JPH01132589A - Intermediate of crystalline penicillin derivative - Google Patents

Abstract

NEW MATERIAL:Dioxane adduct of 6-[D(-)-alpha-(4-ethyl-2,3-dioxo-1-piperazinylcar bonyl-amino)-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-piperazinylcar-bonyl amino)-alpha-(4-hydroxyphenyl)acetamide]penicillanic acid resulting from the reaction of amoxicillin with a carboxyl reactive derivative of 4-ethyl-2,3-dioxo-1- piperazinecarboxylic acid, is allowed to react with a mixed solvent of dioxane and water.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to intermediates for 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-
We refer to the dioxane 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
It is known to exhibit strong antibacterial activity against Durham-positive and Durham-negative bacteria (for example,
No. 20996).

However, 1q of 6-[D (-)-α-(4-ethyl-
2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]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, has insufficient purity, and has poor stability. Ta.

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 stable 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 a dioxane 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-(4
-Ethyl-2,3-dioquine-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)a was found to yield doamido]penicillanic acid. As described above, by using a dioxane adduct, highly pure and stable crystalline penicillin can be obtained, and the various objects mentioned above have been achieved, and the present invention has been completed.

The present invention will be explained in detail below.

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

0 * Lattice spacing d (A) Relative intensity (I) 10.9
6 s 8,79 v s 7,37 w 6.98' w 6,58 w 6.11 vw 5.88 m 5.47' m 5.37 s 5.22 m 5.04 w 4.80 s 4 .48 m 4.34 m 4.18 m 4,10 w 3.90 w 3.84 m3, 71
w3.62
W3, 54 w3.3
9 w3.32
w3, 27 m 3.20 m3.03
w2.74
w2, 67 v w2,
55 v w2.34
vw2.29
vw measurement conditions Apparatus Rigaku Denki Co., Ltd. X-ray diffraction apparatus CuKα rays, 40 KV-80 mA, Ni filter umbrella Relative intensity (1) 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 dioxane adduct can be produced, for example, by the following method.

(1) Amorphous 6-[D
(-)-α-(4-ethyl-2゜3-dioxo-1-
Piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillanic acid is reacted with a mixed solvent of dioxane and water.

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

(iii) 6-aminopenicillanic acid and D(-)-α
-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)
Amorphous 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-( 4-Hydroxyphenyl)acetamido]penicillanic acid is reacted with a mixed solvent of dioxane and water.

Gv) 6-7 minopenicillanic 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 dioxane and water.

In addition, 4-ethyl-2 used in the above reaction.

3-Dioxo-1-piperazinecarboxylic acid O and D-(
-)-α-(4-ethyl-2,3-dioxopiperazinyl-luponylamino)-α-(4-hydroxyphenyl)acetic acid as reactive derivatives at the carboxyl group, respectively, are listed in Japanese Patent Publication No. 53-20996. Items similar to those listed in the No.

In addition, in the above production methods (i) and (iii), amorphous 6-[D (-)-α-(4-ethyl-2.3
-dioxo-1-piperazinylcarbonylamino)-α
- Acylation carried out to obtain (4-hydroxyphenyl)acetamido]penicillanic acid, i.e. an acyl reacting a reactive derivative at the carboxyl group of amoxicillin with 4-ethyl-2,3-dioxo-1-piperazinecarboxylic acid. and reactive derivatives at the carboxyl group of 6-aminopenicillanic acid and D(-)-α-(4-ethyl-2,3-dioxopiperazinyl luponylamino)-α-(4-hydroxyphenyl)acetic acid. For example, acylation without reacting with
This can be carried out by the method described in 996@ etc. In general, the reaction in an aqueous organic solvent in the above production method (it) and ~), that is, the reaction in a mixed solvent of dioxane and water, can be carried out using the usual Schotten-Baumann reaction, and after the reaction. The dioxane adduct can be precipitated as crystals from the reaction system by neutralizing with an acid such as a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as p-toluenesulfonic acid. In this case, to obtain the adduct, the water is finally 0,
The amount used is 0.5 to 6 times (capacity), preferably 1.85 to 4 times ♀ (capacity ratio). 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)acetamide 1 Penicillanic acid is suspended in a mixed solvent of dioxane and water, and then,
An inorganic base, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc. or an organic base, such as triethylamine, is added and dissolved, followed by an acid, such as a mineral acid such as hydrochloric acid, sulfuric acid, or p-toluene. Neutralize with organic acids such as sulfonic acid,
The generated 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 treatment, water is finally used in an amount of 0.05 to 6 times the amount of dioxane (volume ratio), preferably 1.85 to 4 times N (volume ratio). Roughly,
A dioxane adduct can also be obtained by dissolving the penicillanic acid in dioxane which may contain water and adding water therein.

Next, crystalline 6-
A manufacturing method for obtaining [D (-)-α-4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino]-α-(4-hydroxyphenyl)acetamido]penicillanic acid will be described.

After isolating the dioxane 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,
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 ratio of water in each mixed solvent is high and the solubility of the target product is high, it may be necessary to ultimately dilute with methyl acetate or ethyl acetate to increase the yield of the target product. can.

In general, by using the dioxane 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 from 0 to 50°
C 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 pieces, length 250 shoes, mobile phase: acetonitrile 170d and 0.2M acetic acid-sodium acetate buffer solution (1) H5,0> 100 Add water to rrIi to make 1000d, flow arsenal ;27 per minute! ,detection;
UV254nm) Crystalline 6-[D(-)-α-(4-ethyl-2゜3
-dioxo-1-piperazinylcarbonylamino)-α
Purity of -(4-hydroxyphenyl)acetamido]penicillanic acid [obtained in Example 1]: 99.5% [Example] The present invention will be explained in detail below with reference to Examples and Reference Examples. However, the present invention is not limited thereto. In addition, 4-ethyl-2 used in the examples
, 3-dioxo-1-piperazinecarbonyl chloride hydrochloride.

Example 1 6-[D(-)-α-amino-α-(4-hydroxyphenyl)acetamido]penicillanic acid trihydrate 10
! 7 was suspended in a mixed solvent of 307 dioxane and 90 ml of water, and then 3.5 d of hetriethylamine was suspended in a mixed solvent of 307 dioxane and 90 ml of water.
is added dropwise over a period of 5 minutes at 0 to 5°C. Then, 1.169 g of 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride (
(purity 58.7%) was added in portions over 5 minutes, 1.763 ml of sodium hydrogen carbonate was added, and the mixture was stirred at the same temperature for 15 minutes. Roughly, 4-ethyl-2,3 at -6 to -4℃
-dioxo-1-piperazinecarbonyl chloride 6,5
69 (purity 58, 7%) was added in portions over a period of 40 minutes. After stirring at the same temperature for 30 minutes, the temperature was raised to 20°C.
2N-hydrochloric acid 12, f7 was added dropwise over 30 minutes. The mixture was stirred at the same temperature for 30 minutes, then roughly cooled to 5°C.
Stir for an hour. The precipitated crystals are collected by filtration and washed twice with 157 parts of a 20% aqueous dioxane solution (volume ratio). Without drying the obtained crystals, add 22 d of dioxane and 55 m of water.
Suspend in a mixed solvent of
．． An aqueous solution of 4 g dissolved in 15 d of water is added dropwise at 10 to 12° C. over 10 minutes. After stirring at the same temperature for 10 minutes, insoluble matter was filtered off, and the resulting filtrate was added with 8.3 mL of 2N-hydrochloric acid.
4d dropwise over 10 minutes at 20'C. 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 collected by filtration and washed twice with 10 ml of a 20% diquinone aqueous solution (volume ratio) to obtain wet 6-[D (-)-α-(4-ethyl-2,3- Dioxo-1-piperazinylcarbonylaminoacetamide] dioxane adduct of penicillanic acid 11,
Get 49.

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 (nujol>cm-'niji 1780, 171
0, 1660O Reference Example 1 Wet dioxane adduct obtained in Example 1 10.
2 9 at 28°C with 8 d of ethyl acetate and 8 rd of acetone!
and 1.2 In1 of water. Then, after cooling the reaction solution to 25°C, 24ml of ethyl acetate was added.
1 and stirred at the same temperature for 20 minutes. Then, 48d of ethyl acetate 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 filtering the precipitated crystals, add 10 ml of ethyl acetate.
If washed three times and dried, the melting point will be 181-182℃.
Crystalline 6-[D (-')-α-(4
-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-(4-hydroxyphenyl)acetamido]penicillane 115.8 7 (yield 54.7%)
get.

IR (Nujol) cm-':v 1805,17
45,1715.

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

10, 96 S 8, 79 VS 7, 37 w 6, 98 W 6, 56 w 6, 11 VW 5, 88 m 5, 47 m 5, 37 3 5, 22 m 5, 04 W 4, 80 s 4, 48 m 4, 34 m 4, 18 m 4, 10, W 3, 90 W 3, 84 m 3, 71
w3, 82
w3, 54 w3
, 39 w3, 32
w3, 27
m3, 20 m3, 0
3 w2, 74
w2, 67v
w2, 55 v w2, 34
vw2, 29
vw Measurement Conditions Apparatus Rigaku Denki Co., Ltd. X-ray diffractometer CuKα ray, 40KV-80mA, Ni filter *Relative intensity (I) indicates the following arbitrarily set standard.

VS=very strong, S-strong, m=medium, W=weak,
VW = very weak

Claims (1)

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