DE2216623A1 - Penicillin antibiotics - Google Patents

Description

Dr. F. Zumstein Sr. - Dr. E. Assmann * ■ ^ - I Ö DZO

Dr. R. Koenigsbür .-. Cr - Dip !. Phys. R. Holzbauer

Dr. F. Zumstein jun.

Patent attorneys

8 Manchen 2, Briuhouutraß 4/111

12/10 / ka

Penicillin Derivatives 8

GLAXO LABORATORIES LIMITED, Greeford, Middlesex, England

Penicillin antibiotics

The present invention relates to a method of manufacture of 6-aminopenicillanic acid, i.e. 6β ~ amino-2,2-dimethylpenam-3acarboxylic acid.

The compounds of the present description are generally named with reference to Penam (see J. Amer. Ohem. Soc. 1953, 75, 3293).

The N-deacylation of ö-acylamidopenicillin compounds is an important step in the manufacture of penicillin antibiotics. A method for the N-deacylation of a 6-acylamidopenicillin compound is the so-called imide halide technique, which consists in combining the acylamido compound with an agent, e.g. phosphorus pentachloride, believed to be an imide halide

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"Forms, to implement, the reaction product by reacting with a Converting alcohol into a product believed to be it is an imino ether and the latter can be cleaved e.g. by hydrolysis to form the desired 6-amino compound. Although the exact nature of intermediates. not known, they will herein, for reasons of convenience, as imide halides and imino ethers designated.

In order to be able to carry out such a method successfully, it is first necessary to identify the carboxyl group in the 3-position of the penicillin molecule, which could otherwise react with the imide halide-forming agent. Generally one includes Process has its own step to remove the carboxyl protecting group at the end of the reaction sequence and there is the risk of that other parts of the molecule, such as the O-lactam ring, are damaged will.

It has now been found that a 6-acylamidopenicillin compound with an unprotected 3-carboxyl group of the imide halide technology can be subjected if the penicillin first with a phosphorus trihalide, especially with phosphorus trichloride or Phosphorus tribromide is implemented.

The use of a phosphorus trihalide in this way is more economical than protection in the form of carbon or silicon esters and also has the important consequence that no separate step to remove the protecting group from the 3-carboxyl group is necessary at the end of the imide halide process is.

According to one embodiment of the invention, a process for the preparation of 6ß-amino-2,2-dimethylpenam-3a-carboxylic acid is provided, which consists in a salt of a 6β-acylamido-2,2-dimethylpenam-3a-carboxylic acid with a phosphorus trihalide, especially with phosphorus trichloride, in an inert organic

209847/1171

Solvent to react under substantially anhydrous conditions, the resulting solution with an imide halide-forming To bring compound into contact, the reaction mixture obtained with an imino ether-forming compound and connect to mix with water and the formed 6ß-amino-2,2-dimethylpenam-3a-carboxylic acid can be obtained, e.g. by adjusting the pH value to approximately the isoelectric point, through treatment with a base.

Instead of a preformed penicillanic acid salt, a free acid and base can be used. However, it will in general It may be convenient to use a pre-formed salt and the reaction is described below with reference to such salts. It will be understood, however, that the alternative procedure can be used if so desired. .

The starting penicillin used can be given by the general formula _ς

R ¹ CONH

COOR ²

1 2

where R CO is an acyl group and R is Alkali metal atom, e.g. sodium, potassium or ammonium or: one organic ammonium group, e.g. tri (lower-alkyl) ammonium (e.g. triethylammonium), piperidinium, IT- (lower-alkyl) -piperidinium (e.g. N-ethylpiperidinium) or benzylammonium. Just that lower-alkyl groups mentioned can, for example, have 1 to 6 carbon atoms on / iron.

A) Reaction with the phosphorus trihalide

The reaction of the penicillin compound with the phosphorus trihalide can, when R is an alkali metal atom, by the presence of a small amount of an organic base, preferably ■

209847/1171

about 1/2 mole equivalent. Suitable bases include organic tertiary bases, e.g. Ν, Ν-dimethylaniline and Ν, ΙΤ-diethylaniline. The bases used during the stages of formation of the imide halides and the imino ether are required, can at this point in time in full (e.g. up to 4 equivalents) may be added to avoid the need to add additional base during the imide halide forming steps.

The inert organic solvent that is used to convert the penicillin used with the phosphorus trihalide should be essentially anhydrous (e.g., preferably less than $ 0.02 H 0 contain) and is preferably free of alcohol. It is expediently chosen so that it can also be used for subsequent implementation the imide halide technique is suitable. Suitable solvents include such halogenated hydrocarbons, e.g. methylene chloride, 1,2-dichloroethane or chloroform; cyclic or acyclic ethers, e.g. tetrahydrofuran, dioxane, diethyl ether or Diisopropyl ether; or aromatic hydrocarbons such as benzene or toluene. Methylene chloride is particularly preferred, either alone or in a mixture with other solvents.

The reaction of the penicillin compound to the phosphorus trihalide may be at a temperature of +65 ⁰ C or less, preferably at +25 C or less performed. A preferred temperature range for this reaction is from -30 ° to +25 ⁰ C.

The phosphorus trihalide can be used in an amount of 0.20 to 2 moles, e.g. 0.33-1.1 moles, preferably 0.40-0.60 moles, based on the penicillin compound.

The reaction of the penicillin compound with the phosphorus trihalide is advantageous by suspending the penicillin salsa in an inert organic solvent (mixed with a base if desired) at the desired temperature and by adding the phosphorus trihalide to the suspension so that the penicillin goes into solution. The solution obtained of penicillin can last for a short time, e.g. 30 minutes

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the desired temperature can be maintained to full

To secure a reaction and then, if so desired,

must be cooled to allow for any temperature rise that may occur in the next stage.

B) Imide halide formation stage

Imide halide forming compounds that can be used include phosphorus pentachloride, thionyl chloride and phosgene. If phosphorus pentachloride is used, it is expediently added in finely divided form, e.g. 1.48 mm grain size (10 mesh).

The use of phosphorus pentachloride for this reaction is particularly preferred, since the combination of the use of phosphorus trihalide in the initial reaction and the use of phosphorus pentachloride in this reaction, the subsequent solvent recovery and waste recycling is facilitated.

The phosphorus halides are converted into high-boiling organophosphorus compounds by the process according to the invention converted. Solvents can easily be stripped from mixtures of the solvents with these high-boiling compounds.

This reaction with the imide halide-forming compound is carried out in the presence of a base, preferably an organic base carried out. Suitable organic bases, which preferably have a pn value of 4 to 6, include tertiary amines, such as N, N-dimethylaniline and Ν, Ν-diethylaniline. If in the previous Reaction an excess of the base is used, which is convenient, it is usually not necessary in this reaction to use another base.

The imide halide-forming compound can be added to the solution of the Penicillins in molar excess and in amounts of up to 10 molar Excess can be used. It is not economical to use a large excess and it is preferred with that Penicillin compound and with phosphorus pentachloride in molar proportions

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22Ί6623

ratios of 1: 1 to 1: 1.3 worked.

The temperature for the reaction of the Imidhalogenid-forming compound with the penicillin may be from -50 ° C to +25 ⁰ C and 5O ⁰ C. The optimal temperature depends, at least to some extent, on the reactants used. Advantageous
works.

C) Step for the formation of the imino ether

part of the temperature range from -40 ° to ⁰ ° C

The iminoether-forming compound is advantageously a lower alkanol, i.e. an alkanol having 1 to 6 carbon atoms, for example Methanol, ethanol, n-propanol, n-butanol, isopropanol or isobutanol. Straight chain alcohols including methanol are preferred.

Other iminoether forming compounds that can be used include diols of the formula

HO-R ⁵ -OH

wherein R is a divalent alkylene or cycloalkylene group 2,3 or 4 carbon atoms in the carbon chaini that make up the Connecting oxygen atoms together is. Such diols include ethylene glycol, propane-1,2- and -1,3-diol and the various Butanediols, e.g., butane-1,3-diol.

The iminoether-forming compound can be essentially molar Excess, e.g., up to 75 and even up to 100 moles over the penicillin compound.

Although the imino ether-forming compound can be added to the reaction solution, it is preferred to add the reaction solution the iminoether-forming compound as this technique allows better control of the reaction system on a large scale enables.

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The imino ether-forming compound can be mixed with an essentially anhydrous acid as this appears to increase the yield of the end product. The acid can be used in an amount of about 1 mole based on the penicillin compound. Suitable acids include hydrogen chloride, concentrated sulfuric acid, and p-toluenesulfonic acid. The temperature forming iminoether-to reaction with the compound may be from -50 ° C to +10 ^0. The optimum temperature will depend, at least to some extent on the reaction components, and it is generally preferred to perform this step at temperatures from -40 ° to ⁰ ° C.

D) Aqueous treatment

To complete the previous reaction, the reaction mixture is used brought into contact with water. The hydrolysis reactions are completed under the prevailing acidic conditions and the 6β-amino-2,2-dimethylpenam-3a-carboxylic acid is formed.

The reaction with water can be carried out at a temperature of -10 ° to +20 ° C, preferably -5 to +5 ° C can be carried out. The 6β-amino-2,2-dimethylpenam-3a-carboxylic acid can be achieved by raising the pH to its isoelectric point, i.e. about 4, e.g. Treat with a base. This can be done easily Titration can be achieved with aqueous ammonia.

A wide variety of acyl groups can be formed by the invention Procedure to be removed from penicillin compounds. Acyl groups that can be removed can be 1-20 carbon atoms and can be chosen from the wide list of such groups in the literature. Illustrative examples for such groups are those with the general formula:

i) R ^ n- ^ n ⁰⁰ "" * where R ^a substituted an aryl (carbocyclic or heterocyclic), cycloalkyl, substituted aryl

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Cycloalkyl, cyclohexadienyl or a non-aromatic heterocyclic or mesojonic group and η is 0 or is an integer from 1-4. Examples of this group include phenylacetyl-; substituted phenylacetyl- e.g. FTuorphenylacetyl-, Nitrophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methylphenylacetyl, hydroxyphenylacetyl; Thienyl-2- and -3-acetyl and furyl-2- and -3-acetyl groups.

R.
ii) R ^a (CH ") OC-CO-, where R ^a aie defined under i)

R ^c

b c

interpretation, ρ is 0 or 1 and R and R, which are the same or can be different, in each case hydrogen, phenyl, benzyl, Denote phenethyl or lower alkyl groups. An example of such a group is the phenoxyacetyl group.

Important acyl groups of these types include groups found in penicillins, produced by fermentation processes are present, e.g. the phenylacetyl and phenoxyacetyl groups. The method according to the invention is particularly applicable to these last-mentioned two penicillins.

The following examples illustrate the invention without restricting it.

example 1

4.4 ml (0.05 mol) of phosphorus trichloride were added to a cooled (-20 °) suspension of 18.65 g (0.0 ^[ 3 mol) of potassium 2,2-diethyl- () ßphenylacetamidopenam-Ja-carboxylate in 1'30 ml of methylene chloride and 25.4 ml (0.20 mol) of N, N-Diinethyla] iilin /, e added. Me Mi baing was stirred at -20 ° for 1/2 hour and then further cooled to -30 °. 11.45 g (0.055 KuI) of PJiocpliorpeiitachJorid were added in one portion and (the temperature above I-lim-brain; rose

2 0 9 8 A 7/1 1 7 1

- 20 ° at; it was stirred for 1/2 hour at this temperature. This solution was added to 100 ml of cold (-30 °) n-propanol at such a rate that the temperature did not exceed -20 ° and the mixture was added for 1 hour at this Temperature stirred. 100 ml of water were added and the mixture was stirred at 0 ° for 10 minutes. DER pH was raised with aqueous ammonium hydroxide (d = 0.88) to 4.0 and the mixture was cooled and filtered to give 9.10 g (84 i »yield) 6ß-Ami ~ no-2,2-dimethylpenam Gave -3a-carboxylic acid; [a] -Q + 274.5 ° (c 1.0 in 0, In-HCl), bp 206 ° (decomposition).

Example 2

The procedure of Example 1 was followed, except that the reaction temperature was consistently -15 ° and 100 ml n-butanol were used instead of n-propanol. It turned out. 8.75 g ($ 81 yield) 6β-amino-2,2-dimethylpenam-3a-carboxylic acid; [«1 ^ + 276 °.

Example 3

The procedure was as in Example 1, except that 100 ml of methanol were used instead of n-propanol. This resulted in 8.90 g (82.3 io yield) 6ss-amino-2,2-dimethylpenam-3oC-carboxylic acid; [aj ^ + 273 ⁰ ■ (c 1.0 in 0, In-HCl).

Example 4

The procedure was as in Example 1, except that 12.7 ml (0.1 mol) of Ν, ΐϊ-dimethylaniline and 1.62 ml (0.0167 mol) of phosphorus tribromide were used at 0 ° instead of phosphorus trichloride at -20 °. This resulted in 7.81 g (72 fo yield) 6ss-amino-2,2-dimethylpenam-3a-carboxylic acid; [a] °

Beifjpiol ^l >

i ₁ C ¹ , is (0.05 mol) potassium-2,2-dimethyl-6ß-phenylacetamidopenam-

209847/1 171

3a-carboxylate were suspended in 150 ml of dry methylene chloride at -20 ° and 12.8 ml (0.1 mol) of dimethylaniline and 1.47 ml (0.0167 mol) of phosphorus trichloride were added. The mixture was stirred at -20 ° for 1 hour and then cooled to -30 ° while 11.45 g (0.055 mol) of phosphorus pentachloride were added. The mixture was stirred at -20 ° for 30 minutes when all of the phosphorus pentachloride had dissolved. The solution was then slowly added to 115 ml of n-propanol, which had been precooled to -40 °, the temperature being kept below -20 °. The solution was stirred at -20 ° for 30 minutes and then treated with 100 ml of water and the mixture was stirred at 0 ° for 10 minutes. The pH of the solution was raised to 4.0 with concentrated ammonia solution (d = 0.880) and the suspension was stirred at 0 ° for 1 hour, the pH of 4.0 being maintained. The white crystalline product obtained was filtered off, washed with acetone: water (1: 1), acetone and then with ether, dried at 40 ° in vacuo, with 8.38 g (77.4 $> yield) of 6β-amino- 2,2-dimethylpenam-3a-carboxylic acid resulted. Ca] ^ + 275 ° (c 1.08,0, In-HCl).

Example 6

12.8 ml (0.1 mol) of N, N-dimethylaniline and then 2.2 ml Phosphorus trichloride (0.025 mol) was added to a suspension of 18.65 g (0.05 mol) potassium 2,2-dimethyl-6β-phenylacetamidopenam-3a-carboxylate added in 150 ml of methylene chloride at -20 °. The suspension was stirred for 45 minutes at -20 °, cooled to -30 ° and treated with 11.45 g (0.055 mol) of phosphorus pentachloride. The mixture was stirred for 30 minutes at -20 °, during which time all of the phosphorus pentachloride dissolved. The solution was then slowly added to 115 ml of pre-cooled (-40 °) n-propanol, the temperature being kept below -20 °. The solution v / urde stirred for 30 minutes at -20 ° and then mixed with 100 ml of water. After stirring for 10 minutes at 0 °, the pH of the solution with concentrated ammonia solution (d - 0.080) 4.0 raised. The solution was stirred at 0 ° for 1 hour, whereby

209847/117 1

the pH was maintained at 4.0 and then filtered. The product was washed with acetone: water (1: 1), acetone and then with ether, giving 9.18 g (84.9 1 ° yield) of 6β-amino-2,2-dimethylpenam-3oc-carboxylic acid; [«Lp + 273 ° (c 1.1 0, In-HGl).

Example 7

Example 6 was repeated using the phosphorus trichloride reaction 15 minutes at 0 ° and the subsequent steps were carried out as before. It resulted in 9.2 g ($ 85.0 yield) 6β-amino-2,2-dimethylpenam-3a-carboxylic acid; [oc] ^ + 277 ° (c 0.994, 0, In-HCl).

Example 8

Example 6 was repeated, the phosphorus trichloride reaction being carried out for 6 minutes at 20 ° and the subsequent steps being carried out as before. This resulted in 9.18 g (84.8 fo yield) 6ss-amino-2,2-dimethylpenam-3a-carboxylic acid; [a] Jp + 275.5 ° (c 1.13,0, In-HCl).

Example 9

Example 6 was repeated, the phosphorus trichloric. • conversion being carried out at reflux temperature for 2 minutes and the subsequent steps being carried out as above. This resulted in 9.00 g (83.1 ° / o yield) of 6ss-amino-2,2-dimethylpenam-3a-carboxylic acid; [(X] ² J ² + 265.5 ° (c 1.13,0, In-HCl).

Example 10

It procedure was as in Example 1, except that the reaction temperature throughout was -30 ⁰ and 2.5 g of sulfuric acid were added to the n-propanol before use. This gave 9.75 g ( $ 90> yield) of 6β-amino-2,2-dimethylpenam-3a-carboxylic acid;

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Ca] ₁ J + 273 °.
Example 11

15.9 ml (0.125 mol) of Ν, Ν-dimethylaniline and 2.2 ml (0.025 mol) of phosphorus trichloride were successively added to a stirred suspension of 18.65 g (0.05 mol) of potassium 2,2-dimethyl-6β ~ phenylacetamidopenam-3a-carboxylate added to 150 ml of dry methylene chloride cooled to -30 ° C. The mixture was stirred for 30 minutes at -30 ° and cooled to -40 ° and 11.45 g (0.055 mol) of phosphorus pentachloride were added in 1 portion. The suspension was stirred at -30 ° for 1 hour and added to 150 ml of stirred n- Propanol, which contained 2.5 g of concentrated sulfuric acid and was cooled to -30 ° so that the temperature did not exceed -30 °, was added, the mixture was stirred for 1 hour at -30 ° and 100 ml of v / a were added Phase mixture was stirred for 10 minutes at 0 ° and aqueous ammonia solution (d = 0.88) was added to raise the pH to 3.8, the mixture was cooled to 0 ° for 1 hour and filtered. The product was washed with aqueous . acetone (1: 1) and washed with acetone and dried at 40 in vacuo There were 9.68 g (89.5 f <> yield) 6ss-amino-2,2-dimethyl-, penam-3a-carboxylic acid; [<x] _D + 278 ° (c 1.0, In-HCl).

Example 12

12.8 ml (0.1 mol) Ν, Ν-dimethylaniline and 2.2 ml (0.025 mol) phosphorus trichloride were sequentially to a stirred suspension of 18.65 g (0.05 mole) potassium 2,2-dimethyl-6β-phenylacetamidopenam-3a-carboxylate added in 90 ml of dry methylene chloride cooled to -20 °. The mixture was stirred at -20 ° for 30 minutes and cooled to -45 °. 11.45 g (0.055 mole) of phosphorus pentachloride was added in 1 portion and the suspension became Stirred for 1 hour at -30 ° and stirred for 5 minutes to 60 ml Added n-butanol, the 1.33 ml (0.025 mol) concentrated sulfuric acid contained and was cooled to -50 °, so that the temperature did not exceed -30 °. The mixture was 15 minutes at -30 °

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stirred and 60 ml of water was added. The two-phase mixture was stirred at 0 ° for 5 minutes and the product was isolated as in Example 11. This gave 9.57 g (88.5 % yield) of 6β-amino-2,2-dimethylpenam-3a-carboxylic acid; Ca] -J ₅ + 278 ° (c 1.0, In-HCl).

Example 13

Example 12 was repeated, but using 60 ml of n-propanol instead of n-butanol. This gave 9.55 g (88.3 1 ° yield) of 6β-amino-2,2-dimethylpenam-3a-carboxylic acid; Ca] ₃₅ + 272 ° (c 1; 0, In-HCl).

Example 14

25.6 ml (0.2 mol) Ν, Ν-dimethylaniline and 4.4 ml (0.05 mol) phos-. phosphorus trichloride were added successively to a stirred suspension of 37.3 g (0.1 mol) of potassium 2,2-dimethyl-6β-phenylacetamidopenam-3a-carboxylate in 300 ml of dry methylene chloride cooled to -15 °. The mixture was stirred for 30 minutes at -15 ° and cooled to -35 ° and 22.9 g (0.11 mol) of phosphorus pentachloride were added in one portion. The suspension was stirred for 30 minutes at -20 ° and cooled to -40 ° and 360 ml (4 mol) of butane-1,3-diol were added over 10 minutes so that the temperature did not exceed -20 °. The mixture was stirred for 20 minutes at -20 °, 20 ml of water were added and the Zv / ei phase mixture was stirred for 10 minutes at 0 °. Ammonia solution (d = 0.88) was added to raise the pH to 2.2 and the mixture was seeded with 6β-amino-2,2-dimethylpenam-3a-carboxylic acid and then stirred for 5 minutes. Further ammonia solution was added to adjust the pH to 2.5 to lift and the remainder of the inoculum (a total of _0? 3 g) was' added and the mixture was stirred for 10 minutes at 10 ° and ammonia solution was added over 10 minutes to adjust the pH to 4.0 _o The mixture was stirred and cooled to 0 ° for 1 hour and filtered. The product was washed and dried as in Example 11, It gave 19.31 g (87.9 ° p yield after deduction of the inoculum)

2 0 9 8 4 7/1171

6β ~ amino-2,2-dimethylpenam-3oc-cartionic acid; [«! J) + 274 (c 1.2; O, In-HCl).

Example 15

The iminochloride solution was prepared as in Example H from 37.25 g (0.1 mol) of potassium 2,2-dimethyl-6β-phenylacetamidopenam-3a-carboxylate, cooled to -38 ° and added for about 1/2 minute a stirred mixture of 240 ml of dried denatured alcohol (methylated spirit) and 135 ml of methylene chloride, cooled to -47 °, added. The temperature was allowed to rise to -20 ° over 4 minutes and was then held at this temperature for a further 15 minutes and 200 ml of water were added. The two-phase mixture was stirred at 0 ° for 10 minutes and worked up as in Example 14. This gave 19.12 g (87.0 # yield after deduction of the inoculum) of 6β-amino-2,2-dimethylpenam-3a-carboxylic acid; [oc] _D + 278 ° (c 1; 0, Ί n-HCl).

Example 16

The iminochloride solution was prepared as in Example 14 from 37.3 g (0.1 mol) of potassium 2,2-dimethyl-6β-phenylacetamidopenam -3 "-carboxylate, cooled to -35 ° and stirred for 2 minutes Mixture of 240 ml of methanol and 133 ml of methylene chloride, cooled to -40 °, added so that the temperature of the mixture did not exceed -20 °. The mixture was stirred at -20 ° for 9 minutes and 200 ml of water were added and the two-phase mixture was stirred at 0 ° for 10 minutes. Ammonia solution (d = 0.88) was added over 30 minutes to raise the pH to 3.9 while maintaining the temperature at about 10 ° and the mixture was at pH 2.2 and 2.4 for a total of 0.5 g of 6ß-amino-2,2-dimethylpenam-3a? - carboxylic acid inoculated. The suspension was stirred and cooled to 0 ° for 1 hour and filtered. The product was washed with 65 ml of aqueous acetone (1: 1) and with 65 ml of acetone and dried in vacuo at 40 °. The result was 19.80 g (89.2 ° ^C. , 0 yield after deduction of the inoculum) of 6β-amino-2,2-dimethylpenam-3a-carboxylic acid;

7/1171

[α] ^ + 275 ° (c 1; O, In-HCl).
Example 17

12.7 ml (0.1 mol) ΙΪ, Ν-dimethyl aniline and 2.2 ml (0.025 Hol) phosphorus trichloride were successively to a stirred suspension of 19.42 g (0.05 mol) Ealium-2,2- dimethyl-6β-phenoxyacetamido ~ penam-3a-carboxylate in 150 ml of dry methylene chloride, cooled to 4 ° j. The mixture was stirred at 3 to 5 ° for 1 hour and cooled to -30 ° and 11.45 g (0.055 mol) of phosphorus pentachloride were added. The suspension was stirred at -20 ° for 20 minutes, cooled to about -30 ° and added over 2 minutes to 120 ml of stirred methanol, cooled to -30 °, so that the temperature of the mixture did not exceed -20 °. The resulting solution was stirred at -20 ° for 15 minutes, 100 ml of water were added and the two-phase mixture was stirred at 0 ° for 10 minutes. Aqueous ammonia solution (d = 0.88) was added to adjust the pH to 2.8 to raise and the mixture was seeded with 0.1 g of 6ss-amino-2 ₅ 2-dimethylpenam-3tt ~ carboxylic acid and stirred for 5 minutes. Additional ammonia solution was slowly added to raise the pH to 4.0 and the mixture was cooled to about 5 ° for 30 minutes and filtered. The product was washed and dried as in Example 11; there were 8.89 g (81.3 $ yield after deduction of the inoculum) of 6β-amino-2,2-dimethylpenam-3a-carboxylic acid; [a] _D + 271.5 ° (c 1; 0.1n-H01).

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Claims (26)

Patent claims ί "U process for the preparation of 6ß-amino-2,2-dimethylpenam-3acarboxylic acid, characterized in that a salt of a 6ß-acylamido-2,2-dimethylpenam-3a-carboxylic acid with a phosphorus trihalide in an inert organic solvent, under Reacts substantially anhydrous conditions, the resulting solution with an imide halide-forming compound in contact brings the reaction mixture obtained with an imino ether forming Compound and then mixed with water and the 6ß-amino-2,2-dimethylpenam-3a-carboxylic acid formed wins. 2. The method according to claim 1, characterized in that as 6ß-acylamido-2,2-dimethylpenam-3a-carboxylic acid 6ß-phenylacetamid'o- or 6ß-phenoxyacetamido-2,2-dimethylpenam-3a-carboxylic acid is used. 3. The method according to claim 1 or 2, characterized in that phosphorus trichloride is used as the phosphorus trihalide. 4. The method according to any one of the preceding claims, characterized in that the reaction with the phosphorus trihalide at a temperature of -50 ° to +65 ⁰ C is carried out. 5. The method according to claim 4, characterized in that the temperature is -30 ° to +25 ⁰ C. 6. The method according to any one of the preceding claims, characterized in, that the reaction with the phosphorus trihalide is carried out in the presence of an organic base. 7. The method according to claim 6, characterized in that a tertiary amine is used as the base. 209847/117 1 8. The method according to claim 7, characterized in that Ή, N-dimethy! Aniline or Ν, Ν-diethylaniline is used as the base. 9. The method according to any one of claims 6 to 8, characterized in that that the base in an amount of up to 4 molar equivalents is used. 10. The method according to any one of the preceding claims, characterized in that the phosphorus trihalide in an amount of 0.33 "to 1.1 moles per mole of the penicillin compound is used. 11. The method according to any one of the preceding claims, characterized in that the imide halide-forming reagent is phosphorus pentachloride is used. 12. The method according to any one of the preceding claims, characterized in that the reaction with the imide halide "forming Compound carried out in the presence of a tertiary amine base will. 13. The method according to claim 12, characterized in that ϊϊ, Ν-dimethylaniline or N, $ - I3iäthylanilin is used as the base. 14. The method according to any one of the preceding claims, characterized in that the reaction with the imide halide forming Connection is carried out at a temperature of -50 ° to * 25 ° C. 15. The method according to any one of the preceding claims _9, characterized in that an allcanol with 1 to 6 carbon atoms or an alkanol with 2 "to carbon atoms is used as the imino ether-forming compound« 16. The method according to claim 15, characterized in gelcsmiaeicimo-fej, öaß as Alkanol methanol, n-propanol or n-Bu-feanol Te ^ enöet ^ irdo 20 3 8 4 7/11 7 1 17. The method according to any one of the preceding claims, characterized in that the reaction mixture, which is prepared in the reaction with the imide halide-forming compound , .zu the iminoether-forming compound is added. 18. The method according to any one of the preceding claims, characterized in that a chlorinated hydrocarbon is used as the reaction solvent in all stages. 19. The method according to claim 18, characterized in that methylene chloride is used as the solvent. 20. Procedure according to one of the preceding ·.; ..! Claims, characterized in that the phosphorus trihalide is used in an amount of 0.4 to 0.6 mol per mol of the penicillin. 21. The method according to any one of claims 11 to 19, characterized in that a molar ratio of penicillin compound to phosphorus pentachloride in an amount of 1: 1 to 1: 1.3 is used. 22 »Process according to one of claims 1 to 19, characterized in that the reaction with the imide halide-forming compound is carried out at a temperature of -40 to ⁰ ° C. 23. The method according to any one of claims 1 to 19, characterized in that the imino ether-forming compound is mixed with an acid. 24. The method according to claim 23, characterized in that sulfuric acid is used as the acid. 25. The method according to any one of claims 1 to 19, characterized in that the reaction with the imino ether-forming compound at -40 ° to ^{0 0} O is carried out. 209 847 / 1.1 7 1 26. The method according to any one of claims 1 to 19, characterized in that the mixing step, the reaction mixture prepared by reaction with the imino ether "forming compound is carried out ^{at a temperature of -10 ° to +20 0 C,} 209847/117 1