EP2758407A1 - Procédé perfectionné pour l'obtention de cefpodoxime sous forme acide - Google Patents

Procédé perfectionné pour l'obtention de cefpodoxime sous forme acide

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Publication number
EP2758407A1
EP2758407A1 EP12784684.8A EP12784684A EP2758407A1 EP 2758407 A1 EP2758407 A1 EP 2758407A1 EP 12784684 A EP12784684 A EP 12784684A EP 2758407 A1 EP2758407 A1 EP 2758407A1
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European Patent Office
Prior art keywords
acid
amino
reaction mixture
stirred
added
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.)
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EP12784684.8A
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German (de)
English (en)
Inventor
Sandeep Singh
Alok Srivastava
Manish Dhanuka
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Dhanuka Laboratories Ltd
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Dhanuka Laboratories Ltd
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/28—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by an aliphatic carboxylic acid, which is substituted by hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D501/06—Acylation of 7-aminocephalosporanic acid

Definitions

  • the present invention relates to an improved process for the preparation of cefpodoxime acid.
  • cefpodoxime proxetil is 1-isopropoxycarbonyloxyethyl (6R,7R)-7-[2-(2- aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-ceohem-4- carboxylate of formula (IV )and is disclosed in U.S Patent No 4,486,425.
  • Cefpodoxime acid is a precursor of cefpodoxime proxetil.
  • cefpodoxime acid is prepared from 7-Amino cephalosporanic acid in two steps .
  • 7-Amino -3-methoxymethyl-3-cephem-4- carboxylic acid of formula(I) is derivative of 7-Amino cephalosporanic acid (II) and there have been reported many method for the preparation thereof starting from 7- Aminocephalosporanic acid of formula(II).
  • cefbodoxime acid is [(6R-[6a,7P(Z)]-7-[2-(2-aminothiazol-4-yl)-2- metthoxyimino)acetamido]-3-cephem-4-carboxylic acid having formula( III), and is known from U.S.Pat.No. 4,409,215.
  • Cefpodoxime acid is prepared by condensation of 7-Amino -3-methoxymethyl-3-cephem- 4-carboxylic acid (i)with Benzothiazo ⁇ -2- ⁇ (Z)-2-methoxyimino-2-(2-atninothiazoie-4-yl) thioacetate (MAEM) in water miscible solvent under basic condition
  • Cefpodoxime acid is not suitable for oral administration, its ester derivative, 1- (isopropoxycarbonyloxyl)ethyl ester i.e Cefbodoxime proxetil of formula (IV) is used in the treatment.
  • 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid of formula(I) is a precursor of cefpodoxime proxetil, and there have been reported many methods for the preparation thereof starting from 7-aminocephalosphoranic acid (7-ACA) of formula (II).
  • JP Patent No. 82,192,392 and U.S.patent.No. 4,482,710 teaches preparation of 7-Amino 3- methoxy methyl-3-cephem carboxylic acid by the step of protecting the 7-amino group of 7- ACA with a phenylacetyl group; converting the 3-acetoxy group to a methoxy group by the action of methanol-sodium bicarbonate or methanol-calcium chloride; and removing the protection group.
  • this method has the problem that yield obtained are very low(approximately less then 20%) and the process requires multi-steps.
  • JP Patent No . 84,163,387 teaches a method of preparing 7-Amino3-methoxymethyl-3- cephem-4-carboxylic acid by treating 7-Amino cephalosporanic acid with methane sulphonic acid -methanol.
  • this method also has the problem of low yield(approximately 30%) , and the product purity is poor(approximately 30 to40%) due to the formation of by-product such as lactone or the degradition material of the ⁇ -lactam ring.
  • EP Patent 262,744 discloses a method of preparing 7-amino-3-methoxymethyl-3- cephem-4-carboxylic acid by reacting 7-ACA with methanol in the presence of a halide of antimony or zinc.
  • this method is hampered by the problem of low yield (approximately 40%) and is not suitable for mass production due to use of column chromatography for separating final product.
  • JP Patent No 88,115,887 discloses 7-amino-3-methoxymethyl-3-cephem-4- carboxylic acid has been prepared by treating 7-Amino cephalosporanic acid with boron trifluoride-methanol in presence of halo sulfonic acid or alkylsulfonic acid .
  • EP. Patent No.343926 teaches a method of preparing 7-amino-3-methoxymethyl-3- cephem-4-carboxylic acid by reacting 7aminocephalosporanic acid with trimethyl borate in sulfolane, in the presence of sulphuric acid and antimony pentachloride.
  • this method requires the use of expensive antimony pentachloride as well as 98% trimethyl borate which is difficult to handle.
  • EP Patent No.485,204 reveals a method for preparing 7-amino-3-methoxymethyl-3- cephem-4-carboxylic acid by treating 7-ACA in a solution containing an alkoxysulfonic acid with a trialkyl borate and an alkylal.
  • this method still has to deal with the difficulty of handling 98% trimethyl borate which is difficult to handle and also suffers from the problem of poor process controllability.
  • An object of the present invention is to provide a process for preparation of 7-AMCA involving non-aqueous work up starting from 7-Amino cephalosporanic acid.
  • Another object of the present invention is to provide a process for preparation of Cefpodoxime acid with enhanced yield from 7-AMCA.
  • Yet another object of the present invention is to provide a process for preparation of Cefpodoxime Proxetil from cefpodoxime acid having an enhance yield and required purity.
  • the present invention relates to a process for the preparation of 7-AMCA implementing a non-aqueous work up of the reaction mixture involving treating with two different organic bases in two stages, which is further converted to Cefpodoxime acid with an enhanced yield by conventional method.
  • the invention also provides a process for the preparation of Cefpodoxime proxetil with an enhanced yield.
  • present invention relates to an improved process for the preparation Cefpodoxime acid comprising steps of reacting 7-Amino cephalosporanic acid ( 7ACA) with a mixture of methane sulphonic acid and methanol or Methane sulphonic acid , Methanol , trimethylborate or sulpholane , BF3 , Methanol at a temperature ranging between 5°C-50°C, followed by addition of calculated amount of methanol.
  • 7ACA 7-Amino cephalosporanic acid
  • the reaction mixture stirred for 1- 2hours around 5-50°C and worked up by first adjusting the to pH to a value of around 0.5 with methanolic solution of first organic base and then filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 using second organic base .
  • the precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid thus obtained is further converted into Cefpodoxime acid having required purity and enhanced yield by adopting conventional method reported in prior art.
  • Cefpodoxime acid is converted into Cefpodoxime Proxetil with improved yield by any of the conventional method known in the prior art.
  • An embodiment of the present invention provides a process in which non-aqueous work up is performed for the preparation of 7-AMCA.
  • Another embodiment of the present invention provides a process for the preparation of Cefpodoxime acid with enhanced yield.
  • Yet another embodiment of the present invention uses two organic bases in a specific sequential order to obtain 7-AMCA.
  • Still yet another embodiment of the present invention provides a process for the preparation of Cefpodoxime acid from 7-AMCA having enhanced yield and required purity.
  • Another embodiment of the present invention where in the first organic base used for adjusting the pH of the reaction mixture is ammonia in methanol. Yet another embodiment of the present invention wherein the second organic base used for adjusting the pH is selected from triethylamine, diethyl amine, di isopropyl amine and tetramethyl guanidine. Still another r embodiment of present invention provides a process for the conversion of cefpodoxime acid in to cefpodoxime proxetil having an enhance yield.
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (300gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)"2-methoxyimino-2-(2-aminothiazole ⁇ 4 ⁇ yl)thioaceiate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water, adjusting the pH to around 5.5 to 6.0 by using dilute sulphuric acid ..
  • reaction mixture was worked up by adding Hydrochloric acid (2ml) in (20) ml water maintaining the temperature in the range of -15-10°C.Then Reaction mass is transferred in to mixture of ethyl acetate (200 ml), water 400 ml and Sodium thio sulphate (4.0gm) at 10-15°C . stirred the mass for lOmin , separate the layers. Aqueous layer washed with 100 ml Ethyl acetate . Combined both ethyl acetate layer and washed thrice with 150 ml 10% sodium chloride solution at 15°C. Ethyl acetate layer was treated with activated carbon.
  • Example (2) (A)Added 7-Amino cephalosporanic acid (100gm,0.3676 mol) is added to a mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled water (1000ml) . Added cone triethyl amine (780gm) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to attain a pH value of around 0.5 followed by adjusting the pH of the solution to 3.3 to 3.5. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 320gm).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (320gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazo i-2-yi (/ ) ⁇ 2"meihoxyimino ⁇ 2 ⁇ (2"aminoihiazole ⁇ ⁇ yl) ⁇ hioaceiaie (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).
  • Example (3) (A)Added 7-Amino cephalosporanic acid (100gm,0.3676 mol) is added to mixture of methane sulphonic acid(500ml) and methanol(155ml) at a temperature ranging between 5°- 10°C. The reaction mixture stirred for l-2hours around 10-12° and quenched the reaction mass by adding it to chilled methano 1(1000ml). Added methanolic ammonia solution (126 gm in 1000ml) slowly over a period of 60-75min maintaining the temperature in the range of 0-lOC to achieve pH value of around 0.5, Filtering the precipitated solid, followed by adjusting the pH of the filtrate to 3.3 to 3.5 by treating with methanolic ammonia solution. The precipitated 7-Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 230gm).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (230gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • reaction mixture was stirred for 30 min .
  • the reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 23.8gm, Assay 91.5% )
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (250gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (160gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-methoxyimino-2-(2-aminoth1 ⁇ 4zole-4-yl)th.ioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).
  • step A 7-Amino 3 -methoxymethyl 3-cephem carboxylic acid (320gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-methoxyimino-2-(2-aminoth1 ⁇ 4zole-4-yl)th.ioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (180gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-inethoxyimmo-2-(2-arainothia2:ole-4-y].)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).
  • step A ((B) 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (350gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (380gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazo i-2-yi (Z)"2-meihoxyimino-2-(2-aminoihiazole ⁇ 4 ⁇ yl) ⁇ hioaceiate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).
  • step A 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (290gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z) ⁇ 2 ⁇ metlioxyimino-2"(2 ⁇ amiiiotliiazole"4-yl)tliioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (103gm,Assay 91.0%).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (320gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazoi-2-yi (Z)"2-methoxyimino-2-(2-aminothiazole ⁇ 4 ⁇ yl)thioaceiate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (190gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • Example(13) A) 245ml of methane sulphonic acid was mixed with 60.0mlof an azeotropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm, 0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 meanwhile maintaining the temperature at 10-12°C. The reaction mixture stirred for 60-90min and quenched the reaction mass by adding it to chilled water (1000ml) .
  • an azeotropic mixture composed of 70% Trimethyl borate and 30% methanol and solution was cooled to 10°C. 7- amino cephalosporanic acid (100 gm, 0.3676 mole) was slowly added in 30min and dissolve completely. Then additional 63ml of trimethyl borate azeotropic mixture was added slowly in 80-90 meanwhile maintaining the temperature at 10-12°C. The
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (340gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • Benzothiazo l-2-yl (Z)-2-methoxyimino-2-(2-aminothiazole-4-yl) thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours.
  • the reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (85gm,Assay 93.5%>).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (200gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-inethoxyimmo-2-(2-arainothia2:ole-4-y].)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).
  • Example(15) 1000ml of sulpholane was mixed with 225 gm methanol . Purge 360 gm BF3 gas at 30- 40°C in 60-90 min . Then charge 7-amino cephalosporanic acid (100 gm,0.3676 mole) at 45°C in single lot. The reaction mixture stirred for 60-90min at 48-50°C and quenched the reaction mass by adding it to chilled water (1000 ml) . Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers. Again Charge 1000ml methylene chloride , stir 10 min at 30°C .Separate the layers.
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (320gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • Benzothiazoi-2-yi (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours.
  • the reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (99gm,Assay 95.5%).
  • step A 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (300gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • Benzothiazol-2-yl Z)-2-methoxyimino-2-(2-aniinothiazole'-4-yi)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours.
  • the reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (100gm,Assay 97.5%).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (250gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazoi-2-yi (Z)"2-methoxyimino-2-(2-aminothiazole ⁇ 4 ⁇ yl)thioaceiaie (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).
  • step A The precipitated 7- Amino 3-methoxymethyl 3-cephem carboxylic acid(7-AMCA) is isolated(wet yield— 280gm).
  • step B 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (280 gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • BenzothiazoI-2-yi (Z)"2 ⁇ methoxyimino ⁇ 2-(2 ⁇ aminotMazole ⁇ 4-yl)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours.
  • the reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (101gm,Assay 94.2%).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (200 gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • step (B) 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (310gm) Obtained in step (A) above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • Benzochiazo ⁇ -2-yi (Z)-2-meth.oxyimino-2-(2-ainmothia2'.oIe-4-yI) thioacetate (MAE ) in presence of Tri ethyl amine and stirred further for 5-6 hours.
  • the reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (87.0gm,Assay 94.5%).
  • reaction mixture was stirred for 30 min .
  • the reaction mixture was worked up following the procedure as described in example 1 step (C). ( Yield 24.00gm, Assay 94.0% )
  • step (B) 7- Amino 3-methoxymethyl 3-cephem carboxylic acid (180 gm) Obtained in step (A) above is taken in a aqueous methanol and cooled to 15-20°C and treated with
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (158gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)"2-methoxyimino-2-(2-aminothiazole ⁇ 4 ⁇ yl)thioaceiate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B). (lOlgm, Assay 98.2%).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (180gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2 » methoxyimino-2-(2 » amiiiothiazole-4-yl)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).
  • step A 7-Amino 3-methoxymethyl 3-cephem carboxylic acid (190gm) Obtained in step A above is taken in a aqueous methanol and cooled to 15-20°C and treated with Benzothiazol-2-yl (Z)-2-methoxyiinino-2-(2-aminothia x)ie-4-yl)thioacetate (MAEM) in presence of Tri ethyl amine and stirred further for 5-6 hours. The reaction mixture is quenched by adding water and further worked up following the procedure as described in example 1 step (B).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention porte sur un procédé perfectionné pour la préparation de cefpodoxime sous forme acide à partir d'acide 7-aminocéphalosporanique. En outre, l'invention porte sur la préparation de cefpodoxime proxétil à partir de cefpodoxime sous forme acide.
EP12784684.8A 2011-09-20 2012-09-06 Procédé perfectionné pour l'obtention de cefpodoxime sous forme acide Withdrawn EP2758407A1 (fr)

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IN2718DE2011 2011-09-20
PCT/IB2012/054602 WO2013041999A1 (fr) 2011-09-20 2012-09-06 Procédé perfectionné pour l'obtention de cefpodoxime sous forme acide

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CN106046024B (zh) * 2016-06-30 2019-01-15 齐鲁动物保健品有限公司 一种头孢泊肟酯的制备方法
CN106478666B (zh) * 2016-09-22 2018-07-31 湖北凌晟药业有限公司 7-氨基-3-甲氧甲基-3-头孢烯-4-羧酸的制备方法
CN112480144A (zh) * 2020-12-07 2021-03-12 湖北凌晟药业有限公司 一种7-氨基-3-甲氧甲基-3-头孢烯-4-羧酸的制备方法

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