WO2010015107A1 - Synthèse stéréosélective de valiolamine - Google Patents

Synthèse stéréosélective de valiolamine Download PDF

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WO2010015107A1
WO2010015107A1 PCT/CN2008/001436 CN2008001436W WO2010015107A1 WO 2010015107 A1 WO2010015107 A1 WO 2010015107A1 CN 2008001436 W CN2008001436 W CN 2008001436W WO 2010015107 A1 WO2010015107 A1 WO 2010015107A1
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compound
formula
group
reaction
preparing
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PCT/CN2008/001436
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English (en)
Chinese (zh)
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刘立刚
周华荣
周德军
池国友
洪松
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无锡药兴医药科技有限公司
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Priority to CN2008801290786A priority Critical patent/CN102105455B/zh
Priority to KR1020117002735A priority patent/KR101540435B1/ko
Priority to JP2011521422A priority patent/JP5546539B2/ja
Priority to PCT/CN2008/001436 priority patent/WO2010015107A1/fr
Publication of WO2010015107A1 publication Critical patent/WO2010015107A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
    • C07D265/22—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system

Definitions

  • the invention relates to a pharmaceutical intermediate compound and a preparation method thereof, in particular to a well-known alkanolamine
  • Valiolamine (1) chemical name is (IS) - (1 (hydroxy), 2,4,5/1,3) - 5 -amino-1 -carbon-hydroxyl-yl - 1 ,2 3,4-cyclohexanetetraol has a strong ⁇ -D-glucoside inhibitory activity (J. Antibiot., 1984, 37, 1301 - 1307).
  • the first step is the direct production of oxytocin (J. Antibiot., 1984, 37, 1301 - 1307) using the microorganism streptomyces hygroscopicus subsp. Limoneus IFO 12703; later found that validamycin A Using biodegradation, valienamine and validamine can be produced (patent JP57054593, JP58152496, JP62181793, WO2005098014), WO2006107134, WO2004000782, WO2005151967, which can also be prepared from acarbose and its derivatives. The method of jingmen's mesamine can be further converted into jingtanolamine by wells (JP57179174, CN1683320, JP58046044).
  • Reaction Scheme 2 is a method for preparing Jinggang mold from Jinggangmycin (3) disclosed in Japanese Patent No. JP57179174 Road map of alcohol amines (1)
  • the method first acetylates the oxynopamine (3) to form the compound (7), and then selectively epoxidizes to form the compound (8), and finally opens the ring and removes the acetyl group to form the melamine group (1).
  • Both of the reaction routes 2 and 3 are based on the biofermentation of the genus megendronamine (3) as a raw material, and since the biofermentation produces the genus melamine, which is limited by the specific strain, it is not widely used.
  • the post-treatment of the fermentation broth is cumbersome and the yield is low. A large amount of waste liquid needs to be disposed of environmentally, and the industrialization advantage is insufficient.
  • the reaction route 4 is a route for preparing a oxytocin (1) from a porphyrin (9) by a multi-step reaction as disclosed in Japanese Patent No. 58046044:
  • the synthetic route shows that the 13-step chemical reaction from the well-formed mesomycin synthesis well has a 9-step chemical reaction, and the route is long, resulting in lower total yield, higher cost, and poorer competitiveness of the product after scale production. The value is not high.
  • the method based on chemical total synthesis can be mass-produced in a short time, the conditions are easy to control, the yield is high, the cost is low, and the industrialization advantage is obvious.
  • the synthesis method was earlier found in the literature J. Org. Chem. 1992, 57, 3651-3658 to condense the compound (12) with hydroxylamine to form hydrazine (13), and then hydrogenate it into a tetrabenzyl group containing an anomer at the 5-position.
  • the crude product of the base wells (14'), and then the benzyl group is formed to form the oxynolamine (1) and the anomer of the amino group (15).
  • the content of the isomer (15) is about 6%.
  • careful column chromatography separation is required, so industrial mass production will encounter obstacles.
  • WO2005/049547 and WO2005/092834 disclose a process for synthesizing a well-known alkanolamine (1) by reductive amination of compound (12) with ammonium acetate to form a crude tetrabenzylglycosideamine (14'). After the benzyl group is removed, the oxytocinamine (1) is formed, as shown in Reaction Scheme 7.
  • the tetrabenzyl guanamine alcohol (14') obtained by this method has a purity of only 88%. After further debenzylation, a pure jingdamycin amine (1) must be obtained by column chromatography, and the purity can reach 98.7%. .
  • vogelide can be prepared by a one-step reaction, the quality of the oxytocin can directly affect the quality of the final product voglibose, and prepare high-purity voglibose.
  • Sugar requires high purity jingluolamine.
  • the biosynthesis-based method has the disadvantage that the raw materials are not easily obtained, thus limiting the popularization and use of the method; in addition, the raw material preparation process requires a fermentation process, and the fermentation volume is large, and the yield is large. Low, unstable strains, complicated and complicated separation, large amount of labor, and polluted environment.
  • the chemical synthesis method has the advantages of short cycle, easy mass production, low cost, relatively clean, safe and easy to control.
  • the present invention provides an intermediate compound for preparing high-purity Jinggangolamine (1), which has the following structural formula,
  • R is a hydroxy protecting group such as a benzoyl group, a benzyl group, a tert-butyldimethylsilyl group or the like, and is preferably a benzyl group.
  • the compound when the R group is a benzyl group, the compound is a tetrabenzyl succinylamine-1,5-carbamate compound of the formula (2 ⁇ ), and its chemical name is (IS, 5S, 6S, 7R, 8S) 6,7,8-Tris-O-benzyl- 1 -benzyloxyindolyl-3-oxy-2-soxa- 4 -azabicyclo[3.3.1]nonane.
  • the present invention further provides a process for the preparation of a compound of the formula (21), wherein a compound of the formula (14) containing an isomer is subjected to carbonylation to form a bicyclic compound of the formula (21), which is well-indolescent amine-1,5-aminononanoic acid. Ester derivatives,
  • the preparation method further comprises recrystallization of the formula (21) to obtain a crystalline product thereof.
  • the compound of the formula (2 ⁇ ) is further purified by recrystallization to obtain a crystal of the compound of the formula (2 ⁇ ).
  • the crystals had characteristic absorption peaks at about 173.8 °C in differential scanning calorimetry.
  • the crystals were analyzed in infrared spectroscopy with an infrared spectrum as shown in FIG.
  • the compound has a melting point of from 168 to 172 °C.
  • a further object of the present invention is to provide a process for producing a high-purity porphyrin amine (1) using the compound of the formula (21), which is obtained by hydrolyzing a compound of the formula (21) and/or its crystal to form a compound of the formula (22) And then de-R groups to form high-purity scutellarin (1); or the compound of formula (21) and/or its crystals are removed from the R group to form a compound of formula (6), which is then hydrolyzed to form oxytocin (1) ;
  • the reaction route is as follows:
  • the R group is a hydroxy protecting group such as a benzoyl group, a benzyl group, a tert-butyldimethylsilyl group, preferably a benzyl group.
  • the present invention obtains a high-purity wellfareolamine (1) by stereoselective synthesis of a precursor compound (21) of a well-known amphotericinamine, followed by removal of the R group and hydrolysis, or hydrolysis and removal of the R group.
  • High-purity voglibose (2) can be prepared by using the oxytocin of the present invention. Therefore, the present invention also provides a method for preparing voglibose, and the reaction route is as follows:
  • the isomer-containing tetrabenzyl succinylamine (14') is subjected to carbonylation to form a bicyclic compound (21'), ie, tetrabenzyl succinylamine-1,5-carbamate.
  • the cyclic compound (21') can be hydrolyzed and opened to form tetrabenzyl-glycolamine (22'), and then the benzyl group is removed to form high-purity Jinggangmycin.
  • Amine (1) may also be debenzylated from tetrabenzyl sphingosineamine-1, 5-amino decanoate (21') to form compound (6), and then hydrolyzed to form oxytocin (1).
  • the route is as follows:
  • the key to the invention is the passage of the key intermediate (21) in the preparation of the oxytocinamine (1).
  • a bicyclic compound of the formula (21) By forming a bicyclic compound of the formula (21), the hydroxyl group of the S configuration at the 1-position and the amino group at the 5-position of the S configuration are linked through a carbonyl group, and the resulting bicyclic compound (21) is a very stable crystal. Very easy to separate and purify; and the amino group at the 5-position R configuration cannot form a cyclic compound with the 1-position S-configuration hydroxyl group through the condensed group, so that the 5-position amino group is R during the crystallization purification of the compound of the formula (21).
  • the modified anomer derivative and other impurities are all removed to achieve purification purposes, and a highly pure cyclic compound (21) is obtained.
  • the present invention achieves the purpose of stereoselective synthesis of high-purity Jinggangolamine precursor by reacting a compound of the formula (14) with a corresponding carbonylating reagent to form a high-purity bicyclic compound (21) crystal;
  • a compound of the formula (14) with a corresponding carbonylating reagent to form a high-purity bicyclic compound (21) crystal;
  • high purity jingtanolamine (1) can be prepared.
  • the stilbenolamine impurity formed in the reaction is small, and in particular, the 5-amino amino isomer (15) is not contained.
  • the present invention is a reaction of a compound of the formula (14) which may contain an isomer with a carbonylating agent such as phosgene, trichlorodecyl chloroformate or bis(trichlorodecyl) carbonate.
  • a carbonylating agent such as phosgene, trichlorodecyl chloroformate or bis(trichlorodecyl) carbonate.
  • This reaction is stereoselective, and the resulting bicyclic compound (21) is easily crystallized and easily purified, and other impurities such as an anomer and its derivative can be removed, so it is this height.
  • Stereoselectivity allows the prepared jinggangylamine precursor to be of high purity.
  • Compounds of formula (14) which may contain isomers or are impure may be prepared by reference to published literature methods, such as by reduction of the corresponding azide (20) (JP2003146957); or by reduction of compound (12) Amination (WO2005/049547, WO2005/092834); or a method of reduction after deuteration of compound (12) (J. Org. Chem. 1992, 57, 3651-3658); but generated by any method Compounds of formula (14) are not necessarily subjected to other forms of purification, such as The method of column chromatography is directly applicable to the practice of the present invention.
  • the prepared impure compound (14), for example, the compound (14') is dissolved in an aprotic polar solvent or a non-polar solvent, and the aprotic polar solvent may be dichlorosilane or trichloromethane. 1,2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, diethyl ether, diisopropyl ether, diethylene glycol dioxime ether, ethyl acetate, acetone, 2-butanone, cyclohexanone, two One or a mixture of sulfoxide, etc.; the non-polar solvent includes carbon tetrachloride, cyclohexane, n-hexane; then the base is added, which may be an organic or inorganic base, and the aryl/base may be triethylamine.
  • the aprotic polar solvent may be dichlorosilane or trichloromethane. 1,2-dich
  • inorganic bases are potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium carbonate.
  • Aprotic polar or non-polar solvents are added dropwise to the carbonylation reagent at temperatures ranging from -20 to 50 °C.
  • the corresponding carbonylation reagent may be phosgene, trichlorodecyl chloroantimonate or bis(trichlorodecyl) carbonate, preferably bis(trichloromethyl) carbonate, because it is a solid and convenient for weighing.
  • aprotic polar solvent can be dichloromethane, chloroform, 1,2 dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, diethylene a mixture of one or more of an alcohol dioxime ether, ethyl acetate, acetone, 2-butanone, cyclohexanone, disulfoxide, and the like;
  • the non-polar solvent includes carbon tetrachloride, cyclohexane, n-hexane;
  • the non-shield polar solvent is further preferably dichloromethane, diisopropyl ether or tetrahydrofuran; and the carbamoylating agent is added, and the reaction is continued under the same conditions for 1 to 24 hours; preferably 8 to 10 hours; The reaction solution was treated in a conventional manner.
  • the corresponding organic solvent may be aprotic such as trichloromethane, dichlorodecane, ethyl acetate, diethyl ether, diisopropyl ether, butanone or cyclohexanone.
  • the polar solvent is then washed successively, washed with 2N hydrochloric acid, washed with 5% aqueous sodium carbonate solution, washed with saturated brine, dried with anhydrous sodium sulfate. After drying, the solvent for extraction is recovered, and the residual solid is a cyclized product ( 21') of the crude.
  • the crude cyclized product can be efficiently purified by recrystallization to obtain white crystals with a purity of more than 99%.
  • the solvent for recrystallization may be a C1-C5 lower aliphatic alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol; or an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, 4 - dioxane; or an ester such as ethyl acetate or methyl acetate; or a ketone such as acetone, butanone or cyclohexanone. It may be one of the above solvents, or a mixed solvent of several solvents.
  • the obtained product (21') has white needle crystals with a melting point of 168 - fire and its structure undergoes nuclear magnetic resonance spectroscopy, carbon language, infrared spectroscopy, mass spectrometry, elemental analysis, specific rotation, differential scanning calorimetry, etc. Structural confirmation was carried out.
  • the characteristics of the crystal can be characterized by an X-ray diffraction pattern of the powder. Specifically, at 2 ⁇ , it is 4.70 soil 0.2. 6,52 ⁇ 0.2. , 9.40 ⁇ 0.2. , 18.40 ⁇ 0.2. , 24.02 ⁇ 0.2. And 25.36 ⁇ 0, 2. There is an X-ray diffraction peak, and it is further possible to use 2 ⁇ for 8.38 ⁇ 0.2. , 13.06 ⁇ 0.2. 15.64 ⁇ 0.2 ⁇ , 16.14 ⁇ 0.2 ⁇ , 16 ⁇ 82 ⁇ 0.2 ⁇ , 20.60 ⁇ 0.2°, 22.64 ⁇ 0 ⁇ 2 ⁇ , 23 ⁇ 24 ⁇ 0.2°, 27.12 ⁇ 0.2. Characterized by X-ray diffraction peaks.
  • the purified product crystal is subjected to alkaline hydrolysis to obtain a compound of the formula (22), for example, the crystal of the compound (21') is hydrolyzed in an alkaline medium, and the alkali in the alkaline medium may be an inorganic base such as sodium hydroxide or hydrogen.
  • the solvent may be an aqueous solution containing CI-C5 short-chain fatty alcohol such as decyl alcohol, ethanol, isopropanol, the concentration may be 10 % - 90 % ( v / v ) , the medium used may also be acetone, tetrahydrofuran, 1,4 - dioxane, DMF (N, N - dimercaptoamide), DME (N, N - dimethyl
  • An aqueous solution of acetamide) or DMSO may be in a concentration of 10% to 90% (v/v); preferably an aqueous solution of a CI-C5 short-chain fatty alcohol, more preferably ethanol or isopropanol, preferably at a concentration of 75-80% ( Water: Ethanol) (v/v).
  • the reaction temperature is from room temperature to reflux temperature, and the reaction time is from 2 to 48 hours, preferably 24 hours.
  • the end point of the end of the reaction can be traced by thin layer chromatography (TLC), and the disappearance of the starting material is detected as the end point.
  • TLC thin layer chromatography
  • the reaction solution was treated in the usual manner. If the reaction solution is poured into water and extracted with an organic solvent, the corresponding organic solvent may be trichloromethane, dichloromethane, toluene, ethyl acetate, diethyl ether, diisopropyl ether, butanone, cyclohexanone, etc.
  • the reaction solution may also be concentrated first, and then the residue is extracted with an organic solvent and a water layer.
  • the corresponding organic solvent may be trichloromethane, dichloromethane, toluene, diethyl ether, diisopropyl ether, 1,2-dichloroethane.
  • the solvent such as an alkane is preferably a benzene or a chloroform; the extract is washed with water, washed with 2N hydrochloric acid, washed with a 5% aqueous solution of sodium carbonate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent for extraction is recovered.
  • the colorless viscous oil is a compound of the formula (22') which can be used directly in the next step.
  • the compound of the formula (22') can be prepared by a debenzylation reaction, and the specific method can utilize the method of liquid ammonia/metal lithium debenzylation (Reference is Synthesis, 1999, (4), 571-573). It is also possible to use three dilutions of boron debenzylation (reference is J. Am. Chem. Soc, 1999, 121, 6973-6983), or a debenzylization method of 4 bar/hydrogen (reference WO2005/049547; J Am. Chem. Soc, 1999, 121, 6973 - 6983), it is also possible to use palladium black/decanoic acid (Reference J. Org. Chem. 1992, 57, 3651-3658) to facilitate removal Benzyl, obtaining melamine.
  • the oxytocin amine (1) prepared by the method provided by the invention crystallizes in methanol and is white crystal.
  • the structure is confirmed by nuclear magnetic resonance spectroscopy, carbon language, infrared spectroscopy, elemental analysis, mass spectrometry, specific optical rotation, and high efficiency.
  • the purity of the liquid phase color detection is >99%, and in particular, the purity can reach 99.5% or more.
  • the sphingolipidamine (1) can also be prepared by removing the R group, such as a benzyl group, etc., by the compound (21) provided by the present invention, and then preparing the hydrolysis route (as shown in the reaction scheme 8), for example, removing the benzyl group.
  • the method can utilize the method of debenzylation of liquid lithium metal (Reference, Synthesis, 1999, (4), 571-573), or debenzylation with boron tribromide (reference is J. Am. Chem. Soc, 1999, 121, 6973 - 6983 ), debenzylation of palladium / hydrogen can also be used (reference WO2005/049547; J. Am. Chem.
  • the above-mentioned well-killed alkanolamine obtained by the method of first debenzylation and re-hydrolysis is consistent with the well-behavnamine obtained by first hydrolysis and then debenzylation, and the purity is more than 99% by HPLC detection, and in particular, it can reach 99.5%. the above.
  • the high-purity treatment of voglibose can be further prepared by using the high-purity Jinggangolamine prepared by the invention, and the obtained voglibose purity can reach 99.5% or more by HPLC, and in particular, can be achieved. More than 99.8%.
  • 1 to 3 are powder X-ray diffraction patterns of a compound of the formula (2 ⁇ );
  • Figure 4 is a crystalline infrared image of the compound of formula (2 ⁇ );
  • Figure 5 is a nuclear magnetic resonance spectrum of a compound of the formula (2 ⁇ );
  • Figure 6 is a differential scanning calorimetry diagram of the crystal of the compound of formula (21 '). detailed description
  • the elemental analyzer is a vario EL element analyzer from ELEMENTAR.
  • the equipment used for powder X-ray diffraction is D/max-rC type of Nippon Science and Technology Co., Ltd.
  • Divergence slits 1., receiving slits (receiving slit 0.15mm), scattering degree ( Scatter slit 1°)
  • the infrared light meter is Bruker EQUINOX55, which is determined by potassium bromide tableting
  • the crude product was recrystallized from 300 ml of n-propanol to give about 19 g of white needle crystals, mp.
  • the HPLC purity was 99.6 %.
  • the structure confirmation data is the same as in Embodiment 2.
  • the powder X-ray diffraction pattern is shown in Figure 3, and the relevant data is shown in Table 3.
  • the elution stream was concentrated under reduced pressure, and the residue was refluxed with 600 ml of anhydrous ethanol for 30 minutes.
  • the activated carbon was added to 0.3 g of the activated carbon, refluxed for 15 minutes, filtered, and the filtrate was cooled to room temperature, and the resulting white powder was filtered, and vacuum was applied at 40 ° C. After drying for 12 hours, 2.8 g of voglibose powder crystals were obtained, mp: 164.3-165.8 ° C; HPLC purity was 99.9%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention porte sur un composé intermédiaire pour la fabrication de valiolamine et sur un procédé pour la synthèse stéréosélective de valiolamine. Le composé intermédiaire possède la structure chimique représentée par la formule (21). Ledit procédé comprend la carbonylation du composé représenté par la formule (14) pour produire le composé représenté par la formule (21), puis l'élimination du groupe R et/ou l'hydrolyse du composé représenté par la formule (21) pour obtenir de la valiolamine. La valiolamine obtenue a une pureté supérieure ou égale à 99 %. La valiolamine hautement purifiée fabriquée par un procédé de l'invention peut être utilisée pour la fabrication de voglibose hautement purifié qui est un médicament pour le traitement du diabète.
PCT/CN2008/001436 2008-08-08 2008-08-08 Synthèse stéréosélective de valiolamine WO2010015107A1 (fr)

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CN2008801290786A CN102105455B (zh) 2008-08-08 2008-08-08 立体选择性合成伏格列波糖关键中间体井冈霉醇胺
KR1020117002735A KR101540435B1 (ko) 2008-08-08 2008-08-08 발리올아민의 입체선택적 합성
JP2011521422A JP5546539B2 (ja) 2008-08-08 2008-08-08 バリオールアミンの立体選択的合成を行うための物質及び方法
PCT/CN2008/001436 WO2010015107A1 (fr) 2008-08-08 2008-08-08 Synthèse stéréosélective de valiolamine

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CN103588650A (zh) * 2012-08-15 2014-02-19 中国医药集团总公司四川抗菌素工业研究所 一种高纯度伏格列波糖及其制备方法
CN104119301A (zh) * 2013-04-27 2014-10-29 浙江海翔药业股份有限公司 一种伏格列波糖中间体及其制备方法
CN109232322A (zh) * 2018-10-30 2019-01-18 常州博海威医药科技股份有限公司 一种井冈霉醇胺关键中间体的合成方法
CN110317142A (zh) * 2019-07-18 2019-10-11 重庆植恩药业有限公司 一种伏格列波糖的制备方法
CN111747857A (zh) * 2016-02-29 2020-10-09 上海天伟生物制药有限公司 氨基糖类化合物、及其制备方法和用途

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CN103865845B (zh) * 2014-02-21 2016-04-13 杭州华东医药集团新药研究院有限公司 一种吸水链霉菌及其在制备伏格列波糖中的应用
CN105254514B (zh) * 2015-11-12 2017-09-05 重庆植恩药业有限公司 一种四苄基伏格列波糖的制备方法
CN114908130B (zh) * 2022-05-30 2024-02-06 上海凡秦医药科技有限公司 一种酶法制备胺基糖中间体井冈霉烯胺的方法及其应用

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CN111747857B (zh) * 2016-02-29 2023-03-21 上海天伟生物制药有限公司 氨基糖类化合物、及其制备方法和用途
CN109232322A (zh) * 2018-10-30 2019-01-18 常州博海威医药科技股份有限公司 一种井冈霉醇胺关键中间体的合成方法
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