JP3884063B2 - Cefcapene pivoxil methanesulfonate - Google Patents
Cefcapene pivoxil methanesulfonate Download PDFInfo
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Description
本発明は、セフカペン ピボキシルのメタンスルホン酸塩に関する。詳しくは、該メタンスルホン酸塩を経由するセフカペン ピボキシル塩酸塩の製造方法に関する。 The present invention relates to methanesulfonate of cefcapene pivoxil. Specifically, the present invention relates to a method for producing cefcapene pivoxil hydrochloride via the methanesulfonate.
式:
特許文献2の製造例3では、セフカペン ピボキシルの7位アミノ保護体の脱保護反応後の抽出液を濃縮した後、エタノ−ル、メチルイソブチルケトンおよび塩酸の混液中に滴下して粗塩酸塩を晶析させ、メチルイソブチルケトン等の有機溶媒で洗浄して塩酸塩を得ている。しかし、本発明者らが当該方法を追試した結果、結晶の単離工程における濾過および洗浄後の分離液(以下、各分離液を「母液」および「洗液」、合わせた液を「母洗液」ともいう)中にもセフカペン ピボキシル塩酸塩が数%程度残存していることが分かり、大量生産の精製法としては改善が必要であることが判明した。
よって、セフカペン ピボキシル1塩酸塩水和物のさらに好ましい製法の確立が望まれている。In Production Example 3 of
Therefore, establishment of a more preferable production method of cefcapene pivoxil monohydrochloride hydrate is desired.
そこで本発明者らは、上記母洗液中からのセフカペン ピボキシル塩酸塩の回収について種々検討した結果、母洗液中の該塩酸塩を一旦、メタンスルホン酸塩に変換して単離した後、再度、塩酸塩に変換すれば、効率よく回収できることを見出し以下の発明を完成した。
(1)式:
(2)結晶である、上記1記載のメタンスルホン酸塩。
(3)セフカペン ピボキシルの塩酸塩を含有する有機溶媒溶液中にメタンスルホン酸を加えることを特徴とする、上記1または2記載のセフカペン ピボキシルのメタンスルホン酸塩の製造方法。
(4)上記1または2記載のメタンスルホン酸塩をセフカペン ピボキシルに変換した後、塩酸と反応させる工程を包含する、セフカペン ピボキシルの塩酸塩水和物の製造方法。
(5)以下の工程:
(第1工程)
セフカペン ピボキシルの塩酸塩を含有する有機溶媒溶液中にメタンスルホン酸を加えることによりセフカペン ピボキシルのメタンスルホン酸塩を晶析させる工程;および
(第2工程)
該メタンスルホン酸塩をセフカペン ピボキシルに変換した後、塩酸と反応させる工程、
を包含する、上記4記載のセフカペン ピボキシルの塩酸塩水和物の製造方法。
(6)有機溶媒がエタノールとメチルイソブチルケトンとの混合溶媒である、上記5記載の製造方法。
(7)有機溶媒中のエタノールとメチルイソブチルケトンの比率が1:0〜1:100(v/v)である、上記5記載の製造方法。
(8)有機溶媒溶液中のセフカペン ピボキシルの塩酸塩の濃度が、0.05〜10%である、上記5記載の製造方法。
(9)セフカペン ピボキシルの塩酸塩に対してメタンスルホン酸を1〜100モル当量加える、上記5記載の製造方法。Therefore, as a result of various studies on the recovery of cefcapene pivoxil hydrochloride from the mother washing solution, the present inventors once converted the hydrochloride salt in the mother washing solution into methanesulfonate, and then isolated it. The following invention was completed by finding that it can be efficiently recovered by converting it into hydrochloride again.
(1) Formula:
(2) The methanesulfonic acid salt according to 1 above, which is a crystal.
(3) The method for producing methanesulfonate of cefcapene pivoxil according to 1 or 2 above, wherein methanesulfonic acid is added to an organic solvent solution containing cefcapene pivoxil hydrochloride.
(4) A method for producing a hydrochloride hydrate of cefcapene pivoxil, comprising a step of converting the methanesulfonate of the above 1 or 2 into cefcapene pivoxil and then reacting with hydrochloric acid.
(5) The following steps:
(First step)
Crystallization of cefcapene pivoxil methanesulfonate by adding methanesulfonic acid into an organic solvent solution containing cefcapene pivoxil hydrochloride; and (second step)
Converting the methanesulfonate salt to cefcapene pivoxil and then reacting with hydrochloric acid;
The method for producing a hydrochloride hydrate of cefcapene pivoxil according to the above 4, comprising:
(6) The production method according to 5 above, wherein the organic solvent is a mixed solvent of ethanol and methyl isobutyl 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 of cefcapene pivoxil hydrochloride in the organic solvent solution is 0.05 to 10%.
(9) The method according to 5 above, wherein 1 to 100 molar equivalents of methanesulfonic acid are added to cefcapene pivoxil hydrochloride.
本発明により、セフカペン ピボキシルのメタンスルホン酸塩、好ましくはその結晶が提供される。セフカペン ピボキシル塩酸塩の精製工程において、母洗浄液等から該メタンスルホン酸塩を晶析させた後、塩酸塩に変換することにより、セフカペン ピボキシル塩酸塩を効率よく回収できる。よって本発明は、溶媒中に混在するセフカペン ピボキシル塩酸塩の回収方法およびそれを包含する新規製法も提供する。 The present invention provides a methanesulfonate salt of cefcapene pivoxil, preferably a crystal thereof. In the step of purifying cefcapene pivoxil hydrochloride, the methanesulfonic acid salt is crystallized from the mother washing solution, etc., and then converted into the hydrochloride, whereby cefcapene pivoxil hydrochloride can be efficiently recovered. Therefore, the present invention also provides a method for recovering cefcapene pivoxil hydrochloride mixed in a solvent and a novel production method including the same.
(1)メタンスルホン酸塩の調製
本発明のメタンスルホン酸塩は、好ましくは結晶である。該結晶は、溶媒和物であってもよいが、好ましくは非溶媒和物である。溶媒和物の場合、溶媒としては、水、アルコール(例:メタノール、エタノール)、ケトン類(例;メチルイソブチルケトン)等が例示される。
該結晶は粉末X線回折で好ましくは以下に示す主ピークを示す。
2θ=17.93、18.61、19.63、20.17、20.93、22.39、24.79、25.71(単位:度)
該メタンスルホン酸塩の製法は特に限定されないが、好ましくは対応の塩酸塩から製造される。例えば、セフカペン ピボキシルの塩酸塩を含有する溶媒、好ましくは有機溶媒の溶液中にメタンスルホン酸を添加して、メタンスルホン酸塩またはその溶媒和物、好ましくはそれらの結晶を析出させればよい。
メタンスルホン酸は純品でもよいし、工業用に販売されている70%メタンスルホン酸等を使用しても良い。
有機溶媒としては、セフカペン ピボキシルの塩酸塩を溶解し得る溶媒であればよく、例えば、メタノール、エタノール、2−プロパノール、2−メトキシエタノール、エチレングリコール、メトキシエタノール、グリセリン、プロピレングリコールなどのアルコール類、ジオキサン、テトラヒドロフラン、ジメトキシエタン、ジエチレングルコールジメチルエーテルなどのエーテル類、アセトン、メチルエチルケトン、メチルイソブチルケトンなどのケトン類、メチルフォルメート、エチルフォルメート、プロピルフォルメート、酢酸メチル、酢酸エチル、プロピルアセテート、ブチルアセテート、メチルプロピオネート、エチルプロピオネートなどのエステル類、塩化メチレン、クロロホルム、四塩化炭素、1,2―ジクロロエタン、トリクロロエタン、クロロベンゼン、ジクロロベンゼンなどの有機ハロゲン化炭化水素類、アセトニトリル、プロピオニトリルなどのニトリル類、ジメチルホルムアミド、ジメチルスルホキサイド、ジメチルアセトアミド、N−メチルピロリドン、キノリン、ピリジン類、およびトリエチルアミンなど、またはそれらの混合溶媒が例示され、少量の水が含まれていてもよい。より好ましくは、セフカペン ピボキシルのメタンスルホン酸塩よりも塩酸塩の方が溶解性の高くなる有機溶媒であり、例えば、エタノール、メチルイソブチルケトンまたはそれらの混合溶媒である。エタノールとメチルイソブチルケトンの混合比率は、通常1:0〜1:100(v/v)、好ましくは1:0.5〜1:10、より好ましくは1:1〜1:5、特に好ましくは1:1〜1:3である。
有機溶媒中のセフカペン ピボキシル塩酸塩の濃度は、通常0.01〜20%、好ましくは0.05〜10%、より好ましくは0.1〜5%である。
メタンスルホン酸の添加量は、セフカペン ピボキシル塩酸塩に対して、通常1〜100モル当量、好ましくは5〜50モル当量、より好ましくは20〜30モル当量である。
メタンスルホン酸添加後、所望により反応液を温度調節する。好ましくは0℃〜室温、より好ましくは0℃〜10℃に冷却し、数十分〜数時間静置すればよい。また所望によりメタンスルホン酸塩の種晶を添加してもよい。このようにして得られる結晶は、次いで、通常の分離手段(例:濾過、遠心分離等)により溶媒から分離し、所望により乾燥することにより単離することができる。
上記有機溶媒の溶液が、セフカペン ピボキシル塩酸塩を含む反応液、その抽出液、または母洗液等であるような場合、原料や反応副生物等の不純物が混入してくることも有り得るが、メタンスルホン酸塩、好ましくはその結晶として単離することにより該不純物を除去できる。特にエタノールとメチルイソブチルケトンの混合溶媒中からセフカペン ピボキシルを回収する場合、セフカペン ピボキシルのフリー体として単離しようとしても、溶解度が高すぎるため回収率が悪い。またセフカペン ピボキシルを塩酸塩のままで直接単離しようとしても、不純物の除去効果が低く、またゲル化の危険性もあるので、工業的製法としては望ましくない。これらの方法に対して、本発明のメタンスルホン酸塩による回収方法は、不純物の除去効果が高く、回収率も良い(例:約70%以上)。よって、セフカペン ピボキシルまたはその塩酸塩の工業的な回収法、精製法、または製造法として有用である。(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.
2θ = 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 sold for industrial use may be used.
The organic solvent may be any solvent that can dissolve cefcapene pivoxil hydrochloride, for example, alcohols such as methanol, ethanol, 2-propanol, 2-methoxyethanol, ethylene glycol, methoxyethanol, glycerin, propylene glycol, Ethers such as dioxane, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl Esters such as acetate, methyl propionate, ethyl propionate, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, tri Organic halogenated hydrocarbons such as chloroethane, chlorobenzene, dichlorobenzene, nitriles such as acetonitrile and propionitrile, dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone, quinoline, pyridines, and triethylamine Alternatively, a mixed solvent thereof is exemplified, and a small amount of water may be contained. 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 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. 1: 1 to 1: 3.
The concentration of cefcapene pivoxil hydrochloride in the organic solvent is usually 0.01 to 20%, preferably 0.05 to 10%, 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, 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. Preferably it is cooled to 0 ° C. to room temperature, more preferably 0 ° C. to 10 ° C., and it is allowed to stand for several tens of minutes to several hours. If desired, a seed crystal of methanesulfonate may be added. The crystals thus obtained can then be isolated from the solvent by conventional separation means (eg filtration, centrifugation, etc.) and optionally dried.
When the organic solvent solution is a reaction solution containing cefcapene pivoxil hydrochloride, an extract thereof, a mother washing solution, or the like, 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 cefcapene pivoxil is recovered from a mixed solvent of ethanol and methyl isobutyl ketone, even if an attempt is made to isolate cefcapene pivoxil as a free form, the recovery rate is poor because the solubility is too high. Further, even if cefcapene pivoxil is directly isolated in the form of hydrochloride, it is not desirable as an industrial production method because it has a low effect of removing impurities and there is a risk of gelation. In contrast to these methods, the recovery method using 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)メタンスルホン酸塩の塩酸塩への変換
本発明はさらに、セフカペン ピボキシルのメタンスルホン酸塩を塩酸塩に変換する方法を提供する。好ましくは、セフカペン ピボキシルのメタンスルホン酸塩、その溶媒和物またはそれらの結晶を有機溶媒Aに溶解または懸濁させ、次に塩基を含む水溶液を加えて中和溶解した後、水層を除去してセフカペン ピボキシルをフリー体として有機溶媒中に抽出する。より好ましくは該水層を有機溶媒Bで逆抽出して、先に得られた有機溶媒の抽出液と合併してもよい。該抽出液を特開平4−295485号に記載の方法に準じて処理することにより塩酸塩水和物、好ましくはその結晶が得られる。具体的には、該抽出液を濃縮して塩化メチレン等を留去した後、所望により有機溶媒Cで希釈し、これを有機溶媒Dおよび塩酸の混合液中に滴下することにより、セフカペン ピボキシルの塩酸塩またはその水和物結晶を析出させた後、常法により乾燥すればよい(収率例:90%以上)。得られた塩酸塩水和物はそのまま医薬活性成分として使用してもよいが、所望により再度、精製工程における原料や種晶として再利用してもよい。
有機溶媒A、B、Cは、前記有機溶媒から適宜選択され得るが、好ましくは有機溶媒AおよびBは、ジクロロメタン、アルコール(例:エタノール)またはその混合溶媒であり、有機溶媒CおよびDはアルコール(例:エタノール)、メチルイソブチルケトンまたはその混合溶媒である。
中和用の塩基としては、水酸化アルカリ金属(例:NaOH、KOH)や炭酸水素アルカリ金属(例:NaHCO3、KHCO3)等が使用される。例えば水酸化ナトリウム水溶液の場合、好ましくは約15〜25%、炭酸水素ナトリウム水溶液の場合、好ましくは5〜10%である。
塩酸の濃度は、通常10〜50%、好ましくは30〜40%であり、メタンスルホン酸塩に対して通常1〜50モル当量、好ましくは1〜10モル当量使用すればよい。(2) Conversion of methanesulfonate to hydrochloride The present invention further provides a method for converting methanesulfonate of cefcapene pivoxil into 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 removed. Cefcapene pivoxil is extracted as a free form into an organic solvent. More preferably, the aqueous layer may be back-extracted with the organic solvent B and combined 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 crystal, is obtained. Specifically, after concentrating the extract to distill 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 precipitation of hydrochloride or its hydrate crystals, it may be dried by a conventional method (yield example: 90% or more). The obtained hydrochloride hydrate may be used as it is as a pharmaceutically active ingredient, but may be reused as a raw material or seed crystal in the purification step 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 are alcohols. (Example: 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 3 , KHCO 3 ) or the like is used. For example, in the case of a sodium hydroxide aqueous solution, it is preferably about 15 to 25%, and in the case of a sodium hydrogen carbonate aqueous 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 with respect to methanesulfonate.
上記(1)および(2)の方法を行うことにより、セフカペン ピボキシルの塩酸塩を効率よく回収できる。即ち本発明は以下の工程を包含することを特徴とする、セフカペン ピボキシルの塩酸塩水和物の製造方法も提供する。
(第1工程)
セフカペン ピボキシルの塩酸塩を含有する有機溶媒溶液中にメタンスルホン酸を加えることによりセフカペン ピボキシルのメタンスルホン酸塩を晶析させる工程。
(第2工程)
該メタンスルホン酸塩をセフカペン ピボキシルに変換した後、塩酸と反応させる工程。
上記各工程は、前記(1)および(2)の方法に準じて行われる。上記2工程を含む精製法を採用することにより、反応抽出後の母洗液中に残存する塩酸セフカペン ピボキシルを例えば60%以上の収率で回収できる。よって大量生産を行う上で非常に有利である。
上記の通り本発明のセフカペン ピボキシルメタンスルホン酸塩、好ましくはその結晶は、抗菌剤(例:セフカペン ピボキシル塩酸塩)の中間体として有用である。また該メタンスルホン酸塩は、それ自身を医薬活性成分として使用してもよい。
以下に実施例を示す。By carrying out the methods (1) and (2) above, the hydrochloride of cefcapene pivoxil can be efficiently recovered. That is, the present invention also provides a method for producing cefcapene pivoxil hydrochloride hydrate, which comprises the following steps.
(First step)
A step of crystallizing cefcapene pivoxil methanesulfonate by adding methanesulfonic acid to an organic solvent solution containing cefcapene pivoxil hydrochloride.
(Second step)
A step of converting the methanesulfonate to cefcapene pivoxil and then reacting with hydrochloric acid.
Each said process is performed according to the method of said (1) and (2). By adopting the purification method including the above two steps, cefcapene hydrochloride pivoxil hydrochloride remaining in the mother wash after the reaction extraction can be recovered in a yield of 60% or more, for example. Therefore, it is very advantageous for mass production.
As described above, the cefcapene pivoxyl 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.
実施例1(母洗液からメタンスルホン酸塩の回収)
特許第2960790号公報(対応公開番号:特開平4−295485号)の製造例3に記載の方法に準じて、セフカペン ピボキシルの7位アミノ保護体(7β-[(Z)−2−(2−t−ブトキシカルボニルアミノチアゾール−4−イル)−2−ブテノイル]アミノ−3−カルバモイルオキシメチル−3−セフェム−4−カルボン酸ピバロイルオキシメチルエステル)1039gを原料とし、溶媒、試薬類は原料の使用量に応じた比率で増加させた条件で、同様の脱保護反応を行い、セフカペン ピボキシルの塩酸塩を晶析させ、濾過して結晶を濾取した。得られた結晶をメチルイソブチルケトンとジクロルメタンで順次洗浄した。
上記濾過の過程で分離された濾液(母液)6.9L及びメチルイソブチルケトンによる洗浄後に分離された洗浄液(洗液)3.1Lを混合した母洗液(内在量:セフカペン ピボキシル塩酸塩として38.7g、含有溶媒比 エタノール:メチルイソブチルケトン=1:2.6)を8℃に温度調節後、メタンスルホン酸155.6g(25当量)を添加し、8時間撹拌熟成を行った。得られた結晶を濾取し、結晶を95%エタノール200mLで洗浄後、風乾することにより、目的のセフカペン ピボキシル メタンスルホン酸塩結晶 32.1gを得た(母洗液中からの回収率: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,1H) 5.75-5.97(m,3H,7-H) 6.55(m-t,2H) 9.47(d,1H)
元素分析 C23H29N5O8S2・CH3SO3H
理論値 C 43.20, H 5.04, N 10.49, S 14.41
測定値 C 43.32, H 5.06, N 10.47, S 14.53
粉末X線回折パターン:図1、2
(X線回折測定条件:管球CuKα線、管電圧30Kv、管電流15mA、dsinθ=nλ(nは整数、θは回折角))
実施例2(メタンスルホン酸塩の塩酸塩化)
実施例1で得たセフカペン ピボキシル メタンスルホン酸塩20.0 gを塩化メチレン140 mLにスラリー化し、予め60.5%濃度に調節したエタノール水140 mLを加え、撹拌混合する。このものに20%の水酸化ナトリウム水溶液を5.9 g加え、中和溶解せしめた後、抽出にて水層を除去する。更に2.5%塩化ナトリウム水溶液60 mLで2回抽出洗浄を行い、抽出液を得る。また抽出中に得る水層は塩化メチレン60 mLで逆抽出し、得られた逆抽出塩化メチレン層は抽出液に合併する。合併した抽出液を減圧濃縮し、塩化メチレンを留去せしめ、セフカペン ピボキシルのエタノール溶液約48 gを得る。得られた液をメチルイソブチルケトン60mLで希釈し、20±2℃に調節したエタノール8 mL、メチルイソブチルケトン32 mL及び35%塩酸3.4 gの混液中に5分間で滴下して生成物を晶析させる。同温で30分撹拌し、5±2℃で2時間撹拌後、析出する結晶を濾取する。結晶を冷メチルイソブチルケトン60 mLと冷塩化メチレン78 mLで順次洗浄後、風乾して目的のセフカペン ピボキシル1塩酸塩水和物16.2 gを得る(収率 91.9%)。化合物の同定は液体クロマトグラフィー法により行った。
Example 1 (Recovery of methanesulfonate from mother washings)
According to the method described in Production Example 3 of Japanese Patent No. 2960790 (corresponding publication number: Japanese Patent Laid-Open No. 4-295485), the 7-position amino protected form of cefcapene pivoxil (7β-[(Z) -2- (2- t-butoxycarbonylaminothiazol-4-yl) -2-butenoyl] amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester) 1039 g as a raw material, 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.
A mother washing solution (content: cefcapene pivoxil hydrochloride 38.8) mixed with 6.9 L of the filtrate (mother solution) separated in the above filtration process and 3.1 L of the washing solution (washing solution) separated after washing with methyl isobutyl ketone. After adjusting the temperature of 8 g of ethanol: methyl isobutyl ketone = 1: 2.6) to 7 ° C., 155.6 g (25 equivalents) of methanesulfonic acid was added, followed by stirring and aging 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 32.1 g of the target cefcapene pivoxil methanesulfonate salt (recovery rate from the mother washing solution: 73 .1%).
1H-NMR (d6-DMSO)
1.02 (t, 3H) 1.17 (s, 9H) 2.26 (td, 2H,) 2.50 (s, 3H) 3.61 (br-s, 2H) 4,73 (q, 2H)
5.24 (d, 1H) 5.75-5.97 (m, 3H, 7-H) 6.55 (mt, 2H) 9.47 (d, 1H)
Elemental analysis C23H29N5O8S2 / CH3SO3H
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: Figs.
(X-ray diffraction measurement conditions: tube CuKα ray, tube voltage 30 Kv, tube current 15 mA, dsin θ = nλ (n is an integer, θ is a diffraction angle))
Example 2 (hydrochlorination of methanesulfonate)
20.0 g of cefcapene pivoxil methanesulfonate obtained in Example 1 is slurried in 140 mL of methylene chloride, and 140 mL of ethanol water adjusted to a concentration of 60.5% in advance is added and mixed with stirring. 5.9 g of 20% aqueous sodium hydroxide solution is added to this product and neutralized and dissolved, and then the aqueous layer is removed by extraction. Further, the extract is washed twice with 60 mL of 2.5% aqueous sodium chloride solution to obtain an 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. The combined extract is concentrated under reduced pressure, and the methylene chloride is distilled off to obtain about 48 g of an ethanol solution of cefcapene pivoxil. The resulting solution was diluted with 60 mL of methyl isobutyl ketone, and the product was crystallized by dropwise addition over 5 minutes into a mixture of 8 mL of ethanol adjusted to 20 ± 2 ° C, 32 mL of methyl isobutyl ketone and 3.4 g of 35% hydrochloric acid. Let The mixture is stirred at the same temperature for 30 minutes and stirred at 5 ± 2 ° C. for 2 hours, and the precipitated crystals are collected by filtration. The crystals are 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%). The compound was identified by liquid chromatography.
Claims (9)
(第1工程)
セフカペン ピボキシルの塩酸塩を含有する有機溶媒溶液中にメタンスルホン酸を加えることによりセフカペン ピボキシルのメタンスルホン酸塩を晶析させる工程;および
(第2工程)
該メタンスルホン酸塩をセフカペン ピボキシルに変換した後、塩酸と反応させる工程、
を包含する、請求項4記載のセフカペン ピボキシルの塩酸塩水和物の製造方法。The following steps:
(First step)
Crystallization of cefcapene pivoxil methanesulfonate by adding methanesulfonic acid into an organic solvent solution containing cefcapene pivoxil hydrochloride; and (second step)
Converting the methanesulfonate salt to cefcapene pivoxil and then reacting with hydrochloric acid;
A method for producing a hydrochloride hydrate of cefcapene pivoxil according to claim 4, comprising:
The production method according to claim 5, wherein 1 to 100 molar equivalents of methanesulfonic acid are added to cefcapene pivoxil hydrochloride.
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CN103087080B (en) * | 2011-11-03 | 2016-08-31 | 石药集团中奇制药技术(石家庄)有限公司 | The preparation method of a kind of Method of cefcapene pivoxil hydrochloride and synthetic intermediate thereof |
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JP2960790B2 (en) * | 1991-03-25 | 1999-10-12 | 塩野義製薬株式会社 | Cephalosporin hydrate crystals for oral administration |
JP2002205994A (en) * | 2000-11-13 | 2002-07-23 | Meiji Seika Kaisha Ltd | Cefditoren pivoxil organic acid salt, inorganic acid salt thereof, and method for producing the same |
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