Improved synthesis of an ester-type prodrug, 1-acetoxyethyl 7-((Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-((Z)-1-propenyl)-3-cephem-4-carboxylate (BMY-28271).

Kamachi, Hajime; Okita, Takaaki; Okuyama, Satsuki; Hoshi, Hideaki; Naitô, Takayuki

doi:10.7164/antibiotics.43.1564

Cited by 10 publications

(8 citation statements)

References 5 publications

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“…The solid was filtered, washed with 500 mL of chilled ethyl acetate and dried to obtain title compound (11) as a white crystalline powder, 254 g (90%). mp 165-166°C [4] (11) was dissolved in a mixture of 1000 mL of methylene chloride and 200 ml of water at 25-30°C. Thereafter, pH was adjusted to 4.0-4.5 with ammonium hydroxide at 25-30°C.…”

Section: Methodsmentioning

confidence: 99%

“…In reported methods [3,4], trityl protected cefdinir was prepared and isolated as a mixed PTSA and DMAc solvate (11). The deprotection of 11 either with trifluoroacetic acid or with formic acid affords Cefdinir (Scheme II).…”

Section: Introductionmentioning

confidence: 99%

“…The deprotection of 11 either with trifluoroacetic acid or with formic acid affords Cefdinir (Scheme II). This is the unique method for the isolation of trityl protected Cefdinir (11) …”

Section: Introductionmentioning

confidence: 99%

“…Cefdinir bistrimethylsilylacetamide, which is an expensive silylating agent and use of huge quantity of ether to isolate solvate (11) which greatly enhances danger of fire hazard on commercial scale, quantity of output is very low due to high molecular weight of compound (11) and poor solvent recovery. Therefore this procedure is not suitable for commercialization.…”

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confidence: 99%

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Novel compounds for the synthesis of cefdinir

Rao

Dandala

Sivakumaran

et al. 2007

Journal of Heterocyclic Chem

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Preparation of two new compounds 2‐mercapto‐5‐methyl‐1,3,4‐thiadiazolyl‐(Z)‐2‐(2‐amino‐4‐thiazolyl)‐2‐trityloxyiminoacetate (14) and 2‐mercapto‐5‐methyl‐1, 3,4‐thiadiazolyl‐ (Z)‐2‐(2‐amino‐4‐thiazolyl)‐2‐acetyloxyiminoacetate (12) and their use in the preparation of 7β‐[(Z)‐2‐(2‐amino‐4‐thiazolyl)‐2‐hydroxyiminoacetamido]‐3‐vinylcephem‐4‐carboxylic acid, also known by the generic name Cefdinir (1) has been accomplished in a single step by coupling with 7‐amino‐3‐vinylcephem‐4‐carboxylic acid (7) with purity of greater than 99% by HPLC.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The deprotection of 11 either with trifluoroacetic acid or with formic acid affords Cefdinir (Scheme II). This is the unique method for the isolation of trityl protected Cefdinir (11) …”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Novel compounds for the synthesis of cefdinir

Rao

Dandala

Sivakumaran

et al. 2007

Journal of Heterocyclic Chem

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“…The synthesis of the corresponding free acid 3a was published by Kamachi et al, whereas Defossa et al modified the preparation of activated derivatives of 3a due to safety concerns during scale-up investigations.…”

Section: Referencesmentioning

confidence: 99%

Concise Large-Scale Synthesis of the Highly Active Cephalosporin Cefdaloxime

Kammermeier¹,

Beck²,

Reitz³

et al. 1997

Org. Process Res. Dev.

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Cefdaloxime (1a) is the bioactive principle of the 1-(S)-(pivaloyloxy)ethyl ester prodrug HR916K (1b). To provide material for biological investigations a short and efficient large-scale synthesis of 1a was developed, which avoids chromatographic purification steps. Commercially available (6R,7R)-7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (AMCA) (2) is acylated with trityl-protected mercaptobenzothiazole thioester in the presence of bis(trimethylsilyl)acetamide to yield tritylated cefdaloxime. The trityl group is then removed by treatment with formic acid, followed by pH-adjusted precipitation of 1a. For a final purification, which has to consider cefdaloxime specific side reactions, crude 1a is dissolved in dimethyl sulfoxide and precipitated with methanol to obtain 1a in 66% overall yield on a kilogram scale.

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Synthesis of HR 916 K: An Efficient Route to the Pure Diastereomers of the 1‐(Pivaloyloxy)ethyl Esters of Cephalosporins

et al. 1996

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HR 916 K (5), the 1-(S)-(pivaloy1oxy)ethyl prodrug ester of was recycled by acidic saponification or enzymatic cleavage the cephalosporin cefdaloxime, exhibits a significantly to AMCA (7). The amine 10 was acylated with mercaptobenhigher oral bioavailability than the 1-(R) diastereomer HR zothiazole thioesters or mixed anhydrides, prepared from 916 J. An efficient'synthesis of HR 916 K was developed. The carboxylic acids 13 and 14, in almost quantitative yield. Deseparation of the diastereomers was achieved by precipita-protection of the oxime and formation of the tosylate protion of the 1-(R)-hydrochloride 9 followed by crystallization ceeded in one step. Using thioester 18, we obtained HR 916 of the 1-(S)-amine 10 (de > 96%). The 1-(R) diastereomer 9 K (5) from AMCA (7) in 42% yield.Most of the therapeutically useful third-generation cephalosporins are orally not well absorbed. Conversion of the carboxylic acid to prodrug esters, which are cleaved after absorption from the bowl, has been successfully used to obtain orally absorbable cephalosporins. Especially successful are the 1 -acyloxy-and 1 -alkoxycarbonyloxy-substituted methyl and ethyl esters, Typical examples of these types of esters are cefetamed pivoxil 1['] and cefpodoxime proxetil 2F21. In the case of the substituted ethyl esters an additional stereocenter is introduced into the molecule. Cefpodoxime proxetil 2 is on the market as a mixture of diastereomers.,OMe 1: Rf = Me, R2 = CH,OCOCMe, 2: R f = CH,OMe, R2 = CH(Me)OC02CHMe, HR 916 B (3) was selected as a candidate for clinical development, as its active metabolite cefdaloxime . shows broad antibacterial activity against Gram-positive and Gram-negative bacteria"], and the prodrug ester 3 exhibits good oral bioavailability in different animal species [4]. Formation of the toluenesulfonic acid salt increases the stability of the cephalosporin ester15]. The diastereomers could be separated by chromatography of an intermediate. HR 916 J (4) and HR 916 K (5) show comparable bioavailabilities in mice and rats, but in dogs the latter is enterally absorbed to 68%, whereas the former only to 20'Y0 [~]. Phase 1 clinical studies confirmed that HR 916 K (5) is enterally well absorbed [7]. Therefore, the pure diastereomer 5 was chosen as candidate for further clinical development.At that time HR 916 K (5) could be prepared either by separation of the diastereomers by chromatography of an intermediate or by multifold recrystallization[*l of HR 91 6 B (3). For ecological and economical reasons none of these methods was suitable for the large-scale synthesis and therefore, an efficient synthetic access to our compound 5 had to be identified. Results and DiscussionThe most elegant access to the diastereomerically pure prodrug ester would be esterification of the carboxylic acid

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Improved synthesis of an ester-type prodrug, 1-acetoxyethyl 7-((Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-((Z)-1-propenyl)-3-cephem-4-carboxylate (BMY-28271).

Cited by 10 publications

References 5 publications

Novel compounds for the synthesis of cefdinir

Novel compounds for the synthesis of cefdinir

Concise Large-Scale Synthesis of the Highly Active Cephalosporin Cefdaloxime

Synthesis of HR 916 K: An Efficient Route to the Pure Diastereomers of the 1‐(Pivaloyloxy)ethyl Esters of Cephalosporins

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