DK162055B - 6-TRIMETHYLSILYLOXYCARBONYLAMINOPENICILLANIC ACID DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF - Google Patents

Description

in

DK 162055 B

The present invention relates to novel 6-trimethylsilyl-oxycarbonylaminopenicillanic acid derivatives of formula (I) and a process for the preparation thereof, which penicillanic acid derivatives are used as starting materials in a novel process for the preparation of conventional penicillins. The compounds of formula (I) are characterized by the characterizing portion of claim 1.

The first commercial penicillin with an α-amino group on the 6-acylamidoside chain was ampicillin, which is 6- (D-o-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.

978,178, J.Chem.Soc. (London), pages 1920-1922 (1971) and Antimicrobial Agents and Chemotherapy - 1970, pages 407-430 (1971). Its chemical name 15 is 6- [D-α-amino-α- (p-hydroxyphenyl) acetamido] penicilic 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-aminopenicillic acid with a silyl group, as also disclosed in British Patent Nos. 1,008,468 and U.S. Patent Nos. 3,249,622) and in British Patent Specification No. 962,719 in cold aqueous acetone. These 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 (see United States Patent No. 3,008,956). Improved methods for isolating and purifying such penicillins have been disclosed in e.g.

30 U.S.A. U.S. Patent No. 3,180,862 through 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 35 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.

U.S.A. U.S. Patent No. 3,478,018, U.S.A. U.S. Patent No. 3,595,855,

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2 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. U.S. Patent 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 - (-) - a- amino-β-hydroxyphenylacetic acid in which the amino group is protected, then removal of the silyl group or groups by hydrolysis or alcoholysis and then, if possible, 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 isobutyl ketone (4-methylpentan-2-one). Substantially the same approach was used in U.S.A. U.S. Patent No. 3,674,776.

According to the present invention there are provided novel compounds of formula O c.

or,, II,, (CH ~) -Si-O-C-NH-CH-CH · C.- (i)

λ-N-CH

tf I

υ C-O-B

II-0 30 wherein B represents an easily leaving ester protecting group selected from the group consisting of trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichlorethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1 - [(ethoxycarbonyl) oxy] ethyl, pyvaloyl-oxymethyl and acetoxymethyl. To prepare a conventional penicillin, the compounds of formula (I) are reacted in an anhydrous inert organic solvent, and preferably in methylene chloride.

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3 preferably in the presence of a weak base which is preferably propylene oxide, and preferably at a temperature above -10 ° C, and more preferably in the range of -8 ° C to 20 ° C, and even more preferably in the range of 0 ° C to 20 ° C, and most preferably at approx. 20 ° C, with approximately an equimolar 5 weight amount of an acid chloride or chloride hydrogen chloride, the latter being preferably added portionwise to the solution of the former, and if desired, group B is converted to hydrogen.

By "conventional penicillin" herein is meant a penicillin previously described in the patent literature or the scientific literature, including summaries thereof.

Further, according to the present invention, there is provided a process for the preparation of the compound of the formula 15 O yClL · H / P (i) (CH,), Si-O-C-NH-CH-CH C In CH3

i-N-CH

tf 1

u C-O-B

II -

ISLAND

wherein B represents an easily leaving 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) oxy] ethyl, pivaloyloxymethyl and acetoxymethyl, which is characterized by adding dry carbon dioxide as a gas to a solution of a compound of formula 30 / CH5 (CH2 Si-NH-CH-CH C (CH)

/ "? H

«0 C-O-B

35 ||

ISLAND

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4 wherein B has the same meaning as above, in an anhydrous inert organic solvent, preferably methylene chloride, at room temperature or at a temperature ranging from 0 ° C to 100 ° C until the reaction is complete.

Thus, to prepare a 6-α-aminoarylacetamidopenicillanic acid, for stepwise ampicillin or amoxicillin, a compound of the formula is reacted

0 Q

|| / \ yCYU

(CH,), Si-O-C-KH-CH-CH C J {Ia)

^ I I I ^ CH

i-N-CH ^ / i U l-O-SiiCH ^) ^

ISLAND

15 in an anhydrous, inert organic solvent, preferably in methylene chloride, and 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, even more preferably in the range of 0 ° C to 20 ° C, and most preferably at approx. 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, wherein the latter reactant is preferably added portionwise to the solution of the former reactant.

One of the surprising features of the use of the novel intermediates is the stability of the anhydrous acylation solution.

This can be kept for long periods of time, even at room temperature, without any appreciable decomposition of the penicillin molecule. This contrasts with the behavior of acylation solutions by methods known in the art. This stability advantage enables the acylation reaction to be carried out at much higher temperatures (e.g. room temperature) than normally used in the ampicillin preparation, where the temperature is usually below 0 ° C and typically approx. -10 ° C.

Also provided, as a preferred embodiment, is a process for preparing the compound of the formula

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5 0 no

ice

5 (C1-6Si-O-C-MH-CH CH2 ^ cH ^ <Ia)} - * 'f O · C-O-SiCCIU) ^

II

Dry carbon dioxide is added as a gas to a solution of trimethylsilyl-6-trimethylsilylaminopenicillanate in an anhydrous inert organic solvent, preferably methylene chloride, at room temperature, or at a temperature in the range of 0 ° C to 100 ° C. the reaction has ended.

The preferred compound of the invention has the formula I / S \ / CH, 20 (CH2 Si-O-C-ira-CH-CH C

° C-O-Si (CH, U

II ^^ o 25

This compound is referred to herein by various trivial names, such as bis-silylated carbamate of 6-APA, SCA, 6-trimethylsilyloxycarbonyl-penicillanic 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 the 6-trimethyl-s ilyloxycarbonylamino nepi-cilanic acid tri-methyl s in 1-ester (TMS01C, APA, TMS) 35 is in the 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:

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6 6-APA + HMDS + Imidazole- Reflux 1 mole 1.1 mole catalyst 6-8 hours 3-5 mole% 5

Complete carboxyl Add 5 ml of 1% TMCS and "silylation" & approx. reflux overnight 40-65% 6-NH 2 over 10 "silylation" _ TMSNH s - \ -S "NC (6-APA, bis-TMS) lo ..... - __ yd N- \ cr * co2 ™ s

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

Conversion of the trimethylsilylamino group to the trimethyl silyloxy-carbonylamino group is readily achieved by bubbling dry CO 2 in the reaction solution. The conversion is readily followed by NMR because the trimethylsilyl amino singlet at 0.09 ppm declines as a new trimethylsilyloxycarbonylamino group occurs at 0.27 ppm.

When used in the preparation of ampicillin, ampicillin anhydrate, ampicillin intrihydrate, amoxicillin and amoxicillin trihydrate, the final products are isolated and purified according to conventional methods well known in the art as illustrated by 35 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 to produce conventional

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7 penicillins.

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

U.S.A. U.S. Patent No. 3,741,959.

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-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., triethyl) amine, arylmethylenamino, sul phenyl amino or enamine types. Enamine blocking groups are particularly valuable in 15 cases of o-aminomethylphenylacetic 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 convenient 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 M 2 group can also be protected as NH 3 + by using the amino acid halide in it 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 pK - d d value (in water at 25 ° C) of the amino acid carboxy groups. The acid is preferably monovalent. In practice, the acid HQ (see below) will generally have a pK. <3, preferably <1.

d Particularly advantageous results have been found when the acid tail ogenide is a salt of an amino acid halide. Amino acid halogen having the formula

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8

HgN-R 2 COHal wherein R * represents a divalent organic group and Hal represents chloride 5 or bromide. Salts of such amino acid halides have the formula [H3N-R1-COHal] + Q "wherein R * and Hal have the above meanings, and Q" means the anion of the acid, with HQ having a pK. 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) methylammonium chloride, D- [PhCH (NH 3) COCl] + Cl reasons of convenience are referred to as D-α-phenylglycyl chloride d, hydrochloride.

Penicillins having an acylamido group RuCH (NH 4) - CONH-, where Ru L 2 3 has the meaning given above, can be reacted with a ketone R 1 R 2 CO, 2 3 wherein R and R mean lower alkyl groups (C C ^) to form 20 compounds believed to contain the group

CO

». / \ R - CH N- 1_I,

HN__RZ

A3 30

Compounds of this type include hetacillin, sarpicillin, p-hydroxy-hetacillin and sarmoxicillin.

The invention is further illustrated with reference to the drawing, in which:

Figure 1 shows the 80 MHz NMR spectrum of silylated 6-APA in the range 0-2

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9 ppm containing the geminal signal for the two methyl groups in 2-style-1 gene and the signal for 100% silylation of the 3-carboxyl group and 100% silylation of the 6-amino group (in addition to triethylamine, HCl (TEA-HCl), trimethylchlorosilane ( TMCS) and traces of hexamethyldisiloxane (HMDSO)), and Figure 2 shows the 80 MHz NMR spectrum in the range 0-2 ppm of the product of the invention obtained by β-treatment of the silylated 6-APA shown in Figure 1. The 6-aminotrimethyl signal has completely disappeared and a new signal has emerged as a result of the 6-trimethylsilylcarbonylamino group. Integration of the 6-trimethylsilylcarbonylamino signal against the geminal dimethyl signal shows that the conversion to 6-trimethylsilylcarbonylamino is 100%.

The process 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 CD 2 Cl 2 and 1.13 ml of trimethyl chlorosilane at a temperature of 25-27 ° C was added dropwise 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 20 for approx. 3 hours. At the end of this time, NMR (nuclear magnetic resonance) showed the presence of 60% silylated carboxy-6-APA (SCA) with the structure 258 ^ (CH2 Si-O-C-HN-i-p \ CH5

i— N

O C-O-Si (CH U

Il 5 * 30. 0

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% purity) was added in portions as follows:

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ίο

Time in Temperature Gram, added

minutes ° C

0 -8 0.30 5 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 +8 220 +15 10 310 +20

At the end of the 310 minute reaction period, thin layer chromatography (TLC) performed on a sample of the reaction mixture using a solvent system which was 60% ethyl acetate, 15 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.

20

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 2 Cl 2 was refluxed under nitrogen rinsing. for approx.

25 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 amino and carboxyl group of 6-APA. 0.2 ml of HMDS 30 (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 did not show 35 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 (95% purity; 0.026 mol) was added in portions as follows:

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11

Time in Temperature Gram, added

minutes ° C

5 O -3 1.05 20 O 1.30 40 O 1.30 50 O 1.00 60 O 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 Cl 2. After separation, the aqueous phase showed a large zone slower than ampici11 in and 6-APA, which represented new intermediate X.

The aqueous phase was adjusted to pH 3.0 with NH 4 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 isopropyl alcohol 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 Clg for reflux is added 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 12

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a further 0.1 ml of TMCS was then added, leaving only very slight turbidity. 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 15 48 20 1.00 75 20 1.00

After this mixture was stirred for an additional 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 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 stirred for 5 minutes, polished filtered and washed with water and with CH 2 Cl 2. 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 4 OH and stirred at room temperature for 1 hour and then on an ice bath for a further 30 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 testing 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 CDgClg was added dropwise 1.23 ml of TEA over 30 minutes and the mixture was stirred for 35 minutes.

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13 additional 2 hours. Dry carbon dioxide was then refluxed for 4 hours. At this point, 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-5 hydroxy-2-phenylglycyl chloride, hydrochloride in portions were added as follows:

Time in Temperature Gram, added

minutes ° C

10 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 8 15 220 15 310 20

At the end of the 310 minute period, NMR showed approx. 78% amoxicillin and approx. 20% 6-APA.

20

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 trimethyl chlorosilane (11.70 g, 107.75 mmol, 2.33 eq) over a 10-15 minute period, keeping the temperature below ca. 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 30 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. Additional gas addition was sometimes needed. If necessary, the volume of the carboxylation mixture was reset 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 serving of acid chloride was given

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14 allowed to dissolve before the next batch of ten Isattes. (Stirring was discontinued and the mixture examined for any solid on the bottom of the flask. The slurry must not be heated below 5 ° C for this test as the results may be erroneous). This required approx. 20 minutes per portion. This 5 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 10 was removed. The aqueous phase was polished (very low solids) filtered through a thin (Dicalite) coating of diatomaceous earth and the cake 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 ca. 13.5 g (about 70%) of snow white amoxicillin, tri hydrate.

Example 6 6-Aminopenicillanic 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) was stirred and heated. for reflux for 3.3 hours. The reaction mixture was rinsed with dry nitrogen gas under reflux to remove NH 2 formed during the reaction. Next, 2.0 ml of trimethyl chlorosilane (TMCS) (0.016 mol) was added. Reflux was continued with Ng rinsing for a further 19 hours, then the 30 NH 3 Cl sublimated in the condenser was removed and 2.6 ml of TMCS (0.0206 mol) was added to the reaction. Reflux with Ng rinsing was continued for an additional 34 hours. The volume of 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-penicillanic acid. The solution was covered with Ng gas and held for 9 days.

35 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).

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15

This basic mixture was used for the acylation experiments described below. The chemical compound in this solution had the formula 5 '8 (CH}) 3 Si-O-C-HH-1-ζ P'CH 2

)-*-IN

o C-O-Si (CE, 10 II ^ 3 O.)

NMR showed that the bis-trimethylsilylcarboxy-6-aminopenicillanic acid was stable after 9 days.

100 ml of the basic mixture (SCA equivalent of 10.8 g of 6-aminopencillanic 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:

Gram, added Time in Temperature

minutes ° C

25 ..............-..............................

3.0 0 +3 3.0 7 +2 3.0 20 +2 6.5 33 +2 30 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 1.0 ml of DgO was added. After centrifugation, NMR analysis of the aqueous phase showed ca. 6% unacylated 6-aminopenicillanic acid.

Ten minutes later, the reaction mixture was transferred to a 600 ml beaker and the transfer was terminated by washing with 50 ml methyl en 16

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1.0 ml D2O. After centrifugation, NMR analysis of the aqueous phase showed ca. 6% unacylated 6-aminopenicillanic acid.

Ten minutes later, the reaction mixture was transferred to a 600 ml beaker and the transfer was terminated 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.

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 10 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 sulphite) 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 15 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 NaHSOg dissolved in 6.0 ml of water was added over 30 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, which was 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 25 amines wherein each secondary amine has the formula R1 CH3C (CH3) 2CH2C (CH3) 2CH2CH = CH-CH2NHC-R2 30 R3 wherein each of R, R and R is a aliphatic hydrocarbon group and wherein R, R and R in the aggregate contain from 11 to 14 carbon atoms; this particular mixture of secondary amines, sometimes referred to as "Liquid Amine Mixture No. I", is a clear amber liquid having 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 range at 10 mm: up to 160 ° C 4%, 160 to 210 ° C - 5%, 210 to 220 ° C - 74%, above 220 ° C - 17%.

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17

Example 7

A methylene chloride solution (5.0 ml) of trimethylsilyl-6-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 triethylamine, the 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, cl oxacillin, dicloxacillin, staphcillin and nafcillin, were prepared. CMR data on these acylation mixtures showed an extremely pure acylation blend with yields estimated at least 85%.

Example 8

Reaction according to the foregoing methods of a compound of formula n} J i? g = = c, ch3, Λ (CH,) -Si-OC-NH-30 3 3 J1-CH3 ° 35 wherein B is an easily cleavable ester-protecting group selected from the group consisting of trimethyl silyl, benzhydryl, benzyl, p-nitrobenzyl,

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18 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 reagent contains blocking groups as required, followed by removal of any blocking groups whose removal is desirable, yields the following compounds: almecillin, armecillin, azidocillin, azlocillin, bacampicillin, Bay K 4999 of the formula Η0 ”ΐ ^ \ _

15% COOH

J-BL-P1654 of formula 20

(r ° i-cori, yrYcL

25 NH 0 C00K

0 = C-NH-C ^ 2 BL-P1908 of the formula Η0Ί ^ ΐ1 L> 1-ch - com — r-f γ, 35 *

IH OH 0 COOH

0 = C-tjAh 'K,

H

carfeeillin, carindacillin, cyclacillin, clometocillin, cloxacillin, 40

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19 dicloxacillin, EMD-32412 of the formula CH-CONH \ r

NH0 and OH C00H

= 1 in 0 = C-NH

uQ

Epicillin, floxacillin (flucloxacillin), furbucillin, hetacillin, I.S.F.-2664 of formula 20 CH

/ Λ— CH - CONH — i-K

! 33-rCBJs N-CH 2 O 0 = C-CCH 20 C-C (CH

25 I

nh2 · 30 isopropicline lin, methicillin, mezlocillin, nafcillin, oxacillin, phenbenici11in, PC-455 of formula 35

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20 CH2

5 UH 0- ^ COOH

: oIY) aparcillin (PC-904) of formula 15 / -v / CH3 V 'V-CH-CONH-r- \ = / I> -K- CH3.

NHO COOH

I '-HO - -.

2 ° 25 piperacillin, 3,4-dihydroxypiperacillin, pirbenicillin, pivampicillin, PL-385 of the formula 30 H ° Y \ _WS <CH3 l ^ JLcH-coirH - pr I · OH ^ -K-- 5

HH COOH

0 = C-X ί A-i \ - CEO

35 \ _ /

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21 prazocillin, sarmoxicillin, sarpicillin, ticarcillin, cresyl sodium, ticarcillin, carbenicillin, carfecillin, fibracillin and Bay-e-6905 of formula 5

Oc "'" τχ! ^ 4.

m cook 10 c = o N xO I-HH '

Claims (5)

2. A compound according to claim 1, characterized in that it has the formula n »H O r = ς .CH-, on o r 3 20 (CH3) ^ Si-O-C-NH F-f X (1a) 33 CrL · Jr-h- 3 u ° —ND-SiiCrLK ~ ^ 3 3 25 A process for the preparation of 6-trimethylsilyloxycarbonyl-aminopenicillanic acid derivatives according to claim 1 of the formula O (CHO 2 = r / K / 3 (ccH3) 3Si ° T (Hf-TJsCH3 (I) o U ° N) -3 wherein B has the meaning set forth in claim 1, characterized in that dry carbon dioxide is added to a solution of a compound of formula 35 HH:: ς yCH? (CH3) 3SiNH —5 (11) 5. CH3 ° tf X) -3 where B has the meaning given above, in an anhydrous inert organic solvent at a temperature from 0 ° C to 100 ° C until the reaction is complete. 4. A process according to claim 3, characterized in that B is trimethylsilyl. 15 20 25