JPH01132588A - Intermediate of crystalline penicillin derivative - Google Patents

Abstract

NEW MATERIAL:Acetonitrile adduct of 6-[D(-)-alpha(4-ethyl-2,3-dioxo-1-piperazinylcar-bony lamino)-alpha-(4-hydroxyphenyl)acetamide]penicillanic acid. USE:An intermediate of penicillin antibiotics. It gives crystalline and stabilized penicillins of high purity. PREPARATION:For example, amorphous 6-[D(-)alpha-(4-ethyl-2,3-dioxo--1-piperazinyl- carbonylamino)-alpha-(4-hydroxypbenyl)acetamide]penicillanic acid resulting from the reaction of amoxicillin with a carboxyl reactive derivative of 4ethyl-2,3- dioxo-1-piperazinecarboxylic acid, is allowed to react with a mixed solvent of acetonitrile and water.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to intermediates of penicillin antibiotics, more specifically, crystalline 6-[D(-)-α-(4-ethyl-2
,3-dioxo-1-piperazinylcarbonylamino)
-α-(4-hydroxyphenyl)acetamido]penicillanic acid intermediate 6-[D (-)-α-(4-
This invention relates to an acetonitrile adduct of ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid.

[Prior art] 6-[D (-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4
-Hydroxyphenyl)acetamido]penicillanic acid is known to exhibit strong antibacterial activity against Durum-positive and Durum-negative bacteria (for example,
-20996).

However, 6-[D (-)-α-(4-ethyl-
2,3-Dioxo-1-piperazinylcarbonylaminoacetamido]penicillanic acid is amorphous, and no crystalline form is known.

[Problem to be solved by the invention 6- [D (-)-α-(
4-Ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid is amorphous and has insufficient purity and poor stability. there were.

However, 6-[D (-)-α-(4-ethyl-2
,3-dioxo-1-piperazinylcarbonylamino)
-α-(4-Hydroxyphenyl)acetamido]penicillanic acid can be formulated as an injection by converting it into an alkali metal salt and then freeze-drying it or mixing it with an inorganic base according to conventional methods. Possible methods include powder filling, but since there is usually no purification step at this stage of formulation, the penicillanic acid used must be of higher purity and stability during formulation. It was getting worse.

In general, it has been desired to industrially obtain highly pure and stable penicillanic acid in high yield through a simple and safe operation.

[Means for solving the problem] Under these circumstances, the present inventors have solved the problem by
(-)-α-(4-ethyl-2,3-dioxo-1-
forming an acetonitrile adduct of piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid which is then treated with methyl acetate or selected from methyl acetate, ethyl acetate, acetone and water. By treating with a mixed solvent of two or more types, highly pure and stable crystalline 6-[D (-)-α-
It has been found that (4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid can be obtained. As described above, the present inventors have discovered that by using an acetonitrile adduct, highly pure and stable crystalline penicillin can be obtained and the various objects described above can be achieved, and the present invention has been completed.

The present invention will be explained in detail below.

Crystalline 6-D(-)-α obtained through the intermediate of the present invention
-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)
The powder X-ray diffraction pattern of penicillanic acid (acetamido) is as follows.

(Left below) Lattice spacing d(λ) *Relative intensity (I) 10.96
S8.79
VS7.37 W6
．． 98 W6.56
W6.11
vw5.88 m5.47
m5.37
8 5, 22 m5.04
w4.8OS 4.48 m4.34
m4.18
m 4.10 W 3.90
W3.84
m 3, 71 w 3.62 w 3, 54 w 3.39 w 3.32 w 3, 27 m 3, 20 m 3.03 w 2.74 w 2.67 vw 2.55 vw 2.34 vw2. 29
vw measurement conditions device Rigaku Denki Co., Ltd. X-ray diffraction device CuKa ray, 40 KV-80 mA, Ni filter *Relative intensity (I) indicates the following arbitrarily set standard.

vs=very strong, S=strong, m=medium, W=weak,
vw = very weak Next, embodiments of the present invention will be described.

The acetonitrile adduct can be produced, for example, by the following method.

(i) Amorphous 6- obtained by reacting amoxicillin with a reactive derivative at the carboxyl group of 4-ethyl-2,3-dioxo-1-piperazinecarboxylic acid.
CD (-)-α-(4-ethyl-2゜3-dioxo-
1-Piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid is reacted with a mixed solvent of acetonitrile and water.

(ii) Amoxicillin and a reactive derivative at the carboxyl group of 4-ethyl-2,3-dioxo-1-piperazinecarboxylic acid are reacted in a mixed solvent of acetonitrile and water.

(I) 6-aminopenicillanic acid and D(-)-α-(4-
Amorphous 6-[D(-)- obtained by reacting a reactive derivative at the carboxyl group of ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetic acid α-(4-ethyl-2,
3-dioxo-1-piperazinylcarbonylamino)-
α-(4-hydroxyphenyl)acetamido]penicillanic acid is reacted with a mixed solvent of acetonitrile and water.

Gv) 6-aminopenicillanic acid and D(-)-α-(
A reactive derivative at the carboxyl group of 4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetic acid is reacted in a mixed solvent of acetonitrile and water.

In addition, 4-ethyl-2゜3-dioxo-1-piperazine carbon W1 and D-(-)- used in the above reaction
Reactive derivatives at the carboxyl group of α-(4-ethyl-2,3-dioxopiperazinylponylamino)-α-(4-hydroxyphenyl)acetic acid are described in Japanese Patent Publication No. 53-20996. Similar things can be mentioned.

In addition, in the above production method (1) and (iD), amorphous 6-[D (-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(
Acylation carried out to obtain 4-hydroxyphenyl)acetamido]penicillanic acid, i.e. by reacting amoxicillin with a reactive derivative at the carboxyl group of 4-ethyl-2,3-dioxo-1-piperazinecarboxylic acid and 6-7 minopenicillanic acid and D
Acylation in which the carboxyl group of (-)-α-(4-ethyl-2,3-dioxopiperazinylcarliponylamino)-α-(4-hydroxyphenyl)acetic acid is reacted with a reactive derivative is For example,
This can be carried out by the method described in No. 96, etc. Furthermore, for the reaction in an aqueous organic solvent in the above production methods (n) and ~), that is, the reaction in a mixed solvent of acetonitrile and water, a normal Schotten-Baumann reaction can be used, and after the reaction, By neutralizing with an acid, for example, a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as toluenesulfonic acid, the acetonitrile adduct can be precipitated as crystals from the reaction system. in this case,
To obtain the adduct, the final amount of water is 0.05 to 6 times the amount of acetonitrile (volume ratio), preferably 1.85
~4 times the amount (volume ratio) is used. In general, by subjecting the obtained adduct to the neutralization treatment described below again, an adduct with higher purity can be obtained.

Amorphous 6-[D (-)-α-(4-ethyl-2,3-
dioxo-1-piperazinylcarbonylamino)-α-
(4-Hydroxyphenyl)acetamido]penicillanic acid is suspended in a mixed solvent of acetonitrile and water and then treated with an inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc. or an organic base such as triethylamine. and then neutralized with an acid, for example, a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as toluenesulfonic acid,
The produced acetonitrile adduct can be precipitated as crystals from the reaction system. This neutralization process can also be repeated two or more times. In this neutralization treatment, water is finally used in an amount of 0.05 to 6 times (volume ratio), preferably 1.85 to 4 times (volume ratio), relative to acetonitrile.

Roughly, by dissolving the penicillanic acid in acetonitrile which may contain water, and adding water therein,
One acetonitrile adduct can also be provided.

Next, from the acetonitrile adduct obtained above, crystalline 6-[D (-)-α-(4-ethyl-2゜3-dioxo-1-piperazinylcarbonylamino)-α-(4
-Hydroxyphenyl)acetamido]penicillanic acid will be described.

After isolating the acetonitrile adduct, it is treated with methyl acetate or with a mixed solvent of two or more selected from methyl acetate, ethyl acetate, acetone, and water to obtain crystalline 6-[D (-)- α-(4-ethyl-2
,3-dioxo-1-piperazinylcarbonylamino)
-α-(4-hydroxyphenyl)acetamido]penicillanic acid can be obtained.

Specific examples of the mixed solvent used here include mixed solvents such as methyl acetate-water and ethyl acetate-acetone-water. Also, their mixing ratio is
It is appropriately selected depending on the properties of the solvent. In addition, when processing with a mixed solvent in which the proportion of water in each mixed solvent is high and the solubility of the target product is high, it is necessary to increase the yield of the target product by final dilution with methyl acetate or ethyl acetate. can.

Furthermore, by using the acetonitrile adduct used as an intermediate in a wet state without drying it,
The desired crystalline penicillin with high purity can be obtained.

Conversion to the desired crystalline penicillin is usually carried out at 0 to 50°C.
The reaction may be carried out for 10 minutes to 20 hours, preferably at 5 to 30°C for 1 to 10 hours.

[Effect of the invention] Crystalline 6-[D(-)-α obtained through the intermediate of the invention
-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)
The purity of [acetamido]penicillanic acid is shown below.

Purity measurement method High performance liquid chromatography (column: Dicrosolve R
P-18, inner diameter 4 s, length 250 m, mobile phase niacetonitrile 170 d and 0.2 M acetic acid-sodium acetate buffer solution (1) H5, O > 100 d was added with water to make 10007, flow rate; Min2Ini, detection: U
V254nm) Crystalline 6-[D (-)-α-(4-ethyl-2゜3-
dioxo-1-piperazinylcarbonylamino)-α-
Purity of (4-hydroxyphenyl)acetamido]penicillanic acid [obtained in Reference Example 1 (1)]: 99.5% [Example] The present invention will be explained in detail by giving Examples and Reference Examples below. Although it will be explained in detail, the present invention is not limited to small quantities. In addition, 4-ethyl-2 used in the examples
, 3-dioquine-1-piperazinecarbonyl chloride used was a mixture with triethylamine hydrochloride.

Example 1 6-[D(-)-α-amino-α-(4-hydroxyphenyl)acetamido]penicillanic acid trihydrate 3
0'J was suspended in a mixed solvent of 120 parts acetonitrile and 240 parts water, and then 10.5 mA of hetriethylamine was added dropwise thereto at 0 to 5°C over 10 minutes.

Add 1q of 4-ethyl-2,3 to the solution at -10 to -8°C.
-dioxo-1-piperazinecarbonyl chloride 3.4
89 (purity 5, 7%) was added in portions over a period of 15 minutes, and then 5.299 g of sodium hydrogen carbonate was added and stirred at the same temperature for 30 minutes. Roughly, 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride was stirred at -10 to -8 °C for 30 min at 19.79 (fiT! °C).
The temperature was raised to 20°C, and 37.6 m of 2N hydrochloric acid was added dropwise over 20 minutes. After stirring at the same temperature for 30 minutes, roughly cooling to 5° C. and stirring for 30 minutes, the precipitated crystals were collected by filtration and washed twice with 50 d each of a 30% acetonitrile aqueous solution (by volume).

Without drying the obtained crystals, acetonitrile 45
ml and 27 d of water, and then an aqueous solution prepared by dissolving 4.577 ml of sodium bicarbonate in 51 ml of water was added dropwise at 10 to 12° C. over 15 minutes. After stirring at the same temperature for 10 minutes, insoluble matter was filtered off, and 27.2 d of 2N hydrochloric acid was added dropwise to the resulting filtrate at 20° C. over 30 minutes.

After stirring at the same temperature for 30 minutes, roughly cooled to 5℃ and
Stir for an hour. If the precipitated crystals are collected by filtration and washed with a 30% acetonitrile aqueous solution (volume ratio > 30 ml), wet 6-[D(-)-α-(4-ethyl-2°3-dioxo-1-piperazinyl) is obtained. carbonylamino)-α-(4
-Hydroxyphenyl)acetamido]penicillanic acid acetonitrile adduct 30,2 is obtained.

Note that if this wet acetonitrile adduct is dried at 30° C. for 5.5 hours under blowing air, an acetonitrile adduct exhibiting constant IR can be obtained.

IR (Nujol) an-1; Shi1770.171
0.1650O Example 2 D(-)-α-(4-ethyl-2,3-dioxo-1-
3.0 g of piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetic acid is dissolved in a mixed solution of N,N-dimethylformamide 7rIIi and 40 m of methylene chloride and cooled to -15°C.

To this solution, 1.25 rnl of N,N-dimethylaniline and 0.94 rnl of ethyl chlorocarbonate were sequentially added, and -1
After stirring at 5 to -10°C for 2 hours, cool to -50°C.

On the other hand, 6-amitubenicilan 1! ! 1.93 g was suspended in 20 d of methylene chloride, and under water cooling, 2.27 mg of trimethylsilyl chloride and 2.62 d of triethylamine were added.
were added sequentially, and stirred at 10 to 15°C for 1 hour to obtain a silylation solution. This solution is cooled to -15°C, and the previously prepared mixed acid anhydride solution is added all at once. -1
After stirring at 5 to -10°C for 2 hours, 30 d of water is added, and the pH is adjusted to 6.5 with a saturated aqueous sodium bicarbonate solution while cooling with water. The aqueous layer was separated, washed twice with 30 parts of methylene chloride, added with 30 m of methyl acetate, and purified with 2N-hydrochloric acid.
Adjust to H2 or 3. After separating the organic layer, the aqueous layer was extracted three times with 30 ml of methyl acetate each time, and the organic layers were combined and 10 ml of saturated saline solution was added. Wash with water.

After distilling off the solvent under reduced pressure, 9 d of acetonitrile and 4.5 d of water are sequentially added to the resulting residue.

To the colander, 10 d of an aqueous solution containing 6001n3 of sodium hydrogen carbonate is added under water cooling to dissolve the residue. Adjust to 1) H2.3 with 2N hydrochloric acid at the same temperature and stir for 1 hour. If the precipitated crystals are collected by filtration and washed with a 30% acetonitrile aqueous solution (volume ratio > 5 m), wet 6-[D (-)-
4.59 g of acetonitrile adduct of α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid is obtained.

Incidentally, if this wet acetonitrile adduct is dried at 30°C under blowing air for 5.5 hours, an acetonitrile adduct exhibiting the following IR is obtained.

IR (Nujol) cm” Niji 1770.171
0.1650c.

Reference Example 1 (1) After dissolving 12 g of the wet acetonitrile adduct obtained in Example 1 in a mixed solvent of 11 rrIi of ethyl acetate, 11 ml of acetone and 1.18 ml of water at 25°C, 33 d of ethyl acetate was added to this solution. was added dropwise over 5 minutes at 25°C, and stirred at the same temperature for 30 minutes. Acetic acid 66W11 was added dropwise to the mixture over a period of 40 minutes at 25°C, and after stirring at the same temperature for 30 minutes, the mixture was further cooled to 5°C and stirred for 1 hour. After collecting the precipitated crystals by filtration, the crystals are washed twice with 2 Od of ethyl acetate and dried to give a melting point of 181-182°C
116.57 g of 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylaminoacetamido]penisilane (yield 66,
0%).

IR (Nujol) α-1; ν 1805, 174
5, 1715.

O The powder X-ray diffraction pattern of the crystal is as follows.

10.9B S 8.79 vs 7, 37 w 6.98 W 6, 56 w 6, 11 v w 5.88 m 5, 47 m 5.37 5 5.22 m 5.04 w 4.8OS 4. 48 m 4.34 m 4.18 m 4, 10 w 3.90 W 3.84 m 3, 71 W 3.62 W 3, 54 W 3, 39 W 3, 32 w 3, 27 m 3, 20 m 3.03 w 2.74 W 2.67 vw 2.55 vw 2.34 VW 2.29 W Measurement conditions Equipment Rigaku Corporation X-ray diffraction device CuKα ray 1.40 v-80mASNr filter*
Relative strength (1) indicates the following arbitrarily set standard.

VS = very strong, S = strong, m = medium, W = weak,
VW = very weak (2) In the above reaction (1), instead of ethyl acetate-acetone-water, methyl acetate-water (volume ratio 25:1) was used.
) was used to treat the adduct, crystals of the target product were obtained in a yield of 56.1%.

Reference Example 2 The wet adduct obtained in Example 2 was converted into Reference Example 1 (1).
If treated in the same manner as above, crystalline 6- [D (-)-α-
(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid 2.809 (yield 58.7
%).

The physical properties (IR and powder X-ray diffraction patterns) of the obtained crystals matched those obtained in Reference Example 1(1).

Claims (1)

[Claims] (1) 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(
Acetonitrile adduct of 4-hydroxyphenyl)acetamido]penicillanic acid.