JPH01135787A - Crystalline penicillin derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The crystalline 6-[D(-)-alpha-(4-ethyl-2,3-dioxo-1-pyperadinyl carbonylamino)-alpha-(4-hydroxyphenyl)acetamido]penicillanic acid exhibiting the powder X-ray diffraction pattern shown in the table. USE:An antibacterial agent against Gram-positive and Gram-negative bacteria. PREPARATION:Amoxycillin is reacted with a reactive derivative of 4-ethyl-2,3- dioxo-1-piperazine-carboxylic acid in the carboxyl group to form an amorphous 6-[D(-)-alpha-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-alpha-(4- hydroxyphenyl) acetamido]penicillanic acid, which is reacted with a mixed solvent of acetonitrile with water or of dioxane with water to afford an adduct of acetonitrile or dioxane, which is further treated with methyl acetate.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to penicillin antibiotics, more specifically, crystalline 6-[D(-)-α-(4-edyl-2,3-dioxo-1). -piperazinylcarbonylamino) -α-(
4-Hydroxyphenyl)acetamido]penicillanic acid and its production method.

[Prior art] 6-[0(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-
Hydroxyphenyl)acetamido]penicillanic acid is
It is known to exhibit strong antibacterial activity against Durham-positive and Durham-negative bacteria (for example,
No. 20996).

However, 62, [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.

Furthermore, it has been desired to industrially obtain the highly pure and stable penicillanic acid in high yield through simple and safe operations.

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

The present invention will be explained in detail below.

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

10.96 8 8, 79 v s 7.37 w 6.98 w 6, 56 w 6.11 vw 5.88 m 5, 47 m 5, 37 5 5.22 m 5.04 w 4.80 s 4 .48 m 4.34 m 4, 18 m4, 10
w3.90
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 vw2, 55
v w2.34
vw2.29 vw Measurement Conditions Apparatus: Rigaku Denki Co., Ltd. X-ray diffractometer CuKα ray, 40 V-80 mA, Ni filter Main relative intensity (I) indicates the following arbitrarily set standard.

VS = very strong, S = strong, m = medium, W = weak,
VW=Very Weak Next, the actual M aspect of the present invention will be explained.

Crystalline 6-[D (-)-α-(4-ethyl-2゜3-
dioxo-1-piperazinylcarbonylamino)-α-
(4-Hydroxyphenyl)acetamido]penicillanic acid can be obtained by sequentially performing the methods shown in [I] and [I[] below.

The acetonitrile adduct or dioxane 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.
[D (-)-α-(4-ethyl-2゜3-dioxo-
1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid is reacted with a mixed solvent of acetonitrile and water or dioxane 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 or dioxane and water.

) Reactive derivatives at the carboxyl group of 6-aminopenicillanic acid and D(-)-α-4-ethyl-2,3-dioquine-1-piperazinylcarbonylamino)-α-(4-hydroxyenyl)acetic acid Amorphous 6-[D(-)-α-(4-ethyl-2,3-dioquine-1-piperazinylcarbonylamino)-α-(4
-Hydroxyphenyl)acetamido]penicillanic acid is reacted with a mixed solvent of acetonitrile and water or dioxane and water.

0V) 6-aminopenicillanic acid and D(-)-α-(4-
A reactive derivative at the carboxyl group of ethyl-2,3-dioxo-1-piperazinylcarbonylamino>-α-(4-hydroxyphenyl)acetic acid is reacted in a mixed solvent of acetonitrile and water or dioxane and water. .

In addition, 4-ethyl-2゜3-dioxo-1-piperazinecarboxylic acid and D-(-)-α used in the above reaction
The reactive derivatives at the carboxyl group of -(4-ethyl-2,3-dioxopiperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetic acid are the same as those described in Japanese Patent Publication No. 53-20996. Examples include:

In addition, in the above production methods (1) and (iii), amorphous 6-[0(-)-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-aminopenicillanic acid and D
Acylation in which the carboxyl group of (-)-α-(4-ethyl-2,3-dioxopiperazinylcarbonylaminyl)acetic acid is reacted with a reactive derivative is described, for example, in Japanese Patent Publication No. 53-20
This can be carried out by the method described in, for example, No. 996.

In general, the reaction in an aqueous organic solvent in the above production method (111 and -), that is, the reaction in a mixed solvent of acetonitrile and water or dioxane and water, can be carried out using the usual Schotten-Baumann reaction. After the reaction, by neutralizing with an acid, for example a mineral acid such as hydrochloric acid, sulfuric acid, or an organic acid such as p-toluenesulfonic acid.
The acetonitrile or dioxane adduct is precipitated as crystals from the reaction system. In this case, to obtain the adduct, water is finally added at 0.0% to acetonitrile or dioxane. 05 to 6 times the amount (volume ratio), preferably 1.85 to 4 times the amount (capacity ratio). Furthermore, 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 obtained by the above production methods (1) and (i) −(
4-Hydroxyphenyl)acetamido]penicillanic acid is suspended in a mixed solvent of acetonitrile and water or dioxane and water and then treated with an inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc., or with an organic base. Add a base, such as triethylamine, to dissolve, then add an acid, such as
By neutralizing with a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as p-toluenesulfonic acid, the resulting acetonitrile adduct or dioxane adduct can be precipitated as crystals from the reaction system. This neutralization process can also be repeated two or more times. In this neutralization process, water is finally added to acetonitrile or dioxane with a ratio of 0.05 to 6
Double the amount (volume ratio), preferably 1.85 to 4 times the amount (volume ratio) is used. Briefly, the penicillanic acid is dissolved in acetonitrile or dioxane which may contain water,
By adding water therein, acetonitrile or dioxane adducts can also be obtained.

After isolating the acetonitrile adduct or dioxane adduct, the desired crystallinity 6 can be achieved by treatment with methyl acetate or with a mixed solvent of two or more selected from methyl acetate, ethyl acetate, acetone, and water. −[D
(-)-α-(4-ethyl-2,3-dioxo-1-
Piperazinylcarbonylaminoacetamide]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 or dioxane adduct obtained in the above [1] as an intermediate in a wet state without drying, it is possible to obtain the desired crystalline penicillin with high purity.

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.

Furthermore, in (i) and (ii) above, acetonitrile adducts can be obtained in higher yields.

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

Purity measurement method High performance liquid chromatography (column: Dicrosolve R
P-18, inner diameter 4711111, length 250 mm, mobile phase niacetonitrile 170rrIIt and 0
．． 2M acetic acid-sodium acetate buffer solution (pH 5,0>
Water was added to 100 ml to make 1000 d, flow rate: 2 d/min, detection: LIV 254 nm) Crystallinity 6-[D (-)-α-(4-ethyl-2゜3
-dioxo-1-piperazinylcarbonylamino)-α
Purity of -(4-hydroxyphenyl)acetamido]penicillanic acid [obtained in Example 1 (2)]: 99.5% [Example] The present invention will be explained in detail with reference to Examples below. However, the present invention is not limited thereto. Note that 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride used in the examples was a mixture with triethylamine hydrochloride.

Example 1 (1) 30 g of 6-[D (-)-α-amino-α-(4-hydroxyphenyl)acetamido]penicillanic acid trihydrate was mixed with 120 ml of acetonitrile and 24 mL of water.
The suspension is suspended in a mixed solvent of 0 d, and then hetriethylamine io, sy is added dropwise thereto at 0 to 5° C. over a period of 10 minutes. Add 4-ethyl to the resulting solution at -10 to -8°C.
After 3.48 g (purity 58.7%) of 2,3-dioxo-1-piperazine carbonyl chloride was added in portions over 15 minutes, 5.299 g of sodium hydrogen carbonate was added and stirred at the same temperature for 30 minutes. Roughly, at -10 to -8℃ 4
- Ethyl-2,3-dioxo-1-piperazinecarbonyl chloride (19.79% (purity 58.7%)) is added in portions over a period of 90 minutes. After stirring at the same temperature for 30 minutes,
The temperature was raised to 0°C, and 37.6 mi of 2N hydrochloric acid was added dropwise over a period of 20 minutes. After stirring at the same temperature for 30 minutes,
Cool to °C and stir for 30 minutes. The precipitated product was collected by filtration, and
Wash twice with 50 d of % acetonitrile aqueous solution (volume ratio) each time. The obtained crystals were suspended in a mixed solution of 45 d of acetonitrile and 27 d of water without drying, and then an aqueous solution of 4.579 sodium bicarbonate dissolved in 51 d of water was heated at 10 to 12°C for 15 minutes. drip.

After stirring at the same temperature for 10 minutes, insoluble matter was filtered off, and the resulting filtrate was mixed with 2N salt. i27.2d was added dropwise at 20°C for 30 minutes. After stirring at the same temperature for 30 minutes, the mixture was roughly cooled to 5°C and stirred for 1 hour. Collect the precipitated crystals by filtration,
If washed with 0% acetonitrile aqueous solution (volume ratio) 30-, wet 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylaminoacetamide]penicillanic acid) Acetonitrile adduct 3 of
Obtain 0.2 g.

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 (Sujor>cm-1; ν 1770.1710
．． 1650 (2) 12 g of the wet acetonitrile adduct obtained in (1) above was mixed with 11 rn of ethyl acetate at 25°C.
After dissolving R1 in a mixed solvent of 11 ml of acetone and 1.18 ml of water, ethyl acetate 33- was added to this solution for 5 ml at 25°C.
The mixture was added dropwise over a period of 30 minutes, and stirred at the same temperature for 30 minutes. Furthermore, acetic acid 661d was added dropwise over 40 minutes at 25°C, and after stirring at the same temperature for 30 minutes, it was roughly cooled to 5°C and stirred for 1 hour. After collecting the precipitated crystals by filtration, washing twice with 2 Od of ethyl acetate and drying, the melting point is 181-182°C (
Crystalline 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylaminyl)acetamido]penicillane rR6.579 (yield 66, 0%) get.

IR (Sujoor) an-1 Niji 1805, 17
45, 1715.

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

10, 96 5 8, 79 vs 7, 37 w 6, 98 w 6, 56 w 6, 11 vw 5, 88 m 5, 47 m 5, 37 8 5, 22 m 5, 04 w 4, 8O S 4, 48 m 4, 34 m 4, 18 m 4, 10 W 3, 90 W 3, 84
m3, 71
W3, 62 W 3, 54 W3, 39
W 3, 32 W 3, 27
m3, 20
m3, 03 W 2, 74 W 2, 67, VW2, 55
v w2, 34
vw2, 29 vw
Measurement conditions Equipment: Rigakuta Co., Ltd. X-ray diffractometer CuKα ray, 40V-80mASrs4 i filter Relative intensity (1) indicates the following arbitrarily set standard.

vs=very strong, S=strong, m=medium, W=weak,
vw = very weak (3) In the above reaction (2), instead of ethyl acetate-acetone-water, methyl acetate-water (volume ratio 25:1
) was used to treat the adduct, crystals of the target product were obtained in a yield of 56.1%.

Example 2 (1) 6 di[D(-)-α-amino-α-(4-hydroxyphenyl)acetamido]penicillanic acid trihydrate 109% dioxane 30d and water 907%! Then, hetriethylamine was suspended in a mixed solvent of 3.
Add 5 ml dropwise over 5 minutes at 0-5°C. Then,
4-ethyl-2,3-
Dioxo-1-piperazinecarbonyl chloride i. is
After adding 1,769 g (H degree 58.7%) in portions over 5 minutes, 1,769 ml of sodium hydrogen carbonate was added, and 1,769 ml of sodium bicarbonate was added at the same temperature.
Stir for a minute. Roughly, 4-ethyl-2 at -6 to -4℃
．． 3-dioxo-1-piperazinecarbonyl chloride 6
, 56 g (purity 58, 7%) was added in portions over 40 minutes. After stirring at the same temperature for 30 minutes, the temperature was raised to 20°C, and 12.6 m of 2N hydrochloric acid was added dropwise over 30 minutes.

After stirring at the same temperature for 30 minutes, the mixture was roughly cooled to 5°C and stirred for 1 hour. The precipitated crystals are collected by filtration and washed twice with 15 d each of a 20% dioxane aqueous solution (volume ratio). Without drying, 1q of the separated crystals were suspended in a mixed solvent of 22 parts of dioxane and 55 parts of water, and 1.4 g of sodium bicarbonate was added to 157 parts of water. 1 aqueous solution dissolved in
It is added dropwise over a period of 10 minutes at 0-12°C. 10 at the same temperature
After stirring for a minute, insoluble matters were removed by filtration, and the resulting filtrate was added with 2N
- Hydrochloric acid 8.34 is added dropwise at 20°C over a period of 10 minutes. After stirring at the same temperature for 30 minutes, the mixture was roughly cooled to 5°C and stirred for 1 hour. The precipitated product is filtered off and washed twice with 10 l of a 20% aqueous dioxane solution (volume ratio) to obtain wet 6-[D(-)-α-(4-ethyl-2,3).
-dioxo-1-piperazinylcarbonylamino)-α
11.4 g of dioxane adduct of -(4-hydroxyphenyl)acetamido]penicillanic acid are obtained.

Note that, if this wet dioxane adduct is dried at 30° C. under blowing air for 5.5 hours, a dioxane adduct exhibiting the following IR is obtained.

IR (Sujoor) cm-1 Niji 17B0.1710
．． 1660 (2) 10.2 g of the wet dioxane adduct obtained in (1) above is dissolved in a mixed solvent of 8 d of ethyl acetate, 8 d of acetone, and 1.2 rr of water at 28°C. Then, after cooling the reaction solution to 25° C., 24 rni of ethyl acetate was added, and the mixture was stirred at the same temperature for 20 minutes. Then, 48d of ethyl acetate was added dropwise at 25°C over 40 minutes, and after stirring at the same temperature for 30 minutes, it was roughly cooled to 5°C and stirred for 1 hour. After filtering the precipitate, ethyl acetate 1
If washed three times with 0d each and dried, crystalline 6-[D
(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillane 1ft5.89
(yield 54.7%).

The physical properties (IR and powder X-ray diffraction patterns) of the obtained crystals matched those obtained in Example 1 (2).

Example 3 (1) D (−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4
-hydroxyphenyl)acetic acid 3.0 g.

7 ml of N-dimethylformamide and 4 ml of methylene chloride
Dissolve in a mixed solution of M and cool to -15°C.

To this solution, 1.25d of N,N-dimethylaniline and 0.94rr11 of ethyl chlorocarbonate were sequentially added, and -15
After stirring for 2 hours at ~-10'C, cool to -50C.

Separately, 1.93 g of 6-aminopenicilane M was suspended in 20 m of methylene chloride, and 2.27 mg of trimethylsilyl chloride and 2.62 d of triethylamine were sequentially added under cooling with water, followed by stirring at 10 to 15°C for 1 hour to silylate. Obtain a solution. This solution is cooled to -15°C, and the previously prepared mixed acid anhydride solution is added all at once. -15～
- After stirring for 2 hours at io'c, add 30 Ini of water,
Adjust the pH to 6.5 with a saturated aqueous sodium bicarbonate solution under water cooling. Separate the aqueous layer and add 2 ml of methylene chloride (30 d each).
After washing twice, 30 ml of methyl acetate was added, and the mixture was adjusted to 1) H2,3 with 2N hydrochloric acid. After separating the organic layer, the aqueous layer is extracted three times with 30 ml of methyl acetate each time, and the organic layers are combined and washed with 10 ml of saturated brine.

After distilling off the solvent under reduced pressure, 9 d of acetotrile and 4.5 d of water are added to the obtained residual bacteria. In a colander, under water cooling, add 10 ml of an aqueous solution containing 600 tyl of sodium hydrogen carbonate.
Add rnl and dissolve the residue. 2N- at the same temperature
Adjust the pH to 2.3 with hydrochloric acid and stir for 1 hour.

If the precipitated crystals are filtered and washed with 5 d of 30% acetonitrile aqueous solution (volume: 1 ratio), wet 6-[D(-)-α
-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)
Acetamide] Acetonitrile adduct of penicillanic acid 4
．． Obtain 59g. If this adduct is treated in the same manner as in Example 1 (2), crystalline 6-[D (-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α 92.80 g (yield 58.7%) of -(4-hydroxyphenyl)acetamido]penicillane is obtained.

The physical properties (IR and powder X-ray diffraction patterns) of the obtained crystals matched those obtained in Example 1 (2).

Claims (2)

[Claims] (1) Crystalline 6-[D(-)-α-(4-ethyl-2,3
-dioxo-1-piperazinylcarbonylamino)-α
-(4-hydroxyphenyl)acetamido]penicillanic acid. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (2) 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(
4-Hydroxyphenyl)acetamido]penicillanic acid with acetonitrile or dioxane is treated with methyl acetate or with a mixed solvent of two or more selected from methyl acetate, ethyl acetate, acetone and water. crystalline 6-[D(-)-α-(4-
A method for producing ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid.