DK160613B - PROCEDURE FOR PREPARING CONVENTIONAL PENICILLINES - Google Patents

Description

DK 160613B

in

The present invention relates to a particular process for the preparation of conventional penicillins such as ampicillin and amoxicillin.

The first commercial penicillin having an α-amino group of the 6-5 acylamidoside chain was ampicillin, which is 6- (D-α-amino-α-phenylacetamido) penicillanic acid (see U.S. Patent No. 2,985,648).

Amoxicillin is an antibacterial agent used in human therapy and marketed as the trihydrate of the free acid (i.e., the zwitter ion). The compound is e.g. disclosed in British Pat.

10 978,178, J.Chem.Soc. (London), pages 1920-1922 (1971) and Antimicrobial Agents and Chemotherapy - 1970, pages 407-430 (1971). Its chemical name is 6- [D-α-amino-α- (p-hydroxyphenyl) acetamido] penicillanic acid.

The use of amino acid chloride, hydrochlorides for the preparation of such penicillins has been disclosed in the patent literature, e.g. in British Patent Nos. 938,321 and 959,853 under anhydrous conditions (the latter used protection during the acylation of the carboxyl group of 6-aminopeniacillanic acid with a silyl group, as also disclosed in British Patent Nos. 1,008,468 and US Patent Nos. 3,249,622); in British Patent Specification No. 962,719 in cold aqueous acetone. These 20 penicillins are amphoteric amino acids and therefore were used for their isolation (e.g., in U.S. Patent Nos. 3,157,640 and 3,271,389) to certain aliphatic asymmetric branched secondary amines (often called liquid amine resins) which had previously has been used to isolate 6-aminopenicillanic acid, which is also an amphoteric amino acid 25 (see United States Patent No. 3,008,956). Improved methods for isolating and purifying such penicillins have been disclosed in e.g.

U.S.A. U.S. Patent No. 3,180,862 via / J-naphthalene sulfonates and in U.S.A. Patent No. 3,198,804 via intermediate isolation and subsequent light hydrolysis of hetacillin.

The use of a silyl group to protect the carboxyl group in a natural penicillin during chemical cleavage to 6-aminopenicillanic acid was disclosed in U.S.A. U.S. Patent No. 3,499,909. The use of silylated 6-aminopenicillanic acid during anhydrous acylation with amino acid chloride hydrochlorides has been disclosed in numerous patents, e.g.

35 U.S.A. U.S. Patent No. 3,478,018, U.S.A. U.S. Patent No. 3,595,855, U.S.A. U.S. Patent No. 3,654,266, U.S.A. U.S. Patent No. 3,479,338 and U.S.A. U.S. Patent No. 3,487,073. Some of these patents also deal with the use of liquid amine resins. See also U.S.A. 2

DK 1 60613 B

ter Nos. 3,912,719, 3,980,637 and 4,128,547.

British Patent Specification 1,339,605 contains various specific and detailed examples of the preparation of amoxicillin by reacting a silylated derivative of 6-aminopenicilic acid with a reactive derivative (including the chloride, the hydrochloride) of D - (-) - α-amino - p-hydroxyphenylacetic acid wherein the amino group is protected, then in the removal of the silyl group or groups by hydrolysis or alcoholysis and then, if possible, the recovery of amoxicillin, usually as the crystalline trihydrate. Thus, crystalline amoxicillin in Example 1 was obtained by isoelectric precipitation from an aqueous solution, e.g. at pH 4.7. Purification was probably achieved in this example by dissolving the crude product (before isoelectric precipitation) in water at an acidic pH such as 1.0 (e.g., in aqueous hydrochloric acid) in the presence of a water-immiscible organic solvent. such as methyl iso- Butyl ketone (4-methylpentan-2-one). Substantially the same procedure j was used in U.S.A. U.S. Patent No. 3,674,776. From US Pat.

4,064,151, it is known to prepare isocyanates directly from amines by a process which comprises reacting with halogenosilyl compounds to form halogenosilyl carbonates. However, this patent does not contain anything which may draw attention to the fact that penicillin compounds can be subjected to a similar reaction to obtain carbamate intermediates which are resistant to acylation to form the desired penicillins, since the β-λactamrin in penicillin is known is very sensitive.

The present invention provides a method for preparing a conventional penicillin of the formula

η Η H

S = = R -C-NH-r-γ | \ 30. J- N-; CH3 P °

^ OH

Wherein R-C- represents the residue after removal of the hydroxyl group from an organic carboxylic acid containing from 2 to 20 carbon atoms, acylated with the acid chloride of the organic carboxylic acid of a silylated nucleus of formula

DK 160613 B

3

Η H

i i c XH, (CH3) -SiNH-5 i-N- CH3 ° if

X) -B

wherein B represents a readily cleavable ester-protecting group and then group B is converted to hydrogen, which method is characterized in that before the acylation, the silylated core is converted to a compound of formula o S? S in S / S 2 / CH 15 (CH 2) 3 Si-O-C-NH-f-r

Jr- N- CtI3 0 hf

X) -B

Wherein B has the same meaning as set forth above by adding dry carbon dioxide to a solution of a compound of the formula

Η H

25 l / K / CH 3

(CH ^ si.NK-pr'K

J ~ * - C 3 ° hf

X) ~ B

Wherein B is as defined above, in an anhydrous inert organic solvent at a temperature in the range of 0 ° C to 100 ° C, until the reaction is complete.

A conventional penicillin as defined herein is a penicillin which has been previously described in the patent or scientific literature, including summaries thereof.

In a preferred embodiment, the present invention provides a process for preparing a 6-α-aminoarylacetate.

DK 160613 B

4 amidopenicillanic acid, preferably ampicillin or amgoxillin, by which a compound of the formula, II / CH, 5 (CH-) Si-O-C-BH-CH-CH C 5 73 | In I ^ CH, λ-N-CH>

tf I

C-O-Si ^ ^ H

ISLAND

10 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 at a temperature above -10 ° C, more preferably in the range of -8 ° C to 20 ° C. still more preferably in the range of 0 ° C to 20 ° C, and most preferably at about 20 ° C, with approximately an equimolar amount of a D - (-) - α-aminoarylacetyl chloride, hydrochloride, preferably D - (-) - 2-phenylglycyl chloride, hydrochloride or D - (-) - 2-p hydroxyphenylglycyl chloride, hydrochloride, the latter being preferably added portionwise to the solution of the former.

One of the surprising features of the novel process is the stability of the anhydrous acylation solution. This can be kept for long periods of time, even at room temperature, without remarkable decomposers! ng of the penicillin molecule. This contrasts with the behavior of 25 acylation solutions in the previously described methods. This stability advantage enables the acylation reaction to be carried out at much higher temperatures (here, room temperature was used) than normally used in the ampicillin preparation, which is usually below 0 ° C and typically approx. -10 ° C.

The compound of the formula

0 Q

, λ II / \ / CH 5 (CH,), Si-O-C-BH-CH— CH C 3 * 3 II I ^ CH, λ-N-CH>

35 / I

υ C “O-Si (CH-.

11 53

ISLAND

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5 are referred to herein by various trivial names such as bis-silylated carbamate of 6-APA, SCA, 6-trimethylsilyloxycarbonylpenicillanic acid TMS ester and TMSO2C, APA, TMS.

The very existence of this compound is surprising considering the well-known fact that reacting 6-APA with carbon dioxide destroys 6-APA and yields 8-hydroxypenicillanic acid as contemplated e.g. in USA. U.S. Patent No. 3,225,033.

An agent for obtaining quantitative yields of 6-trimethylsilyloxycarbonylaminopenicillanic acid trimethylsil ester (TMS01C, APA, TMS) 10 is in complete preparation of the 6-APA bis-TMS precursor in the first place. This has been achieved by reacting 6-APA with hexa-methyldisilazane (HMDS) as in the following reaction scheme: 6-APA + HMDS + Imidazole- For reflux inq 1 mole 1.1 mole of catalyst 6-8 hours 3- 5 mole% 20 Full carboxyl Add 5 mole% TMCS and "silylation" & approx. reflux overnight 40-65% 6-NH 2 over "silylation" TMSNH g \ -S (6-APA, bis-TMS) J-N- \ 6 '* co2tms 30

The termination of the bis-trimethylsilylation reaction can be readily followed using NMR. The 3-trimethylsilyloxycarbonyl group shows a methyl silyl group at 0.31 ppm (tetramethylsilane = 0), while the 6-trimethylsilylamine group shows a methylsilyl singlet at 0.09 ppm.

The 6-APA trimethylsilylation reaction has so far been carried out only in methylene chloride. However, other solvents may be used, such as e.g. acetonitrile, dimethyl formamide or even HMDS itself.

6

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Conversion of the trimethyl silylamino group to the trimethylsilyloxy-carbonylamino group is readily achieved by bubbling dry COg in the reaction solution. The conversion is easily followed by NMR because the trimethylsilyl amino singlet at 0.09 ppm declines as a new trimethyl silyloxycarbonylamino group occurs at 0.27 ppm.

When the process of the present invention is used to prepare ampicillin, ampicillin anhydrate, ampicillin trihydrate, amoxicillin and amoxicillin trihydrate, the final products are isolated and purified according to conventional methods well known in the art as illustrated by U.S.A. Patent Nos. 3,912,719, 3,980,637 and 4,128,547, as well as other patents and publications therein.

The acid chlorides used in the following examples can be replaced by! a wide variety of other acid chlorides for the production of conventional penicillins.

Thus, the acyl halide may also be selected to introduce any desired acyl group into the 6-amino position, as is well known in the art, e.g.

U.S.A. U.S. Patent No. 3,741,959. Therefore, it is possible to introduce specific acyl radicals, including, but not limited to, those defined by the following general formulas: (i) RUcnH2nCO2 wherein rU means aryl (carboxyl in sk or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl or a non-aromatic or mesoionic heterocyclic group, and n is an integer from 1 to 4. Examples of this group include phenyl acetyl, j substituted phenyl acetyl, e.g. fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methphenylacetyl or hydroxyphenylacetyl; N, N-bis (2-chloroethyl) aminophenyl-propionyl; thien-3-and-3-acetyl; 4-isoxazolyl and substituted 4-isoxazolylacetyl; pyridylacetyl; tetrazolylacetyl or a south nonacetyl group. The substituted 4-isoxazolyl group may be a 3-aryl-5-30 methyl isoxazol-4-yl group, wherein the aryl group e.g. is phenyl or halophenyl, e.g. chloro- or bromo-phenyl. An acyl group of this type is 3-o-chlorophenyl-5-methylisoxazol-4-yl-acetyl.

(ii) CnH2n + IC0 ~ where n is a number 177 may be straight or branched and optionally interrupted by an oxygen or sulfur atom or substituted by e.g. a cyano group. Examples of such groups include cyanoacetyl, hexanoyl, heptanoyl, octanoyl and butyl thi oacetyl.

(iii) ^ η ^ η.ι ^ Ο-, where n is an integer from 2 to 7. The group can

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7 be straight or branched and, if desired, interrupted by an oxygen or sulfur atom. An example of such a group is allylthi oacetyl.

(Iv>

Rus __-- C ------

RW

Wherein R Ru is as defined in (i) and may additionally be benzyl, and Rv and Rw, which may be the same or different, each represent hydrogen, phenyl, benZyl, phenethyl or lower alkyl. Examples of such groups include phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybutyryl, benzyloxycarbonyl, 2-methyl-2-phenoxypropionyl, p-cresoxyacetyl and p-methylthiophenoxyacetyl.

(v) | V

Rus-c-CO-

RW

wherein Ru has the meaning given under (i) and in addition may be benzyl and Rv and Rw have the meanings given under (iv). Examples of such groups include S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl and S-benzylthioacetyl.

(vi) RuZ (CH2) mC0- wherein Ru has the meaning set forth in (i) and may additionally be benzyl, m is an oxygen or sulfur atom, and m is an integer from 2 to 5. An example of a such group is S-benzylthio-propionyl.

(vii) RuCO-, where Ru has the meaning set forth in (i). Examples of such groups include benzoyl, substituted benzoyl (e.g., amino-benzoyl), 4-isoxazolyl, and substituted 4-isoxazolylcarbonyl, cyclopentanecarbonyl, sydoncarbonyl, naphthoyl and substituted naphthoyl (e.g., 2-ethoxynaphthoyl), quinoxylcarbonyl and substituted quinoxalinylcarbonyl (eg 3-carboxy-2-quinoxalinylcarbonyl). Other possible benzoyl substituents include alkyl, alkoxy, phenyl 8

DK 160613 B

or phenyl substituted with carboxy, alkylamido, cycloalkylamido, allylamido, phenyl (lower) -alkylamido, morpholinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, tetrahydropyridino, furfurylamido or N-alkyl-N-anilino or derivatives thereof and such substituents may be in the 2 or 2 and 6 positions. Examples of such substituted benzoyl groups are 2,6-dimethoxybenzoyl, 2-biphenyl carbonyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. Where the group Ru represents an in-substituted 4-isoxazolyl group, the substituents may be as set forth above (i). Examples of such 4-isoxazole groups are 3-phenyl-5- 10 methyl isoxazol-4-yl-carbonyl, 3-o-chlorophenyl-5-methylisoxazol-4-yl-carbonyl and 3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl-carbonyl.

(viii) RU-CH-CO-

15 I

x wherein Ru has the meaning set forth in (i) and X represents amino, 20 substituted amino (e.g., acylamido or a group obtained by reaction of amino groups and / or the group or groups in the 7-side chain with an aldehyde or ketone (e.g., acetone, methyl ethyl ketone or ethyl acetoacetate), hydroxy, carboxy, esterified carboxy, triazolyl, tetrazolyl, cyano, halo, acyloxy (e.g., formyloxy or lower alkanoyloxy) or etherified hydroxy group . Examples of such acyl groups are α-aminophenylacetyl, α-carboxyphenylacetyl and 2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl.

(Ix)

RX

30 j

Ry-c-co-I,

RZ

wherein Rx, Ry and Rz, which may be the same or different, may each represent lower alkyl, phenyl or substituted phenyl. An example of such an acyl group is tri phenyl carbonyl.

35 (X)

II

9

DK 160613 B

R-NH-C

ISLAND

wherein Ru has the meaning set forth in (i) and in addition may be hydrogen, lower alkyl or halogen-substituted lower alkyl, and Y represents oxygen or sulfur. An example of such a group is 10 ci (ch 2) 2 nhco.

(xi) (CHJn J> C-C ° -

15 X

where X is as defined above (viii) and n is an integer of from 1 to 4. An example of such an acyl group is 1-aminocyclohexanecarbonyl.

(xii) Aminoacyl, e.g. RWCH (NH 2).

(CH2) nCO, where n is an integer from 1 to 10, or NH2,

Si ^ 2nAr ^ CH2 ^ mC® 'where m is 0 e ^ is a whole ta ^ ra * to 10 and n is 0, 25 1 or 2, Rw represents a hydrogen atom or an alkyl, aralkyl or carboxy group or a group as defined above under Ru, and Ar represents an arylene group, e.g. p-phenylene or 1,4-naphthylene.

Examples of such groups are set forth in British Pat.

1054806. One group of this type is the p-aminophenylacetyl group. Other 30 acyl groups of this type include, e.g. α-aminoadipoyl derived from naturally occurring amino acids and derivatives thereof, e.g.

N-benzoyl-α-aminoadipoyl.

(xiii) Substituted giyoxylyl groups of the formula R 1, C0, C0- wherein Ry represents an aliphatic, an araliphatic or an aromatic group, e.g. a thienyl group, a phenyl group or a mono-, di- or tri-substituted phenyl group, wherein the substituents e.g. are one or more halogen atoms (F, Cl, Br or I), methoxy groups, methyl groups or amino groups or a condensed benzene ring.

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When the acyl group to be introduced contains an amino group, it may be necessary to protect it during the various reaction stages. The protecting group is conveniently one that can be removed by hydrolysis without affecting the rest of the molecule, especially the lactam and 7-5 amido bonds. The amine protecting group and the esterifying group in the 4-C00H pathway can be removed using the same reagent. An advantageous method consists of removing both groups in the last step of the sequence. Protected amine groups include urethane, arylmethyl (e.g., trityl) amino, arylmethyleneamino, sul phenyl amino 10 or enamine types. Enamine blocking groups are particularly valuable in the case of o-aminomethylphenyl acetic acid. Such groups can generally be removed by one or more reagents selected from dilute mineral acids, e.g. dilute hydrochloric acid, concentrated organic acids, e.g. concentrated acetic acid, trifluoroacetic acid and liquid hydrogen bromide at very low temperatures, e.g. -80. A suitable protecting group is the t-butoxycarbonyl group which is readily removed by dilution with dilute mineral acid, e.g. diluted hydrochloric acid, or preferably with a strong organic acid (e.g. formic acid or trifluoroacetic acid), e.g. at a temperature of 0-40 ° C, preferably at room temperature (15-25 ° C). Another suitable protecting group is the 2,2,2-trichloroethoxycarbonyl group which can be cleaved off with an agent such as zinc / acetic acid, zinc / formic acid, zinc / lower alcohols or zinc / pyridine.

The NH 2 group can also be protected as NHg + using the amino acid moiety and the anide as an acid addition salt under conditions where the amino group remains protonated.

The acid used to form the acid addition salt is preferably an acid having a pK value (in water at 25 ° C) of> X + 1, where X is the α pK value (in water at 25 ° C) of the amino acid carboxy groups. The acid is

CL

Preferably monovalent. In practice, the acid HQ (see below) will generally have a pK <3, preferably <1.

α Particularly advantageous results have been found to be obtained with the process of the invention when the acid halide is a salt of an amino acid halide. Amino acid halides have the formula 35

HgN-R 2 COHal wherein R * represents a divalent organic group and Hal represents chloride

DK 160613 B

π or bromide. Salts of such amino acid halides have the formula [H3N-R1-COHal] + Q "5 wherein R * and Hal have the meanings set forth above and Q" means the anion of the acid, HQ having a pKa as defined above. The acid HQ is preferably a strong mineral acid, e.g. a hydrohalic acid such as hydrochloric or hydrobromic acid. An important amino acid halide is, because of the valuable penicillin antibiotics containing the resulting group, DN- (α-chlorocarbonyl-α-phenyl) methylammoniuni 'chloride, D- [PhCH (NH)) COCl] + Cl, which here for convenience reasons are referred to as D-α-phenylgiycylchlori d, hydrochlori d.

Penicillins obtained by the process of the present invention having an acylamido group RUCH (NH 2) -CONH-, where R 1 has the meaning given above, can be reacted with a ketone 2 3 2 3 R R and R are lower alkyl groups (Cj-C ^) to form compounds believed to contain the group:

CO

2 ° \ RU.-CH N- HN___R2 R3

Compounds of this type include hetacillin, sarpi ci11 i n, p-hydroxyhetacillin and sarmoxicillin.

Also included within the scope are the acyl groups listed in U.S.A. No. 4,013,648, column 7-20 inclusive, which is considered part of the present disclosure.

When the acylation process of the present invention is used to prepare penicillins, the final products are isolated and purified according to conventional methods well known in the art.

Preferred acyl chlorides used in the invention to acylate a compound of formula 12

DK 16061-3 B

η Η H

8 in § ^ S ^ CH 3 (CH 2), Si-O-C-NH-f-f 33 l CH-.

/ y ^ - 3

ISLAND

N) -a; wherein A is (CHg) gSi or a readily cleavable ester protecting group comprises the following: a) A-CHgC-1h, wherein A means _XH2NHR! Wherein R is hydrogen, hydroxy or methoxy, and R 'is hydrogen or methyl and the amino group is blocked, if desired, by conventional blocking groups, including especially by protonation. B) B-CH-Ch, HCl, wherein B represents nh2 R 2 - or or

UL

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Wherein R is hydrogen, hydroxy or acetoxy, and R is 1 2 hydrogen, chlorine or hydroxy, wherein R is hydroxy, and R is hydrogen when R * is hydrogen or acetoxy.

C) fi [1 0

I I π

Vs ^ CHgC-Cl; * 1 ° d) Π il ° 11 Ji-C-C-Ol; E) ° 20 wherein R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexa-1,4-dien-1-yl, f)

CnHc-N N-C-NH-CH-C-C1 25 2 5 v_y. Where R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexa-1,4-dien-1-yl, 30 g)? iH-c-cl

N- 'O-C-H

II

h) HN ^^ v-C-NH-CH-C-Cl

O ^ N ^ O R

H

DK 160613B

Wherein R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexadien-1-yl, i) R 2 O 0 O 5 N 2 c-nh

WaJ in which R * is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or 2 cyclohexadien-1-yl, and R is hydrogen or hydroxy,

ISLAND

II n j) F3C-S-CH2C-C1 k) p = \ '? ^ I-CH 2 C-Cl; 15

DK 160613 B

ISLAND

1) NC-CH2C-C1, m> / = \ s N χ /> "S-CH2C-C1;

ISLAND

x II

n) Br-CH 2 Cl-Cl

o) H, iL_lT

ά J — 1 <\ J i? N-uCH2C-C1 o

, II

p) N = C-CH2-S-CH2-C-C1,

g)> TU S

ιΗΎ ^^ 0 I il HN-U — C-C-Cl 5 I! N-OCH3 r-π I-1 0 0 • Γ I ii ii r> U ^ 0 ^> - CH = N-N JJ-C-NH-CH-C-C1

O R

t 16

DK 160613 B

wherein R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexadien-1-yl,

s) O

li x O.

5 11 H

A-N N-C-NH-CH-C-Cl

\ -1 R

in which A represents hydrogen or alkyl of 1-4 carbon atoms or CH 3 SO 2, X represents oxygen or sulfur and R represents phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexa-1,4-dien-1-yl , 15 t> / = Λ R ft / 7) -oco-ci 'c' 3 20 wherein R means hydrogen or methyl, '/ = / ° ¾ o (Ty-c-ci: 25 AND' v> _ / R1 0 O-lMp "C1

Mr2> kOACH3 35 wherein each of R and R is hydrogen, chlorine or fluorine,

DK 160613 B

17

ISLAND

5 Cif-ci OCH2CK3 10 o

II

x) B-CH-C-Cl, HCl, wherein B represents

NH

C = NH

Wherein R is hydrogen, hydroxy or acetoxy, and R is hydrogen, chlorine or hydroxy when R is hydroxy and R is hydrogen when R * is hydrogen or acetoxy, 30

OtLli

-IN

18

DK 160613 B

z) _x; h2n3 I

4 /) - 2-1 · j> 0 0

^ -CH-C-C1 \ rrr / NH

/ = \ H

II 5 0 bb)) = \ ii 0 = \ N-CHOC-C1 Cl, k 0

cc) / - \ II

[CH] C-C1 dd)

DK 160613 B

19

ISLAND

H

ee) B-CH-C-C1!

NH

in C = 0

5 NHR

wherein B represents 1 ° B2

R 1 represents C 1-12 wherein R represents hydrogen, hydroxy or acetoxy, and R represents hydrogen, chlorine or hydroxy when R is hydroxy and R represents hydrogen when R * is hydrogen or acetoxy and R represents hydrogen or cyanomethyl,

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20 ff) _ o N-OH ^ -Cl j i o II, gg) CH2 = CH-CH2-S-CH2-C-C1 hh> ΓΥξΗ5 LAc-d O i o

II

ii) B-CH-C-C1, wherein B represents NH .NH!

1 X

0 = C-NH-C ^

Xnh2 R2 ..

- or or in i -

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Wherein R represents hydrogen, hydroxy or acetoxy, and R represents hydrogen, chlorine or hydroxy when R is hydroxy and R represents hydrogen when R 1 is hydrogen or acetoxy;

/ = \ S

/ - CH-C-Cl - \ J / SO% / r o '-' 10 wherein R represents hydrogen or methyl, 15 kk> / = \ 3 20

11) Oh

The II 25 V_ / NnH 2 and the amino group are blocked, if desired, by conventional blocking groups, including in particular by protonation,

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22 mm) il

Cl CH-C-C1 '* 1 11 ° 0¾

Cl nn) H ° ..

Y ^ i O L IL ». ^ X ^ CHC-Cl NH O ^ KH! 0 = C-CH 2 -NH-C-! H-C 2 d nh 2

HAY

"Χλ

CH-C-C1 in OH

HH i 0 = 0-ΝΗ _ ^^ γΝ ^

pp) 0

(CH2 CHC2 CHC-Cl - o-fi-k0 /

ISLAND

M) / = L / V-CH-C-C1 h-CH-

V

DK 160613B

23 as the hydrochloride, if desired,

ISLAND

rr) B-CH-C-Cl 5 ft 0 "-ύ 10 wherein B represents R2 15 or or ii in which R represents hydrogen, hydroxy or acetoxy and R represents hydrogen, 2 gene, chlorine or hydroxy, when R is hydroxy and R is hydrogen when R 1 is hydrogen or acetoxy, 25

SS) O

B-CH-C-Cl 0 = C-ChTgNH-C - ((j

30 xmzJ

wherein B represents R2 is R 1 "v" - (iiL is present in which R represents hydrogen, hydroxy or acetoxy, and R represents hydrogen, chlorine or hydroxy when R is hydroxy, and R represents hydrogen when R is hydrogen or acetoxy,

B-CH-C-C1® OH

° = c / L

15 L]! J — K N-CKO

wherein B represents 20 R

- or 25 O-30 1 2 wherein R represents hydrogen, hydroxy or acetoxy, and R represents hydrogen, chlorine or hydroxy when R is hydroxy, and R represents hydrogen when R * is hydrogen or acetoxy,

DK 160613 B

25 "A.

M II

5 <Η · ^ 1-C-Cl iL \ '' CHj 0 w), ___ CHC-C1 ”5X r» 0 15

K

wherein R represents hydrogen or methyl, 20 ww) 0 B-CH-C-C1

KH

c = o H5C-C-CH3 O <* 30 *

Cl wherein B represents 35 H 2 or ML or

DK 160613 B

26 - | Ό-5 1 2 wherein R represents hydrogen, hydroxy or acetoxy, and R represents hydrogen, chlorine or hydroxy when R is hydroxy and R represents hydrogen when R * is hydrogen or acetoxy.

Acid chlorides are usually prepared under severe conditions, such as by treating the acid under reflux with thionyl chloride, but when sensitive groups are present, including sensitive blocking groups, they can be prepared under virtually neutral conditions by reacting a salt of the acid with oxalyl chloride.

The method according to the invention is illustrated in more detail in the following examples.

Example 1

To a mixture of 6-aminopenicillanic acid (6-APA) and 10 ml of CD2 Cl2 and 1.13 ml of trimethyl chlorosilane at a temperature of 25-27 ° C was added dropwise 20 1.23 ml of triethylamine over a period of 30 minutes. Stirring was continued for another 2 hours. Dry carbon dioxide gas is then bubbled into the mixture for approx. 3 hours. At the end of this time, NMR (nuclear magnetic resonance) showed the presence of 60% silylated carboxy-6-APA (SCA) of structure 25 (CH2 Si-O-C-HN-j-f P'CH2 30 - y ~ N_

O C-O-Si (CH, U

Il 33 0 35

The mixture was kept in the refrigerator overnight. The next morning, 0.77 ml of Ν, Ν-dimethylaniline was added and the mixture was cooled to -8 ° C. Next, 1.2 g of D - (-) - p-hydroxy-2-phenylglycyl chloride, hydrochloride (79%

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27 purity) in portions as follows:

Time in Temperature Gram, added minutes _ ° C_ 50 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 +8 10 220 +15 310 +20

At the end of the 310 minute reaction period, thin layer chromatography (TLC) performed on a sample of reaction mixture 15 using a solvent system which was 60% ethyl acetate, 20% acetic acid and 20% water, showed the presence of amoxicillin.

To a cold 2 ml sample of the final reaction mixture was added 1.0 ml of D 2 O. After separation by centrifugation, the aqueous phase was found by NMR to contain 78% amoxicillin and ca. 20% 6-APA. The presence of amoxicillin was also confirmed by TLC.

Example 2

A mixture of 5.4 g (0.025 mol) of 6-aminopenicillanic acid and 6.2 ml of 93% hexamethyldisilazane (HMDS; 0.0275 mol) as well as 0.07 g (about 0.001 mol) of imidazole in 40 ml of CH nitrogen rinsing for approx.

17.5 hours. At the end of this period, 0.13 ml (about 0.001 mol) of trimethyl chlorosilane (TMCS) was added. The solution became fuzzy. Reflux was continued for a further 7 hours and deposits of NH 2 Cl were observed in the capacitor. At this point, the NMR showed approx. 100% silylation of both the 30 amino and carboxyl group of 6-APA. 0.2 ml of HMDS (0.00125 mol; about 5 mol%) and 0.06 ml of TMCS (about 0.0005 mol) were then added and reflux with nitrogen rinsing continued for an additional 17 hours. At this point, the NMR spectrum was the same as before with the addition of small amounts of HMDS and TMCS. Dry carbon dioxide was then bubbled into the reaction mixture at room temperature for 75 minutes, after which NMR showed no HMDS and more than 92% silylated carboxy-6-APA (SCA). Then, 4.45 ml of Ν, Ν-dimethylaniline (DMA) (0.035 mol) was added and the mixture was cooled to -3 ° C. Then 5.65 g of D - {-) - 2-phenylglycyl chloride DK 160613B was added: in 28 (95% purity; 0.026 mol) in portions as follows:

Time in Temperature Gram, added minutes _ ° C__ 5 0-3 1.05 20 0 1.30 40 0 1.30 50 0 1.00 60 0 1.00 10

The reaction was followed by NMR which showed very little change approx. 5 hours after the start of the reaction. The temperature was then 3 ° C. The reaction mixture was kept packed in ice for the next 16 hours. It was then removed from cooling and stirred for 3.5 hours at room temperature (about 20-15 24 ° C). A large amount of solid material was still present. The reaction mixture was then stirred at room temperature (22-24 ° C) for approx. 63 hours.

At the end of this time, there was only slight obscurity. Upon DgO extraction of a sample, NMR showed ampicillin and 6-APA. !

The reaction mixture was cooled to ca. 0 ° C and stirred for 5 minutes in the cold after adding 35 ml of ice water. After polishing filtration, the mixture was washed with cold water and CH 2 Clg. The aqueous phase showed | after separation, see by TLC a large zone which was slower than ampicillin and 6-APA and represented new intermediate X.

The aqueous phase was adjusted to pH 3.0 with NH 2 OH and inoculated with ampicillin. Methyl isobutyl ketone (MIBK; 35 ml) was added and the mixture was stirred, adjusted to pH 5.2 with more NH 3 OH, stirred at 20 ° C for 1 hour, stirred in an ice bath for an additional 1 hour and cooled overnight. The precipitate of ampicillin was collected by filtration, washed first with 25 ml of cold water and then with 40 ml of MIBK and finally with 40 ml of 30 a mixture of 85 parts of isopropylal carbon and 15 parts of water, dried at 50 ° C and weighed 4.5 g with its identity as ampicillin confirmed by TLC.

Example 3 A mixture of 5.4 g of 6-APA, 6.2 ml of HMDS (93%) and 0.06 g of imidazole in 50 ml of CH 2 Cl 2 was refluxed under nitrogen rinsing for 18 hours. Next, 0.1 ml of TMCS was added which caused turbidity. Reflux for a further 2 hours gave a clear solution of NH4 Cl in the condenser. there

DK 160613 B

29 was then added an additional 0.1 ml of TMCS, leaving only very slight haze. Reflux was continued without nitrogen rinsing for the next 65 hours. The mixture was then cooled to ca. 22 ° C and addition of dry carbon dioxide was started. After 75 minutes, the NMR showed the formation of more than 90% bis-silylated carbamate (SCA). Then 4.45 ml of DMA and then 5.6 g of D - (-) - 2-phenylglycyl chloride, hydrochloride (97% purity) were added in portions as follows:

Time in Temperature Gram, added 10 minutes _ ° C_ 0 20 1.35 20 20 1.30 32 20 1.00 48 20 1.00 15 75 20 1.00

After this mixture was stirred for a further 17 hours, TLC was performed on samples of the reaction mixture and on diluted reaction mixture (1 ml of the reaction mixture diluted with 2 ml CHgCl 2) and 20 showed in each a small zone of ampicillin and a large zone of new intermediate X .

The reaction mixture was then cooled to 0 ° C, 40 ml of ice water was added and the mixture was stirred for 5 minutes, polished filtered and washed with water and with Ch 2 Clg. The aqueous phase was separated, 10% removed for testing and the residue adjusted to pH 3.0 with NH 2 OH, inoculated with ampicillin and stirred. After adding an additional 40 ml of MIBK, the mixture was stirred and the pH was adjusted to 5.2 with NH 3 OH and stirred at room temperature for 1 hour and then on an ice bath for a further 1 hour. Crystals precipitated. After cooling overnight, the crystalline product was collected by filtration, washed successively with MIBK, water and MIBK And then with 40 ml of isopropanol-water (85-15) and dried at 45 ° C to give 6.25 g of ampicillin (6). 8 g corrected for test or 68% yield).

Example 4

To a mixture of 1.0 g of 6-APA and 1.13 ml of TMCS in 10 ml of CDgCl 3 was added dropwise 1.23 ml of TEA over 30 minutes and the mixture was stirred for a further 2 hours. Dry carbon dioxide was then refluxed for 4 hours. On

DK 160613B

At this time, the NMR showed approx. 55-60% carboxysilylation. The mixture was kept in the refrigerator overnight. In the morning, 0.77 ml of DMA was added, the mixture was stirred, cooled to -8 ° C and 1.2 g of D - (-) - p-hydroxy-2-phenylglycyl chloride, hydrochloride in portions were added as follows:

Time in Temperature Gram, added minutes __ ° C_; 0 -8 0.30 20 -4 0.30 10 40 -4 0.30 60 -4 0.30 120 8 220 15 310 20 15! ;

At the end of the 310 minute period, NMR showed approx. 78% amoxy cillin and approx. 20% 6-APA. 'i

Example 5 Dry 6-aminopenicillanic acid (10.0 g, 46.24 mmol, 1.0 eq) was suspended in anhydrous methylene chloride (175 ml) with stirring at 25 ° C. Triethylamine (10.76 g, 106.36 mmol, 2.30 eq) was added at 25 ° C followed by addition of trimethylchlorosilane (11.70 g, 107.75 mmol, 2.33 eq) over a 10-15 minutes, keeping the temperature below 25 approx. 32 ° C using the addition rate of trimethyl chlorosilane.

After stirring for 20-30 minutes, the mixture containing precipitated triethylamine hydrochloride was analyzed for complete silylation at 80 MHz NMR. The mixture was then gasified with carbon dioxide at 20 ° C for approx.

2 hours and analyzed for complete carboxylation at 80 MHz NMR.

30 Additional gas addition was sometimes needed. The volume of the carboxylation mixture is reset if necessary to approx. 175 ml with dry methylene chloride. When the carboxylation was complete, the slurry was treated with propylene oxide (2.95 g, 3.56 ml, 50.87 mmol, 1.1 eq) and cooled to 0-5 ° C. D - (-) - 2- (p-hydroxyphenyl) glycyl chloride, hydrochloride hemidioxane solvate was added in 5 x 2.71 g portions at ca. 2 ° C [a total of 13.54 g (50.87 mmol, 1.1 eq) was added]. Each batch of acid chloride was allowed to dissolve before the next batch was added. (Stirring was stopped and the mixture examined for any solid on the bottom of the flask.

DK 160613 B

31

The slurry must not be heated below 5 ° C for this test as results may be erroneous). This required approx. 20 minutes per portion. This portion addition was very important. The final acylation mixture was investigated for any undissolved acid chloride, hydrochloride. The mixture was kept at 0-5 ° C for 30 minutes and treated with cold (0-5 ° C) deionized water (DI) (100 ml) with very rapid stirring for 10 minutes. The mixture was allowed to separate and the lower methylene chloride phase was removed. The aqueous phase was polished (very low solids) filtered through a thin (Dicalite) coating of diatomaceous earth and the cake was washed with cold (0-5 ° C) DI water (15 ml). Any lower layer of organic layer was removed before crystallization. The clear, pale yellow aqueous solution (pH 2-2.5) was adjusted to pH 3.5 at 0-5 ° C and seeded if necessary. The slurry was kept at 0-5 ° C for 40 minutes and the pH was adjusted to 4.8-5.0 with 6N ammonium hydroxide and crystallized for 2 hours. The slurry was filtered and the thus obtained solid amoxicillin was washed with a mixture of cold (0-5 ° C) 1: 1 isopropanol / water and the cake washed with methylene chloride (30 ml) to give approx. 13.5 g (about 70%) of snow-white amoxic acid in trihydrate.

Example 6 6-Aminopenicilic acid (108 g, 0.5 mol), 1.0 g imidazole (0.017 ml), 800 ml dry methylene chloride and 120 ml (0.56 mol) HMDS (about 98% purity) were stirred and heated. for reflux for 3.3 hours. The reaction mixture was rinsed with dry nitrogen gas under reflux to remove NHg formed during the reaction. Next, 2.0 ml of trimethyl chlorosilane (TMCS) (0.016 mol) was added. Reflux was continued with N 2 rinsing for a further 19 hours, then the NH 1 Cl sublimated in the capacitor was removed and 2.6 ml of TMCS (0.0206 mol) was added to the reaction. Reflux with N2 rinsing was continued for an additional 34 hours. The volume of the reaction mixture was brought to 1000 ml with dry methylene chloride.

NMR then showed 100% silylation of the amino and carboxyl group of the 6-amino-penicilic acid. The solution was covered with N2 gas and held for 9 days.

NMR confirmed the above and the stability. The solution was stirred and CO 2 refluxed for approx. 90 minutes. Temperature 20-22 ° C. NMR showed 100% conversion of bis-trimethylsilyl-6-aminopenicillanic acid to bis-trimethylsilylcarboxy-6-aminopenicillanic acid (SCA).

This basic mixture was used for the acylation experiments described below. The chemical compound in this solution had the formula

DK 160613 B

32 S / s 5 (CH 2 Si-O-C-HN-j-f p-CH 5 i} ~ K-1 'i

O C-O-Si (CH2) - ^ I

0 in 10 in NMR showed that the bis-trimethylsilylcarboxy-6-aminopenicinanoic acid was stable after 9 days. in 100 ml of the base mixture (SCA equivalent of 10.8 g of 6-aminophenicillanic acid, 0.05 mol) was stirred at 22 ° C and 0.0 g TEA, HCl (0.058 mol) and 4.2 ml of propylene oxide (0.06 mol) (see U.S. Patent No. 3,741,959) was added. Some TEA, HC1 precipitated. The mixture was stirred and cooled to + 3 ° C. 15.5 g of D - (-) - p-hydroxyphenylglycyl chloride, hydrochloride hemidioxane solvate (79% purity, 0.055 mol) were added to the reaction mixture in portions as follows:

Grams, added Time in Temperature minutes _ ° C_ 3.0 0 +3 3.0 7 +2 25 3.0 20 +2 6.5 33 +2 15.5

After another 70 minutes, approx. 50 ml of dry methylene chloride to the reaction mixture to reduce the viscosity.

After another 160 minutes, a 2 ml sample was removed and added to 1.0 ml DgO. After centrifugation, NMR analysis of the aqueous phase showed approximately 6% of unacylated 6-aminopenicillanic acid.

Ten minutes later, the reaction mixture was transferred to a 600 ml beaker and the transfer was completed by washing with 50 ml of methylene chloride. While stirring in an ice bath, 60 ml of cold deionized ice water was added to give a solution of two phases without solids content and having a pH of 1.0.

DK 160613 B

33 15.0 ml of liquid anion exchange resin ("LA-1") was added to the two-phase system with stirring and grafting at pH 2.0. Crystallization accelerated. An additional 10.0 ml of LA-1 was added slowly over ca. 5 minutes. The pH was 3.0. 0.15 g of NaBH 4 was then added. Next, 5.0 ml of LA-1 was added; The pH was 4.5. Stirring was continued and 1.0 g of NaHSO 3 (sodium bisulfite) in 4.0 ml of water was added dropwise. 10.0 ml of LA-1 was then added; The pH value continued to rise. A total of 40 ml of LA-1, the final pH was 5.6. Then 5 ml of acetone was added. At this point, 1.5 g of NaH503 dissolved in 6.0 ml of water was added over 10 minutes. Stirring in ice bath was continued. The precipitated product was collected by filtration and the cake was washed successively with 50 ml of methylene chloride, 40 ml of water, 100 ml of isopropyl alcohol (80:20) and 100 ml of methylene chloride. The cake was then dried at atmospheric pressure and 45 ° C to give 18.2 g of amoxicillin trihydrate, yielding 87% yield based on 6-aminopenicillanic acid; corrected for 1% for testing, the total yield was approx. 88%.

"LA-1" liquid anion exchange resin is a mixture of 10 secondary amines wherein each secondary amine has the formula 20 R1 ch3c (ch3) 2ch2c (ch3) 2ch2ch = ch-ch2nhc-r2 H3 12 3 wherein each of R, R and R is an all in hydrocarbon group and wherein 25 R, R and R in the aggregate contain from 11 to 14 carbon atoms; this particular blend of secondary amines, sometimes referred to as "Liquid Amine Mixture No. I", is a clear amber liquid with the following physical properties: viscosity at 25 ° C at 70 cps; specific gravity at 20 ° C of 0.845; refractive index at 45 ° C of 1.467; distillation interval at 30 10 mm: up to 160 ° C 4%, 160 to 210 ° C - 5%, 210 to 220 ° C - 74%, above 220 ° C - 17%.

Example 7

A methylene chloride solution (5.0 ml) of trimethylsilyl 6-35 trimethylsilyloxycarbonylaminopenicillinate (0.54 g, 2.497 mmol) was treated with triethylamine hydrochloride (0.20 g, 1.45 mmol) followed by propylene oxide (0.162 g, 2.75 mmol) at 25 ° C. The mixture was stirred at 25 ° C for 20 minutes to facilitate dissolution of most of the triethyl ether.

DK 160613 B

The / 34 amine, hydrochloride, phenoxyacetyl chloride (0.43 g, 2.75 mmol) was added dropwise at 25 ° C and the mixture was stirred at 25 ° C for 30 minutes. A sample was removed and analyzed by CMR at 20.0 MHz. CMR (carbon-13 nuclear magnetic resonance spectroscopy) data showed complete disappearance of phenoxyacetyl chloride as well as the APA carbamate and the presence of penicillin V trimethylsilyl ester. The presence of penicillin V trimethylsilyl ester was detected by spectral comparison with an identical sample prepared by silylation of the free penicillin V acid with triethylamine and trimethylchlorosilane. The yield was estimated from the CMR spectrum to be 85-.

90%. Similarly, using the same molar amounts of reagents and the appropriate acid chloride cloxacillin, the same was prepared. dicloxacillin, staphci1lin and nafcillin. CMR data on these acylation mixtures showed an extremely pure acylation mixture with yields estimated at 15 to at least 85%. j

Example 8 j

Reaction according to the foregoing methods of a compound of formula 20

n HH

8 ij / KzCH3 (CH3) 3Si-O-C-NH-W2J \ CH3 25 cT Lo-O-B ____ 30 wherein B is a readily cleavable ester protecting group selected from the group consisting of trimethylsilyl, benzhydryl, benzyl, p nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1 - [(ethoxycarbonyl) oxyl] ethyl, pivaloyloxymethyl and acetoxymethyl with a reagent as the appropriate acid chloride or acid chloride, hydrochloride, which contains blocking groups as required, followed by removal of any blocking groups whose removal is desirable, gives the following compounds:

DK 160613 B

almecillin, armecillin, azidocillin, azlocillin, bacampicillin, Bay K 4999 of the formula 5 H ° ~ fX * 'S VCH5 j-CH-CONH-r-f

Xk—. CH3

I «0 o COOH

10 = C 8, '] j Π 0 BL-P1654 of formula 15 / = \ CH_ \ J-f - COHH-pY3 ^ "I J — N- Cti3 m o ^ i

COOH

O = C-NH- (r XNH2 BL-P1908 of the formula HO-CH, X ii-CH-CONH-S X '

jT ^ C HL

Λ — H- j)

OH 0 COOH

30 I

0 = cli f

H

Carfecillin, carindacillin, cyclacillin, clometocillin, cl oxacillin, dicloxacillin, EMD-32412 of formula 40

DK 160613 B

36

° H -CH

S / 3 ^ / ^ “CH-CONH —- r

| J-N- CH3 I

5 f * ° OH COOH! 0 = C-NH ^ I ^^ is isr epicillin, floxacillin (flucloxacillin), furbucillin, hetacillin, I.S.F.-2664 of formula 15

S

L CH - CONH-j-S

VJ ^ i T3_b «, 8 N-Cl · ^ 0 ^ O ^ -OCHgOC-CCCK ^) ^ 20 '.

nh2 isopropylene lin, methicillin, mezlocillin, nafcillin, oxacillin, phenbenicillin, PC-455 of the formula / = \ .s Λ H ° - (\ /) - CH - CONH —- f V v I_jr__ CH3

30: ra o 0 C00H

"apar 35 aparcillin (PC-904) of formula

DK 160613 B

37 / ch5 \ y — CH-CONH — r — f S> 1 \ \ = / I Ti-CH?

5 ψ - 0 COOH

I HO

10 = piperacillin, 3,4-dihydroxypiperaciHin, pirbenicillin, pivampicillin, PL-385 of the formula 15 w ~ f ^ il s./c"3 JJ- CH-CONH · —if \ I. Λ. τ 'CH-, I Ori ^ —N- 3

on ® in ° COOH

0 = C I / \

'S - N N - CHO

N \ _ / 25 prazocillin, sarmoxicillin, sarpicillin, ticarcillin, cresyl sodium, ticarcillin, carbenicillin, carfecillin, fibracillin and Bay-e-6905 in the form of a Q> -ch - connjY ^ fcib

iH COOH

C = O

35 I

N / 0 rΫ

"NH

Claims (5)

5 DK 160613 B 38. A process for preparing a conventional penicillin of formula s Ls / * 3 R-C-NHtl> cH3 * 10. OH 0 wherein R-i- represents the residue after removal of the hydroxyl group from an organic carboxylic acid containing from 2 to 20 carbon atoms, acylated with the acid chloride of the organic carboxylic acid of the formula i | CH, 20 (ch3) 3sinh (\ CH Λ-Ν - \ 3 Wherein B represents a readily cleavable ester-protecting group and then the group B is converted to hydrogen, characterized in that before the acylation the silylated core is converted to a compound of formula 30 n Η H »I: V ch3 0. u ° Nd-B wherein B has the same meaning as set forth above by adding dry carbon dioxide to a solution of a compound of the formula in L ^ / ch3 o U ° ^ OB 10 wherein B is as defined above, in an anhydrous inert organic solvent at a temperature in the range of 0 ° C to 100 ° C until the reaction is complete. Method according to claim 1 for the preparation of a 6-α-aminoarylacetamidopenicillanic acid, characterized in that a compound of the formula O - ς / C'RL · II / S \ / 3 (CH 2 Si-OC-HH-3) is reacted. CH-CH C. ^. 20 J-K- An anhydrous inert organic solvent with approximately an equimolar amount of a D - (-) - α-aminoarylacetyl chloride, hydrochloride, preferably at a temperature above -10 ° C. . A process according to claim 1 for the preparation of amoxicillin, characterized in that a compound of the formula 30 '- (CH 2) - Si-O-C-NH-CH-CH] -N-CH is reacted. CT C-O-Si (CH2) II 3 3 o DK 1606.13 B in an anhydrous inert organic solvent with approximately an equimolar amount of D - (-) - 2-p-hydroxyphenylglycyl chloride, hydrochloride, preferably at a temperature above - 10 ° C. The method of claim 1 for the preparation of ampicillin, 5 THE CHARACTERISTICS OF KNOWING TO COMPLETE A COMPOUND OF THE FORMULA! (CH5) 3 Si-O-C-NK-CH-CH i-K-CH O /. In an anhydrous inert organic solvent with approximately an equimolar amount of D - (-) - 2-phenylglycyl chloride, hydrochloride, preferably at a temperature above -10 ° C.