KR20070098893A - Cefcapene pivoxil methanesulfonate - Google Patents

Abstract

A process for producing cefcapene pivoxil methanesulfonate and, with the use thereof as an intermediate, corresponding hydrochloride. There is provided methanesulfonate of the compound of the formula (!).

Description

Methanesulfonate of cefkaphen coating room {CEFCAPENE PIVOXIL METHANESULFONATE}

TECHNICAL FIELD This invention relates to the methanesulfonic acid salt of a cefecapene coating room. Specifically, the present invention relates to a method for producing cefecapene-coated chamber hydrochloride via the methanesulfonate.

Compound (I) represented by the following formula:

(General name: chef carpen cover room;

Chemical name: 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-butenoyl] amino-3-carbamoyloxymethyl-3-cepm-4-carboxylic acid pivaloyl Oxymethyl ester) is a cefem antibacterial agent (see Patent Document 1).

An antimicrobial agent containing the monohydrochloride monohydrate (general name: cefecapene hydrochloride coating, see Patent Document 2) as an active ingredient is commercially available as Flumox tablet (trade name, Shionogi & Co., Ltd.). . In patent document 1, trifluoro acetate is synthesize | combined from the cefekafen coating chamber by which 7-position amino was protected through free (sepafen coating chamber) (Example 6). In Patent Document 2, hydrochloride crystals are similarly separated from the cefekafen coating chamber in which the 7-position amino is protected via the free cefecapene coating chamber (Production Example 3). However, none of the documents describe the methanesulfonic acid salt of the cefkaphene coating chamber.

[Patent Document 1] Japanese Patent Laid-Open No. 62-89

[Patent Document 2] Japanese Patent Application Laid-Open No. 4-295485

[Problem to Solve Invention]

In Preparation Example 3 of Patent Literature 2, the extract after the deprotection reaction of the cefkafen coating chamber protected with 7-position amino was concentrated, and then dropwise added to a mixed solution of ethanol, methyl isobutyl ketone and hydrochloric acid to precipitate crude hydrochloride. Then, the mixture is washed with an organic solvent such as methyl isobutyl ketone to obtain hydrochloride. However, the inventors reproduced the method, and as a result, the separation liquid after filtration and washing in the crystal separation step (hereinafter, each separation liquid is also referred to as "mother liquor" and "washing liquid", and the combined liquid is also referred to as "washing liquid"). Among them, it was observed that several percent of cefecapene-coated chamber hydrochloride remained, and improvement was needed as a purification method for large-scale production.

Therefore, the establishment of the manufacturing method of a more preferable manufacturing process of a cefecapene coating monohydrochloride hydrate is desired.

[Means for solving the problem]

Accordingly, the inventors of the present invention have conducted various studies on the recovery of cefecapene-coated chamber hydrochloride from the capillary spinal fluid. As a result, the hydrochloride in the capillary spinal fluid is once converted to methanesulfonate, separated, and then converted to hydrochloride. It discovered that it can collect | recover efficiently, and completed the following invention.

(1) Methanesulfonic acid salt of cefecapene coating chamber represented by the following formula (2):

[Formula 2]

(2) The methanesulfonate salt according to the above 1, which is a crystal.

(3) A method for producing methanesulfonic acid salt of ceftafene coating chamber as defined in 1 or 2 above, comprising adding methanesulfonic acid to an organic solvent solution containing a hydrochloride salt of ceftafene coating chamber.

(4) converting the methanesulfonic acid salt as defined in 1 or 2 into a cefecapene coating chamber, and then reacting it with hydrochloric acid.

(5) A process for producing the hydrochloride hydrate of the ceftafene coating chamber of 4 comprising the following steps:

(First step) methanesulfonic acid was added to the organic solvent solution containing hydrochloride of the cefecapene coating chamber to crystallize the methanesulfonate of the cefecapene coating chamber; and

(Second step) converting the methanesulfonic acid salt into the cefecapene coating chamber and then reacting it with hydrochloric acid.

(6) The method according to 5 above, wherein the organic solvent is a mixed solvent of ethanol and methyl isobutyl ketone.

(7) The method according to the above 5, wherein the ratio of ethanol and methyl isobutyl ketone in the organic solvent is from 1: 0 to 1: 100 (v / v).

(8) The method according to the above 5, wherein the concentration of the hydrochloride salt in the ceftafene coating chamber in the organic solvent solution is 0.05 to 10%.

(9) The method according to the above 5, wherein 1 to 100 molar equivalents of methanesulfonic acid are added to the hydrochloride of the cefecapene coating chamber.

[Effects of the Invention]

According to the present invention there is provided a methanesulfonate, preferably a crystal, of the cefekafen coating chamber. The methane sulfonate hydrochloride can be efficiently recovered by crystallizing methanesulfonic acid salt from capillary spine and the like and converting it to hydrochloride in the purification step of the cephafene cladding hydrochloride. Accordingly, the present invention also provides a method for recovering ceftafene coated chamber hydrochloride mixed in a solvent and a novel method including the same.

[Brief Description of Drawings]

1

1 shows a powder X-ray diffraction pattern of methanesulfonic acid crystals of the cefecapene coating chamber obtained in Example 1. FIG. The vertical axis represents peak intensity and the horizontal axis represents diffraction angle.

2

Fig. 2 shows a data-treated figure of powder X-ray diffraction patterns of methanesulfonate crystals of the cefecapene coating chamber obtained in Example 1; The vertical axis represents peak intensity and the horizontal axis represents diffraction angle.

Best Mode for Carrying Out the Invention

(1) Preparation of Methanesulfonate

The methane sulfonate of the present invention is preferably a crystal. The crystal may be a solvate, but is preferably a nonsolvate. In the case of a solvate, water, alcohols (for example, methanol, ethanol), ketones (for example, methyl isobutyl ketone), etc. are illustrated as a solvent.

The crystal preferably exhibits the following main peaks in powder X-ray diffraction.

2θ = 17.93, 18.61, 19.63, 20.17, 20.93, 22.39, 24.79, 25.71 (unit: angle)

The preparation method of methanesulfonic acid salt is not particularly limited, but is preferably prepared from the corresponding hydrochloride salt. For example, methanesulfonic acid or a solvate thereof, preferably its crystals, can be precipitated by adding methanesulfonic acid in a solution containing a hydrochloride salt of the cefecapene coating chamber, preferably an organic solvent.

Methanesulfonic acid may use pure water or 70% methanesulfonic acid sold for industrial use.

As an organic solvent, what is necessary is just a solvent which can dissolve the hydrochloride of a cefecapen coating room, for example, methanol, ethanol, 2-propanol, 2-methoxy ethanol, ethylene glycol, methoxyethanol, glycerol, and propylene glycol; Alcohols such as dioxane, tetrahydrofuran, dimethoxyethane, and ethers such as diethylene glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, methyl formate, ethyl formate, propylform Esters such as mate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, and ethyl propionate, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, chlorobenzene, And organic halogenated hydrocarbons such as dichlorobenzene, acetonitrile, and propionitrile Trill acids, may be contained in dimethylformamide, dimethylsulfoxide, dimethylacetamide, N- methylpyrrolidone, quinoline, pyridines, and triethylamine, and the number of their mixed solvent, and a small amount of water. More preferred is an organic solvent having a higher solubility of cefecapene-covered hydrochloride than the methanesulfonate of the cefe-capene-covered chamber, for example, ethanol, methyl isobutyl ketone or a mixed solvent thereof. The mixing ratio of ethanol and methyl isobutyl ketone is usually 1: 0 to 1: 100 (v / v), preferably 1: 0.5 to 1:10, more preferably 1: 1 to 1: 5, particularly preferably Preferably 1: 1 to 1: 3.

The concentration of cefecapene-coated chamber hydrochloride in the organic solvent is usually 0.01 to 20%, preferably 0.05 to 10%, and more preferably 0.1 to 5%.

The amount of methanesulfonic acid added is usually 1 to 100 molar equivalents, preferably 5 to 50 molar equivalents, and more preferably 20 to 30 molar equivalents relative to the cefecapene-coated chamber hydrochloride.

After the addition of methanesulfonic acid, the temperature of the reaction solution is optionally adjusted. The reaction solution is preferably 0 ° C to room temperature, more preferably 0 ° C to 10 ° C, and can be left for several tens of minutes to several hours. Optionally, seed crystals of methanesulfonate may be added. The crystal thus obtained can then be separated from the solvent by ordinary separation means (e.g., filtration, centrifugation, etc.), and optionally by drying it.

In the case where the solution of the organic solvent is a reaction solution containing ceftafene coating chamber hydrochloride, an extract thereof, or a capillary spinal fluid, impurities such as raw materials or reaction by-products may be mixed, and methane sulfonate, preferably as a crystal. The impurities can be removed by separation. In particular, in the case of recovering the cefekaphene coating chamber from the mixed solvent of ethanol and methyl isobutyl ketone, the recovery rate is lowered because the solubility is too high even if it is to be separated as the vitreous of the cekaphene coating chamber. In addition, even if the cefkaphen coating chamber is to be separated immediately with hydrochloride, the effect of removing impurities is low and there is a risk of gelation, which is not preferable as an industrial method. Compared with these methods, the recovery method using the methanesulfonic acid salt of the present invention has a high effect of removing impurities and a good recovery rate (for example, about 70% or more). Therefore, this recovery method is useful as an industrial recovery method, a purification method, or a manufacturing method of a cefecapene coating chamber or its hydrochloride.

(2) Conversion of Methanesulfonate to Hydrochloride

The present invention also provides a method for converting methanesulfonic acid salt of the cefkaphene coating chamber into its hydrochloride salt. Preferably, methanesulfonic acid salt, solvate or crystals thereof in the cefkafen coating chamber is dissolved or suspended in organic solvent A, and then neutralized and dissolved by adding an aqueous solution containing a base, and then the aqueous layer is removed as a glass product. The cefekaphene coating chamber is extracted in an organic solvent. More preferably, the aqueous layer is back extracted with the organic solvent B, and the extract of the organic solvent obtained first can be mixed with this. By treating the extract according to the method described in JP-A-4-295485, hydrochloride hydrate, preferably its crystals can be obtained. Specifically, the extract is concentrated and distilled off methylene chloride, which is then diluted with an organic solvent C, which is then added dropwise into a mixed solution of organic solvent D and hydrochloric acid to precipitate hydrochloride or its hydrate crystals in the cefecapene coating chamber. After making it dry, it can dry by a conventional method (yield example: 90% or more). The obtained hydrochloride hydrate can be used as a medicinal active ingredient as it is, or optionally reused as raw material or seed crystals in the purification step.

The organic solvents A, B, and C may be appropriately selected from the above organic solvents. Preferably, the organic solvents A and B are dichloromethane, alcohol (e.g. ethanol) or a mixed solvent thereof, and the organic solvents C and D Is alcohol (e.g. ethanol), methyl isobutyl ketone or a mixed solvent thereof.

As the base for neutralization, alkali metal hydroxides (e.g., NaOH, KOH) and alkali metal hydrogen carbonates (e.g., NaHCO ₃ , KHCO ₃ ) are used. For example, in the case of aqueous sodium hydroxide solution, the concentration is preferably about 15 to 25%, and in the case of aqueous sodium hydrogencarbonate solution, the concentration is preferably 5 to 10%.

The concentration of hydrochloric acid is usually 10 to 50%, preferably 30 to 40%, and usually 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents of hydrochloric acid can be used relative to methanesulfonic acid salts.

By carrying out the above methods (1) and (2), the hydrochloride of the cefecapene coating chamber can be efficiently recovered. That is, the present invention also provides a method for producing a hydrochloride hydrate of a cefecapene coating chamber, which comprises the following steps.

(First step) Methanesulfonic acid is added to the organic solvent solution containing the hydrochloride salt of the cefkaphen coating chamber to crystallize the methanesulfonic acid salt of the cefekaphen coating chamber.

(Second step) converting the methanesulfonic acid salt into the cefecapene coating chamber and then reacting it with hydrochloric acid.

Each step is performed according to the method (1) and (2). By using a purification method comprising the two steps, the ceftkafen coating chamber hydrochloride remaining in the capillary fluid after the reaction extraction can be recovered, for example, in a yield of 60% or more. This is therefore very advantageous for large scale production.

As described above, the cefecapene-coated chamber methanesulfonic acid salt of the present invention, preferably the crystal is useful as an intermediate of an antimicrobial agent (e.g., cefecapene-coated chamber hydrochloride). Alternatively, the methanesulfonic acid salt can be used as a pharmaceutically active ingredient by itself.

An example is shown below.

Example 1 (Recovery of methanesulfonic acid salt from the wash liquor)

According to the method of manufacture example 3 of patent 2960790 (correspondence publication number: Unexamined-Japanese-Patent No. 4-295485), the 7-amino amino-protected capcafen coating chamber (7 (beta)-[(Z) -2- ( 2-t-butoxycarbonylaminothiazol-4-yl) -2-butenoyl] amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester) 1039 g Using as a raw material, the solvent and reagents were subjected to a similar deprotection reaction under conditions that increased at a rate according to the amount of the raw material used to crystallize the hydrochloride salt in the cefecapen coating room and filtered to collect the crystals. The obtained crystal was washed sequentially with methyl isobutyl ketone and dichloromethane.

6.9 L of the filtrate (mother liquor) separated in the course of the filtration and 3.1 L of the washing liquid (washing solution) separated after washing with methyl isobutyl ketone were mixed to obtain a capillary spinal fluid (intrinsic content: 38.7 g as a cefecapene coating chamber hydrochloride), Containing solvent ratio ethanol: methyl isobutyl ketone = 1: 2.6) was obtained, and after temperature control to 8 ° C., 155.6 g (25 equivalents) of methanesulfonic acid were added, and the mixture was stirred for 8 hours. The obtained crystals are collected by filtration, and the crystals are washed with 200 mL of 95% ethanol, followed by drying in air to obtain 32.1 g of the desired cefecapene-coated methanesulfonate crystal (recovery rate from the wash solution: 73.1%).

1 H-NMR (d6-DMSO) 1.02 (t, 3 H) 1.17 (s, 9 H) 2.26 (td, 2 H) 2.50 (s, 3 H) 3.61 (br-s, 2 H) 4.73 (q, 2 H) 5.24 (d, 1 H) 5.75-5.97 (m, 3 H, 7-H) 6.55 (mt, 2 H) 9.47 (d, 1 H)

Elemental Analysis C23H29N5O8S2CH3SO3H

Theoretic C 43.20, H 5.04, N 10.49, S 14.41

Found C 43.32, H 5.06, N 10.47, S 14.53

Powder X-ray Diffraction Pattern: FIGS. 1 and 2

(X-ray diffraction measurement conditions:

Tubular CuKα line, tube voltage 30 Kv, tube current 15 mA, dsinθ = nλ (n is an integer and θ is a diffraction angle)).

Example 2 (Conversion of Methanesulfonate to Hydrochloride)

20.0 g of cefecapene-coated methanesulfonate obtained in Example 1 were slurried in 140 mL of methylene chloride, and 140 mL of aqueous ethanol, which had been adjusted to a concentration of 60.5% in advance, was added thereto, and stirred and mixed. 5.9 g of 20% aqueous sodium hydroxide solution was added thereto to neutralize and dissolve the above, and the aqueous layer was removed by extraction. In addition, extraction and washing were performed twice with 60 mL of 2.5% aqueous sodium chloride solution to obtain an extract. The aqueous layer obtained during extraction was back extracted with 60 mL of methylene chloride, and the obtained back extracted methylene chloride layer was merged with the extract. The combined extracts were concentrated under reduced pressure, and methylene chloride was distilled off to obtain about 48 g of an ethanol solution in the cefkaphen coating chamber. The resulting solution was diluted with 60 mL of methyl isobutyl ketone and added dropwise into a mixed solution of 8 mL of ethanol adjusted to 20 ± 2 ° C., 32 mL of methyl isobutyl ketone and 3.4 g of 35% hydrochloric acid for 5 minutes to crystallize the product. It stirs at the same temperature for 30 minutes, and after stirring for 2 hours at 5 +/- 2 degreeC, precipitate crystals are collected by filtration. The crystals were washed sequentially with 60 mL of cold methyl isobutyl ketone and 78 mL of cold methylene chloride, followed by air drying to give 16.2 g of the desired cefecapene coating chamber monohydrochloride hydrate (yield 91.9%). The compound was identified by liquid chromatography.

Claims (9)

Methanesulfonic acid salt of cefekafen coating chamber represented by the following general formula (1): [Formula 1]

The methanesulfonate of Claim 1 which is a crystal. A method for producing methanesulfonic acid salt of ceftafene coating chamber as defined in claim 1 or 2, comprising adding methanesulfonic acid to an organic solvent solution containing hydrochloride of ceftafene coating chamber. A method for producing a hydrochloride hydrate of ceftafene cladding comprising converting the methanesulfonate as defined in claim 1 or 2 into cefkafen cladding and reacting it with hydrochloric acid. The method of claim 4, wherein the hydrochloride hydrate of the cefecapene coating chamber comprises the following steps: (First step) methanesulfonic acid was added to the organic solvent solution containing hydrochloride of the cefecapene coating chamber to crystallize the methanesulfonate of the cefecapene coating chamber; and (Second step) converting the methanesulfonic acid salt into the cefecapene coating chamber and then reacting it with hydrochloric acid. 6. The process of claim 5 wherein the organic solvent is a mixed solvent of ethanol and methyl isobutyl ketone. The method according to claim 5, wherein the ratio of ethanol and methyl isobutyl ketone in the organic solvent is from 1: 0 to 1: 100 (v / v). The method according to claim 5, wherein the concentration of the hydrochloride salt in the cefkaphen coating chamber in the organic solvent solution is 0.05 to 10%. The method according to claim 5, wherein 1 to 100 molar equivalents of methanesulfonic acid are added to the hydrochloride salt in the cefecapene coating chamber.

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