NO853188L - CRYSTALLIC SODIUM SALT OF D-6- (D - ((2-OXO-3-FURFURYLI-DEN-AMINO-IMIDAZOLIDIN-1-YL) CARBONYL-AMINO) -TIENYL-2-ACET-AMIDO) -PENICILLANIC ACID PREPARATIVE PROCESS AND ITS USE IN PHARMACEUTICALS. - Google Patents

Abstract

1. Sodium salt of D-6-{alpha-[(2-oxo-3- furfurylideneamino-imidazolidin-1-yl)-carbonylamino]-2- thienylacetamido}-penicillanic acid of the formula (I) see diagramm : EP0176716,P8,F2 in pure crystalline form, characterized by the following NMR signals : delta = 9.36 (1H), 9.23 (1H), 7.8 (2H), 7.5 (1H), 7.25 (1H), 7.05 (1H), 6.89 (1H), 6.62 (1H), 6.2 (1H), 5.74 (1H), 5.56 (1H), 4.35 (1H), 3.92 (4H), 1.6 (3H) and 1,5 ppm (3H) (in DMF-d7 ).

Description

The invention relates to the sodium salt of D-6-£α-/-(2-oxo-3-furfurylidene-amino-imidazolidin-1-yl)carbonylamino/-thienyl-2-acetamido}-penicillanic acid in pure crystalline form, process for its preparation , as well as its use in pharmaceuticals.

European patent no. 392 mentions, among other things, the compound with formula I

The starting material for the production of this penicillin was D,L-a-amino-thienylacetic acid. By reaction with 6-aminopenicillanic acid, a-amino-thienyl-2-acetamido-penicillanic acid is obtained in poor yield (11-31%). At the same time, diastereomer separation occurred. More accurate investigations showed diastereomer ratios of D:L = 55-61:45-39.

By reacting α-amino-thienyl-2-acetamido-penicillanic acid with 1-chlorocarboxyl-2-oxo-3-furfurylidene-amino-imidazoline, the penicillanic acid of formula I is obtained in pure crystalline form (D:L = 92:8).

To prepare the sodium salt, the penicillanic acid (I) was dissolved in the calculated amount of 0.5 N caustic soda and this solution was lyophilized (IR spectrum in Fig. 1). This amorphous sodium salt formed by freeze-drying an aqueous solution is in itself very soluble in water. Depending on the production portions, however, the concentrated aqueous solutions (for example 15%) only become clear and runny for a more or less short time. Some gel already after a few minutes, so that you can place the tub on your head without anything leaking out. There is so far no explanation for this uncontrollable ratio of the concentrated aqueous solutions, which would make an intravenous application very difficult or impossible.

It is not successful in numerous attempts by crystallization from solvents to obtain crystalline sodium salt, thus, for example, during the precipitation, aqueous alcoholic solutions with isopropanol form an amorphous product that stubbornly sticks to isopropanol even in high vacuum and these solutions form gels (IR spectrum see Fig. 2).

Surprisingly, it was now found that from aqueous ethanol a sodium salt of the penicillanic acid with formula I is obtained in crystalline form (IR spectrum see Fig. 3) is stable, can be easily freed from attached alcohol and its solution remains clear and thin-flowing for days and forms a gel not.

It was found that the sodium salt of the penicillanic acid of formula I is in crystalline form when (A) the amorphous sodium salt is crystallized from ethanol-water mixtures of suitable proportions,

or

(B) the crystalline acid of formula I is transferred in solution in its sodium salt, and this crystallizes from ethanol-water mixtures of suitable proportions.

The synthesis of the penicillanic acid of formula I used as starting material and its sodium salt was carried out differently from that in European patent no. 39 2 in a way that led to a diastereomeric uniform product. The crystallization took place from ethanol-water mixtures in a ratio of ethanol to water in the range 5:1 to 15:1.

The procedures are carried out in a temperature range from 0 to 50°C, preferably from 20° to 40°C. Usually work at room temperature.

The procedure can be carried out at normal pressure or at elevated pressure. Normally you work at normal pressure.

The ratio of the amount of the solvent mixture to the amount of solute can be varied within a wide range. Preferred is per 0.1 mol of solute an amount of solvent mixture from 0.5 to 3 litres.

The crystalline pure sodium salt of D-penicillanic acid with formula (I) is effective as an active substance against a wide spectrum of microorganisms. Due to its property of forming solutions which remain clear and thin for days and do not form gels, the active substance according to the invention is particularly suitable for the preparation of solutions for injection.

Pharmaceutical preparations contain, in addition to non-toxic pharmaceutical suitable carriers, the active substance according to the invention. By -non-toxic pharmaceutical suitable carriers is meant liquid diluents of any type, especially water.

For parenteral application, the solutions may also be available

in sterile and blood isotone: form.

The pharmaceutical preparations may be available in dosage units. This means that the preparations are available in the form of ampoules whose active substance content corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. contain 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. The single dose preferably contains the amount of active substance that is administered by application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose. The therapeutically active compounds must be present in the above-mentioned pharmaceutical preparations, preferably in a concentration of approx. 0.1 to 99.5, preferably from approx. 0.5 to 95% by weight of the overall mixture.

The above-mentioned pharmaceutical preparations can besides

the active substance according to the invention also contain further pharmaceutically active substances.

The production of the above-mentioned pharmaceutical preparations takes place in the usual way according to known methods, e.g. by mixing the active substance with the carrier substances or substances.

The active substances or pharmaceutical preparations can be applied parenterally, intravenously or intramuscularly.

Generally, it has proven beneficial in humans, as well as in veterinary medicine, to administer the active substance according to the invention in total amounts from approx. 5 to 1000, preferably 20 to 200 mg/kg body weight per 24 hours, possibly in the form of several individual submissions to achieve the desired results.

A single administration contains the active substance according to the invention, preferably in amounts from approx. 1 to approx. 250, especially 10 to 100 mg/kg body weight. It may be necessary to deviate from the dosages mentioned, namely depending on the type and body weight of the object to be treated as well as the type and severity of the illness, type of preparation and application of the medicine, as well as the time period or the interval within which the administration takes place.

Thus, in some cases it may be sufficient to come out with less than the above-mentioned amount of active substance, while in other cases the above-mentioned amount of active substance must be exceeded. The fixing of the resp. necessary optimal dosage and application type and the active substance can easily be carried out by any professional due to his professional knowledge. Fig. 1 shows an IR spectrum of the amorphous sodium salt (lyophilic according to example 5, EP 392). ON the X-axis is the wavelength in cm. The numbers on the Y-axis correspond to the permeability in %. The numbers on the upper edge of the spectrum correspond to the frequency in microns. Nujol was used as solvent. Fig. 2 shows an IR spectrum of the amorphous sodium salt of i-PrOH (comparative example 2). Fig. 3 shows an IR spectrum of the crystalline sodium salt of from EtOH (examples 1, 2).

In the drawings fig. 2 and 3 correspond to the numbers on X and The Y-axis de for fig. 1 specified units.

Comparison example 1. 1.

1.142 kg (7.3 M) of D, L-ct-thienyl-(2)-glycine and 1.83 kg (7.3 M)

(+)-camphor sulphonic acid hydrate (CSS technique) was brought into solution with 2.03 liters of water at 7 2°C internal temperature, aspirated hot from small impurities of CSS, inoculated and set aside. After 1 hour it was placed in an ice bath and further cooled to 10° C. internal temperature (approx. 1 hour's duration). It was carefully aspirated, squeezed off, washed with acetone and dried in a vacuum cabinet.

Yield: 898.3 g (31.7%).

IR band at 3260-2100, 1746, 1699, 1620, 1500, 1200,

1140, 1031 and 751 cm<-1> (in Nujol).

Comparison example 1. 2

800 g of camphor sulphonic acid salt of D-thienylglycine from comparative example 1.1 was suspended in 2 liters of water and diluted with 2.5 liters of i-propanol. With 2 N NaOH, pH = 6.0 was set. and the pH was kept at 6 until it was constant. Now a further 2.5 liters of i-propanol were stirred, then stirred for 30 minutes, sucked off and washed with i-propanol and then with ether. It was dried for 24 hours in a drying cabinet at 50°C above P2°5'

292 g (90%). ln HC1: Z~^7D ="115.4°. IR spectrum is different from that of racemic thienylglycine.

IR band at 3250-2000, 1600, 1498, 1275, 1122,

904, 850, 719 and 688 cm<-1> (in Nujol).

The D = R configuration of the acid was confirmed by circular dichroism measurement.

Comparison example 1. 3

573 g (3.65 mol) (D)-α-thienyl-(2)-glycine were added to 4.5 liters of THF/1^0 (1:1) with stirring and further cooling with ice/water with triethylamine adjusted to pH 7. (If you use NaOH as a base, then

at the present concentration, the Na salt of the precursor acid frequently crystallizes out). During further cooling, 881 g (3.65 mol) of 1-chlorocarbonyl-2-oxo-3-furfurylideneamino-imidazolidinone were now introduced and at the same time the pH was maintained with triethylamine at 6.5-7.0. The internal temperature must not exceed 35°C. It was stirred until the pH remained constant at 7. 1.5 liters of water were added, THF was removed in a vacuum rotary evaporator and the aqueous phase was stirred for 15 minutes with 3 50 g of diatomaceous earth. Now it was sucked off, washed with approx. 1 liter of water, and the combined filtrates adjusted with IN HC1 to pH = 2, after a short time sucked off and washed with water, then with ethanol and ether and dried in a drying cabinet at 60°C.

The product (1121 g, 85%) (decomposition > 243°C) contained, according to the NMR spectrum, approx. 1.7% 1-furfurylideneamino-2-oxo-imidazol-idine, approx. 2% ether and some ethanol.

IR band at 3600-2100, 1721, 1676, 1508, 1324, 1267,

1182, 1012 and 736 cm<-1> (in Nujol).

NMR signals at δ = 9.18, (D, J = 7.5, Hz, 1H), 7.86

(S, 1H), 7.84 (D, J = 1.5 Hz, 1H) ,

7.55 (D, J = 5 Hz, 1H), 7.22 (D,

J = 4 Hz, 1H), 7.1 (Q, J = 5 Hz,

J2= 4Hz, 1H),,6.9 (D, J = 4Hz,

1H), 6.65 (Q, J1= 4 Hz, J2= 1.5 Hz,

1H), 5.78 (D, J = 7.5 Hz, 1H), 3.95

(S, 4H) (in DMF-d7).

Comparison example 1. 4

1 mol (362 g + 15 g, 96% product) precursor acid from example 1.3 was suspended in 5.5 liters of acetone, mixed at room temperature with 1 mol (14 0 mo) of triethylamine, stirred for as long (approx. 10 minutes ) until a clear solution had formed. It was now cooled to -40°C internal temperature and thereby added 4.5

ml of 3-dimethylaminopropanol. At -40°C, 1.05 mol (100 ml) of ethyl chloroformate was added and then stirred for 15 minutes at -35 to -30°C (internal temperature). It was then cooled at an internal temperature of -55°.

Meanwhile, a solution of 6-APS-Na salt diluted with 1 liter of acetone was prepared from 1.05 mol (227 g) of 6-amino-penicillanic acid in 800 ml of water by adding 2 n NaOH to a maximum pH of 7.8 and cooled to -10°C (just yet no ice formation).

This solution was completely -55°C cold mixture of the mixed anhydride at once as quickly as possible as the internal temperature rose to -35 to -33°C. The cold bath was removed and the flask was finally heated with water so that after approx. 50 minutes later, +12°C internal temperature was reached. Now 3 liters of water were added, the acetone was removed under vacuum on a rotary evaporator, 6.5 liters of water and 125 g of diatomaceous earth were again added, the pH was set to 7, stirred for 15 minutes and aspirated off (centrifugation should be better as the aspiration with some mixtures lasted for several hours). The aqueous phase was now carefully acidified with 1 n HCl, when pH 4.5-5 was achieved, seed crystals of D-penicillanic acid were added and stirred for a few minutes for crystal formation before further acidification to pH 2. The suspension was stirred for 20 minutes, and then the highly crystalline product was well suctioned off. The moist crude product was weighed and, obtaining a 90% yield (505 g), mixed with water to a total amount of 2240 ml of water. 5 liters of acetone were added and dissolved with 2 N NaOH at pH = 7 and quickly acidified again to pH 2 with 1 n HC1, within a few seconds the product began to crystallize out. After 2 hours' rest in an ice bath, it was suctioned off, washed with water, dried in a vacuum drying cabinet above P2°5*

Yield: 64% (375 g).

According to the NMR spectrum, the product showed a D:L ratio of > 95:

•"C 5.,. By adding a lot of water, decanting and working through or stirring overnight with fresh water in 10 - 30% yield, penicillanic acid was obtained with a D:L ratio of approx. 40: 60.

1.5.

If the product's content is below 95% D and above 5% L, it can be cleaned as follows:

(feasible up to a D:L ratio of 4:1).

850 g (I) with D:L = 90:10 was dissolved in 3.8 liters of I^O + 3.8 liters of acetone with 2 n NaOH at pH = 7 under water cooling (internal temperature ^ 20°C ) stirred with 150 g diatomaceous earth for 15 minutes, suctioned off and mixed with a further 3.8 liters of acetone. It was acidified to pH = 2 with 1 n HC1, inoculated, left to stand for 2 hours in ice with occasional stirring, suctioned off, washed with water and dried in a vacuum drying cabinet.

Yield: 672 g (D:L according to NMR spectrum 98.5:1.5).

From the mother liquor, a further 55 g of penicillanic acid (D:L = 63:37) was obtained by adding a lot of water, decanting and stirring overnight.

Comparative example 2

377 g of crystallized penicillanic acid from comparative example 1 was suspended in 1500 ml of water + 450 ml of ethanol and with 1 n NaOH brought into solution with pH 7.0-7.5 (if necessary suctioned off over a G4 frit). 6 liters of i-propanol were then added and stirred for 45 minutes. It was sucked off well, suspended with i-propanol and again sucked off and dried for 24 hours at 40°C in a drying cabinet over ^ 2°s' 318 g of product (70.5% yield, calculated as Na salt . 5 H 2 O). The content of i-PrOH 1-2% which neither

was lowered by 4 days of further drying in a circulating air cabinet.

DC (butyl acetate, butanol, glacial acetic acid, phosphate buffer pH = 7)

practically uniform.

IR band at 3650-2500, 1764, 1725, 1660, 1597, 1528,

1512, 1271, 1234, 1161, 1018, 742 and 718 cm"<1>

(in Nujol).

NMR signals at δ = 7.42 (S, 1H), 7.3 (D, J = 5 Hz, 1H),

7.25 (D, J ^ Hz, 1H), 7.06 (D, J = 4 Hz,

1H) , 6.9 (T, 4-5 Hz, 1H) , 6.4 (D,

J = 4 Hz, 1H), 6.2 (Q, Jx ^<4>Hz, J2-

1 Hz, 1H), 5.5 (S, 1H), 5.35 (S, 2H),

4.05 (S, 1H), 3.65-3.25 (M, 4H), 1.38 +

1.3 (D, 6H), (in D 2 O).

From the mother liquor, acidification to pH 2 was achieved by dilution with a lot of water, extraction, washing with water and drying in a desiccator over P-jOj. regenerate 44 g of acid which after recrystallization could be used again so that the total yield referred to consumed acid increased to ^ 75%.

Example 1

Crystalline sodium salt of D-6-[α-/~(2-oxo-3-furfurylidene-amino-imidazolidin-1-yl)-carbonylamino7-thienyl-2-acetamidoJ-penicillanic acid, prepared from amorphous sodium salt.

462 g of the amorphous, according to comparative example 2 prepared sodium salt of D-6-£a-/~(2-oxo-3-furfurylidene-amino-imida-zolidin-1-yl)-carbonylamino7-thienyl-2-acetamido]- penicillanic acid was dissolved in portions in a mixture of 810 ml of water and 1000 ml of ethanol and then mixed with 5 1 of ethanol while stirring at room temperature. It was inoculated and, after 30 minutes of stirring, a further 1.1 1 of ethanol was added, stirred for 1 hour and left

leave it overnight.

It was now thoroughly sucked off and dried in a circulation cabinet to constant weight.

Yield: 64% of the theoretical. IR spectrum see fig. 3.

NMR signals at 6 = 9.36 (1H), 9.23 (1H), 7.8 (2H),

7.5 (1H), 7.25 (1H), 7.05 (1H),

6.89 (1H), 6.62 (1H), 6.2 (1H),

5.74 (1H), 5.56 (1H), 4.35 (1H),

3.92 (4H), 1.6 (3H), and 1.5 ppm (3H)

in DMF-d7).

The spectrum is identical to that of the product from comparative example 2 in the same solvent. 15% solutions in water remained clear and gelled at room temperature for 24 hours.

Example 2

Crystalline sodium salt of D-6-£ a -/~(2-oxo-3-furfurylidene-amino-imidazolidin-1-yl)-carbonylamino7-thienyl-2-acetamidoJ-penicillanic acid from crystalline acid of Comparative Example 1.

112 g (0.2 mol) D-6-α-[(2-oxo-3-furfurylideneamino-imidazolidin-1-yl)-carbonylamino]-thienyl-2-acetamido-penicillanic acid (prepared according to comparative example 1) suspend 1 70 ml H20 + 240 ml ethanol and adjust with a mixture of 96 ml

2 n NaOH + 96 mL EtOH to pH = 7.5. The clear solution was mixed with 1420 ml of ethanol, the precipitated dark flecks were allowed to settle for 10 minutes, decanted over a G 4 glass filter nut, and the settled suspension was also suctioned off. The solution is then inoculated and quickly stirred magnetically. After 30 minutes, mix with 200 ml of ethanol, stirred for 7 hours, mix again with 300

ml of ethanol, stir overnight, suction well and wash with ethanol. Dry over a P»Oci vacuum desiccator.

2.D

Dividend: 60t7 3%. IR and NMR spectra agree with those from Example 1.

Claims (10)

1. sodium salt of D-6-α-/(2-oxo-3-furfurylidene-amino-imidazolidin-1-yl)-carbonylamino7-thienyl-2-acetamido J-penicillanic acid of formula (I) in pure crystalline form. 2. Crystalline sodium salt according to claim 1, characterized by NMR signals at 6 = 9.36 (1H), 9.23 (1H), 7.8 (2H), 7.5 (1H), 7.25 (1H), 7.05 (1H), 6.89 (1H), 6.62 (1H), 6.2 (1H), 5.74 (1H), 5.56 (1H), 4.35 (1H), 3.92 (4H), 1.6 (3H), and 1.5 ppm (3H). (in DMF-d7). 3. Process for preparing the sodium salt of the compound with formula I in pure crystalline form, characterized in that the amorphous sodium salt of D-penicillanic acid with formula (I) is crystallized from ethanol-water mixtures. 4. Method according to claim 3, characterized in that it crystallized from an ethanol-water mixture in a quantity ratio of ethanol:water in the range from 5:1 to 15:1. 5. Method according to claims 3 and 4, characterized in that the method is carried out at temperatures from 0°C to 50°C. 6. Process for producing the sodium salt of D-penicillanic acid with formula I according to claim 2 in pure crystalline form, characterized in that the crystalline acid with formula I according to claim 2 is transferred to the sodium salt and crystallized from ethanol-water mixtures. 7. Medicine containing the crystalline sodium salt with D-penicillin acid of formula I according to claim 2 as active substance. 8. Process for the production of pharmaceuticals according to claim 4, characterized in that the active substance is transferred into a suitable application form, possibly using common excipients and carriers. 9. Use of a substance according to claim 1 to combat disease. 10. Use of substance according to claim 1 in the manufacture of medicinal products.