SI8811140A8 - Process for preparation of active thioesters of 2,3-dioxo-1- piperazinecarboxylic acid - Google Patents

Description

KRKA, drug factory, n.sol.o.

Process for the preparation of active thioesters

2,3-Dioxo-1-piperazinecarboxylic acid

FIELD OF THE INVENTION

The invention relates to the field of organic chemical synthesis and relates to a process for the preparation of new active thioesters of 4-ethyl 2,3-dioxo-1-piperazinecarboxylic acid of formula (II)

COR i

where R is 2-mercaptobenzimidazole, 2-mercaptobenzoxazole is not, and preferably a 2-mercaptobenzothiazole residue.

The new compounds are suitable as intermediates for the further condensation of the silylated form of 6- / D (-) - alpha-amino phenylacetamido / penicillanic acid (ampicillin) of formula (III)

III to 6- [D (-) - alpha- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) phenylacetamido] -penicillanic acid (piperacillin) and its pharmaceutically acceptable alkali salts of formula (I)

where A is a hydrogen, sodium or potassium atom, which is a valuable semi-synthetic antibiotic.

A technical problem

There was a need to provide a new intermediate that would allow a technologically advantageous further process for the synthesis of piperacillin.

The state of the art

The basic intermediate is known to be 4-ethyl-2,3-dioxo

1-Piperazine-4-carbonyl chloride, which is commonly used in the synthesis of piperacillin, is unstable and should be used immediately after preparation for further reaction. Synthesis of 4-ethyl-1,2,3-dioxo-1-piperazine-4-carbonyl chloride is only done using phosgene, where special equipment and occupational safety are required. Therefore, there are a small number of factories in Europe that can perform synthesis on a larger scale. In an additional step, the desired stable derivative, useful as a novel intermediate for synthesis according to the present invention, can be made from said unstable derivative.

However, since the invention is a new intermediate, the preparation process has not yet been described.

Description of solution to a technical problem with implementation examples

The compound of formula II can be synthesized from freshly prepared 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride of formula (IV)

COC1

I

Et and 2-mercaptobenzimidazole or 2-mercaptobenzoxazole or preferably 2-mercaptobenzothiazole. The active thioesters of formula (II) are prepared in inert organic solvents, preferably in methylene chloride, in the presence of a base, preferably triethylamine, at a temperature from 0 ° C to a solvent reflux temperature, preferably at room temperature.

Thioesters of formula (II) are solid, stable, non-aggressive compounds, very suitable for transport and storage, with great advantages in this regard against sensitive and aggressive

4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride, which decomposes very quickly at high temperature and humidity, and must be stored and transported in a cool place.

The new thioesters of formula (II) are reactive compounds that react smoothly at room temperature with silylated ampicillin in dry conditions in an organic solvent, preferably in methylene chloride, and the reaction produces compound (I) with high yield and good quality (at minimum) piperacillin presence of degradation products - up to 1%) «

We explain the process in more detail, but are not limited by the following embodiments.

EXAMPLE 1

Preparation of starting material

2-mercaptobenzothiazole

In 500 ml of methylene chloride layer, which remains after hydrolysis and extraction of piperacillin, 200 ml of 10% hydrochloric acid (pH = 0.5-1.0) is added while stirring at room temperature.

The mixture was stirred for 4 hours and the resulting precipitate was filtered.

9 g of 2- mercaptobenzothiazole are obtained from m.p. 174 to 178 ° C (54% yield).

EXAMPLE 2

Preparation of Compound of Formula (II)

S-2-benzothiazolyl-4-ethyl-2,3-dioxo-1-piperazintiocarboxylate 16.7 g (0.1 mol) of 2-mercaptobenzothiazole was suspended in 500 ml of methylene chloride and 14 ml (0.1 mol) of triethylamine were added with stirring. at room temperature. When the solution was formed, 20.4 g (0.1 mol) of 4-ethyl-2,3-dioxo-1-piperazine carbonyl chloride were added while stirring. The reaction mixture was allowed to stir for 4 hours at room temperature, filtered and the resulting product was washed with 50 ml of acetone. After drying in an air dryer, 30 g of S-2-benzothiazolyl-4-ethyl-2,3-dioxo-1-piperazintiocarboxylate (yield 93%) are obtained from mp 217 to 220 ° C.

The product structure was confirmed by IR and NMR spectra

EXAMPLE 3

Preparation of Compounds of Formula (II) i

S-2-benzoxazolyl-4-ethyl-2,3-dioxo-1-piperazinethiocarboxylate

15.1 g (0.1 mol) of 2-mercaptobenzoxazole were suspended in 300 ml of methylene chloride and dissolved with the addition of 14 ml (0.1 mol) of triethylamine at room temperature and stirring vigorously. 20.4 g (0.1 mol) of 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride are then added and the reaction mixture is stirred for another two hours at room temperature. Vacuum the methylene chloride at 20 ° C to 2/3 of the volume. The product begins to precipitate. The suspension was stirred for another 2 hours and filtered. The precipitate was washed with 50 ml of methylene chloride. After drying in an air dryer, 19.9 g of S-2-benzoxazolyl-4-ethyl-2,3-dioxo-1-piperazintiocarboxylate (65% yield) was obtained from m.p. 168 to 170 ° C.

The product structure was confirmed by IR and NMR spectra.

EXAMPLE 4

Use of intermediate (II) for the preparation of piperacillin

6- (D) - [alpha] - (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -phenylacetamido / penicillanic acid monohydrate g (0.1 mol) 6- [D (-) - alpha-aminophenylacetamido / penicillanic acid (anhydrous ampicillin) was suspended in 500 ml of anhydrous methylene chloride and 35 ml (0.14 mol) of N, O-bis (trimethylsilyl) acetarai <h were added while stirring at room temperature. The reaction mixture was stirred for 1 hour at room temperature to allow ampicillin to be silylated and soluble in methylene chloride. Then 33.5 g (0.1 mol) of S-2-benzothiazolyl-4-ethyl-2,3-dioxo-1-piperazintiocarboxylate were added and stirred for 3 hours at 22 to 24 ° C. After completion of the reaction, pour a solution of 10 g of KHCO3 and 500 ml of demineralized water into the mixture and stir for half an hour (pH 6.8). After the hydrolysis is complete, the methylene chloride layer is separated from the aqueous layer and washed with 100 ml of demineralized water. The aqueous layers were combined and the remaining methylene chloride was vacuum evaporated and filtered. The clear filtrate was added with vigorous stirring at room temperature with 10% aqueous HCl solution to pH 2.1-2.2. The stirring was reduced and stirred for another 3 hours. The product was filtered off, washed with demineralised water and dried at 35 ° C in a vacuum oven, up to 4% moisture according to Karl Fischer (K.F.).

4.8 g of 6- [D (-) - alpha- (4-ethyl-2,3-dioxo-1-piperazinecarboxaraido) -phenylacetamido / penicillanic acid monohydrate (4.8% yield) are obtained.

The structure of the compound was confirmed by IR and NMR spectra.

0

Optical rotation (oL = 170 ° dry matter

Humidity (K.F.) = 3.35%

Content: 994 pg / mg of dry matter (microbiological)

9 ^ 0% dry matter (HPLC)

- 7 EXAMPLE 5

Use of intermediate (II) for the preparation of piperacillin

06-R7D (-) - alpha- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -phenylacetamido / penicillanic acid sodium salt g (0.1 mol) 6- (D) - [alpha] -aminophenylacetamido / of penicillanic acid (ampicillin) was suspended in 350 ml of dry methylene chloride. The mixture was cooled to 15 [deg.] C. and 29 ml (0.2 mol) of triethylamine were slowly added dropwise, 20 minutes were allowed to dissolve, and 28.3 ml (0.22 mol) of trimethyl chlorosilane were added. The mixture was stirred for 1 hour at room temperature and 33.5 g (0.1 mol) of S-2-benzothiazolyl-4-ethyl-2,3-dioxo-1-piperazintiocarboxylate were added. The reaction mixture was stirred for 3 hours at room temperature, 450 ml of demineralized water was added and the pH was adjusted with KHCO3.

7-7,5. The layers were separated and the organic layer was washed with 100 ml of demineralized water. The aqueous layers were combined and the remaining methylene chloride was vacuum distilled off. A dilute hydrochloric acid (1: 5) was added to the clear aqueous layer while stirring to pH 2.1 to 2.2. The resulting product is filtered, washed with demineralised water and dried to 4% moisture (K.F.).

g (0.085 moles) of the resulting product 'is suspended in 386 acres of acetone at room temperature and a solution of 14.1 g (0.085 moles) of sodium 2-ethylhexanoate in 193 ml of acetone is added dropwise while stirring. Stirred for another half hour, the resulting product was filtered, washed with acetone and dried in a vacuum oven at 35 ° C.

42 g of the 6- (D) - (-) - alpha- (4-ethyl-2,3-dioxo-1-piperazine side-to-) -phenylacetamido / penicillanic acid sodium salt are obtained (yield 77%).

The structure of the compound was confirmed by IR and NMR spectra. Humidity (K.F.): 1.69%

Optical rotation: (ct ») p +182,64 dry matter _t Content: 956 pg / mg dry matter (microbiological)

98.26% dry matter (HPLC).

EXAMPLE 6

Use of intermediate (II) for the preparation of piperacillin

6- (D) - (-) - alpha- (4-ethyl-2,3-dioxo-1-piperazycarboxamido) -phenylacetamido / _pen and _c ii _an3 k _a acid - monohydrate g (0.1 mol) 6- / D ( -) - Alpha-aminophenylacetamido / penicillanic acid is suspended in 500 ml of anhydrous methylene chloride, and 35 acres (0.14 mol) of N, O-bis (trimethylsilyl) acetamide are added while stirring at room temperature. The reaction mixture was stirred for 1 hour at room temperature to allow ampicillin to be silylated and soluble in methylene chloride. 33.5 g (0.1 mol) of S-2-benzothiazolyl-4-ethyl-2,3-dioxo-1-piperazintiocarboxylate are then added and stirred for 3 hours at 22 to 24 ° C. The reaction mixture was poured into 500 ml of demineralized water under vigorous stirring and the pH adjusted to 1.5 with dilute hydrochloric acid (1: 5). Stir for 30 minutes at room temperature and separate the layers. The aqueous layer was washed with 200 ml of methylene chloride. Combine the organic layers, add 100 acres of demineralized water while stirring, and adjust the pH to 7.1-7.3 with dilute ammonia. The layers are separated again and the methylene chloride layer washed with 600 ml of demineralized water. The aqueous layers were combined and the remaining methylene chloride was vacuum evaporated. 180 ml of methanol were added to the solution, warmed to 35 ° C and acidified with dilute HCl to pH 2.1-2.4 with vigorous stirring. The reaction mixture was cooled to 5 to 10 ° qt _er meg ^ for 2 hours.

The product is filtered, washed with demineralized water and air-dried at 35 ° C to 4% moisture by K.F.

44 g of 6- [D (-) - alpha- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -phenylacetamido / penicillanic acid-monohydrate (44% yield) are obtained.

The structure of the compound was confirmed by IR and NMR spectra.

•• V '·' · y

Humidity (K.F.): 3.84%

Optical rotation: +170.5 ⁰ dry matter

Content: 992 pg / mg of dry matter (microbiological)

98.3% dry matter (HPLC) ~ Ά & -

The best way to make economic use of the invention

S-2-benzothiazolyl-4-ethyl-2,3-dioxo-1-piperazintiocarboxylate 16.7 g (0.1 mol) of 2-mercaptobenzothiazole was suspended in 500 ml of methylene chloride and 14 ml (0.1 mol) of triethylamine were added with stirring. at room temperature. When the solution was formed, 20.4 g (0.1 mol) of 4-ethyl-2,3-dioxo-1-piperazine carbonyl chloride were added while stirring. The reaction mixture was allowed to stir for 4 hours at room temperature, filtered and the resulting product was washed with 50 ml of acetone. After drying in an air dryer, 30 g of S-2-benzothiazolyl-4-ethyl-2,3-dioxo-1-piperazintiocarboxylate (93% yield) are obtained, mp 217 to 220 ° C.

The product structure was confirmed by IR and NMR spectra.

For

KRKA, Medicines Factory, n.sol.o .:

- APPLICATION APPLICATION

A process for the preparation of the active thioesters of 2,3-dioxo-1-piperazinecarboxylic acid of formula (II)

tt wherein R is 2-mercaptobenzoxazole and preferably 2-mercaptobenzothiazole residue, characterized in that freshly prepared 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride formula (IV)

COC1 and

i

Et is reacted with 2-mercaptobenzoxazole or preferably 2 mercaptobenzothiazole.

Process according to claim 1, characterized in that the reaction is carried out in inert organic solvents, preferably in raethylene chloride in the presence of a base, preferably triethylamine, at room temperature.

2O457-I-9O / KA

For

KRKA, drug factory, n.sol.o

Claims (1)

SUMMARY A process for the preparation of 2,3-dioxo-1-piperazinecarboxylic acid active thioesters of formula (II) is described wherein R is 2-mercaptobenzoxazole and preferably 2-mercaptobenzothiazole residue, characterized in that freshly prepared 4-ethyl-2,3 -Dioxo-1-piperazinecarbonyl chloride of formula (IV) COC1 and Et is reacted with 2-mercaptobenzoxazole or preferably 2-mercaptobenzothiazole. The novel compounds are suitable as intermediates for the synthesis of piperacillin.