JPH01242588A - Crystal of 7-cyanomethylthioacetamide-7alpha-methoxy-3-(1-methyl-1h-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and production thereof - Google Patents
Crystal of 7-cyanomethylthioacetamide-7alpha-methoxy-3-(1-methyl-1h-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and production thereofInfo
- Publication number
- JPH01242588A JPH01242588A JP6928988A JP6928988A JPH01242588A JP H01242588 A JPH01242588 A JP H01242588A JP 6928988 A JP6928988 A JP 6928988A JP 6928988 A JP6928988 A JP 6928988A JP H01242588 A JPH01242588 A JP H01242588A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- cyanomethylthioacetamide
- cephem
- thiomethyl
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 36
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 53
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 9
- 239000011780 sodium chloride Substances 0.000 claims abstract description 5
- 238000000354 decomposition reaction Methods 0.000 claims abstract description 3
- 238000002844 melting Methods 0.000 claims abstract description 3
- 230000008018 melting Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 150000001447 alkali salts Chemical class 0.000 claims description 9
- 235000002639 sodium chloride Nutrition 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000012047 saturated solution Substances 0.000 claims 3
- 230000009102 absorption Effects 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 6
- 229930186147 Cephalosporin Natural products 0.000 abstract description 3
- 229940124587 cephalosporin Drugs 0.000 abstract description 3
- 150000001780 cephalosporins Chemical class 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229940088710 antibiotic agent Drugs 0.000 abstract description 2
- 229940093499 ethyl acetate Drugs 0.000 abstract 1
- 235000019439 ethyl acetate Nutrition 0.000 abstract 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 229920006395 saturated elastomer Polymers 0.000 abstract 1
- 159000000000 sodium salts Chemical class 0.000 abstract 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000000034 method Methods 0.000 description 6
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 4
- SVYKKECYCPFKGB-UHFFFAOYSA-N N,N-dimethylcyclohexylamine Chemical class CN(C)C1CCCCC1 SVYKKECYCPFKGB-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- ZWRDBWDXRLPESY-UHFFFAOYSA-N n-benzyl-n-ethylethanamine Chemical compound CCN(CC)CC1=CC=CC=C1 ZWRDBWDXRLPESY-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 1
- 229960002676 cefmetazole sodium Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- JQQHKTPQFWSNBC-UHFFFAOYSA-J hydrogen carbonate thorium(4+) Chemical compound [Th+4].OC([O-])=O.OC([O-])=O.OC([O-])=O.OC([O-])=O JQQHKTPQFWSNBC-UHFFFAOYSA-J 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野」
本発明は著効なセファロスポリン系抗生物質である７−
シアノメチルチオアセトアミド−アセト７ミドー７α−
メトキシ−３−（１−−メチル−１Ｈ−テトラゾール−
５−イル）チオメチル−３−セフェム−４−カルボン酸
ナトリウム（一般名 セフメタゾールナトリウム：
ＣＭＺＮａと略称することがある）を製造するための安
定な中間体である。７−シアノメチルチオアセトアミド
−７セトアミドー７α−メトキシ−３−（１−−メチル
−１Ｈ−テトラゾール−５−イル）チオメチル−３−セ
フェム−４−カルボン酸（ＣＭＺと略称することがある
）結晶に係るものである。[Detailed Description of the Invention] [Industrial Application Field] The present invention provides highly effective cephalosporin antibiotics.
Cyanomethylthioacetamide-aceto7mido7α-
Methoxy-3-(1--methyl-1H-tetrazole-
Sodium 5-yl)thiomethyl-3-cephem-4-carboxylate (generic name cefmetazole sodium:
It is a stable intermediate for producing CMZNa (sometimes abbreviated as CMZNa). 7-cyanomethylthioacetamide-7cetamido 7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (sometimes abbreviated as CMZ) crystal It is something.
本発明目的物のＮａ塩であるＣＭＺＮａは抗菌性物質と
して開発され０日本国内に於ては昭和５５年に発売され
た。この化合物はセファロスポリン系抗生物質として長
期に亘って製造され、海外にも広く販売されて来ている
。その製造方法については、特公昭５４−１７７５５を
はじめ多くの方法が特許出願されているが、その全ては
中間体であるＣＭＺが抽出溶媒である酢酸エチルエステ
ルを留去して得られる無晶形粉末であるため、この段階
における精製が実施できず、ＣＭＺのジメチルシクロヘ
キシルアミン塩等（特公昭５５−７４３９ ）。CMZNa, which is a Na salt targeted by the present invention, was developed as an antibacterial substance and was released in Japan in 1982. This compound has been manufactured as a cephalosporin antibiotic for a long time and has been widely sold overseas. Many patent applications have been filed for manufacturing methods, including Japanese Patent Publication No. 54-17755, but in all of them, CMZ, which is an intermediate, is an amorphous powder obtained by distilling off ethyl acetate, which is an extraction solvent. Therefore, purification at this stage cannot be carried out, and dimethylcyclohexylamine salt of CMZ etc. (Japanese Patent Publication No. 55-7439).
又はジシクロヘキシルアミン塩（特公昭５５−１２０３
４ ） として結晶化させ精製を行つていた。or dicyclohexylamine salt (Japanese Patent Publication No. 55-1203
4) was crystallized and purified.
〔発明が解決しようとする問題点ｌ
ＣＭＺはジメチルシクロヘキシルアミン塩、ジシクロヘ
キシルアミン塩などの有機塩基性塩としては結晶化する
ため、この段階での精製は可能でありたが、ＣＭＺＮａ
での安定性に乏しく精製が困雌であるので、塩の状態か
らより最終物質に近いＣＭＺでの精製を行なうための結
晶化が望まれていた。[Problem to be solved by the invention CMZ crystallizes as an organic basic salt such as dimethylcyclohexylamine salt or dicyclohexylamine salt, so purification at this stage was possible, but CMZNa
Since it has poor stability and is difficult to purify, it has been desired to crystallize it from a salt state in order to purify it in CMZ, which is closer to the final substance.
上記技術状況に檻へ１本発明者らは種々の溶媒に対する
ＣＭＺ及びＣＭＺ・塩の溶解及びＣＭＺの単離方法の開
発を推進していた処、ＣＭＺ・有機塩基性塩を用いて高
収率で高純度のＣＭＺ結晶を得ることに成功し９本発明
を完成させた。本発明になる方法は特公昭５５−７４３
９．特公昭５５−１２０３４Ｋ。In response to the above technical situation, the present inventors have been promoting the development of a method for dissolving CMZ and CMZ/salts in various solvents and isolating CMZ, and found that CMZ/organic basic salts can be used in high yields. We succeeded in obtaining highly pure CMZ crystals and completed the present invention. The method of the present invention is disclosed in Japanese Patent Publication No. 55-743.
9. Special Public Service 1977-12034K.
記載のＣＭＺ・有機塩基性塩結晶よりＣＭＺ無品無段性
粉末ている製造方法を基本とするが、その中間段階に塩
析の操作を挿入することによって、ＣＭＺが結晶として
得られたことを基礎にしたものである。The basic manufacturing method is to produce stepless powder of CMZ from CMZ/organic basic salt crystals, but by inserting a salting-out operation in the intermediate stage, CMZ can be obtained as crystals. This is the basis.
本発明方法を順を追って更に詳しく説明すると、■ＣＭ
Ｚ・有機塩基性塩を水及び酢酸エチルエステルに分散さ
せる。To explain the method of the present invention in more detail step by step, ■CM
Z.Disperse the organic basic salt in water and acetic acid ethyl ester.
■酸を加えてｐＨを１．５〜２．５に調整する。■この
液の水層３部に対してほぼ１部の割合いで食塩を加え、
水層な飽和食塩水溶液とする。■析出する塩を濾別する
。■析出した塩を酢酸エチルエステルで洗浄する。■酢
酸エチルエステル層を分取する。■水層を酢酸エチルエ
ステルで抽出する。■酢酸エチルエステル層を合する。■ Add acid to adjust pH to 1.5-2.5. ■ Add salt at a ratio of approximately 1 part to 3 parts of the water layer of this liquid,
Make an aqueous saturated saline solution. ■ Filter out the precipitated salt. ■Wash the precipitated salt with ethyl acetate. ■Separate the ethyl acetate layer. ■Extract the aqueous layer with ethyl acetate. ■ Combine the acetic acid ethyl ester layers.
■酢酸エチルエステル層な飽和食塩水で洗浄する。■メ
チルアルコールを加える。■乾燥剤を加える。■乾燥剤
を濾去する。■活性炭処理を行う。■酢酸・エチル層を
濃縮する。■種晶を加え゛る。［相］晶出するＣＭＺ結
晶を濾取する。Ｏ母液よりＣＭＺ結晶の回収を行う。■Wash the acetic acid ethyl ester layer with saturated saline. ■Add methyl alcohol. ■Add desiccant. ■ Filter off the desiccant. ■Perform activated carbon treatment. ■Concentrate the acetic acid/ethyl layer. ■Add seed crystals. [Phase] Collect the crystallized CMZ crystals by filtration. CMZ crystals are recovered from the O mother liquor.
出発物質であるＣＭＺ・有機塩基性塩に用いられる有機
塩基としてはジシクロヘキシルアミン、ジメチルシクロ
ヘキシルアミン、ジエチルベンジルアミンの他、ジエチ
ルシクロヘキシルアミン１ジメチルベンジル７ミンなど
が挙げられる。Examples of the organic base used in the starting material CMZ/organic basic salt include dicyclohexylamine, dimethylcyclohexylamine, diethylbenzylamine, and diethylcyclohexylamine-1-dimethylbenzyl-7mine.
ＣＭＺ・有機塩基性塩の純度により、ＣＭＺ結晶の晶出
速度、収量は変動し、結晶としては■、■の段階で取得
する事もできるが、純度、収量については０又は■の段
階で晶出させるのこ
するものが使用でき、■の乾燥剤としては硫酸マグネシ
ウム。Depending on the purity of CMZ/organic basic salt, the crystallization rate and yield of CMZ crystals will vary, and crystals can be obtained at stages ■ and ■; however, regarding purity and yield, crystals may be obtained at stages 0 or ■. You can use something to rub it out, and the drying agent for (■) is magnesium sulfate.
硫酸ナトリウムなど固形で溶質に影響を与えない薬品が
好しい。■の濃縮は公知の技術の如き乾固の要はなく、
液量なほぼ％〜にとすれば充分であった。A solid chemical that does not affect the solute, such as sodium sulfate, is preferred. Concentration in (3) does not require drying as in known techniques;
It was sufficient to keep the liquid amount to about 1%.
本発明になるＣＭＺ結晶は、従来のＣＭＺ無品無段性粉
末ＣＭＺＮａに比較して著しく安定であり、精製、保存
及び輸送に適格である。The CMZ crystal of the present invention is significantly more stable than conventional CMZ stepless powder CMZNa, and is suitable for purification, storage, and transportation.
本結晶は４〜５倍の水に分散し、炭酸水素力トリウムで
ｐＨ５，３〜５．４に調整し凍結乾燥することによりて
ＣＭＺＮａに変換できた。This crystal could be converted to CMZNa by dispersing it in 4 to 5 times the amount of water, adjusting the pH to 5.3 to 5.4 with thorium bicarbonate, and freeze-drying.
以下に本発明を実施例によって説明する。The present invention will be explained below by way of examples.
実施例１゜
ＣＭＺ・ジシクロヘキシルアミン塩５ｔを水２０ＴＬｔ
、 ｆｆ［エチルエステル１５１に分散し、４規定塩酸
にてｐＨを約２に調整した。この液に７．５ｔの食塩を
加えて水層な飽和とし、析出する無色の結晶を濾別のの
ち酢酸エチルエステル層を分取した。Example 1゜5t of CMZ dicyclohexylamine salt to 20TLt of water
, ff [ethyl ester 151] and the pH was adjusted to about 2 with 4N hydrochloric acid. 7.5 tons of common salt was added to this liquid to saturate the aqueous layer, and after filtering off the precipitated colorless crystals, the ethyl acetate layer was separated.
この層に結晶を１０１１７で２回洗浄した酢酸エチルエ
ステル及び水層を同じく１０ｄで２回抽出した酢酸エチ
ルエステルを合し。Ethyl acetate obtained by washing the crystals twice with 10117 and ethyl acetate obtained by extracting the aqueous layer twice with 10d were combined with this layer.
飽和食塩水１０１Ｌｔで洗浄ののち、硫酸マグネシウム
で乾燥し。After washing with 101 Lt of saturated saline, drying with magnesium sulfate.
これを濾別した。得た酢酸エチルエステル層を減圧下に
２５罰まで濃縮し１種晶を投入し晶出した無色結晶を濾
取し、減圧下に乾燥した。−次結晶として取得した結晶
は３．２７？であり、融点は１５０〜１５２℃（分解）
であった。This was filtered. The obtained ethyl acetate layer was concentrated to 25% under reduced pressure, one seed crystal was added, and the colorless crystals crystallized were collected by filtration and dried under reduced pressure. -The crystal obtained as the next crystal is 3.27? and the melting point is 150-152℃ (decomposition)
Met.
Ｎ、 Ｍ、Ｒ，（ＤＭＳ Ｏ−ｄ ｓ ）δ、ｐｐｍ
３．４１（３Ｈ，ｓ）、３．４８（１Ｈ，ｄ、Ｊ＝１
７．８Ｈｚ）、３．４９（２Ｈ％ｓ）、３．７３（１Ｈ
，ｄＳＪ−１７，８Ｈｚ）、３．７７（２Ｈ，ｓ）＋
３．９４（３Ｈ，ｓ）、 ４．２９（２Ｈ，ＡＢｑ、
Ｊ＝１３．４Ｈｚ＞、 ５．１２（１Ｈ，ｓ）。N, M, R, (DMS O-ds) δ, ppm
3.41 (3H, s), 3.48 (1H, d, J=1
7.8Hz), 3.49 (2H%s), 3.73 (1H
, dSJ-17,8Hz), 3.77(2H,s)+
3.94 (3H, s), 4.29 (2H, ABq,
J=13.4Hz>, 5.12 (1H, s).
９．５６（１Ｈ，ｓ）、 １３．８（１Ｈ％ｂｒ、 ｓ
）実施例２゜
硫酸マグネシウムで乾燥するに当り、メチルアルコール
を加えておく以外は実施例１．と同様に操作し、 ３．
２０♂のＣＭＺを一次結晶として得た。9.56 (1H, s), 13.8 (1H%br, s
) Example 2゜ Example 1 except that methyl alcohol was added during drying with magnesium sulfate. Operate in the same manner as 3.
20♂ CMZ was obtained as a primary crystal.
実施例３゜
実施例１．において、硫酸マグネシウムで乾燥ののち、
得られた酢酸エチルエステル層を濃縮して一夜放置して
２．６５ｆｔのＣＭＺを一次結晶として得た。Example 3゜Example 1. After drying with magnesium sulfate,
The obtained ethyl acetate layer was concentrated and left overnight to obtain 2.65 ft of CMZ as primary crystals.
実施例４゜
出発物質としてＣＭＺ・ジメチルシクロヘキシルアミン
塩のＢを使用する他は、実施例１．と同様に処理して６
７０Ｍ９のＣＭＺ結晶を一次晶七して得た。Example 4 Example 1 except that CMZ dimethylcyclohexylamine salt B was used as the starting material. Process in the same way as 6
A 70M9 CMZ crystal was obtained by primary crystallization.
実施例５゜
１１＋物１としてＣＭＺ・ジエチルベンジルアミン塩の
１ｆを使用する他は、実施例１．と同様に処理して６０
０ Ｍ９のＣＭＺ結晶を一次晶として得た。Example 5゜11+ Example 1 except that 1f of CMZ diethylbenzylamine salt was used as product 1. Process in the same way as 60
A CMZ crystal of 0 M9 was obtained as a primary crystal.
Claims (1)
シ−３−（１−メチル−１Ｈ−テトラゾール−５−イル
）チオメチル−３−セフェム−４−カルボン酸の結晶２
）融点が１５０〜１５２℃（分解）である特許請求の範
囲１）項の結晶 ３）Ｈ′−核磁気共鳴スペクトルによってδｐｐｍ（Ｄ
ＭＳＯ−ｄ＿■）３．４１（３Ｈ、ｓ）、３．４８（１
Ｈ、ｄ、Ｊ＝１７．８Ｈｚ）、３．４９（２Ｈ、ｓ）、
３．７３（１Ｈ、ｄ、Ｊ＝１７．８Ｈｚ）、３．７７（
２Ｈ、ｓ）、３．９４（３Ｈ、ｓ）、４．２９（２Ｈ、
ＡＢｑ、Ｊ＝１３．４Ｈｚ）、５．１２（１Ｈ、ｓ）、
９．５６（１Ｈ、ｓ）、１３．８（１Ｈ、ｂｒ、ｓ） に特徴的な吸収を有する特許請求の範囲１）項の結晶４
）７−シアノメチルチオアセトアミド−７α−メトキシ
−３−（１−メチル−１Ｈ−テトラゾール−５−イル）
チオメチル−３−セフェム−４−カルボン酸・有機塩基
性塩を水、酢酸エチルエステルに分散させ、ｐＨを１．
５〜２．５に調整し更に食塩の飽和溶液となしてのち、
酢酸エチルエステル層より晶出する結晶を取得すること
を特徴とする７−シアノメチルチオアセトアミド−７α
−メトキシ−３−（１−メチル−１Ｈ−テトラゾール−
５−イル）チオメチル−３−セフェム−４−カルボン酸
結晶の製造方法 ５）７−シアノメチルチオアセトアミド−７α−メトキ
シ−３−（１−メチル−１Ｈ−テトラゾール−５−イル
）チオメチル−３−セフェム−４−カルボン酸：有機塩
基性塩を水、酢酸エチルエステルに分散させ、ｐＨを１
．５〜２．５に調整し、更に食塩の飽和溶液となしての
ち、酢酸エチルエステル層を分取し、乾燥して晶出する
結晶を取得することを特徴とする７−シアノメチルチオ
アセトアミド−７α−メトキシ−３−（１−メチル−１
Ｈ−テトラゾール−５−イル）チオメチル−３−セフェ
ム−４−カルボン酸結晶の製造方法 ６）７−シアノメチルチオアセトアミド−７α−メトキ
シ−３−（１−メチル−１Ｈ−テトラゾール−５−イル
）チオメチル−３−セフェム−４−カルボン酸・有機塩
基性塩を水、酢酸エチルエステルに分散させ、ｐＨを１
．５〜２．５に調整し、更に食塩の飽和溶液となしての
ち、酢酸エチルエステル層を分取し、メチルアルコール
を加えてから乾燥した該層内のメチルアルコールを留去
することを特徴とする７−シアノメチルチオアセトアミ
ド−７α−メトキシ−３−（１−メチル−１Ｈ−テトラ
ゾール−５−イル）チオメチル−３−セフェム−４−カ
ルボン酸結晶の製造方法 ７）食塩の飽和溶液となしたのちの酢酸エチルエステル
層より７−シアノメチルチオアセトアミド−７α−メト
キシ−３−（１−メチル−１Ｈ−テトラゾール−５−イ
ル）チオメチル−３−セフェム−４−カルボン酸結晶を
得るに当り、酢酸エチルエステル層に種晶を投入するこ
とによる特許請求の範囲４）、５）及び６）項の製造方
法[Claims] 1) Crystals of 7-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 2
) The crystal of claim 1) has a melting point of 150 to 152°C (decomposition).
MSO-d_■) 3.41 (3H, s), 3.48 (1
H, d, J = 17.8Hz), 3.49 (2H, s),
3.73 (1H, d, J = 17.8Hz), 3.77 (
2H, s), 3.94 (3H, s), 4.29 (2H,
ABq, J=13.4Hz), 5.12 (1H, s),
Crystal 4 according to claim 1) having characteristic absorptions of 9.56 (1H, s) and 13.8 (1H, br, s)
) 7-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid/organic basic salt was dispersed in water and ethyl acetate, and the pH was adjusted to 1.
After adjusting to 5 to 2.5 and making it into a saturated solution of common salt,
7-cyanomethylthioacetamide-7α characterized by obtaining crystals crystallized from an acetic acid ethyl ester layer
-methoxy-3-(1-methyl-1H-tetrazole-
Method for producing 5-yl)thiomethyl-3-cephem-4-carboxylic acid crystals 5) 7-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem -4-Carboxylic acid: Disperse the organic basic salt in water and ethyl acetate, and adjust the pH to 1.
．． 7-cyanomethylthioacetamide-7α, which is characterized in that the 7-cyanomethylthioacetamide-7α is adjusted to 5 to 2.5 and further made into a saturated solution of common salt, and then the acetic acid ethyl ester layer is separated and dried to obtain crystals. -methoxy-3-(1-methyl-1
Method for producing H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid crystals 6) 7-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl -3-cephem-4-carboxylic acid/organic basic salt was dispersed in water and acetic acid ethyl ester, and the pH was adjusted to 1.
．． 5 to 2.5, and further made into a saturated solution of common salt, the ethyl acetate layer is separated, methyl alcohol is added thereto, and the methyl alcohol in the dried layer is distilled off. Method for producing 7-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid crystals 7) In order to obtain 7-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid crystals from the acetic acid ethyl ester layer, The manufacturing method according to claims 4), 5) and 6) by introducing seed crystals into the layer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6928988A JPH01242588A (en) | 1988-03-25 | 1988-03-25 | Crystal of 7-cyanomethylthioacetamide-7alpha-methoxy-3-(1-methyl-1h-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6928988A JPH01242588A (en) | 1988-03-25 | 1988-03-25 | Crystal of 7-cyanomethylthioacetamide-7alpha-methoxy-3-(1-methyl-1h-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01242588A true JPH01242588A (en) | 1989-09-27 |
Family
ID=13398289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6928988A Pending JPH01242588A (en) | 1988-03-25 | 1988-03-25 | Crystal of 7-cyanomethylthioacetamide-7alpha-methoxy-3-(1-methyl-1h-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01242588A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006528609A (en) * | 2003-07-24 | 2006-12-21 | ノバルティス アクチエンゲゼルシャフト | Stable modification of tegaserod hydrogen maleate |
| CN104370942A (en) * | 2013-08-13 | 2015-02-25 | 山东信立泰药业有限公司 | Cefmetazole crystal form, preparation method thereof, and pharmaceutical composition containing cefmetazole |
-
1988
- 1988-03-25 JP JP6928988A patent/JPH01242588A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006528609A (en) * | 2003-07-24 | 2006-12-21 | ノバルティス アクチエンゲゼルシャフト | Stable modification of tegaserod hydrogen maleate |
| CN104370942A (en) * | 2013-08-13 | 2015-02-25 | 山东信立泰药业有限公司 | Cefmetazole crystal form, preparation method thereof, and pharmaceutical composition containing cefmetazole |
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