HU185445B - Process for preparing panam-carboxylic acid derivatives - Google Patents

Abstract

The present invention relates to a process of formula XVII wherein R is phenyl optionally substituted with hydroxy. naphthyl, phenoxy or naphthyloxy- (C 1 -C 4) alkyl, optionally substituted on the carbamoyl-linked carbon atom to produce a conventional penicillin derivative substituted by an amino group. (XVII) -1-

Description

The present invention relates to an improved process for the preparation of certain antimicrobial synthesized olein derivates and, preferably, of these compounds having an amino group at the α-position of the acyl group at the 6-position of the amino group such as ampicillin and amoxicillin.

The first commercially available penicillin derivative that contains an amino group at the α-position of the acylamino group at position 6 is ampicillin [6- (Da-amino-α-phenylacetylamino) penicillanic acid, see U.S. Pat. 648th U.S. Pat.

The antibacterial agent amoxicillin is used in human medicine and is commercially available as the trihydrate of the free acid form (i.e. the zwitterionic form). For a description, see, for example, U.S. Pat. United Kingdom Patent No. 15,192; and J. Chem. Soc. (London), 1971, 19201922; Antimicrobial Agents and Chemotherapy, 1970, 407-430 (1971). The chemical name of amoxicillin is 6- [D-α-amino-α- (p-hydroxyphenyl) acetammo] penicillanic acid. 20

The patent literature describes how to prepare such penicillin derivatives using amino acid chloride hydrochlorides under anhydrous conditions (see, for example, British Patent No. 938,321 and British Patent No. 959,853, the latter of which is incorporated herein by reference). the carboxyl group of 6-aminopenicillanic acid is protected with a silyl ester group prior to the acylation, this silylation is disclosed in British Patent Nos. 1,008,468 and 3,249,622, or cold, aqueous acetone (see British Patent No. 962,719). These penicillin derivatives are amphoteric amino acids and have therefore used certain aliphatic, asymmetric, branched-chain secondary amines (often referred to as liquid amine resins) for their isolation (as disclosed in U.S. Patent Nos. 3,157,640 and 3,271,389 35). previously used for the isolation of the amphoteric amino acid type 6-anenopenicillanic acid (see zq., U.S. Patent No. 3,008,956). Improved methods for the isolation and purification of such penicillin derivatives have also been described, for example, via β-naphthalene sulfonates (U.S. Patent No. 3,180,862), or by isolation of the intermediate followed by easy hydrolysis of hetacillin (3,198,804). U.S. Pat.

No. 3,499,909. U.S. Pat. Several patents relate to the acylation of silylated 6-aminopenicillanic acid with amino acid chloride hydrochlorides under anhydrous conditions, such as, for example, 3,479,018, 3,595,855, 3,654,266, 55,3479,338. and 3.487.073. U.S. Pat. Some of these patents also report the use of liquid amine resins.

See U.S. Patent Nos. 3,912,719, 3,980,637. and 4,128,547. See also U.S. Pat. 60

No. 1,339,605. United Kingdom Patent No. 4,600,119 provides various specific and detailed examples of the preparation of amoxicillin by the silylation of the 6-aminopenicillanic acid by amino-protected D - (-) -? - amino - (- hydroxyphenyl) acetic acid. 65 2 is reacted with a reactive derivative (including chloride hydrochloride), followed by removal of the silyl group (s) by hydrolysis or alcoholysis and, where possible, the isolation of amoxicillin, usually in the form of crystalline trihydrate. Thus, as in Example 1, crystalline amoxicillin is obtained by precipitating the product from the aqueous solution at an isoelectric point, e.g., pH 4.7. According to this example, the product is presumably purified by precipitating the crude product at an acidic pH, e.g., pH 1.0 (e.g., aqueous hydrochloric acid), prior to precipitation at the isoelectric point, with an organic solvent immiscible with water, such as methyl isobutyl ketone. In the presence of 4-methyl psnant-2-one) and dissolved in water. Essentially the same procedure is described in U.S. Patent 3,674,776. U.S. Pat.

The present invention relates to a process for the preparation of a conventional penicillin derivative by reacting a compound of formula IV wherein B is an easily cleavable group, such as trimethylsilyl, benzhydryl, benzyl, ρ-nitrobenzyl, , p-methoxybenzyl ·, trichloroethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1 - [(ethoxycarbonyl) oxy] ethyl, pivaloyloxy methyl or acetoxymethyl, in a dry, inert organic solvent, preferably dichloromethane, preferably in the presence of a weak base, preferably propylene oxide, and preferably above -10 ° C, more preferably below -8 ° C. at a temperature of from about 20 ° C to about 20 ° C, more preferably from about 0 ° C to about 20 ° C, and most preferably about 20 ° C, with about the same amount of an acid chloride or an acid chloride hydrochloride. Preferably, the latter reagent is added in portions to a solution of a compound of formula IV and optionally B is replaced by a hydrogen atom.

The conventional .penicillin derivative referred to in the above paragraph has the general formula XVU wherein

R is phenyl, naphthyl, phenoxy or naphthyloxy (C 1 -C 4) alkyl optionally substituted with hydroxy, optionally substituted with amino on the carbon atom attached to the carbamoyl group.

I is preferably of formula IV, wherein

B is an easily cleavable ester-forming group such as trimethylsilyl, benzhydryl, benzyl, ρ-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetonyl, methoxy. methyl, 5-indanyl, 3-phthalidyl, 1 - [(ethoxycarbonyl) oxy] ethyl, pivaloyloxymethyl or acetoxymethyl group, the compounds of formula II, wherein B is a solution of the above compound in anhydrous inert organic solvent, preferably dichloromethane, at room temperature or at 0 ° C to 100 ° C until the reaction is complete.

The invention further relates to a process for the preparation of 6 - [(a-amino) -anyl-acetamino] -penicillanic acid derivatives, preferably ampicillin and amoxicillin, by reacting a compound of formula III with water.

185,445 in an inert organic solvent, preferably dichloromethane, preferably in the presence of a weak base, preferably propylene oxide, preferably above -10 ° C, more preferably between -8 ° C and 20 ° C, more preferably between 0 ° C and 20 ° C. And most preferably about 20 ° C to a hydrochloride of D - (-) -? -Amino-arylacetic acid chloride and preferably D - (-) - 2-phenylglycyl chloride hydrochloride or The reaction is carried out with about the same molar amount of D - (-) - 2- (p -hydroxy-phenyl) -glycyl chloride hydrochloride, preferably by adding the latter reagent in portions to a solution of the compound of formula III.

One surprising feature of the novel process of the invention is that the anhydrous acylation reaction mixture is stable. The acylation solution can be stored for long periods of time even at room temperature without the penicillin molecule being noticeably degraded. This is different from the behavior of the acylation mixtures used in the methods described so far. This stability advantage allows the acylation reaction to be carried out at temperatures substantially below 0 ° C (20 ° C) and substantially above room temperature (usually -10 ° C) for the production of ampicillin.

The compound of Formula III is prepared by reacting the trimethylsilyl 6-trimethylsilylaminopenicillanic acid ester with anhydrous inert organic solvent, preferably dichloromethane, at room temperature or at 0 ° C to 100 ° C. Anhydrous carbon dioxide gas is passed until the reaction is complete. 30

The compound of formula III is named: bis-silylcarbamate of 6-aminopenicillanic acid (6-APA); SCA; 6- (trimethylsilyloxycarbonylamino) penicillanic acid terimethylsilyl ester; or abbreviated: TMSO ₂ C.APA.TMS.

The fact that the compound of formula III is obtainable and viable is surprising, since it is known that when carbon dioxide is reacted with 6-aminopenicillanic acid, the latter is decomposed and 8-hydroxypenicillanic acid is formed, as described in 3.225. 033rd U.S. Pat. 40

The quantitative preparation of the trimethylsilyl ester of 6- (trimethylsilyloxycarbonylamino) penicillanic acid requires that the double silylation of 6-aminopenicillanic acid be carried out completely in the preparation of the necessary starting material. To this end, 6-aminopenicillanic acid is hexamethyldisil;

we respond as follows:

izannal (HMDS) is the scheme below

6-Amino-hexamethylpenicillyl-disilazanoic acid mole 1.1 moles irididazole 6-8 hours (catalyst) boiling 3-5 mole% total carboxylation and about 40-65% amine silylation 5% more trimethylchlorosil- (trimethylsilylamino) pemcillanoic acid thiomethyl · silyl ester, followed by reflux overnight «η

By NMR spectroscopy, it is easy to verify that the double silylation reaction is complete. The methyl 65 silyl singlet of the 3-trimethylsilyloxycarbonyl group is 0.3! ppm-nc1 (tetramethylsilma; 0 ppm) and the methyl silyl sign of the 6-trimethylsilyl anino group is found at 0.09 ppm.

Trimethylsilylation of 6-anno-penicillanic acid has so far been carried out only in dichloromethane, but other solvents such as acetonitrile, dimethylformamide, or the reaction can be carried out in excess of the hexamethyldisilazane itself as a solvent.

The trimethylsilylamino group can be easily converted to the trimethylsilyloxycarbonylamino group by introducing anhydrous carbon dioxide into the reaction mixture. The transformation can be easily followed by ΝΜΛ-spectroscopy: the singlet of the trimethylsilylamino group disappears at 0.09 ppm and is replaced by the new singlet of the trimethylsilyloxycarbonylamino group at 0.27 ppm.

Wood is prepared by the process of the present invention to obtain ampicillin, anhydrous ampicillin, ampicillin trihydrate, amoxicillin or amoxicillin trihydrate, and the final products are isolated and purified by conventional methods known per se, as described in Nos. 3,912,719, 3S83,637 and 4,383,637. U.S. Patent No. 128,547 and the publications cited therein.

In addition to the acid chlorides used in the examples below, a number of other acid chlorides may be used to provide conventional penicillin derivatives.

Since the acyl group to be incorporated contains an amino group, it is convenient to protect this amino group before each reaction step. Preferably, a protecting group is selected which can be hydrolytically removed without compromising the remainder of the molecule, and in particular the lactam ring and the 7-amino linkage. The amino-protecting group and the ester-type protecting group at the 4-position carboxyl group can be removed with the same reagent. It is preferred that both protecting groups are removed in the final step of the reaction sequence. Protected amino groups may include urethanes, arylmethyl (e.g. trityl) allyl, arylmethylene anino, sulfenylamino or enamino groups. Enamine-type protecting groups are particularly well suited for use in. o-aminomethylphenylacetic acid. Such protecting groups may generally be cleaved off with dilute mineral acids) such as dilute hydrochloric acid, concentrated organic acids such as concentrated acetic acid, trifluoroacetic acid, or liquid hydrobromic acid at very low temperatures, e.g. -80 ° C, or by combining these reagents. . A suitable protecting group is a tert-butoxycarbonyl group which is readily removed by hydrolysis, for example with a dilute mineral acid such as dilute hydrochloric acid, or preferably with a strong organic acid such as formic acid or trifluoroacetic acid such as 0 ° C and 40 ° C. And preferably room temperature (15 ° C to 25 ° C). Another suitable protecting group is the 2,2,2-trichloroethoxy carboxyl group which may be cleaved, for example, with zinc and acetic acid, zinc and formic acid, zinc and a lower alcohol, or with zinc and pyridine.

The amino group may also be protected in the form of a cation while the amino acid halide is used in the form of its acid addition salt under conditions where the amino group remains unchanged in proton.

85445

Preferably, the acid addition salt is formed with an acid having a pK _a value in water at 25 ° C of not more than X + 1, where X is a pK _a value for _the carboxyl group of a given amino acid at 25 ° C; and the acid used for salt formation is preferably monovalent. Generally, the acids of formula HQ (see below) used have a pK _a value of less than 3, and preferably less than 1.

Particularly good results can be obtained by using the process according to the invention when an amino acid halide is used as the acid halide. Amino acid halides have the general formula: H ₂ N-R _t -CO-Hal, where

Ri is a divalent organic group, and

Fish means chlorine or bromine.

Salts of such amino acid halides have the general formula: [H ₃ N-R _t- CO-Halj ⁺ Q, where R 1 and Hal are as defined above and

Q 'is as defined above _pKa -értékű HQ anion of the acid of formula.

The acid of formula HQ is preferably a strong mineral acid such as hydrochloric acid or hydrobromic acid. An important amino acid halide that can be used to make valuable penicillin backbone antibiotics is DN (dichlorocarbonyl-a-phenyl) methylammonium chloride ([D-PhCH (NH ₃ ) COCl] ⁺ Cl), which is for purposes of simplicity, it will be referred to herein as D-phenylglycyl chloride hydrochloride.

When penicillin derivatives are prepared by the acylation process of the invention, the final products are isolated and purified by methods known per se,

Acid chlorides are generally prepared under vigorous conditions, for example by boiling the acid with thionyl chloride, but if acid sensitive groups are present, including sensitive protecting groups, they can be prepared under substantially neutral conditions such that acid salt with oxalyl chloride.

The process of the invention; Without limiting the scope of the invention, the following examples are set forth below:

Example 1

To a mixture of 6-aminopenicillanic acid (6-APA), dichlorodideuteromethane (10 ml) and trimethylchlorosilane (1.13 ml) was added dropwise triethylamine (1.23 ml) at 25-27 ° C over half an hour, followed by the mixture was stirred for an additional 2 hours. Anhydrous carbon dioxide gas was then added to the mixture for about 3 hours. The NMR spectrum then shows that 60% of the penicillin derivatives present in the mixture are trimethylsilyl 6- (trimethylsilyloxycarbonylamino) penicillanic acid (formula III). The mixture was kept in the refrigerator overnight, then 0.77 ml of Ν, Ν-dinethylaniline was added, followed by cooling to -8 ° C with 1.2 g of 79% pure D - (-) - (- hydroxy). -phenyl) -glycyl-chloro-id-hydrochloride ot:

Time (minutes) Temperature (° C) Added weight of acid chloride (g) 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 8 220 15 310 20

After 310 minutes of reaction, a sample of the reaction mixture was subjected to thin layer chromatography (eluent: ethyl acetate: acetic acid: water 60:20:20) to detect amoxicillin.

To a 2 ml sample of the finished reaction mixture was added 1.0 ml deuterium oxide. After separation of the phases by centrifugation, the aqueous solution was found to contain 78% amoxicillin and about 20% 6-aminopenylanilic acid by NMR. The presence of amoxicillin is also confirmed by thin layer chromatography.

Example 2

5.4 g (0.025 mol) of 6-aminopenicillanic acid, 6.2 ml (0.0275 mol) of 93% pure hexamethyldisilazane (HMDS), 0.07 g (approximately 0.001 mol) of imidazole and 40 ml of dichloro methane is heated under nitrogen for about 17.5 hours. Trimethylchlorosilane (TMSC) (0.13 mL, about 0.001 mol) was added and the solution was turbid. The mixture is refluxed for a further 7 hours, during which time ammonium chloride is deposited in the refrigerator. NMR analysis of the mixture showed that both the amino and carboxyl groups of the 6-aminopenicillanic acid were nearly 100% silylated. Thereafter, 0.2 ml of hexamethyldisilazane (0.00125 mol, about 5 mol%) and 0.06 ml of trimethylchlorosilane (about 0.0005 mol) were added and nitrogen was added for a further 17 hours. Thereafter, the mixture was subjected to NMR analysis as before the addition of small amounts of the two reagents. Anhydrous carbon dioxide gas was then added at room temperature for 75 minutes. At this point, according to the NMR spectrum, the mixture contained no hexamethyldisilazane and contained more than 92% trimethylsilyl 6- (trimethylsilyloxycarbonylamino) -enicillanic acid. Subsequently, 4.45 ml of Ν, Ν-dimethylaniline (0.035 mol) was added and the mixture was cooled to -3 ° C. At this temperature, 5.65 g (0.026 mol) of 95% pure D - (-) - 2-phenylglycyl chloride is added at the following rate:

185,445

Time (minutes) Temperature f C) Added weight of acid chloride (g) 0 -3 1.05 20 0 1.30 40 0 1.30 50 0 1.00 60 0 1.00

Added

Time (minutes) Temperature (° C) quantity (G) 0 20 1.35 20 20 1.30 32 20 1.00 48 20 1.00 75 20 1.00

The reaction was monitored by NMR spectroscopy, showing only a very small change 5 hours after the reaction was started. At this time, the temperature of the mixture was 15 ° C. The mixture was cooled in ice for the next 16 hours and then stirred at room temperature at about 20-24 ° C for 3.5 hours. At this time, the mixture still contained large amounts of solids. Stirring is continued at room temperature (22-24 ° C) for about 63 hours, after which time only slight turbidity is observed. A sample of the mixture was shaken with deuterium oxide and the NMR spectrum confirmed the presence of ampicillin and 6-aminopenyl penicillanic acid.

The reaction mixture was cooled to about 0 ° C, treated with ice water (35 mL) and stirred cold for 5 minutes. The insolubles were filtered off, washed with cold water and dichloromethane. Separation of the aqueous phase by thin layer chromatography indicates 6-aminopenicillanic acid and a broad band of a new intermediate, a slower moving material than ampicillin.

The aqueous phase was adjusted to pH 3.0 with ammonium hydroxide and inoculated with ampicillin. Methylisobutyl ketone (35 mL) was added, stirred, the pH was adjusted to 5.2 with additional ammonium hydroxide, stirred for 35 hours at 20 ° C, then stirred in an ice bath for 1 hour and then refrigerated overnight. The precipitated ampicillin is filtered off, washed with 25 ml of cold water, then with 40 ml of methyl isobutyl ketone and finally with 34 ml of methyl isobutyl ketone and finally with 34 ml of isopropyl alcohol 40 ml and dried at 50 ° C. . 4.5 g of ampicillin were obtained, which was identified by thin layer chromatography.

Example 3

A mixture of 5.4 g of 6-aminopenicillanic acid, 6.2 ml of 93% pure hexamethyldisilazane, 0.06 g of imidazole and 50 ml of dichloro-50-methane is refluxed under nitrogen for 1 hour. Then 0.1 ml of trinethyl chlorosilane was added, causing the solution to become cloudy. After refluxing for a further 2 hours, a clear solution was obtained and ammonium chloride appeared in the refrigerator. Then 0.1 ml of trimethylchlorosilane (55 ml) was added again, causing only a slight clouding of the solution. The mixture was refluxed for an additional 65 hours without introducing nitrogen. It is then cooled to about 22 ° C and anhydrous carbon dioxide is introduced for 75 minutes. NMR analysis of the reaction θθ indicates more than 90% trimethylsilyl ester of 6- (trimethylsilyl, oxycarbonylamino) penicillanic acid. 4.45 ml of Ν, Ν-dimethylaniline are added, followed by 5.6 g of 97% pure D - (-) - 2-phenylglycyl chloride hydrochloride:

After stirring for a further 17 hours, the reaction was monitored by thin-layer chromatography on samples of the mixture as well as diluted samples (1 mL of reaction mixture diluted with 2 mL of dichloromethane). Chromatograms show low levels of ampicillin and large amounts of new intermediates.

The reaction mixture is cooled to 0 ° C, 40 ml of ice water are added, the insolubles are filtered off, washed with water and dichloromethane. The aqueous phase is separated off, 10% is set aside as a sample, the rest is adjusted to pH 3.0 with ammonium hydroxide, injected with ampicillin and stirred. After addition of 40 ml of methyl isobutyl ketone, the mixture is stirred further and adjusted to pH 5.2 with additional ammonium hydroxide. The mixture was stirred for one hour at room temperature and then for one hour in an ice bath, whereupon crystallization began. After being kept in the refrigerator overnight, the crystalline product is filtered off, washed with methyl isobutyl ketone followed by water and methyl isobutyl ketone followed by 34 ml of isopropanol and 6 ml of water and dried at 45 ° C. 6.25 g of ampicillin are obtained (corrected for sample taken: 6.8 g, 68% yield).

Example 4

To a mixture of 1.0 g of 6-amino-penicillanic acid, 1.13 ml of trimethylchlorosilane and 10 ml of dichloromethane, 1.23 ml of triethylamine is added dropwise over half an hour, and the mixture is stirred for 2 hours. Anhydrous carbon dioxide gas was then added for 4 hours. NMR of the mixture showed carboxysilylation of about 55-60%. The mixture was kept in the refrigerator overnight, the next day 0.77 ml of Ν, Ν-dimethylaniline was added, the mixture was cooled to -8 ° C and 1.2 g of D - (-) - 2- (p) was added with stirring as follows. hydroxyphenyl) glycyl chloride hydrochloride.

Added

Time (minutes) Temperature (° C) quantity (G) 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 8 220 15 310 20

-5185 445

After 310 minutes of reaction, the NMR showed about 78% amoxicillin and about 20% 6-aminopenicillanic acid.

Example 5

Dry 6-aminopenicillanic acid (10.0 g, 46.24 mmol) was suspended in anhydrous dichloromethane (175 mL) at 25 ° C with stirring. 10.76 g (106.36 mmol, 2.30 equivalents) of triethylamine are added, followed by 11.70 g (107.75 mmol, 2.33 equivalents) of trimethylchlorosilane over 10 to 15 minutes at a rate such that the temperature of the mixture should not exceed 32 ° C. After stirring for 20-30 minutes, the mixture containing the precipitated triethylamine hydrochloride was analyzed for silylation by 80 MHz NMR spectroscopy. Carbon dioxide gas was then introduced at 20 ° C for 2 hours and then tested for the degree of carboxylation by the same method. In some cases the gas supply still has to be continued. If necessary, make up to 175 ml with anhydrous dichloromethane. When the required amount of carbon dioxide has been added, 2.95 g (3.56 mL, 50.87 mmol, 1.1 eq.) Of propylene oxide are added to the suspension and cooled to 0-5 ° C. 5.54 g (50.87 mmol, 1.1 eq.) Of D - (-) - 2- (p-hydroxyphenyl) glycyl chloride are added in five portions weighing 2.71 g at approximately 2 ° C. hydrochloride hemidioxane solvate by waiting for each dose of the acid chloride to dissolve and then adding the next portion. (To check dissolution, stop stirring and observe for solids at the bottom of the flask. Do not allow the temperature of the mixture to exceed 5 ° C, otherwise false results may be obtained.) It takes about 20 minutes for each detail to dissolve. . It is very important that the acid chloride is then added in portions. After the last dose, check for any undissolved portion of the mixture. After half an hour at 0-5 ° C, 100 ml of cold (0-5 ° C) deionized water are added and the mixture is stirred at high speed for 10 minutes. After separation of the phases, the lower dichloromethane phase is drained, the very insoluble portion of the aqueous solution is filtered through a thin layer of diatomaceous earth (Dicalite) and the layer is washed with 15 ml of cold (0-5 ° C) deionized water. Before the crystallization, any lower organic phase which is still present is completely removed. The pH of the clear, light yellow aqueous solution (pH 2 to 2.5) is adjusted to 3.5 and inoculated if necessary. After 40 minutes at 0-5 ° C, the suspension was adjusted to pH 4.8-5.0 with 6N ammonium hydroxide solution. After allowing to crystallize for 2 hours, the solid amoxicillin was filtered off, washed with a 1: 1 mixture of isopropanol / water (0-5 ° C) and then with dichloromethane (30 mL) to give approximately 13.5 g (about 70%) of a snow-white colored amoxicillin trihydrate.

Example 6

108 g (0.5 mol) of 6-aminopenicillanic acid, 1.0 g (0.017 mol) of imidazole, 800 ml of anhydrous dichloromethane and 120 ml (0.56 mol) of approximately 98% pure hexamethyl

-disilazane was stirred at reflux for 3.3 hours while continuously purging with nitrogen gas to remove the ammonia formed. Trimethylchlorosilane (2.0 mL, 0.016 mol) was added and refluxed for 19 hours under nitrogen. The sublimed ammonium chloride was removed in the condenser and an additional 2.6 mL (0.0206 mol) of trimethylchlorosilane was added. The mixture is heated under reflux for 34 hours. The reaction mixture was then made up to 1000 ml with anhydrous dichloromethane. NMR showed 100% silylation of the amino and carboxyl groups of 6-aminopenicillanic acid. Nitrogen was passed over the solution, sealed and allowed to stand for 9 days. Recent NMR analysis confirms the above result and the stability of the solution. Carbon dioxide gas was then added with stirring at 20-22 ° C for 1.5 hours. NMR showed that the trimethylsilyl ester of 6-trimethylsilylaminopenicillanic acid was completely converted to the trimethylsilyl ester of 6- (trimethylsilyloxycarbonylamino) penicillanic acid (formula III).

This stock solution is used for the acylation reactions described below. NMR showed that the solution was stable for 9 days.

To a 100 ml portion of the above stock solution (corresponding to 0.05 mole of 6- (trimethylsilyloxycarbonylamino) penicillan-v-trimethylsilyl ester) was added 8.0 g (0.058 mole) at 22 ° C with stirring. triethylamine hydrochloride and 4.2 ml (0.06 mol) of propylene oxide (see U.S. Patent No. 3,471,959). Little triethylamine hydrochloride precipitates from the mixture. The mixture was cooled to +3 ° C with stirring and 15.5 g (0.055 mol) of 73% pure D - (-) - 2- (p-hydroxyphenyl) glycyl chloride hydrochloride was added in the following step. -hemidioxán solvate:

Added material (G) Time (minutes) . Temperatures) 3.0 0 3 3.0 7 2 3.0 20 2 6.5 33 2. 15.5

After stirring for an additional 70 minutes, approximately 50 ml of anhydrous dichloromethane was added to reduce the viscosity of the mixture.

After stirring for an additional 160 minutes, a 2 ml sample is removed from the mixture and 1.0 ml of deuterium oxide is added. After centrifugation, NMR analysis of the aqueous phase indicated about 6% unacylated 6-aminopenicillanic acid.

minutes later, the mixture was transferred to a 600 mL beaker and washed with 50 mL dichloromethane. 60 ml of cold, deionized water are added with stirring in an ice bath to obtain a biphasic mixture of pH 1.0 with no soluble solid.

To the biphasic system was added 15.0 ml of liquid anion exchange resin ("LA-1") with stirring and inoculated at pH 2.0, and the

185,445 oozing begins. A further 10 mL of LA-1 is then added slowly over about 5 minutes to a pH of 3.0. Sodium borohydride (0.15 g) was added followed by 5.0 mL of LA-1 to give a pH of 4.5. With further stirring, a solution of 1.0 g of sodium bisulfite in 4.0 mL of water was added dropwise. A further 10.0 mL of LA-1 was added and the pH of the mixture continued to rise. A total of 40 ml of LA-1 was added and the final pH of the mixture was 5.6. Acetone (5 mL) was added followed by a solution of sodium hydrogen sulfite (1.5 g) in water (6.0 mL) over half an hour and the mixture was further stirred in an ice bath. The precipitated product is filtered off, washed with 50 ml of dichloromethane, 40 ml of water, 80 ml of isopropyl alcohol and 20 ml of water and finally 100 ml of dichloromethane. The filtered material was dried at atmospheric pressure at 45 ° C to give 18.2 g of amoxicillin trihydrate corresponding to 87% yield of 6-aminopenicillanic acid. Adjusting for sampling (1%), total production is about 88%.

The "LA-1" liquid anion exchange resin is a mixture of secondary amines, all of which are characterized by Formula VI, wherein

R ^1, R ² and R ³ is an aliphatic hydrocarbon group containing 11-14 carbon atoms;

secondary amines of the above type according to Claim ^{7 of} the present invention

Mixture of a process according to the method of authors “I. liquid amine beats ” , a pure amber has the following characteristics: colored liquid, physical viscosity at 25 ° C 70 eps specific gravity at 20 ° C 0.845 refractive index at 25 ° C 1,467 boiling point distribution At a pressure of 10 mmHg: 160 ° C 4% 160-210 ° C 5% 210-220 ° C 74% Above 220 ° C 17%.

Example 7

To a solution of 6- (trimethylsilyloxycarbonylamino) penicillanic acid trimethylsilyl ester (5.04 mL) in dichloromethane (0.54 g substrate, 2.497 mmol) was added 0.20 g (1, 45 mmol of triethylamine hydrochloride followed by 0.162 g (2.75 mmol) of propylene oxide. The mixture was stirred at the same temperature for 20 minutes to facilitate dissolution of triethylamine hydrochloride. Phenoxyacetyl chloride (0.43 g, 2.75 mmol) was then added dropwise at this temperature and the mixture was stirred for another half hour. A sample is then taken and examined at 20.0 MHz by CMR spectroscopy (13 C nuclear magnetic resonance). According to this assay, neither trimethylsilyl ester of phenoxyacetyl chloride nor trimethylsilyloxycarbonylamino) penicillanic acid is present, but trimethylsilyl ester of penicillin V can be detected. To detect the trimethylsilyl ester of penicillin V, the spectrum of the reaction mixture is compared with that of an authentic sample.

The authentic sample is prepared by silylation of penicillin V, the free acid form, with trimethylcis-silane in the presence of triethylamine. Estimated yield based on the CMR spectrum: 85-90%.

Claims (7)

Patent claims A process according to any one of Formula XVII wherein R is a phenyl, naphthyl, phenoxy or naphthyloxy (C 1 -C 4) alkyl optionally substituted with hydroxy, optionally substituted on its carbamoyl carbon atom with a penicillin moiety, for the preparation of a) of the general formula wherein B is an easily cleavable ester-forming group, reacted with anhydrous carbon dioxide in anhydrous organic solvent at 0-100 ° C, and then the resulting compound of formula V, where B is the above-R-COOH-organic acid chloride - R a ferti - acylate and then replace group B with hydrogen, or a) Acylating a compound of formula IV, wherein B is B, with the above-mentioned organic acid chloride of the above-mentioned R-COOH, where R is above, and then replacing group B with hydrogen. (Priority: July 18, 1979) 2. The process of claim 1, wherein R-COOH and XVI and XII are as defined above. Starting from the compounds of formula IV wherein Rase is as defined in claim 1 and B is trimethylsilyl, benzhydryl, benzyl, p-nitro benzyl, p-methoxybenzyl, trichloroethyl, phenacyl, acetoyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1 - [(ethoxycarbonyl) oxy] ethyl, pivaloyloxymethyl or acetoxymethyl. (Priority: March 19, 1979) The process according to claim 1, wherein XVII is a general formulation R is phenyl, naphthyl, phenoxy or naphthyloxy (C1-C4) -alkyl optionally substituted with hydroxy and substituted with amino on the carbon atom to which the carbamoyl group is attached, characterized in that R-CCOH and Compounds of Formula XVI and IV, wherein R is as defined above and B is trimethylsilyl. (Priority: December 18, 1978) 4. A process according to claim 2, wherein the D - (-) - (α-amino-α-aryl) -acetyl chloride hydrochloride is preferably molar in anhydrous, inert organic solvent. . (Els'ibbscge: December 18, 1978) The process for the preparation of amoxicillin according to claim 1, wherein the compound of formula III in an anhydrous, inert organic solvent is preferably D - (-) - 2- (p-hydroxyphenyl) glycyl chloride hydrochloride. of the same amount. (Priority: December 18, 1978) 185,445 6. A process for the preparation of ampicillin according to claim 1, wherein the compound of formula III is reacted in an anhydrous, inert organic solvent, preferably in the molar amount of D - (-) - 2-phenylglycyl chloride hydrochloride. 5 tats. (Priority: December 18, 1978) 7. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature above -10 ° C. (Priority: March 19, 1979) 6 pieces of figure