WO2006080484A1

WO2006080484A1 - Cefcapene pivoxil methanesulfonate

Info

Publication number: WO2006080484A1
Application number: PCT/JP2006/301409
Authority: WO
Inventors: Masaaki Uenaka; Yutaka Ide; Shigeru Wakahara; Osamu Nishidate
Original assignee: Shionogi & Co., Ltd.
Priority date: 2005-01-31
Filing date: 2006-01-30
Publication date: 2006-08-03
Also published as: JPWO2006080484A1; CN101111498B; JP3884063B2; TWI364282B; KR20070098893A; KR100872759B1; CN101111498A; TW200637867A

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 (Ι).

Description

Cefcapene pivoxil methanesulfonate

Technical field

[0001] The present invention relates to a methanesulfonate salt of cefcapene pivoxil. Specifically, the present invention relates to a method for producing cefcapene pivoxil hydrochloride via the methanesulfonate. Background art

[0002] Formula:

[Chemical 1]

Compound (I) (generic name: cefcapene pivoxil; chemical name: 7 β-[(Ζ)-2- (2 aminothiazole 4 yl) 2 butenoyl] amino-3 rubamoyloxymethyl — 3— Cef-4-carboxylic acid bivalyloxymethyl ester) is a cefme antibacterial agent (see Patent Document 1). An antibacterial agent containing the monohydrochloride monohydrate (generic name: cefcabene pivoxil hydrochloride, see: Patent Document 2) as an active ingredient is commercially available as Fromotas Tablets (trade name, Shionogi). In Patent Document 1, trifluoroacetate is synthesized via the protective strength free form (cefcapene pivoxil) of the 7-position amino of cefcapene pivoxil (Example 6). In Patent Document 2, hydrochloride crystals are also isolated via the free integration of the 7th amino amino protector (Production Example 3). However, in all of the documents, cefcapene pivoxil methanesulfonate is described!

Patent Document 1: Japanese Patent Laid-Open No. 62-89

Patent Document 2: Japanese Patent Laid-Open No. 4-295485

Disclosure of the invention

Problems to be solved by the invention [0003] In Production Example 3 of Patent Document 2, the extract after the deprotection reaction of the 7-position amino protector of cefcapene pivoxil was concentrated and then dripped into a mixed solution of ethanol, methylisobutyl ketone and hydrochloric acid. The hydrochloride is crystallized and washed with an organic solvent such as methylisobutyl ketone to obtain the hydrochloride. However, as a result of further examination of the method by the present inventors, the separation liquid after filtration and washing in the crystal isolation process (hereinafter, each separation liquid is referred to as “mother liquid” and “washing liquid”, and the combined liquid is referred to as “ It was found that about several percent of cefcapene pivoxil hydrochloride remained in the mother washing solution (i), and it was found that improvement was necessary as a purification method for mass production. Therefore, establishment of a more preferable production method of cefcapene pivoxil monohydrochloride hydrate is desired.

Means for solving the problem

[0004] Accordingly, as a result of various studies on the recovery of cefcapene pivoxil hydrochloride having the above-mentioned mother washing solution neutral force, the present inventors converted the hydrochloride salt contained in the mother washing solution into methanesulfonate. After isolation, the inventors found that efficient conversion can be achieved by converting it to hydrochloride again, and the following inventions were completed.

(1 set:

[Chemical 2]

Cefcapene pivoxil methanesulfonate represented by

(2) The methanesulfonic acid salt according to 1 above, which is a crystal.

(3) The method for producing methanesulfonate of cefcapene pivoxil according to the above 1 or 2, characterized in that methanesulfonic acid is carotenized in an organic solvent solution containing cefcapene pivoxil hydrochloride.

(4) Production of cefcapene pivoxil hydrochloride hydrate, comprising the step of converting the methanesulfonate according to 1 or 2 above to cefcapene pivoxil and then reacting with hydrochloric acid Method.

(5) The following steps:

(First step)

Crystallizing methanesulfonate of cefcapene pivoxil by refining methanesulfonic acid in an organic solvent solution containing hydrochloride of cefcapene pivoxil; and

(Second process)

Converting the methanesulfonate to cefcapene pivoxil and then reacting with hydrochloric acid;

5. A process for producing a hydrochloride hydrate of cefcapene pivoxil according to 4 above, comprising

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

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

(8) The production method according to 5 above, wherein the concentration power of hydrochloride of cefcapene pivoxil in the organic solvent solution is 0.05 to 10%.

(9) The production method according to 5 above, wherein 1 to 100 molar equivalents of methanesulfonic acid are added to the hydrochloride of cefcapene pivoxil.

The invention's effect

[0005] According to the present invention, a methanesulfonate salt of cefcapene pivoxil, preferably a crystal thereof, is provided. In the step of purifying cefcapene pivoxil hydrochloride, the methanesulfonate is crystallized from the mother washing solution, etc., and then converted to hydrochloride, whereby cefcapene pivoxil hydrochloride can be efficiently recovered. Thus, the present invention also provides a method for recovering cefcabene pivoxil hydrochloride mixed in a solvent and a novel production method including the same. Brief Description of Drawings

[0006] [Fig.1] Cefcapene pivoxil methanesulfonate obtained in Example 1

The powder X-ray diffraction pattern of the crystal is shown. The vertical axis represents peak intensity, and the horizontal axis represents diffraction angle. FIG. 2 Cefcapene pivoxil methanesulfonate obtained in Example 1

The figure which processed the data of the powder X-ray diffraction pattern of the crystal | crystallization is shown. 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 methanesulfonate of the present invention is preferably a crystal. The crystal may be a solvate, but is preferably a non-solvate. In the case of a solvate, examples of the solvent include water, alcohol (eg, methanol, ethanol), ketones (eg, methyl isobutyl ketone) and the like.

The crystals preferably show the following main peaks by powder X-ray diffraction.

2 Θ = 17.93, 18.61, 19.63, 20.17, 20.93, 22.39, 24.79, 25.71 (unit: degree)

Although the manufacturing method of this methanesulfonate is not specifically limited, Preferably it manufactures from corresponding hydrochloride. For example, methanesulfonic acid or a solvate thereof, preferably a crystal thereof, may be precipitated by adding methanesulfonic acid to a solvent containing cefcapene pivoxil hydrochloride, preferably an organic solvent solution. .

Methanesulfonic acid may be a pure product, or 70% methanesulfonic acid etc. sold for industrial use may be used.

The organic solvent may be any solvent that can dissolve hydrochloride of cefcapene pivoxil, for example, alcohols such as methanol, ethanol, 2-propanol, 2-methoxyethanol, ethylene glycol, methoxyethanol, glycerin, and propylene glycol. , Ethers such as dioxane, tetrahydrofuran, dimethoxyethane, diethylene alcohol dimethyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl formate, ethyl formate, propyl formate , Esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, Kuroroetan, black hole benzene, organic halogenation hydrocarbons such as dichlorobenzene, Asetonitoriru, propionic - tolyl etc. - tolyl ethers, dimethylformamide Examples include amide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, quinoline, pyridines, and triethylamine, or a mixed solvent thereof, and may contain a small amount of water. More preferably, hydrochloride is an organic solvent having higher solubility than methanesulfonate of cefcapene pivoxil, such as ethanol, methyl isobutyl ketone, or a mixed solvent thereof. The mixing ratio of ethanol and methylisobutylketone is usually 1: 0 to 1: 100 (v / v), preferably 1: 0.5-1 to 10, more preferably 1: 1 to 1: 5, particularly preferably. Is 1: 1 to 1: 3.

Concentration of Sefukapen pivoxil hydrochloride in an organic solvent is usually from 0.01 to 20%, preferably rather ί or 0. 05~: L0 ⁰ / _o, more preferably ί or 0.1 to 5 ^_0/0.

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 cefcapene pivoxil hydrochloride. After adding methanesulfonic acid, the temperature of the reaction solution is adjusted as desired. It is preferably cooled to 0 ° C. to room temperature, more preferably 0 ° C. to 10 ° C., and the mixture is allowed to stand for several tens of minutes to several hours. If desired, seed crystals of methanesulfonate may be added. The crystals obtained in this manner can then be isolated by separating the solvent power by ordinary separation means (eg, filtration, centrifugation, etc.) and, if desired, drying.

When the organic solvent solution is a reaction solution containing cefcapene pivoxil hydrochloride, an extract thereof, or a mother washing solution, impurities such as raw materials and reaction by-products may be mixed. The impurities can be removed by isolation as a sulfonate salt, preferably its crystals. In particular, when recovering cef force pen pivoxil from a mixed solvent of ethanol and methyl isobutyl ketone, even if it is isolated as a free form of cefcapene pivoxil, the recovery rate is poor because of its high solubility. Even if cefcapene pivoxil is isolated directly in the form of hydrochloride, it is not desirable as an industrial production method because the effect of removing impurities is low and there is a risk of gelling. In contrast to these methods, the recovery method using the methanesulfonate of the present invention has a high effect of removing impurities and a good recovery rate (eg, about 70% or more). Therefore, it is useful as an industrial recovery method, purification method, or production method of cefcapene pivoxil or its hydrochloride.

(2) Conversion of methanesulfonate to hydrochloride The present invention further provides a method for converting cefcapene pivoxil methanesulfonate to hydrochloride. Preferably, methanesulfonate of cefcapene pivoxil, its solvate or crystal thereof is dissolved or suspended in organic solvent A, then neutralized and dissolved by adding an aqueous solution containing a base, and then the aqueous layer is dissolved. Remove cefcapene pivoxil as a free form and extract into an organic solvent. More preferably, the aqueous layer may be back-extracted with the organic solvent B and merged with the previously obtained organic solvent extract. By treating the extract according to the method described in JP-A-4-295485, hydrochloride hydrate, preferably its crystals, can be obtained. Specifically, after concentrating the extract and distilling off methylene chloride and the like, it is diluted with an organic solvent C as desired, and added dropwise to a mixture of the organic solvent D and hydrochloric acid, whereby cefcapene pivoxil. After the hydrochloride salt or hydrate crystal thereof is precipitated, it can be dried by a conventional method! (Yield example: 90% or more). The obtained hydrochloride hydrate may be used as a pharmaceutically active ingredient as it is, but may be reused as a seed crystal in the purification process if desired.

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

As the base for neutralization, alkali metal hydroxide (eg, NaOH, KOH), alkali metal hydrogen carbonate (eg, NaHCO, KHCO) or the like is used. For example, sodium hydroxide aqueous solution

3 3

In this case, it is preferably about 15 to 25%, and in the case of an aqueous sodium hydrogen carbonate solution, it 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 to methanesulfonate.

By carrying out the methods (1) and (2) above, cefcapene pivoxil hydrochloride can be efficiently recovered. That is, the present invention also provides a process for producing a hydrochloride hydrate of cefcabene pivoxil characterized by including the following steps.

(First step)

Methanesulfonic acid in an organic solvent solution containing cefcapene pivoxil hydrochloride A process of crystallizing methanesulphonate of cefcapene pivoxinole by calorie.

(Second process)

Converting the methanesulfonate to cefcapene pivoxil and then reacting with hydrochloric acid.

Each of the above steps is performed according to the methods (1) and (2). By adopting a purification method including the above two steps, cefcapene hydrochloride pivoxil hydrochloride remaining in the mother liquor after reaction extraction can be recovered, for example, in a yield of 60% or more. Therefore, it is very advantageous for mass production.

As described above, the cefcapene pivoxil methanesulfonate of the present invention, preferably the crystal thereof, is useful as an intermediate of an antibacterial agent (eg, cefcapene pivoxil hydrochloride). The methanesulfonate may itself be used as a pharmaceutically active ingredient.

Examples are shown below.

Example 1 (Recovery of methanesulfonate from mother wash)

According to the method described in Production Example 3 of Japanese Patent No. 2960790 (corresponding publication number: JP-A-4-295485), the 7-position amino protector of cefcapene pivoxil (7 β-[(Ζ)-2- ( 2 t-butoxycarbo-laminothiazole 4 yl) 2-butenoyl] amino-3—strong rubamoyloxymethyl 3-cepheme 4 carboxylate pivaloyloxymethyl ester) 1039 g as raw materials, solvent and reagents as raw materials The same deprotection reaction was carried out under the conditions where the ratio was increased in accordance with the amount used, and the hydrochloride salt of cefcapene pivoxil was crystallized, filtered, and the crystals were collected by filtration. The obtained crystals were washed successively with methyl isobutyl ketone and dichloromethane.

Filtrate separated in the above filtration process (mother liquor) 6.9L and washing solution separated after washing with methyl isobutyl ketone (washing solution) 3.1L mixed mother washing solution (content: 38.7g as cefcapene pivoxil hydrochloride, The solvent ratio ethanol: methyl isobutyl ketone = 1: 2.6) was adjusted to 8 ° C., 155.6 g (25 equivalents) of methanesulfonic acid was added, and the mixture was aged and stirred for 8 hours. The obtained crystals were collected by filtration, and the crystals were washed with 200 mL of 95% ethanol and air-dried to obtain 32. lg of the desired cefcapene pivoxyl methanesulfonate crystals (recovery rate from the mother washing solution: 73.1 %). 1H-NMR (d6-DMSO)

1.02 (t, 3H) 1.17 (s, 9H) 2.26 (t-d, 2H,) 2.50 (s, 3H) 3.61 (br-s, 2H) 4,73 (q, 2H)

5.24 (d, lH) 5.75-5.97 (m, 3H, 7-H) 6.55 (m- t, 2H) 9.47 (d, lH)

Elemental analysis C23H29N508S2, CH3S03H

Theoretical value C 43.20, H 5.04, N 10.49, S 14.41

Measured value C 43.32, H 5.06, N 10.47, S 14.53

Powder X-ray diffraction pattern: Fig. 1 and 2

(X-ray diffraction measurement conditions: tube CuK o; line, tube voltage 30 Kv, tube current 15 mA, dsin θ = η λ (η is an integer, θ is the diffraction angle))

Example 2 (hydrochlorination of methanesulfonate)

20.0 g of cefcapene pivoxyl methanesulfonate obtained in Example 1 is slurried in 40 mL of methylene chloride, and 140 mL of ethanol water adjusted to a concentration of 60.5% in advance is added and mixed by stirring. Add 5.9 g of 20% aqueous sodium hydroxide solution to this solution, and neutralize and dissolve, then remove the aqueous layer by extraction. Further, extract and wash twice with 60 mL of 2.5% sodium chloride aqueous solution to obtain the extract. The aqueous layer obtained during extraction is back-extracted with 60 mL of methylene chloride, and the resulting back-extracted methylene chloride layer is combined with the extract. Concentrate the combined extracts under reduced pressure and distill off the methylene chloride to obtain about 48 g of an ethanol solution of cefcapene pivoxil. Dilute the resulting solution with 60 mL of methyl isobutyl ketone and add dropwise to the mixture of ethanol 8 mL, methyl isobutyl ketone 32 mL, and 35% hydrochloric acid 3.4 g adjusted to 2 ° C over 20 minutes. Crystallize. Stir at the same temperature for 30 minutes, stir at 5 ± 2 ° C for 2 hours, and filter the precipitated crystals. The crystals were washed sequentially with 60 mL of cold methyl isobutyl ketone and 78 mL of cold methylene chloride, and then air-dried to obtain 16.2 g of the desired cefcapene pivoxil monohydrochloride hydrate (yield 91.9%). It went by.

Claims

The scope of the claims

[Chemical 1]

Cefcapene pivoxil methanesulfonate represented by

[2] The methanesulfonate according to claim 1, which is a crystal.

[3] The process for producing methanesulfonate of cefcapene pivoxil according to claim 1 or 2, wherein methanesulfonic acid is added to an organic solvent solution containing hydrochloride of cefcapene pivoxil.

[4] A process for producing a hydrochloride hydrate of cefcapene pivoxil comprising a step of converting the methanesulfonate according to claim 1 or 2 to cefcapene pivoxil and then reacting with hydrochloric acid.

[5] The following steps:

(First step)

(Second process)

A process for producing a hydrochloride hydrate of cefcapene pivoxil according to claim 4, comprising

6. The production method according to claim 5, wherein the organic solvent is a mixed solvent of ethanol and methylisobutyl ketone.

[7] Ratio of ethanol and methyl isobutyl ketone in organic solvent 1: 0 to 1: 100 (v / v) 6. The production method according to claim 5, wherein:

[8] Concentration power of cefcapene pivoxil hydrochloride in organic solvent solution is 0.05-10%

The production method according to claim 5.

[9] The process according to claim 5, wherein 1 to 100 molar equivalents of methanesulfonic acid are obtained relative to hydrochloride of cefcapene pivoxil.