is DU- (a-chlorocarbonyl-a-phenyl Methylammonium chloride, also called for convenience Da-phenyl-glycyl chloride hydrochloride .

The penicillins obtained by the process of the invention and comprising the acylamido radical of formula EaOH (HH2) .COHH- where R11 has the above meaning can be reacted with a ketone of formula R .E ^ CO where R and R0 represent lower alkyl radicals G - ^ - G ^, for the formation of compounds comprising, it is believed, 'the radical of formula:

.CO

R -CH U- 1 2 HH - ΐΓ r3

Compounds of this kind are in particular 1 * hetacillin, sar-picillin, p-hydroxyhetacillin and sarmoxicillin.

Mention should also be made in this connection of the acyl radicals mentioned in columns 7 to. 20 of U.S. Patent No. 4 · .013.64-8.

When the acylation process according to the invention is applied to the production of penicillins, the products. end products are isolated and purified using standard techniques.

Preferred acyl chlorides used for the purposes of the invention for acylating a compound of formula:% »Ο Η Η S CH,, II! I / 3 (ΟΗ ^) gSi-0-C-RH —-- CH ^ J-Ν- 1 / σ 'νο-α where A represents a radical (CHj) jSi- or an easy-to-remove protective esterifying radical are in particular the following: a) 0

II

A-CH-C-Cl where A represents ^ GEpHHR '^^^ CiyJHR' ^ GBÿSHB '-Ö- “O- °° 0- where R represents a hydrogen atom or a hydroxyl or methoxy radical and R' represents a hydrogen atom or a methyl radical and the amino radical is blocked, if necessary, by conventional blocking radicals, in particular by protonation; b) 0

II

B-GH-G-Gl.HCl ML, where B represents ** - 0- - O- 'U- where R · * "represents a hydrogen atom or a hydroxyl or 2 acetoxy radical and R represents an atom of hydrogen or chlorine or a hydroxyl radical when R "*" represents a hydroxyl radical, • 2% 1 and R represents a hydrogen atom when R represents an 'I-1 0

Ο) \\ I II

IL j— οη0ο-οι xs 2 d) [\ il 11 k0> C-C-Cl N - OCH,

OH O O

iiyV- g - m -oh-Ü-ci

e) he I

b where B. represents a phenyl, 4-hydroxyphenyl, 3, Ù-di-hydroxyphenyl or cyclohexa-1,4-diene-1-yl radical; f) 0 0) - \ P 0

/ \ Il II

o9h, -n h - c - nh -CH -G -Cl 25 w l

E

where E represents a phenyl, 4-hydroxyphenyl, 3,4-dihy-droxyphenyl or cyclohexa-1,4-diene-1-yl radical; g) 4 Von-c-d

O-C-H

0,. 0 0

^ ** H

^ T— G - KH - CH-C-C1 Ί Γ 1

H

where R represents a phenyl, 4-hydroxyphenyl, J ^ -d-ihy-droxyphenyl or cyclohexadiene-1-yl radical; i) R2 9 0 0 ^ Nni / ^ nV c-rh -Gïï-R-Gl where R1 represents a phenyl, 4-hydroxyphenyl, 3? 4-di- 2 hydroxyph enyl or cyclohexadiene-1-yl radical and R represents a hydrogen atom or hydroxide radical: ü) 0

II

I ^ C-S-CI ^ C-Cl 0

It k) | F-CH2C-G1 ή = ή '0, Il l) UC-CH2C-C1 / = \ _ 8 m) R ^ Λ- S - CH2C - Cl 0

, H

n) Br-CH2C-Cl *

H0R

o) <_ 8 -CH2C-G1 0, Il p) R = C-GÏÏ2-S-CR2-G-C1 π ') 1ΝΗ σ g) ν' S ο Τ ι h hu -— c -σ -σι

II

U-OCHj r) I-1 I-10 0 I ι I1 i il

0 JJ-CH = U-U ^^ - U-C-UH-CH-C-C1 0 R

where R represents a phenyl, 4-hydroxyphenyl, 3,4-di-oxyphenyl on cyclohexadiene-1-yl radical.

II

C X 0

, / \ Il II

s) A-H U-C-HH-CH-C-Cl

\ / I

R

where A represents nn hydrogen atom nn alkyl radical from 1 to 4 carbon atoms on CH ^ SC ^ -, Σ represents nn oxygen atom or sulfur and R represents nn phenyl, 4-hydroxy-phenyl radical, 3 54-dihydr oxyphenyl e on cyclohexa-1,4-diene-1-yl; R 0 t) /. \ 0 — C — C — Cl

L

where R represents a hydrogen atom or an methyl radical; n) / 3 cP- N OCH * E1 v) (/ \) -, - C - Cl \ = / 1 '1 \ „2 12 where R and R each represents a hydrogen, chlorine or fluorine atom; w> (T ~ '\

/ \ H

W-0'01 'och2ch5

II

B-CH-0-C1.HCl V I

x) HH

C = KH

RH2 where B represents "“ "Ô-“ O- ° u O- where R1 represents a hydrogen atom or a hydroxyl 2 or acetoxy radical and R represents a hydrogen or chlorine atom or a hydroxyl radical when R ^ represents a hydroxyl radical, and R 2 represents a hydrogen atom when R represents a hydrogen atom or an aetoxy radical; y) / == \ _ "\ _J ~ T" C_C1 * 3 • CH2N,> “} / Γ \» / '' S — CH-C-Cl

Eh

___ c = o \ j) ~~ N- o

THIS

J> = \ t

Hb) 0 = (E-CH2C-C1

THIS

___ 0 cc) / \ CI ^ -C-Cl ee) 0 11 B-CH-C-Cl

Eh

c = o

'EHR

<i where B represents * -0- “" u- where R ^ represents a hydrogen atom or a hydroxyl p or acetoxy radical and R represents a hydrogen or chlorine atom.

p 1 and R represents a hydrogen atom when R represents a hydrogen atom or an acetoxy radical, and R represents a hydrogen atom or a cyanomethyl radical; r \ s ff) N-CH2G-G1 0

II

gg) Cïï2 = CH-CH2-S-CH2-C-C1 V ° 6H5

hh) X

/ NC-C1

II

O

0

II

B-CH-C-C1

ii) HH

I ^ 0 = C-HÏÏ-C ^ ^ hh2 where B represents • “-O-“ Ql “C7X- where R *" represents a hydrogen atom or a hydroxyl radical p or acetoxy and R represents a hydrogen atom or chlorine \ or a hydroxyl radical when R ^ represents a hydroxyl radical, and R represents a hydrogen atom when R represents a hydrogen atom or an acetoxy radical; 0 OH "1 / = v 3i) r— \ / r 'where B. represents a hydrogen atom or a methyl radical, -y 0 m - o = co XX; 0 11) / \! .C1 \ _ / ^ M2 whose amino radical is "blocked, if desired, by a" classic blocking radical, in particular in particular by protonation; 0

II

mm) ^ GH-G-G1 .XX “3" XX »CHC-Cl h nn) HH '0 I II JB & 0 = 0-0¾-NH-C-HH-C ^ ^ ^ hh2" XX ·, CH- C-C1

oo) HH ° jH

0 = C-HH ^^ \ ^ N N.

»Ο pp) (CH,) 0CHCHo0h !! - C1, -1

32 2I N

° -p »J

. / “X fi qq) \\ j) - CH-C-C1 '-' H-CH, I 5 11¾ in the hydrochloride state, if the thing is desired; 0

II

b-ch-o-ci rr) |

HH

I o «Jk

I I

Ί3 ^ where B represents Â_ 011 0- or O-

_ V

where represents nn hydrogen atom on a hydroxyl radical p on acetoxy and E represents nn hydrogen atom on chlorine on nn hydroxyl radical when R ^ represents nn hydroxy radical - i 2 i le, and E represents nn hydrogen atom when R represents a hydrogen atom, there is an acetoxy radical; a 0, Il ss) B-CH-C-C1 HH KH t v I II JT \

0 = C-CHgtIH-0-Γ S

r2

lHö_ - Ο- ~ UL

where R1 represents a hydrogen atom or a hydroxyl radical p or acetoxy and R represents a hydrogen or chlorine atom or a hydroxyl radical when R · * "represents a hy-droxyl radical, and R represents a hydrogen atom when R represents a hydrogen atom or an acetoxy radical; 0 tt) B-CH-I-C1

HH OH

where B represents r \ ° u (3- ° ui 'x where R represents a hydrogen atom or a hydroxyl o or acetoxy radical and R represents a hydrogen or chlorine atom "or a hydroxyl radical when R ^ represents a hy- 2 i droxyl radical, and R represents a hydrogen atom when R represents a hydrogen atom or an acetoxy radical;

H

H] -C -01

Ü-A

CH,

O

ο --CHC-Cl I I 1 vr) l ^ gJJ C = 0

O

0

R

where R represents a hydrogen atom or an methyl radical; 0

II

B-CH-C-C1 l

ww) | IH

C = 0 Φ

Cl where B represents p ET_ ..

KD- O- ”U- where R ^ represents nn hydrogen atom on nn hydroxyl radical p on acetoxy and R represents nn hydrogen atom on chlorine on nn hydroxyl radical when R1 represents nn hy- l-, 2„ i droxyl, and E represents nn hydrogen atom when E represents nn hydrogen atom or nn acetoxy radical.

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 blocking radicals, they can be prepared under practically AA * 4— A Λ AA A · "AAA 4-" î Am J t Vt Λ Λ Π J a T ta> î J aa Π aa Ία Ί a oxalyle.

EXAMPLE 1.-

1.23 ml of triethylamine is added dropwise over 30 minutes to a mixture of 6-aminopenicillanic acid, 10 ml of CD2Cl2 and 1.13 ml of trimethylchlorosilane. Agitation is continued for another 2 hours. Then dry carbon dioxide gas is bubbled through the mixture for approximately 3 hours. At the end of this period, the nuclear magnetic resonance spectrum indicates the presence of 60% of trimethylsilyl ester of 6-trimethylsilyloxycarbonyl-penicillanic acid of formula: 0

It .S ^ ^ CH, (CH ^ Si-O-C-HH - f ^

D - * - I

0 C-0-Si (CHx) x

Il 3 3 0

The mixture is kept overnight in the refrigerator. The following morning, 0.77 ml of F, H-dimethylaniline is added and the mixture is cooled to -8 ° C. 1.2 g of D - (-) - 2-p-hydroxyphenyl-glycyl chloride hydrochloride with a purity of 79% is then added little by little as specified below:

Time in Temperature Supply minutes ° C g 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 +8 220 +15 310 +20

At the end of the 310 minutes of reaction, the chromatography in thin conohe of a sample of mela-neO rde -rea-hinn 4 using a mixture of 60% ethyl acetate, 20% acetic acid and 20% water reveals the presence of amoxicillin.

1.0 ml of D20 is added to a cold 2 ml sample of the final reaction mixture. After being separated by centrifugation, the aqueous phase is revealed to the nuclear magnetic resonance spectroscopy to contain 78% of amoxicillin and approximately 20% of 6-aminopenicillanic acid. Thin layer chroma- tography also confirms the presence of amoxicillin.

EXAMPLE 2, -

The mixture is refluxed for approximately 17 hours and 30 minutes under a stream of nitrogen, a mixture of 5g (0.025 mole) of 6-aminopenicillanic acid, of 6.2 ml of 93% hexamethyldisi-lazane (0.0275 mole) and 0.07 S (approximately 0.001 mole) of imidazole in 40 ml of After this time, 0.13 ml (approximately 0.001 mole) of trimethylchlorosilane is added, which makes the solution cloudy. Heating under reflux is continued for a further 7 hours during which deposits of ammonium chloride are observed in the condenser. At this time, nuclear magnetic resonance spectroscopy reveals the silylation at about 100% of the amino radical and the carboxyl radical of 6-aminopenicillanic acid. 0.2 ml is then added. (0.00125 mole or about 5 mole%) of hexamethyldisilazane and 0.06 ml (about 0.0005 mole) of trimethylchlorosilane and the heating is continued under reflux under a stream of nitrogen for a further 17 hours. At this time, nuclear magnetic resonance spectroscopy gives the same results as above, except for the presence of small amounts of hexa-methyldisilazane and trimethylchlorosilane. Dry carbon dioxide is bubbled through the reaction mixture at room temperature for 75 minutes after which it detects hexamethyldisilazane and reveals the presence of more than $ 92 of trimethylsilyloxycarbonylpenicillanic acid trimethylsilyl ester. 4.45 ml (0.035 mole) of Ν, Ν-dimethylaniline are then added and the mixture is cooled to -3 ° 0. Then added 5 ”65 g of D - (-) - 2-phenylglycyl chloride with a purity of 95% (0.026 mole) little by little as specified below:

Time in Temperature Supply minutes ° C g 0 -3 1.05 20 0 1.30 40 0 1.30 50 0 1.00 60 0 1.00

The progress of the reaction is omitted by nuclear magnetic resonance spectroscopy which indicates very little change at about 5 hours after the start of the reaction, the temperature then being 3 ° 0. The reaction mixture is stored in ice for 16 hours. The refrigeration is then removed and the mixture is stirred for 3 hours and 30 minutes at room temperature (about 20 to 24 ° C). The mixture still contains a large amount of solids. The reaction mixture is stirred at room temperature (22 to 24 ° 0) for about 63 hours after which it is only "slightly cloudy". After extracting a sample using D2O, nuclear magnetic resonance spectroscopy reveals the presence of ampicillin and 6-aminopenicil-lanic acid.

The reaction mixture is cooled to about 0 ° C and stirred for 5 minutes while keeping it cold after addition of 35 ml of ice water. After clarification by film. After separation, the thin layer chromatography on the aqueous phase reveals a large area slower than those of ampicillin and 6-aminopenicillanic acid and due to the new intermediate compound X.

The aqueous phase is adjusted to pH 3.0 using ammonium hydroxide, then inoculated with ampicillin.

35 ml of methyl isobutyl ketone are added and the mixture is stirred, the pH of which is adjusted to 5? 2 with additional ammonium hydroxide, after which the stirring is continued at 20 ° G for 1 hour and in the "ice bath" for an additional 1 hour before storing the mixture in a refrigerated cabinet overnight. The ampicillin precipitate is collected by filtration, which is first washed with 25 ml of cold water, then 40 ml of methyl-isobutyl ketone and finally 40 ml of a mixture of 85 parts of isopropanol and 15 parts of water, after which the solids, whose weight turns out to be 4.5 g, are dried at 50 ° C. and whose thin layer chromatography confirms that 'they consist of ampicillin.

EXAMPLE 3, -

Is heated under reflux for 18 hours under a stream of nitrogen a mixture of 5j4- g of 6-aminopenicillanic acid, 6.2 ml of hexamethyldisilazane at 93% and 0.06 g of imidazole, in 50 of dichloromethane “0.1 ml of tri-methyl chlorosilane is then added, which cloudes the mixture. By heating at "reflux for another 2 hours, a clear solution is obtained, while ammonium chloride is found in the condenser. An additional 0.1 ml of trimethylchlo-rosilane is then added, causing only very slight turbidity. Heating is continued under reflux under a stream of nitrogen for a further 65 hours. The mixture is then cooled to about 22 ° C and we begin to add dry carbon dioxide to it. After 75 minutes the formation of pins of 90% of trimethylsilyl ester of trimethylsilyloxycarbonylpenicillanic acid. 4.45 ml of N, N-dimethylaniline are then added, then 5 × 6 g of D - (-) - 2-phenylglycyl chloride hydrochloride (97% purity) Gradually as indicated below:

Time in Temperature Supply minutes ° C g 0 20 1.35 20 20 1.30 32 20 1.00 48 20 1.00 75 20 1.00

After stirring this mixture for another 17 hours, thin layer chromatography is carried out on samples of the reaction mixture and of the diluted reaction mixture (1 ml of reaction mixture and 2 ml of methylene chloride) which reveals in each case a small area of ampicillin and a large area of the new intermediate compound X.

The reaction mixture is then cooled to 0 ° C and 40 ml of ice water is added thereto, then the new mixture is stirred for 5 minutes and clarified by filtration, after which it is washed with water and with methylene chloride. The aqueous phase is separated from which 10% is collected as a sample, then the remainder is adjusted to 350 with ammonium hydroxide, the new mixture is seeded with ampicillin and stirred. After adding 40 ml of methyl isohutylketone, the mixture is stirred and its pH is adjusted to 5> 2 using ammonium hydroxide, after which the stirring is continued at room temperature for 1 hour, then in an ice bath for another 1 hour. A precipitate of crystals is formed.

After overnight refrigeration, the methylisobutylketone product is collected with water and methylisobutylketone, followed by 40 ml of an 85% mixture of isopropanol and water, after which the solids are dried to 45 ° C to obtain 6.25 g of ampicillin (6.8 g if the sampling is taken into account, the yield therefore being 68%).

EXAMPLE 4, -

1.23 ml of triethylamine is added dropwise over 30 minutes to a mixture of 1.0 g of 6-aminopenicillinic acid and 1.13 ml of trimethylchlorosilane in 10 ml of bis-deuterated methylene chloride, then the mixture is stirred for a further 2 hours. Dry carbon dioxide is bubbled through the mixture for 4 hours. At this time, nuclear magnetic resonance spectroscopy reveals a carboxy-silylation of about 55 to 60%. The mixture is kept in the refrigeration cabinet overnight. The next morning, 0.77 ml of N, N-dimethylaniline is added and the mixture is stirred, then cooled to -8 ° C and 1.2 g of D - (-) - chloride hydrochloride are added. 2-p-hydroxyphenylglÿcyle little by little as specified below:

Time in Temperature Supply _ minutes ° C g 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 8 220 15 310 20

After 310 minutes, nuclear magnetic resonance spectroscopy reveals the presence of approximately 78% amoxicillin and approximately 20% 6-aminopenicillanic acid.

EXAMPLE 5.-

By stirring at 25 ° C., 10.0 g (0.04624 mol or

1.0 equivalent) of dry 6-aminopenicillanic acid suspended in 175 ml of anhydrous methylene chloride. We add at 25 ° G

10.76 g (0.10656 mole or 2.50 equivalents) of triethylamine, then 11.70 g (0.10775 mole or 2.55 equivalents) of trimethyl-chlorosilane in 10 to 15 minutes while keeping the temperature below about 52 ° G by acting on the addition rate of trimethylchlorosilane. After 20 to 50 minutes of stirring, it is determined by nuclear magnetic resonance spectroscopy at 80 MHz whether the silylation is complete in the mixture containing a precipitate of triethylamine hydrochloride. Carbon dioxide is bubbled through at 20 ° C. for approximately 2 hours in the mixture, which is assessed by nuclear magnetic resonance spectroscopy at 80 MHz if the carboxylation is complete. Sometimes it is necessary to continue the bubbling. If necessary, the volume of the carboxylation mixture is reduced to approximately 175 ml with dry methylene chloride. At the end of the carboxylation, 2.95 g (0.05087 mol or

5.56 ml or 1.1 equivalent) of propylene oxide and the mixture is cooled to 0-5 ° C. The hemisolvate formed by D - (-) - 2-p-hydroxyphenylgly- hydrochloride is then added. cyle with dioxane in 5 fractions of 2.71 g at about 2 ° G

or a total of 15.54 g (0.05087 mole or 1.1 equivalent). Each aliquot of acid chloride is allowed to dissolve before adding the next. To this end, the stirring is stopped and the mixture is examined to assess the presence of a solid at the bottom of the flask. The suspension is not heated to more than 5 ° C for this examination which would otherwise give erroneous results. The time required is approximately 20 minutes per aliquot. This addition by successive fractions is very important, if necessary, of undissolved acid chloride hydrochloride.

The mixture is stored at 0-5 ° C for 30 minutes, then 100 ml of cold deionized water (0 to 5 ° 0) is added thereto with vigorous stirring over 10 minutes. The mixture is allowed to separate and the lower phase formed by methylene chloride is collected. The rich aqueous mixture having a very weak solids content is clarified by filtration by passing it over a thin layer of diatomaceous earth sold under the name of Dicalite and the solids are washed with 15 ml of cold deionized water (0 to 5 ° 0). Before crystallization, the optional lower organic phase is separated. The clear, light yellow aqueous phase is adjusted from pH 2 to 2.5 to 3.5 to 5 to 0 to 5 ° C and seeded, if necessary. The suspension is kept at 0-5 ° 0 for 40 minutes, then it is adjusted to pH 4.8-5.0 with 6 ST ammonium hydroxide and it is allowed to crystallize for 2 hours. The suspension is filtered and the collected solid amoxicillin is washed with a cold mixture (0 to 5 ° C) of isopropanol and water in the ratio 1: 1, after which the solids are washed with 30 ml of methylene chloride to obtain approximately 13.5 S (approximately 70%) of snow white amoxicillin trihydrate.

EXAMPLE 6 - Stirred and heated at reflux for 3 hours and 18 minutes 108 g (0.5 mole) of 6-aminopenicillanic acid,% 1.0 g (0.017 mole) of imidazole, 800 ml of chloride dry methylene and 120 ml (0.56 mole) of hexamethyldisilazane (about 98% purity). The reaction mixture is purged with dry nitrogen during reflux heating to entrain ammonia which is evolved during the reaction. 2.0 ml (0.016 mole) of trimethylchlorosilane are then added. Heating is continued under reflux under a stream of nitrogen for a further 19 hours, then condenser is added and 2.6 ml (0.0206 mol) of trimethylchlo-rosilane are added to the reaction mixture. Heating is continued at reflux under a stream of nitrogen for a further hour. The volume of the reaction mixture is brought to 1,000 ml with dry methylene chloride. Nuclear magnetic resonance spectroscopy reveals 100% silylation of the amino radical and the carhoxyl radical of 6-aminopenicillanic acid. The solution is protected by a nitrogen atmosphere and stored for 9 days. Nuclear magnetic resonance spectroscopy confirms the above results and the stability of the system. The solution is stirred and bubbled carbon dioxide for about 90 minutes at a temperature of 20 to 22 ° C. Nuclear magnetic resonance spectroscopy reveals the conversion of 100% of bis-trimethylsilyl-6-aminopenicillanic acid to bis-trimethylsilylcarboxy-6-amino-penicillanic acid.

This masterbatch is used for the acylation experiments described below. The dissolved active compound has the formula:

0 S

(CH ^ Si-O-C-BH - / CH-, _TT_ o O ^ 0-0-Si (CH-z) -z

Nuclear magnetic resonance spectroscopy confirms that bis-trimethylsilyloxycarbonyl-6-aminopenicillanic acid remains stable after 9 days.

100 ml of the master mixture (containing bis-trimethylsilylcarboxy-6-aminopenicillanic acid in an amount corresponding to 10.8 g of 6-aminopenicillanic acid, ie 0.05 mol) are stirred at 22 ° C. and 8 are added, 0 g (0.0 ^ 8 mole) of chlorhy- 1 I nt "Sil -1 ·" r. λ η / λ λχ ”. ^ N _i · ____ Λ _ Jl _ lene (see "United States Patent No. 3-74-1.959) -A certain amount of triethylamine hydrochloride precipitates. The mixture is stirred and cooled to + 3 ° C.

15.5 g of the hemisolvate formed by the hydrochloride of D - (-) - p-hydroxyphenylglycyl chloride with dioxane (79% purity; 0.055 mol) are added thereto little by little as indicated below. :

Time contribution in temperature

g minutes ° C

3.0 0 +3 3.0 7 +2 3.0 20 +2 6.3 33 +2 15.5

After another 70 minutes, about 50 ml of dry methylene chloride is added to the reaction mixture to make it fluid.

After another 160 minutes, a 2 ml sample is taken, which is added to 1.0 ml of D ^ O. After centrifugation, the nuclear magnetic resonance spectrum of the aqueous phase indicates the presence of approximately 6% of non-acylated 6-aminopenicillanic acid.

The reaction mixture is transferred 10 minutes later to a 600 ml beaker and the transfer is completed by rinsing with 50 ml of methylene chloride. 60 ml of ice-cold deionized water are added with stirring. to obtain two phases free of solids and having a pH of 1.0.

While stirring, 15.0 ml of a liquid anion exchange resin ("LA-1") is added to the "biphasic" system and the new mixture is seeded at pH 2.0. Crystallization begins. In about 5 minutes, a further 0.15 g of sodium borohydride is added slowly, then 5.0 ml of resin LA-1 is added, the pH then being 4.5 - stirring is continued and added dropwise a solution of 1.0 g of sodium bisulfite in 4.0 ml of water, then 10.0 ml of LA.-1 resin is added, the pH thus continuing to rise.

The total amount of LiL-1 resin is 40 ml and the final pIi is 5> 6. 5 ml of acetone are added. At this point, a solution of 1.5 g of sodium bisulfite in 6.0 ml of water is added over 30 minutes. Stirring is continued in an ice bath, u The precipitated product is collected by filtration and the filter cake is washed successively with 50 ml of methylene chloride, 40 ml of water, 100 ml of a mixture 80:20 d 'iso-propanol and water and 100 ml of methylene chloride. The filter cake is dried under atmospheric pressure at 45 ° C to obtain 18.2 g of amoxicillin trihydrate, the yield of which is therefore 87% on the basis of 6-amino-penicillanic acid, the yield of together being about 88% taking into account the 1% sampling.

The liquid anion exchange resin "IA-1" is a mixture of secondary amines, each secondary amine of which has the formula: E1 1?

CH ^ C (Cïï ^) 2CÏÏ2C (Cïï5) 2CH2CH = CH-CH2mC-R

έΡ *> 1 2 3 where E, E and E ^ each represent an aliphatic hydrocarbon radical and together have 11 to 14 carbon atoms. This particular mixture of secondary amines, sometimes called "mixture of liquid amines No. 1", is a clear amber liquid having a viscosity of 70 centipoise at 25 ° C; a density of 0.845 at 20 ° C; a refractive index of 1.467 at 25 ° C; a distillation interval at 10 mmïg up to 160 ° C - 4%, from 160 to 210 ° C - 5%, 4 EXAMPLE 7.-

0.20 g (0.00145 mole) of triethylamine hydrochloride are added, then 0.162 g (0.00275 mole) of propylene oxide at 25 ° C. to 550 ml of a solution of 0.54 g ( 0.002497 mol) of trimethylsilyl 6-trimethylsilyloxycarbonylaminopenicillanate in methylene chloride. The mixture is stirred at 25 ° C for 20 minutes to facilitate the dissolution of most of the triethylamine hydrochloride. 0.45 g (0.00275 mole) of phenoxyacetyl chloride is added dropwise at 25 ° C and the mixture is stirred at 25 ° C for 50 minutes. A sample is taken from which the nuclear magnetic resonance spectrum of carbon 15 is recorded at 20.0 MHz. The results indicate the complete disappearance of phenoxyacetyl chloride and 6-aminopenicylic acid carbamate and the appearance of the trimethylsilyl ester of penicillin Y.

The presence of the trimethylsilyl ester of penicillin Y is proved by comparison of the spectrum with that of an authentic sample prepared by silylation of penicillin V in the form of free acid using triethylamine and trimethylchlorosilane. The yield estimated from the carbon 15 nuclear magnetic resonance spectrum is 85 to 90%.

Cloxacillin, dicloxacillin, staphcillin and * nafcillin are prepared analogously with the same molar amounts of reagents and the appropriate acid chloride. The carbon 15 nuclear magnetic resonance spectra of these acylation mixtures indicate that the estimated yield is at least 85% and that the acation mixtures are very pure.

EXAMPLE 8, -

A compound of formula: 4 is reacted according to the above procedures.

0 HH

Π: 1 s. πττ (CHz) 2Si-0-0-HH-f-3 3 3 \ ^ 0K3

^ 0-B

where B represents an easy-to-remove protective esterifying radical chosen from trimethylsilyl, benzhy-dryle, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5 ~ indanyl, 3-phthalidyl, l- radicals [(ethoxycarbonyl) oxy] ethyl, pivaloyloxymethyl and acetoxymethyl, with a reagent which is acid chloride or suitable acid chloride hydrochloride containing, if necessary, blocking radicals, then eliminating any blocking radicals, suppression is desired so as to obtain the following compounds: almecillin; Armecillin; Azidocillin; Azlocillin; bacampicillin; Bay K 4-999 of formula: În.3— ch-cohh ~ ί — fsN <CH5 * I J «ch., HH 0 ^ Ή 5

\ 0 COOH

0 = C 5 r-n H H-H = GH _> * \ _ / ° "the BL-P1654 of formula: aS ^ GH3 CH - COM - f 1 I Cïï3 HH 0 => - K-?

oi-rnX C00E

BL-P1908 of formula: H ° - I S ^ ^ OH, U. JJ — CH - COM - τ 'NX 5 XX I I ^ CH, M OH QJ-H- ^

0 = o —COOH M J = rO

H

carfecillin; carindacillin; cyclacillin; clometocillin; cloxacillin; dicloxacillin; EMD-32412 of formula: HO— CH - COM - fSN <^ M ^ -H- CH3

0 = C-M O0 COOH

yx epicillin; floxacillin or flucloxacillin; furbucillin; Hetacillin; 1'I.S.F.-2664- of formula: / ^ Λ s CR,

(v Λ- GH - COM - r ^ 3 ^ iC

\ // I 1 ^ CH, „

'-' ÏÏ-CH, J-N- 3 O

| 3 CT H

m2 o = o- och2og-g (ch3) 3 11 isopropicillin; methicillin; mezlocillin; nafcilliue ·, 11oxacilliue; phenlenicillin; the formula PC-4-55: H0 - \\ /) - CH - COM - GE3

\ // I I

- 'M A-N— 5 I ο

0 = C h GOOH

X) * aparcillin (or PG-904) of formula: C -GH - COM —j-f 3 \ - / I I CH-, M nA- ^ - 5

I HO

0 = C I COOH

piperacillin; 3,4-dihydroxypiperacillin; pirbenicillin; pivampicillin; PL-385 of formula: HO- I / Cïï3 U. JJ — CH - COHH - I I gh ^ m o ^ -

n-n COOH

° "Gv OH

T I i a ~ \ _

prazocillin; ^ G®-G

sarmoxicillin; sarpicillin; sodium ticarcillin cresyle; ticarcillin; carbenicillin; carfecillin; fibracillin and Bay-e-6905 of formula: / \ —CH - COHH - r ^ SVC 5 I 'CIi3 * N-' HH J-H- *! 0 ^

G ~ ° COOH

0

-HH

The present invention is capable of numerous industrial applications.

Claims (15)

1.- Compound of formula: S? ^ S / CH3 (CH ^ Si-O-C-NEi - γ j \ CH J - * - \ J <0-B where B represents an easily esterifying protective radical. 2.- Compound of formula: 2. H Il:: ^ D ΛΙΓΓ (CH,), Si-0-Cm —- 3 3y3 J \ gh, I-] j- p <V0-B where B represents an easy-to-remove protective esterifying radical chosen from trimethylsilyl radicals, henzhydryl, henzyl, p-nitrohenzyl, p-methoxÿbenzyl, trichloroethyl, phe-nacyl, acetonyl, methoxymethyl, 5-iudanyl, 3-phthalidyl, 1- [(ethoxycarbonyl) oxy] ethyl, pivaloyloxy; 3 · - the compound of formula: î? / S. CBL '' (CH3) 3Si-0-C-HH — j-γ \ / 3 J-H- Cn5 * C ^ ° '^ 0-Si (CH3) 3 4 -.- Process for the production of a compound of formula: 2. H „It s; ^ c> / -irr (GH ^) ^ Si-O-G-KH— = t-3 J — ir - 3 1 ^ 0 X0-B where B represents an easily esterifying protective esterifying radical. characterized in that dry carbon dioxide is added to a solution of a compound of formula: HH rTT: 8 yo (CH5) 5siira-ij- "'Ch3 JH- CT ^ 0-B where B has the meaning which was given above, in an anhydrous inert organic solvent at a temperature of 0 to 100 ° C until completion of the reaction. 5 · - Process according to claim 4, characterized in that B represents an easy-to-remove protective esterifying radical chosen from trimethylsilyl, benz-hydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloro-ethyl, phenacyl, acetonyl radicals, methoxymethyl, 5 ~ indanyl, J-phthalidyl, 1- [(ethoxycarbonyl) oxy] ethyl, pivaloyloxymethyl and acetoxymethyl. " 6. Method according to claim 4 or 5) characterized in that B represents a trimethylsilyl radical. 7.- Improved process for the production of a known penicillin of formula: 0 HH 11 î / ch3 EC-EH-ip P — fr ^ OH Ja ο where R -!) - represents the radical remaining after the elimination of the hydroxyl radical of an organic carboxylic acid of 2 to 20 carbon atoms, according to which is carried out by means of the chloride of the organic carboxylic acid the acylation of a silylated nucleus of formula: HH S QU (CH ^ SiM —- 5 JH- 3 ° c ^ °; ^ ob where B represents an esterifying radical protector easy to remove and then the radical B is replaced by a hydrogen atom, characterized in that before the acylation, the silylated nucleus is converted into the compound of formula: fi? Vs \ / 0¾ (CH,), Si -0-C-HH —-- Y 7 3 5 ^ -CH, Ju- 3 cr „γΡ 'Vb where B has the meaning given to it above, by a process according to any one of claims 4 to 6. 8.- Process for the production of a 6 - a- amino ar yl - »acetamidopenicillanic acid, characterized in that the compound of formula: 0 Il / CH, (CH,), Si-0-C- is reacted NH-GH-GH CC 3 3 «| | O3 / 3-C-O-Si (CH ^) ^ .0 in an anhydrous inert organic solvent with a weight about κ equimolar of a chloride hydrochloride of D - (-) - cx- amino arylac etyl. 9 · - Process for the production of amoxicillin, characterized in that the compound of formula is reacted: 0 s It \ ^ (CH-,) * Si-0-C-NH-CH-OH 0 ^? 5. I I I OHj À-K-GH 0 ^ I 0-0-Si (0H *) * Il 5 3 0? . in an anhydrous inert organic solvent with an approximately equimolar weight of D - (-) - 2-p-hydroxyphenylglycyl chloride hydrochloride. 10.- Process for producing ampicillin, characterized in that the compound of formula is reacted: 0 S (CH *) * Si-0-C-HH-CH-OH 0 ^? 3. I, I J-11-® 0 0-0-Si (CH,), Il 3 3 0 in an anhydrous inert organic solvent with a roughly equimolar weight of D chloride chloride hydrochloride - (-) - 2 -phenyl-glycyl. 11. Process according to any one of Claims 8 to 10, characterized in that the reaction is carried out at a temperature above -10 ° C. "