WO2001014366A1 - Procede de preparation de derives optiquement actifs de sulfoxyde - Google Patents

Procede de preparation de derives optiquement actifs de sulfoxyde Download PDF

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Publication number
WO2001014366A1
WO2001014366A1 PCT/JP2000/005682 JP0005682W WO0114366A1 WO 2001014366 A1 WO2001014366 A1 WO 2001014366A1 JP 0005682 W JP0005682 W JP 0005682W WO 0114366 A1 WO0114366 A1 WO 0114366A1
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Prior art keywords
substituent
optically active
molecular sieve
compound
group
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PCT/JP2000/005682
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English (en)
Japanese (ja)
Inventor
Mitsuru Kawada
Toru Yamano
Naohiro Taya
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Priority to AU67277/00A priority Critical patent/AU6727700A/en
Publication of WO2001014366A1 publication Critical patent/WO2001014366A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a method for producing an optically active sulfoxide derivative having an anti-ulcer action.
  • an optically active sulfoxide derivative having an anti-ulcer action for example, a method for obtaining an optically active sulfoxide compound by reacting with an oxidizing agent in an organic solvent in the presence of a chiral titanium complex and a base ( WO96 / 025355, JP-T-H10-10504290), a racemic sulfoxide compound is stereoselectively reduced using a microorganism to perform optical resolution to perform optical resolution.
  • a method for obtaining a sulfoxide compound (W ⁇ 96 / 17077) is known.
  • Tet rahedron, Vol. 43, No. 2, p. 5135, 1987 introduced methyl p-tolyl sulfide, activated molecular sieve, dichloromethane, dichloromethane, (+)-getyl tartrate, titanium ( IV) It is described to react with cumene hydroperoxide in the presence of isopropoxide and water.
  • the present inventors studied various methods for producing an optically active sulfoxide derivative, and by oxidizing the sulfide derivative in the presence of a substance having a molecular sieve action, the target optically active sulfoxide derivative was unexpectedly produced. Significantly improved yield and enantiomeric excess, making this method satisfactory on an industrial scale. For the first time, they found that it was a production method, and made extensive research based on these findings and completed the present invention.
  • ring A is a benzene ring which may have a substituent
  • R 1 is a hydrogen atom, an aralkyl group which may have a substituent, an acyl group or an acyloxy group
  • R 2 , R 3 and R 4 is a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent or an amino group which may have a substituent
  • X is a nitrogen atom or CH and Y each represent a nitrogen atom or CH
  • a salt thereof hereinafter abbreviated as compound (I)
  • each symbol is as defined above, and * indicates an asymmetric center; or a method for producing an optically active compound or a salt thereof [hereinafter abbreviated as compound (II)]; [2] X Is the nitrogen atom, the production method according to the above [1];
  • the present invention relates to the production method described in the above [1], further comprising performing an oxidation reaction in the presence of a base.
  • Compound (II) has a sulfur atom serving as an asymmetric center, and the following two types of optical isomers exist.
  • examples of the “substituent” of the “optionally substituted benzene ring” represented by ring A include a halogen atom, cyano, nitro, and an optionally substituted alkyl. , Hydroxy, optionally substituted alkoxy, aryl, aryloxy, carboxy, acyl, acyloxy, 5- to 10-membered heterocyclic group and the like.
  • each substituent may be the same or different.
  • halogen atom, alkyl which may have a substituent alkoxy which may have a substituent, etc. Is preferred.
  • halogen atom examples include fluorine, chlorine, bromine and the like. Of these, fluorine is preferred.
  • alkyl of the “alkyl optionally having a substituent”
  • alkyl e.g., methyl, Echiru, propyl, isopropyl, heptyl, isobutyl, sec- butyl, t er t-butylpentyl , Hexyl, heptyl and the like).
  • Examples of the “substituent” of the “alkyl which may have a substituent” include a halogen atom, hydroxy, methoxy- 6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), ⁇ alkoxy-carbonyl ( Examples include 1 to 3 methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) and carbamoyl. When the number of substituents is two or more, each substituent may be the same or different.
  • alkoxy of the “alkoxy optionally having a substituent”
  • alkoxy eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, etc.
  • substituted of the “alkoxy optionally having a substituent”
  • the same number as the “substituent” of the above “alkyl optionally having a substituent” can be mentioned. .
  • Ariru for example C 6 _ 1 4 Ariru (e.g., phenyl, 1 - naphthyl, 2-naphthyl, Bifue two Lil, 2-anthryl etc.) and the like.
  • Riruokishi for example C 6 _ 1 4 7 Riruokishi (e.g., Fueniruokishi, 1 one Nafuchiruokishi, 2 Nafuchiruokishi etc.) and the like.
  • acyl examples include formyl, alkylcarbonyl, alkoxycarbonyl, potassium rubamoyl, alkyl rubamoyl, alkylsulfinyl, alkylsulfonyl and the like.
  • alkylcarbonyl examples include alkyl monopropionyl (eg, acetyl, propionyl, etc.).
  • alkoxycarbonyl includes, for example, alkoxy-carboxy (Eg, methoxycarbonyl, ethoxycarbonyl, propoxyl-ponyl, butoxycarbonyl, etc.).
  • alkyl rubamoyl examples include N—C ⁇ e alkyl rubamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), N, N-dialkyl-rubumbamoyl (eg, N, N-dimethylcarbamoyl, N, N-ethylcarbamoyl, etc.).
  • alkylsulfinyl examples include alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl and the like).
  • alkylsulfonyl examples include C ⁇ -alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, etc.).
  • acylsoxy examples include alkylcarbonyloxy, alkoxycarbonyloxy, rubamoyloxy, alkyl rubamoyloxy, alkylsulfinyloxy, alkylsulfonyloxy and the like.
  • alkylcarbonyloxy includes: 6- alkyl monophenyloxy (eg, acetyloxy, propionyloxy, etc.) and the like.
  • alkoxycarbonyl O alkoxy for example, C -! 6 alkoxy
  • Power Ruponiruokishi eg methoxycarbonyl O alkoxy, ethoxycarbonyl two Ruoki shea, propoxycarbonyl O alkoxy, butoxycarbonyl O alkoxy, etc.
  • alkyl rubamoyloxy examples include alkyl rubamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.).
  • alkylsulfinyloxy examples include (for example: ( 7 ) alkylsulfinyloxy (eg, methylsulfinyloxy, ethylsulfinyloxy, propylsulfinyloxy, isopropylsulfinyloxy, etc.).
  • alkylsulfonyloxy includes, for example, (: trialkylsulfonyloxy (eg, methylsulfonyloxy, ethylsulfonyloxy, propyl Rusulfonyloxy, isopropylsulfonyloxy, etc.).
  • Examples of the “5- to 10-membered heterocyclic group” include, for example, 5- to 10-membered heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one or more (eg, 1 to 3) atoms other than carbon atoms.
  • a 10-membered (preferably 5- or 6-membered) heterocyclic group is mentioned, and specific examples thereof include 2- or 3-phenyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, Or 3-pyrrolyl, 21,3-, 4_, 5 or 8_quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1,2-, or 3-indolyl.
  • a 5- or 6-membered heterocyclic group such as 1,2-, or 3-pyrrolyl is preferred.
  • Ring A preferably has one or two substituents selected from a halogen atom, an optionally halogenated — 4 alkyl, an optionally halogenated alkoxy and a 5- or 6-membered heterocyclic group. Is a good benzene ring.
  • each symbol is as defined above, is preferably a group represented by the formula:
  • R 5 is a hydrogen atom, optionally halogenated — 4 alkyl, optionally halogenated alkoxy or a 5- or 6-membered heterocyclic group, and R 1 has the same meaning as defined above. It is a group represented. R 5 is preferably (1) a hydrogen atom,
  • alkoxy which may be halogenated; or (3) 1 _, 2- or 3-pyrrolyl.
  • R 1 in the "optionally substituted Ararukiru group” as “Ararukiru group”, for example, C 7 _ 1 6 Ararukiru (e.g., benzyl, phenethyl, etc. of . Aryl- 6 alkyl, etc.).
  • Ararukiru group for example, C 7 _ 1 6 Ararukiru (e.g., benzyl, phenethyl, etc. of . Aryl- 6 alkyl, etc.).
  • the “substituent” in the “optionally substituted aralkyl group” include 1 to 4 same groups as the “substituent” in the above “optionally substituted alkyl”. It is possible. When the number of substituents is two or more, each substituent may be the same or different.
  • R 1 is preferably a hydrogen atom.
  • the ⁇ alkyl group optionally having substituent (s) '' for R 2 , R 3 or R 4 the ⁇ alkyl group optionally having substituent (s) ''"Kill".
  • Examples of the “optionally substituted amino group” represented by R 2 , R 3 or R 4 include, for example, amino, mono-Ci- 6 alkylamino (eg, methylamino, ethylamino, etc.), monoamine ⁇ 6 - 14 Ariruamino (eg, Fueniruamino, 1 over Na Fuchiruamino, 2 Nafuchiruamino etc.), di - flicking 6 alkylamino (e.g., di-Mechiruamino, Jechiruamino etc.), di-one C 6 - 14 Ariruamino (eg, diphenyl Eniruamino etc. ) And the like.
  • amino, mono-Ci- 6 alkylamino eg, methylamino, ethylamino, etc.
  • monoamine ⁇ 6 - 14 Ariruamino eg, Fueniruamino, 1 over Na Fuchirua
  • R 2 is preferably, C ⁇ e alkyl, (: Bok 6 alkoxy, alkoxy one
  • R 3 is preferably a hydrogen atom, 6 alkoxy mono ( ⁇ _ 6 alkoxy or optionally halogenated alkoxy. More preferably, it is optionally halogenated alkoxy.
  • R 4 is preferably a hydrogen atom or a ( ⁇ _ 6 alkyl. More preferably a hydrogen atom.
  • X is preferably a nitrogen atom.
  • Y is preferably a nitrogen atom.
  • compound (I) examples include 2-[[[3-Methyl-4-1 (2,2,2-trifluoroethoxy) —2-pyridinyl] methyl] thio] -1H-benzimidazole,
  • Compound (I) is preferably a compound represented by the formula
  • a pharmaceutically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, a salt with a basic amino acid and the like. No.
  • the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and ammonium salt.
  • salts with organic bases include, for example, trimethylamine, Salts with rumamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like can be mentioned.
  • salts with basic amino acids include salts with arginine, lysine, orditin and the like.
  • Compound (I) can be produced by a method known per se, for example, 2-[[[3-Methyl-14- (2,2,2-trifluoroethoxy) -12-pyridinyl] methyl] thio] — In the case of 1 H-benzimidazole or a salt thereof, the method described in JP-A-61-50978, USP 4,628,098, JP-A-10-195608, WO 98/21201, or the like; It is manufactured by a method according to The production method of the present invention is a method of obtaining compound (II) by oxidizing compound (I) in the presence of a substance having a molecular sieve action and an asymmetric induction catalyst.
  • “substance having a molecular sieve action” examples include zeolite having moderately sized pores, aluminum phosphate, an inorganic ion-exchanged montmorillonite interlayer compound, and activated carbon. Among them, zeolite having moderately sized pores is preferable because it has an action of adsorbing a polar compound, a catalyst action, an ion exchange action, and the like.
  • a specific example is molecular sieve (trade name). .
  • the molecular sieve is commonly used as a dehydrating agent.
  • the molecular sieve 3 A K 9 Na 3 [(A 10 2 ) 12 (S i 0 2 ) 12 ] ⁇ 27H 2 O
  • the molecular sieve 4 A Na 12 [(A 10 2 ) 12 (S i 0 2 ) 12 ]
  • molecular sieve 13 X Na 86 [(A 10 2) 86 (S I_ ⁇ 2) 106] ⁇ ⁇ 2 ⁇
  • molecular sieve 3A molecular sieve 4A.
  • the molecular sieve is activated before use (Firing) or the purchased product may be used as it is.
  • the amount of the “substance having a molecular sieve action” to be used is about 0.001 to 20 times, preferably about 0.1 to 5 times the weight of compound (I).
  • asymmetric induction catalyst examples include a complex of an optically active diol and a titanium (IV) alkoxide.
  • optically active diol examples include an alkyl diol and an aromatic diol.
  • alkyl diol includes, for example, (+) — or (I) dimethyl monotartrate, (+) — or (I) —getyl tartrate, (+) — or (I) optically active tartaric acid ester such as diisopropyl tartrate And optically active diene diols such as (R, R)-or (S, S) -diphenylethane 1,2-diol.
  • aromatic diols include, for example, optically active phenols such as (+)-or (1-)-binaphthol.
  • (+)-or (-)-getyl tartrate (+)-or (-) diisopropyl monotartrate, and the like.
  • the amount of the “optically active diol” to be used is about 0.001 to 4 molar equivalents, preferably about 0.06 to 3.0 molar equivalents, relative to compound (I).
  • titanium (IV) alkoxide examples include titanium (IV) isopropoxide, titanium (IV) ethoxide, titanium (IV) methoxide and the like. Preference is given to titanium (IV) isopropoxide.
  • the amount of the "titanium (IV) alkoxide" to be used is about 0.001 to 5 molar equivalents, preferably about 0.03 to 2 molar equivalents, relative to compound (I).
  • the oxidation reaction may be carried out using an oxidizing agent.
  • oxidizing agent include peroxides (eg, hydrogen peroxide, tert-butyl hydroperoxide, cumene peroxide, etc.). No. Preferably, tert-butyl hydroperoxide and cumene hydroperoxide, more preferably cumene hydroperoxide.
  • the oxidizing agent is used in an amount of about 0.5 to 5 molar equivalents relative to compound (I). Preferably it is about 1.0 to 2.0 molar equivalents.
  • the oxidation reaction is preferably performed in the presence of water.
  • the “water” may be contained in a crystal of the compound (I), in a reaction reagent (eg, an optically active diol), in a solvent, or may be added as water.
  • a reaction reagent eg, an optically active diol
  • the amount of the "water” to be used is about 0.1-3.0 molar equivalents, preferably about 0.5-2.5 molar equivalents, relative to compound (I).
  • the oxidation reaction is preferably performed in an organic solvent.
  • organic solvent examples include alcohols such as methanol, ethanol, propanol and isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as getyl ether, diisopropyl ether, butyl methyl ether, dioxane and tetrahydrofuran.
  • alcohols such as methanol, ethanol, propanol and isopropanol
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as getyl ether, diisopropyl ether, butyl methyl ether, dioxane and tetrahydrofuran.
  • Esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl isobutyl ketone, halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride and carbon tetrachloride, and N, N-dimethylformamide , Dimethyl sulfoxide, acetic acid and the like.
  • Preferred are toluene and ethyl acetate.
  • a base may be added as necessary.
  • the base for example, an inorganic base, an organic base, a basic amino acid and the like can be mentioned.
  • the inorganic base include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal hydrides such as sodium hydride and potassium hydride. Is mentioned.
  • organic base examples include alkali metal alkoxides such as sodium methoxide and sodium methoxide; alkali metal carboxylate salts such as sodium acetate; piperidine, piperazine, pyrrolidine, morpholine, getylamine, diisopropylethyla
  • alkali metal alkoxides such as sodium methoxide and sodium methoxide
  • alkali metal carboxylate salts such as sodium acetate
  • amines such as mines and pyridines such as pyridine and dimethylaminopyridine.
  • they are amines, and specifically, getylamine and diisopropylethylamine.
  • the amount of the “base” to be used is about 0.1 to 10 molar equivalents relative to compound (I). Preferably it is about 0.5-3 molar equivalents.
  • the compound (I) is reacted with an oxidizing agent in the presence of a substance having a molecular sieve action, an asymmetric induction catalyst, water, an organic solvent and a base.
  • the steps of the reaction include, for example,
  • the reaction solution it is preferable to stir the reaction solution while heating it after adding the titanium (IV) alkoxide.
  • the heating temperature is usually about 20 to 100 ° C, preferably 40 to 70 ° C.
  • the stirring time is usually about 0.1 to 12 hours, preferably about 0.5 to 3 hours.
  • the reaction is cooled to about 120 to 100 ° C, preferably to 10 to 50 ° C.
  • the mixture is stirred for about 0.5 to 50 hours, preferably for about 1 to 24 hours.
  • the compound ( ⁇ ) thus obtained may be isolated by a separation and purification means known per se, for example, concentration, solvent extraction, crystallization, phase transfer, chromatography and the like.
  • the “chromatography” includes a basic group (eg, an aminopropyl group, etc.) Chromatography using silica gel chemically modified with is preferred.
  • D aisoge 1 I R_ 60- APS trade name, manufactured by Daiso Co., Ltd.
  • YFLC gel NH 2 (Amino) (trade name, manufactured by Yamazen Corporation), etc. can be mentioned.
  • Compound (II) has excellent anti-ulcer action, gastric acid secretion inhibitory action, mucosal protective action, lycopactor pylori action on piles, and has low toxicity, and is therefore useful as a pharmaceutical.
  • peptic ulcers eg, gastric ulcers, duodenal ulcers, anastomotic ulcers
  • mammals eg, humans, monkeys, sheep, wedges, pomas, dogs, dogs, cats, egrets, rats, mice, etc.
  • Zollinger-'Zollinger-Ellison syndrome, etc. gastritis
  • reflux esophagitis NUD (Non Ulcer Dyspepsia)
  • gastric cancer gastric cancer, treatment and prevention of gastric MALT lymphoma, etc.
  • Nuclear magnetic resonance spectrum was measured by JMTC 0400Z54 (400MHz) using tetramethylsilane as an internal standard, and the ⁇ value was shown in ppm.
  • IR infrared absorption spectrum
  • Enantiomeric excess (% e e) was measured by high performance liquid chromatography using an optically active column.
  • reaction solution was allowed to cool to room temperature, and diisopropylethylamine (1. Oml, 6. Ommol) and cumene hydroperoxide (0.9 ml, 6. Ommol) were sequentially added. Stir for 3 hours. The resulting reaction solution was analyzed by high performance liquid chromatography to confirm the title compound (yield 83%, enantiomeric excess 96% ee).
  • an optically active sulfoxide derivative eg, compound (II)
  • compound (II) can be efficiently produced on an industrial large-scale by an extremely high enantiomeric excess, a high yield, and a simple method. it can.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur un procédé de préparation facile de composés optiquement actifs de formule générale (II) ou de leurs sels, en très fort excès énantiomérique et avec un très fort rendement, consistant à oxyder des composés de formule générale (I) ou leurs sels en présence à la fois d'une substance servant de tamis moléculaire et d'un catalyseur à induction asymétrique. Dans les formules: A est un cycle benzène facultativement substitué; R1 est H ou analogue; R?2, R3, et R4¿ sont chacun H, alkyle facultativement substitué, alkoxy facultativement substitué, ou analogue; X est N ou CH; et * représente un centre asymétrique.
PCT/JP2000/005682 1999-08-25 2000-08-24 Procede de preparation de derives optiquement actifs de sulfoxyde Ceased WO2001014366A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU67277/00A AU6727700A (en) 1999-08-25 2000-08-24 Process for the preparation of optically active sulfoxide derivatives

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JP23847199 1999-08-25
JP11/238471 1999-08-25

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WO2001014366A1 true WO2001014366A1 (fr) 2001-03-01

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083473A1 (fr) * 2000-04-28 2001-11-08 Takeda Chemical Industries, Ltd. Procede de production d'un derive de sulfoxide optiquement actif
WO2003082854A1 (fr) * 2002-03-29 2003-10-09 Zeria Pharmaceutical Co., Ltd. Derives 1-n-aminobenzimidazole
US7271182B2 (en) 2000-08-04 2007-09-18 Takeda Pharmaceutical Company Limited Salts of benzimidazole compound and use thereof
US7285668B2 (en) 2000-12-01 2007-10-23 Takeda Pharmaceutical Company Limited Process for the crystallization of (R)- or (S)-lansoprazole
CN104840831A (zh) * 2015-05-21 2015-08-19 李玉芬 一种治疗小儿食积的中药制剂及制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996002535A1 (fr) * 1994-07-15 1996-02-01 Astra Aktiebolag Procede de synthese de sulfoxydes substitues
WO1996017076A1 (fr) * 1994-11-28 1996-06-06 Astra Aktiebolag Preparation enantioselective de sulfoxydes actifs sur le plan pharmaceutique obtenue par bio-oxydation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996002535A1 (fr) * 1994-07-15 1996-02-01 Astra Aktiebolag Procede de synthese de sulfoxydes substitues
WO1996017076A1 (fr) * 1994-11-28 1996-06-06 Astra Aktiebolag Preparation enantioselective de sulfoxydes actifs sur le plan pharmaceutique obtenue par bio-oxydation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083473A1 (fr) * 2000-04-28 2001-11-08 Takeda Chemical Industries, Ltd. Procede de production d'un derive de sulfoxide optiquement actif
US6982275B2 (en) 2000-04-28 2006-01-03 Takeda Pharmaceutical Company Limited Process for producing optically active sulfoxide derivative
US7271182B2 (en) 2000-08-04 2007-09-18 Takeda Pharmaceutical Company Limited Salts of benzimidazole compound and use thereof
US8809542B2 (en) 2000-08-04 2014-08-19 Takeda Pharmaceutical Company Limited Salts of benzimidazole compound and use thereof
US7285668B2 (en) 2000-12-01 2007-10-23 Takeda Pharmaceutical Company Limited Process for the crystallization of (R)- or (S)-lansoprazole
WO2003082854A1 (fr) * 2002-03-29 2003-10-09 Zeria Pharmaceutical Co., Ltd. Derives 1-n-aminobenzimidazole
CN104840831A (zh) * 2015-05-21 2015-08-19 李玉芬 一种治疗小儿食积的中药制剂及制备方法

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