FI69846C - VID FRAMSTAELLNING AV PENICILLINER SAOSOM MELLANPRODUKT ANVAENDBAR FOERENING OCH FOERFARANDE FOER DESS FRAMSTAELLNING - Google Patents

Description

UjJfcpJ rBl ri1. ANNOUNCEMENT / Q

Jiff 11 UTLÄG G NIN G SSKRIFT D ^ 040 • 2 ^ 0 c (45) Pate :. It i ray'Jane tty

Γ “t C:.: T r \? '· A t C o; . JG

(51) Kv.lk.4 / lnt.Ci.4 C 07 D * + 99/02, C 07 F 7/18 FINLAND —FINLAND (21) Patenttlhememu * - Patentansöknlng 791732 (22) Application date - Ansökningsdag 30.05.79 ( 23) Start Date - Giltighetsdag 30.05 79 (41) Become Public - Blivit offentllg ig gg gg

Patent and Registration Office .... ...... ... . .

* (44) Date of display and of publication—

Patent- oeh registerstyrelsen v 'Ansökan utlagd och utl.skrfften publicerad 21 .12.85 (32) (33) (31) Privilege requested — Begärd priority -jg ^ 78 19.01.79, 19.03.79 USA (US) 970704, 001 + 780 , 1821852 Proven-Styrkt (71) Bristol-Myers Company, 3 ^ 5 Park Avenue, New York, New York 10022, USA (72) Derek Walker, Jamesville, New York, Herbert H. Silvestri, Dewitt,

New York, Chester Sapino, East Syracuse, New York, David A. Johnson, Fayetteville, New York, USA (US) (7 * 0 Oy Koister Ab (5 * 0 Compound useful as an intermediate in the manufacture of penicillins and method for its preparation - Vid framstälIning av This invention relates to a new process for the preparation of antibacterial agents, commonly referred to as semisynthetic penicillins, and in particular to a subgroup thereof, which are known in the 6-position asyl. , such as ampicillin and amoxicillin, has an amino group.

The first commercial penicillin with a Qt amino group on the 6-acylamido side was ampicillin, 6- (D-Oc.-amino-O · -phenylacetamido) penicillanic acid (see U.S. Patent No. 2,985,648). . Amoxicillin is an antibacterial agent that has been used to treat humans and is marketed as a free acid trihydrate (i.e., a zwitterion). It is described, for example, in GB Patent 978,178; in J. Chem. Soc. (London), ss. 1920-1922 (1971); and Antimicrobial Agents and Chemotherapy - 1970, p. 407 - 430 (1 971). Its chemical name is 6- [D-Cl-amino-Q1- (p-hydroxyphenyl) -acetamide] penicillanic acid.

2 69846

The use of amino acid chloride hydrochlorides for the preparation of such penicillins under dry conditions is known, for example, from GB Patents Nos. 938,321 and 959,853 (for the protection of the carboxyl group of 6-aminopenicillanic acid during acylation, the latter also used a silyl group, such as U.S. Patent No. 1,008,468 and U.S. Patent No. 3,249,622), and GB Patent No. 962,719 in cold aqueous acetone. These penicillins are amphoteric amino acids and were therefore isolated (e.g., as described in U.S. Patent Nos. 3,157,640 and 3,271,389) by certain secondary amines containing aliphatic asymmetric side chains (often referred to as liquid amine resins). had previously been used to isolate 6-aminopenicillanic acid, which is also an amphoteric amino acid (see U.S. Patent No. 3,008,956). Improved methods for isolating and purifying such penicillins are known, e.g., from U.S. Patent No. 3,808,862 / 5 using naphthalenesulfonates, and U.S. Patent No. 3,198,804 by isolating an intermediate and followed by readily hydrolysis of hetacillin.

The use of a silyl group to protect the carboxyl group of natural penicillin during cleavage to 6-aminopenicillanic acid is known from U.S. Patent No. 3,499,909. The use of silylated 6-aminopenicillanic acid during anhydrous acylation with amino acid chloride hydrochlorides is known from numerous patents. .it No. 3,479,018, No. 3,595,855, No. 3,654,266, No. 3,479,338 and No. 3,487,073. The use of liquid amine resins is also known in some of these patents. See also U.S. Patents 3,912,719, 3,980,637 and 4,128,547.

GB Patent No. 1,339,605 provides various specific and detailed examples for the preparation of amoxicillin by reacting a silylated derivative of 6-amopenic silicic acid with D - (-) - CX. -amino-p-hydroxyphenylacetic acid with a reactive derivative (including chloride di-hydrochloride) in which the amino group is protected, followed by removal of the silyl group (s) by hydrolysis or alcoholysis and, where possible, recovery of amoxicillin, usually crystalline trihydraatt.i-na. Thus, crystalline amoxicillin was obtained as shown in Example 1 by isoelectric precipitation from aqueous solution, e.g. at pH 4.7. Purification was performed in this example by probing 3,69846 ti by dissolving the crude product (before isoelectric precipitation) in water, at acidic pH, e.g. 1.0, (e.g. in aqueous hydrochloric acid) with a water-immiscible organic solvent such as methyl isobutyl ketone (4-methylpentane-2 -on). A fairly similar method has been used in U.S. Patent No. 3,674,776.

This invention relates to a process for the preparation of penicillins using a novel compound of formula as an intermediate

O H H. CH

- I I / S / (CH.) -Si-O-C-NH-C -— C ^ C— J J I v ^ rl ^ S- N - 1 ° / ° <

O-B

wherein B is an easily cleavable ester protecting group such as trimethylsilyl. The new intermediate is reacted in a dry inert organic solvent such as methylene chloride, preferably in the presence of a weak base such as propylene oxide, and at a temperature above -10 ° C, preferably -8 ° C to + 20 ° C, preferably 0 ° C to 20 ° C, and most preferably about 20 ° C, with an approximately equimolar amount of acid chloride or chloride or chloride hydrochloride, the latter preferably being added portionwise to the solution of the former, and then, if desired, the group B is converted to hydrogen.

The present invention also comprises a process for the preparation of a compound of formula I; according to this method, dry carbon dioxide is added in a manner known per se as a gas to a solution of a compound of formula 4 69846

H H

'= / S / CH3 (CH3) 3Si-NH-C -C "ν'

I ch3 II

^ -N- O ^ 0 c \

0-B

wherein B has the same meaning as above, in an anhydrous inert organic solvent at a temperature of about 20 to 27 ° C until the reaction is complete.

The present invention also encompasses a process for the preparation of 6-O 2 -aminoarylacetamidopenicillanic acid, such as ampicillin or amoxicillin, which process comprises preparing a compound of formula

(CH) Si-O-C-NH-CH-CYf '"V

| I! ^ Ch3

^ - N - CH

0 I

C-O-Si (CHO) 0

II

o is reacted in a dry inert organic solvent and mainly in methylene chloride, preferably in the presence of a weak base, mainly propylene oxide, and at a temperature above -10 ° C, preferably -8 ° C to + 20 ° C, preferably 0 ° C to 20 ° C, and most preferably about 20 ° C, an approximately equimolar amount of D - (-) - C 1-4 aminoaryl-acetyl chloride hydrochloride, such as D- (-) - 2-phenylglycyl chloride hydrochloride or D- (-) -2 with p-hydroxyphenylglycyl chloride hydrochloride, the latter being preferably added portionwise to the solution of the former.

Il 69846

One of the surprising features of the new method is the Stability of the anhydrous acylation solution. It can be stored for long periods of time even at room temperature without noticeable cleavage of the penicillin molecule. This is in contrast to the behavior of the acylation solutions of the previously described methods. This stability advantage allows the acylation reaction to be performed at much higher temperatures (room temperature used) than are normally used in the preparation of ampicillin, usually below 0 ° C and typically about -10 ° C.

For the compound of formula I wherein B is a trimethylsilyl group, various trivial designations are used herein, such as the bis-silylated carbamate of 6-APA, SCA, 6-trimethylsilyloxycarbonylpenicillan TMS ester, and TMSO 2 C.APA.TMS.

The presence of this compound is surprising given the well-known fact that the reaction of 6-APA with carbon dioxide destroys 6-APA to form 8-hydroxypenicillanic acid, as is known, for example, from U.S. Pat. No. 3,225,033.

The explanation that 6-trimethylsilyl-oxycarbonylaminopenicillanic acid trimethylsilyl ester (TMSC 2 C.APA.TMS) is obtained in quantitative yields is that in the first step the 6-APA-b.is-TMS precursor is completely formed. This has been possible by reacting 6-APA with hexamethyldisilazane (HMDS) according to the following scheme: - Ή 6-APA + HMDS ♦ imidazole-boiling complete carboxylated oxylated salylated; 11 6 - 8 h as well as about 1 mole to 1.1 moles 3-5 mole% 6h 6-NH - silyl it news "L j

TMSNH S

5 -m ° —-> N-f (6-APA. Bis. TMS)

TMCS addition and J

boiling overnight β — N

o / co2tms 69846 The events of the B.is-trimethylsilylation reaction can be completely monitored by NMR analysis. The 3-trimethylsilyloxycarbonyl group gives 0.31 ppm for the methyl silyl singlet (tetramethylsilane = 0), while the 6-trimethylsilylamine group gives 0.09 ppm for the methylsilyl singlet.

The 6-APA-trimethylsilylation reaction has so far only been performed in methylene chloride. Still, other solvents, e.g. acetonitrile, dimethylformamide or even hexamethyldisilazane, can be used.

Conversion of the trimethylsilylamino group to the trimethylsilyloxycarbonylamino group can be easily accomplished by bubbling dry carbon dioxide into the reaction solution. The conversion is easy to monitor by NMR because the trimethylsilylamino singlet at 0.09 ppm deteriorates with the appearance of a new trimethylsilyloxycarbonylamino group singlet at 0.27 ppm.

When using the process of this invention 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 (see, e.g., U.S. Pat. Nos. 3,921,271). 8, 3,980,637 and 4,128,547; as well as other patents and publications cited herein.

The acid chlorides used in the following examples can be replaced with various other acid chlorides to prepare common penicillins.

Thus, to introduce any desired acyl group at the 6-amino position, the acyl halide may be selected in a manner well known in the art, such as in U.S. Patent 3,741,959. Thus, specific acyl groups including, but not limited to, acyl groups as defined below can be placed: (i) RUC H C0 - n 2n wherein RU is aryl (carboxylic or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl or a non-aromatic or mesionic heterocyclic group, and n is 1 to 4.

II

7 69846 of the group are phenylacetyl, substituted phenylacetyl, e.g. fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methphenylacetyl or hydroxyphenylacetyl; Ν, Ν-bis (2-chloroethyl.i) aminophenylpropionyl; t.ien-3- and 3-acetyl; 4-isoxazolyl and substituted 4-isoxazolylacetyl; pyridylacetyl; tetrazolylacetyl or sydnoneacetyl group. The substituted 4-isoxazolyl group may be a 3-aryl-5-methylisoxazol-4-yl group, the aryl group being e.g. phenyl or halophenyl, e.g. chlorine or bromophenyl. The acyl group of this type is 3-o-chlorophenyl-5-methylisoxazol-4-ylacetyl.

11l »CnH2n * 1CO 'where n is 1 to 7. The alkyl group may be straight or side chain and, if desired, may be cleaved by an oxygen or sulfur atom, or may have as a substituent e.g. a cyano group. Examples of such groups are cyanoacetyl, hexanoyl, heptanoyl, octanoyl and butylthioacetyl.

(Ui) CnH2n-1C ° - where n is 2 to 7. The group may be straight or side chain and, if desired, may be cleaved by an oxygen or sulfur atom. An example of such a group is allylthioacetyl.

... Rv (1V) u 1

R S-C-CO

; » ♦ wherein Ru has the meaning defined in (i) above and may in addition be v w benzyl, and R and R, which may be the same or different, are each hydrogen, phenyl, benzyl, phenethyl or lower alkyl. Examples of such groups are phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybutyryl, benzyloxycarbonyl, 2-methyl-2-phenoxypropionyl, p-kresoxyacetyl and p- methylthio-phenoxyacetyl.

8 69846

RV

(v) RUS-C-CO- wherein RU has the meaning defined in (i) and in addition may be benzyl, and RV and RW have the meanings defined in (iv). Examples of such groups are S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl and S-benzylthioacetyl.

(vi) RUZ (CH) CO-2 m wherein RU has the meaning defined in (i) and may further be benzyl, Z is an oxygen or sulfur atom and m is 2 to 5. An example of such a group is S-benzylthiopropionyl.

(vii) RUCO- wherein RU has the meaning defined in (i). Examples of such groups are benzoyl, substituted benzoyl (e.g. aminobenzoyl), 4-isoxazolyl and substituted 4-isoxazolylcarbonyl, cyclopentanecarbonyl, zidonecarbonyl, naphthoyl and substituted naphthoyl (e.g. 2-ethoxynaphthaloyl) carbinoyl) (e.g. 3-carboxy-2-quinoxalinylcarbonyl). Other possible benzoyl substituents are alkyl, alkoxy, phenyl, or phenyl substituted with carboxy, alkylamido, cycloalkylamido, allylamido, phenyl (lower) alkylamido, morpholinocarbonyl, pyrrolidinocarbonyl, piperidine, tetrahydropyridino, furfurylamido or N-alkyl-N-anilino, or derivatives thereof, and which substituents may be in the 2- or 2- and 6-positions. Examples of such substituted benzoyl groups are 2,6-dimethoxybenzoyl, 2-biphenylcarbonyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. When the group Ru corresponds to a substituted 4-isoxazolyl group, the substituents may be those described in (i) above. Examples of such 4-isoxazolyl groups are 3-phenyl-9,69846 5-methylisoxazol-4-ylcarbonyl, 3-o-chlorophenyl-5-methylisoxazol-4-ylcarbonyl and 3- (2,6-Dichloro-phenyl) -5-methyl-isoxazol-4-ylcarbonyl.

(viii) RU-CH-CO-

V

X

wherein RU is as defined in (i) and X is amino, substituted amino (e.g. acylamido or a group obtained by reacting a 7-side chain amino group and / or groups with an aldehyde or ketone, e.g. acetone, methyl ethyl ketone or ethyl acetone). acetate), hydroxy, carboxy, esterified carboxy, triazolyl, tetrazoyl, cyano, halo, acyloxy (e.g. formyloxy or lower alkanoyloxy) or an etherified hydroxy group. Examples of such acyl groups are Gt-aminophenylacetyl, CX-carboxyphenylacetyl and 2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl.

RX

(ix) RY-C-CO-

RZ

XV z wherein R, RJ and R, which may be the same or different, may each be lower alkyl, phenyl or substituted phenyl. An example of such an acyl group is triphenylcarbonyl.

Y

(x) RU-NH-C

wherein RU is as defined in (i) and which may be further hydrogen, lower alkyl or lower alkyl having a halogen substituent, and Y is oxygen or sulfur. An example of such a group is C1 (CH2) 2NHCO.

1 o 69846 (xi) (CH) ^ C-CO-2 n, \ ch2 ^ x wherein X has the meaning defined in (vi.ii) and n is 1 to 4. An example of such an acyl group is 1-aminocyclohexane .ikar-carbonyl.

(xii) Aminoacyl, for example RWCH (NH2). (CH2) ^ CO, where n is 1 to 10, or NH_.C H_ Ar (CH) CO, 2 n 2n 2 m where m is 0 or 1 to 10 and n is 0, 1 or 2, w R is a hydrogen atom or an alkyl, aralkyl or carboxy group or a group as defined above for RU, and

Ar is an arylene group, e.g. p-phenylene or 1,4-naphthylene. Examples of such groups are known from GB Patent No. 1,054,806. Such a group is a p-aminophenethylacetyl group. Other such acyl groups include, for example, 6-aminoadipoyl, a derivative of naturally occurring amino acids, and derivatives thereof, e.g., N-benzoyl- (5-aminoadipoyl).

(xii.i) Substituted glyoxyllyl groups of the formula RY.CO.CO- wherein RY is an aliphatic, araliphatic or aromatic group, e.g. a thienyl group, a phenyl group, or a mono-, di- or trisubstituted phenyl group, wherein the substituents are, for example, one or more halogen atoms (fluorine, chlorine, bromine or iodine), methoxy groups, methyl groups or amino groups or a fused benzene ring. *

II

69846

If the acyl group to be attached has an amino group, it may be necessary to protect this during various reaction steps. The protecting group can be removed by hydrolysis without affecting the rest of the molecule, especially the lactam and 7-amido moieties. The amine protecting group and the esterifying group at the 4-C00H position can be removed using the same reagent. The preferred method is to remove both groups in the last step of the reaction sequence. Protected amine groups include urethane, arylmethyl (e.g. trityl) amino, arylmethyleneamino, sulfenylamino or enamine groups. Enamine protecting groups are particularly useful in the case of o-aminomethylphenyl.-acetic acid. Such groups can generally be removed with one or more reagents such as 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 ° C. . A suitable protecting group is a t-butoxycarbonyl group which is readily removed by hydrolysis with a dilute mineral acid, e.g. dilute hydrochloric acid, or mainly a strong organic acid (e.g. formic acid or trifluoroacetic acid), e.g. at a temperature of 0 to 40 ° C, especially at a temperature of 15 to 25 ° C. ° C. Another suitable protecting group is the 2,2,2-trichloroethoxycarbonyl group, which may be cleaved off with, for example, zinc / acetic acid, zinc / formic acid, zinc / low molecular weight alcohols or zinc / pyridine.

The N1 group can also be protected as an NH4 ion using an amino acid halide in the form of an acid addition salt under conditions in which the amino group remains protonated.

The acid used to form the acid addition salt is essentially an acid having a pK (in water at 25 ° C) of X + 1, where X is the pK value of the carboxy groups of the amino acid cl (in water at 25 ° C); the acid is essentially basic. In practice, the HQ of the acid (see below) is usually <3, preferably <1.

Particularly advantageous results have been obtained with the process according to the invention when the acyl halide is a salt of an amino acid halide. The amino acid halides have the formula H2N-R1-COHal 12 69846 having a divalent organic group and Hal is chloride or bromine di. Salts of salts of such amino acid halides are / H_N-R-COHal7 + Q_ ^ 31 wherein R1 and Hal are as defined above and Q is the anion of an acid HQ having a kP as defined above. The acid HQ is essentially a strong cl inorganic acid such as hydrohalic acid such as hydrochloric acid or hydrobromic acid. An important amino acid halide due to the valuable penicillin antibiotics containing its derivative group is DN- (Cfc-chlorocarbonyl-N-phenyl) -methyl-ammonium chloride, D- / PhCH (CH2) COClJ7 + Cl, which is referred to herein as D- Oc-phenylglycyl chloride hydrochloride.

Penicillins having an acylamido group RUCH (NH9) -CONH- obtained according to the process of this invention, wherein RU

1 2 3 is the same as above, can be reacted with the ketone R, R CO 2 3, wherein R and R are lower alkyl groups (C 1 -C 4) to give compounds which are likely to contain a group

RU-CH

HN ------- R2 R3 Compounds of this type include hetacillin, sarpicillin, p-hydroxyhetazine and sarmoxicillin.

Suitable acyl groups are disclosed in U.S. Patent 4,013,648, columns 7-20.

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

n 13 69846

Acid chlorides are usually prepared by reacting an acid with thienyl chloride at elevated temperature. If readily reactive groups, such as protecting groups, are present, the acid chlorides can be prepared under virtually neutral conditions by reacting the acid salt with oxalyl chloride.

Example 1

To a mixture of 6-aminopenicillanic acid (6-APA) and 10 ml and 1.13 ml of trimethylchlorosilane was added dropwise at 25-27 ° C 1.23 ml of triethylamine over 30 minutes. Stirring was continued for another 2 hours. Dry carbon dioxide gas was then bubbled into the mixture for about 3 hours. According to NMR assay (methylsilyl singlet at 0.09 ppm), the reaction mixture contained 60% silylated carboxy-6-APA (SCA) of the formula O CH 3 (CH 3) 3 Si-O-C-HN-1 I CH, ^ _ N_ 3

O

C-O-Si (CH0)

Il 3 3 o

The mixture was kept in the refrigerator overnight. The next morning, 0.77 ml of N, N-dimethylaniline was added thereto, and the mixture was cooled to -8 ° C. 1.2 g of D - (-) - p-hydroxy-2-phenyl-glycyl chloride hydrochloride (purity 79%) were then added portionwise as follows:

Time, min Temperature, C Amount added, g 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 +8 220 +15 310 +20 1 4 69846

Thin layer chromatographic analysis (TLC) performed at 310 minutes after completion of the reaction on a sample of the reaction mixture using a mixture of 60% ethyl acetate, 20% acetic acid and 20% water as solvent showed the presence of amoxicillin.

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

Esimerkki_2

A mixture of 5.4 g (0.025 mol) of 6-arainopenicillanic acid and 6.2 ml of 93% hexamethyldisilazane (0.0275 mol) and 0.07 g (about 0.001 mol) of imidazole in 40 ml of Cl 2 ^ boiled under a stream of nitrogen for about 17.5 hours. 0.13 ml (about 0.001 mol) of trimethylchlorosilane was then added; the solution became cloudy. Cooking was continued for another 7 hours; a precipitate of NH 4 Cl was observed in the condenser. NMR showed silylation to be approximately 100% for both the amino and carboxyl groups of 6-APA (singlet at 0.09 ppm and 0.27 ppm, respectively). Then, 0.2 ml of hexamethyldisilazane (0.00125 mol; about 5 mol-1%) and 0.06 ml of trimethylchlorosilane (about 0.0005 mol) were added, and boiling under nitrogen was continued for another 17 hours. The NMR spectrum was the same as above with the addition of small amounts of hexamethyldisilazane and trimethylchlorosilane. Dry carbon dioxide was then bubbled into the reaction mixture at room temperature for 75 minutes. NMR then showed no hexamethyldisilazane and the mixture contained more than 92% silylated carboxy-6-APA (SCA). 4.45 ml of Ν, Ν-dimethylaniline (0.035 mol) were added and the mixture was cooled to -3 ° C. 5.65 g of D - (-) - 2-phenylglycyl chloride (95% purity; 0.026 mol) were then added portionwise as follows:

Time, min Temperature, ° C Amount added, g 0 -3 1.05 20 0 1.30 40 0 1.30 50 0 1.00 60 0 1.00

II

15 69846

The reaction was monitored by NMR, which showed very little change about 5 hours after the start of the reaction; the temperature was then 3 ° C. The reaction vessel was then kept immersed in ice for the next 16 hours. It was then removed from the cooling vessel and stirred for 3.5 hours at room temperature (about 20-24 ° C). There was still a large amount of solid in the mixture. The reaction mixture was then stirred at room temperature (22-24 ° C) for about 63 hours, after which the mixture had only slight turbidity. Finally, the sample was extracted with D 2 O; According to NMR, the sample contained ampicillin and 6-APA.

The reaction mixture was cooled to about 0 ° C, 35 ml of ice water was added and stirred for 5 minutes. After fine filtration, the mixture was washed with cold water and CH 2 Cl 2. The aqueous phase was separated; TLC analysis revealed a slower range than ampicillin and 6-APA, indicating the presence of the new intermediate X.

The pH of the aqueous phase was adjusted to 3.0 with ammonia and a small amount of ampicillin crystals was added. Methyl iso-butyl ketone (35 ml) was added and the mixture was stirred, the pH was adjusted to 5.2 with ammonia, stirred for 1 hour at 20 ° C, for another hour in an ice bath and then kept in the refrigerator overnight. The Ampisil line precipitate was collected by filtration, washed first with 25 ml of cold water and then with 40 ml of methyl isobutyl ketone and finally with 40 ml of a mixture of 85 parts of isopropyl alcohol and 15 parts of water, dried at 50 ° C; yield 4.5 g. Identity with the ampis.il line was confirmed by TLC.

Example 3

A mixture of 5.4 g of 6-APA, 6.2 ml of hexamethyldisilazane (93%) and 0.06 g of imidazole in 50 ml of CH 2 Cl 2 was boiled under a stream of nitrogen for 18 hours. Then 0.1 ml of trimethylchlorosilane was added, whereupon the solution became cloudy, and boiled for another 2 hours to give a clear solution; salmia condensed in the condenser. Another 0.1 ml of trimethylchlorosilane was then added with very little turbidity. Cooking was continued without nitrogen protection for the next 65 hours. The mixture was then cooled to about 22 ° C and the addition of dry carbon dioxide was started.

After 75 minutes, NMR showed that more than 90% of the bis-silylated carbamate (SCA) had been formed. Then 4.45 ml of dimethylaniline and then 5.6 g of D- (-) - 2-phenylglycyl chloride hydrochloride (purity 97%) were added portionwise as follows: 16,69846

Time, min Temperature, ° C Amount added, g O 20 1.35 20 20 1.30 r 32 20 1.00 48 20 1.00 75 20 1.00

The mixture was stirred for an additional 17 hours, after which time TLC analysis was performed on samples taken from the reaction mixture and the diluted reaction mixture (1 ml of the reaction mixture diluted with 2 ml of Cl 2 Cl 2); in both there was a small region of ampin 11 and a large region corresponding to the 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, fine filtered and washed with water and CH 2 Cl 2. The aqueous phase was separated, 10% sampled and the remainder adjusted to pH 3.0 with ammonia; then ampicillin crystals were added to the remainder and mixed.

After an additional 40 ml of methyl isobutyl ketone was added to the mixture, it was stirred and the pH was adjusted to 5.2 with ammonia and stirred at room temperature for one hour and in an ice bath for another hour. Crystals precipitated. The mixture was kept in an ice bath overnight, after which the crystalline product was collected by filtration, washed successively with methyl isobutyl ketone, water and methyl isobutyl ketone 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 taking into account the sample or yield 68%).

Example 4

To a mixture of 1.0 g of 6-APA and 1.3 ml of trimethylchlorosilane in 10 ml of CD 2 Cl 2 was added dropwise 1.23 g of tritylamine over 30 minutes and the mixture was stirred for a further 2 minutes. hours. Dry carbon dioxide was then bubbled in for 4 hours. The NHR then showed carboxylation to be about 55-60%. The mixture was then kept in the refrigerator overnight. In the morning, 0.77 ml of dimethylaniline was added, the mixture was stirred, cooled to -8 ° C, and 1.2 g of D - (-) - p-hydroxy-2-phenylglycyl chloride hydrochloride was added portionwise as follows:

II

17 69846

Time, min Temperature / ° C Amount added »g O -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 8 220 15 310 20 310 minutes After NMR the mixture showed about 78 % amoxicillin and about 20% 6-APA.

Example 5

Dry 6-aminopenicillanic acid (10.0 g, 46.24 mmol, 1.0 eq) was suspended in dry methylene chloride (175 mL) at 25 ° C with stirring. At 25 ° C, triethylamine (10.76 g, 106.36 mmol, 2.30 eq.) Was added, followed by trimethylchlorosilane (11.70 g, 107.75 mmol, 2.33 eq.). - for 15 minutes, keeping the temperature below about 32 ° C by means of the addition rate of trimethylchlorosilane. After stirring for 20-30 minutes, the mixture containing precipitated triethylamine hydrochloride was analyzed for completeness of silylation by NMR (80 MHz). Carbon dioxide was then bubbled into the mixture at 20 ° C for about 2 hours and the degree of carboxylation was analyzed by NMR (80 MHz). In some cases, gas pipeline had to be continued. If necessary, the volume of the carboxylation mixture was readjusted to about 175 ml with dry methylene chloride. After complete carboxylation, 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 about 2 ° C, a total of 13.54 g (50.87 ml, 1.1 eq.y./Each acid chloride ferrous was allowed to dissolve for about 20 minutes per batch before the next batch was added. (Stirring was stopped and any solid that had settled to the bottom of the vessel was examined; the slurry should not be warmed above 5 ° C in this experiment. This batch addition was very important.The final acylation mixture was assayed for any insoluble acid 18 69846 hydrochloride hydrochloride and was kept at 0-5 ° C for 30 minutes and treated with cold (0-5 ° C) deionized water. (100 ml) and stirred for 10 minutes using a high speed stirrer, the mixture was allowed to separate and the lower methylene chloride phase was removed. and the cake was washed with cold (0-5 ° C) deionized water (15 mL). The lower organic phase solution was carefully removed before crystallization. The pH of the clear, pale yellow aqueous solution (pH 2 to 2.5) was adjusted to 3.5 at 0 to 5 ° C and seed crystals were added. The slurry was kept at 0-5 ° C for 40 minutes and the pH was adjusted to 4.8-5.0 with 6N ammonia and allowed to crystallize for 2 hours. The slurry was filtered and the solid amoxicillin thus recovered was washed with a cold (0-5 ° C) mixture of isopropanol and water (1: 1) and the cake was washed with methylene chloride (30 mL) to give about 13.5 g (about 70%) of snow-white amoxicillin. silliini trihydrate.

Example 6 108 g of 6-aminopenicillanic acid (0.5 mol), 1.0 g of imidazole (0.017 mol), 800 ml of dry methylene chloride and 120 ml (0.56 mol) of hexamethyldisilazane (purity about 98%) stirred and heated at reflux for 3.3 hours, during which time dry nitrogen gas was bubbled into the reaction mixture to purge off the ΝΗ ^: η formed in the reaction. 2.0 ml of trimethylchlorosilane (0.016 mol) were then added. Cooking was continued under nitrogen for a further 19 hours, after which the Salmiak condensed in the condenser was removed and 2.6 g of trimethylchlorosilane (0.0206 mol) were added to the reaction mixture. Cooking under a nitrogen blanket was continued for another 34 hours. The volume of the reaction mixture was adjusted to 1000 ml with dry methylene chloride. NMR then showed that the amino and carboxyl group of 6-aminopenicillanic acid was 100% silylated.

The solution was kept under nitrogen for 9 days; NMR showed no change. The solution was stirred and bubbled with carbon dioxide for about 90 minutes. The temperature was 20-22 ° C. NMR showed 100% conversion of bis-trimethylsilyl-6-aminopenicillanic acid to bis-trimethylsilylcarboxy-6-aminopenicillanic acid (SCA) of formula

II

69846 19 o S. CH3 (CH) Si-O-C-HN - | - ('NCf

Il ch3 o ^ —N- C-O-Si (CH)

II

o NMR showed that bis-trimethylsilylcarboxy-6-aminopenicillanic acid was retained after 9 days.

100 ml of the basic mixture obtained above (containing SCA corresponding to 10.8 g of 6-aminopenicillanic acid; 0.05 mol) were stirred at 22 [deg.] C. and 8.0 g of TEA.HCl (0.058 mol) and 4.2 ml of propylene oxide (0.06 moles) (see U.S. Patent 3,741,959). Some precipitation of TEA.HC1 precipitated. The mixture was stirred and cooled to + 3 ° C. To the reaction mixture was added portionwise 15.5 g of D - (-) - p-hydroxyphenylglycyl chloride-hydrochloride-hemidioxane solvate (purity 79%; 0.055 mol) as follows:

Time, min Temperature, ° C Amount added, g 0 +3 3.0 7 +2 3.0 20 +2 3.0 33 +2 6.5 15.5

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

After an additional 160 minutes, a 2 mL sample of the mixture was taken and added to 1.0 mL of D 2 O. After centrifugation, NMR analysis of the aqueous phase showed that the mixture contained about 6% unacylated 6-aminopenicillanic acid.

10,69846 10 minutes later, the reaction mixture was transferred to a 600 mL beaker and the transfer was completed by rinsing with 50 mL of methylene chloride. With stirring in an ice bath, 60 ml of cold deionized ice water was added to give a biphasic solution with no solids and a pH of 1.0.

To the biphasic solution was added, with stirring and seeding (at pH 2.0), 15.0 ml of liquid anion exchange resin ("LA-1"). Crystallization began. Within about 5 minutes, an additional 10.0 mL of LA-1 was slowly added; The pH was 3.0. 0.15 g of NaBH 4 was then added. Then 5.0 ml of LA-1 was added; The pH was 4.5. Stirring was continued and 1.0 g of sodium hydrogen sulfite in 4.0 ml of water was added dropwise. An additional 10.0 mL of LA-1 was added; The pH continued to rise. The total amount of LA-1 was 40 ml; the final pH was 5.6. I then added 5 ml of acetone. At this time, 1.5 g of sodium bisulfite dissolved in 6.0 ml of water was added over 30 minutes. Stirring was continued in an ice bath. The precipitated product was collected by filtration and the precipitate cake was washed successively with 50 ml of methylene chloride, 40 ml of water, 100 ml of isopropyl alcohol / water (80:20) and 100 ml of methylene chloride. The cake was then dried at atmospheric pressure at 45 ° C to give 18.2 g of amoxicillin trihydrate, corresponding to a yield of 87% based on 6-aminopenicillanic acid; by correcting for a 1% sample, the total yield was about 88%.

"LA-1" liquid anion exchange resin is a mixture of secondary amines wherein each secondary amine has the formula R 1 CH 3 C (CH 3) 2 CH 2 C (CH 3) 2 CH 2 CH = CH ~ CH 2 NHC ~ r 2 R 3 1 2 3 wherein R, R and R are each an aliphatic hydrocarbon group and when

Il 2 3 2 R, R and R have 11 to 14 carbon atoms, this special mixture of secondary amines, sometimes referred to as "Liquid Amine Mixture No. I", is a clear golden brown liquid with the following physical properties : viscosity at 25 ° C 70 sen-type; specific gravity at 20 ° C 0.845; refractive index at 25 ° C 1.467; 3 distillation range under 10 mm vacuum: not more than 160 ° C to 4%, 160 to 210 ° C to 5%, 210 to 220 ° C to 74%, more than 220 ° C to 17%.

21 69846

Example 7

To a solution of methylene chloride (5 mL) in trimethylsilyl-6-trimethylsilyloxycarbonylaminopenicillanate (0.54 g, 2.497 mmol) was added triethylamine hydrochloride (0.20 g, 1.45 mmol) followed by propylene oxide (0.162 g, 2.262 g). 75 mmol) at 25 ° C. The mixture was stirred at 25 ° C for 20 minutes to facilitate dissolution of the triethylamine hydrochloride moiety. 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. It was sampled and analyzed by CMR (carbon-13 nuclear nuclear magnetic resonance spectroscopy? 20.0 MHz). CMR values indicated complete disappearance of phenoxyacetyl chloride and APA carbamate and was replaced by penicillin-V-trimethylsilyl ester. The presence of penicillin V-trimethylsilyl ester was demonstrated by comparing the spectra with an identical sample prepared by silylating the free acid of penicillin V with triethylamine and trimethylchlorosilane. The yield calculated from the CMR spectrum was 85-90%.

In a similar manner, using the same molar amounts of reagents and the appropriate acid chloride, cloxacillin, dicloxacillin, staficillin and nafcillin were prepared. The CMR values of these acylation mixtures indicated the presence of an extremely pure acylation mixture with yields of at least 85% of the calculated values.

Example 8

In the reaction according to the above methods, by giving a compound of the formula • / S ^ / CH3 (CH3) 3Si-O-C-NH - f I CH3 ^ -N- *

O-B

wherein B is an easily cleavable ester protecting group such as trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1- ( ethoxycarbonyl) oxy-ethyl, pivaloyl-oxymethyl and acetoxymethyl, react with a reagent suitable acid chloride or acid chloride hydrochloride, said reagent optionally containing protecting groups, and deprotecting if necessary to give the following compounds: almesillin, armesilillin, azidesillin, , azlosillin, bacampicillin, Bay K 4999 with the formula HO—

i l! CH

—CH-CONH -S 'S

I I ^ CH3

NH 0 ^ N

I o C00H

0 = cx H _, \ - "c ^ I l! N n-N = CH-L j BL-P1654 of formula / = Λ s ch3

L Λ— CH - - CONH -1-S

_ / J | ! ^ ch3 I 0 1

1 H NH 2 OH

O = C-NH-Cl 2 NH 2

II

69846 23 BL-P1908 with the formula HO- | CH3

s \ / - CH -CONH --- S S xNC

I 'I ph I, I CH3 NH OH _ ^ -N-

| I

o-c-tT ^ n COOH

N> 0

B

carfecillin, carindacillin, cyclasillin, clometosillin, cloxacillin, dicloxacillin, EMD-32412 of the formula H0-T ^] / S ^ / CH3

CH - CONH-J-S

I j 'CH3 NH -N-

O

0 = C-NH 7 C00H

Vv% u.30 epicillin, phloxacillin (flucloxacillin), furbusillin, hetacillin, 24 6 9 8 4 6 ISF-2664 of formula ^ / = \ / CH3 / CH-CONH -: - ζ ^] <Γ v _ (/ CH3 N-CH2-N- J 0 0 NH 0 = C-OCH2OC-C (CH3) 3 isopropicillin, methicillin, methlosillin, nafcillin, oxacillin, phenbenzillin, PC-455 with the formula / = \ CH3 HO —L CH - CONH --SS ^ Y__y | ch3 NH Λ - N- I o 0

o = c || C00H

u 25 aparsillin (PC-904) of formula 698 4 6 CH-.

/ Γ ~ \ -s ν '

Γ) - CH- CONH -! - 1 X

NH ^ N

I HO °

o = c 1 C00H

^ N

piperacillin, 3,4-dihydroxypiperacillin, pirbenicillin, piv-ampicillin (PL-385) of formula

HO — r ^ Tl CH

I 3 - CH - CONH -1- <I CH3

N J

NH OH - -

I COOH

ΛΛ

x Λ / 2-N N

Prazosillin, sarmoxillin, sarpicillin, ticarcillin-cresyl sodium, ticarcillin, carbenicillin, carfenicillin, fibracillin and Bay-e-6905 of the formula ch3 L /) CH-CONH-- S '\ // I> H, I ^ - - c = oo'

1 _ COOH

/ ° Νγ

-NH

Claims (6)

26 6984 6 A compound of formula for use as an intermediate in the preparation of penicillins 0 H - ς CH (CH) -jSi-O-C-NH-C - C γΓ 33. CH3 J- N-- 0 '^ 0 C' 0-B wherein B is an easily cleavable ester protecting group such as trimethylsilyl. Process for the preparation of a compound according to claim 1, characterized in that dry carbon dioxide is introduced into a solution of a compound of the formula (CH) Si-NH-C -C YT in a manner known per se. I ch3> --- N-- 0 C \ 0-B wherein B has the same meaning as above, in an anhydrous inert organic solvent at a temperature of about 20 to 27 ° C until the reaction is complete, 3. A process for the preparation of penicillin of the formula II 69846 27 0? - e CH »- = /" S v / 3 RC-NH-C -Cl CH 2 -N-- O c- ° OH wherein R is a conventional 6-position substituent in penicillin chemistry, according to which the compound of formula II is acylated with the corresponding organic with a carboxylic acid acid chloride, after which the group B is converted to hydrogen, characterized in that a compound of the formula I is used in the acylation step. Process for the preparation of 6-N-aminoarylacetamidopenicillanic acid, such as 6-CL-aminophenylacetamidopenicillanic acid or 6-Ct-amino- (p-hydroxyphenyl) -acetamidopenicillanic acid, according to Claim 3, characterized in that the compound of the formula I is administered per se react in a known manner in an anhydrous inert organic solvent with an approximately equimolar amount of the corresponding D - (-) - β-aminoarylacetyl chloride hydrochloride. Process for the preparation of amoxicillin according to Claim 3, characterized in that the compound of the formula I is reacted in a manner known per se in an anhydrous inert organic solvent with an approximately equimolar amount of D - (-) - 2-p-hydroxyphenylglycyl chloride hydrochloride. Process for the preparation of ampicillin according to Claim 3, characterized in that the compound of the formula I is reacted in a manner known per se in an anhydrous inert organic solvent with an approximately equimolar amount of D - (-) - 2-phenylglycyl chloride hydrochloride. 28 69846