ChemicalBook CAS DataBase List Chloramphenicol

Chloramphenicol synthesis

11synthesis methods

Product Name:Chloramphenicol
CAS Number:56-75-7
Molecular formula:C11H12Cl2N2O5
Molecular Weight:323.13

Chloramphenicol, D-threo-2,2-dichloro-N-[β-hydroxy-α-(hydroxymethyl)]-n-nitrophenylacetamide (32.6.7), was first isolated in 1947 from a culture fluid of the actinomycete Streptomyces venezuelae; however, it is only currently produced synthetically. When using a synthetic racemic mixture without having previously separated it into D- and L-threo forms, it is called sintomycin. Two ways of synthesizing chloramphenicol are suggested. The first begins with 4-nitroacetophenone, which is brominated with molecular bromine to make ω-bromo-4-nitroacetophenone (32.6.1). This is transformed to ω-amino- 4-nitroacetophenone (32.6.2) by successive production of a quaternary salt with urotropine and subsequent break up to an amine using hydrogen chloride. The resulting aminoketone is acylated with acetic anhydride to make ω-acetamido-4-nitroacetophenone (32.6.3), and the product undergoes acylmethylation with paraform aldehyde to give α-acetamido- β-hydroxy-4-nitropropiophenone (32.6.4). Reducing the carbonyl group in the resulting compound with aluminum isopropoxide in isopropyl alcohol gives D,L-threo-2-acetamido- 1-(4-nitrophenyl)-1,3-propandiol (32.6.5). The acetyl group is hydrolyzed in hydrochloric acid to form D,L-threo-2-amino-1(4-nitrophenyl)-1,3-propandiol. The resulting racemic mixture of amines is treated with camphor-D-sulfonic acid, and the resulting enantiomeric salts are separated. After alkaline hydrolysis of the selected salt, the product D, (?)-threo-2- amino-1-(4-nitrophenyl)-1,3-propandiol (32.6.6) is synthesized. Acylating the aminogroup of this compound with the methyl ester of dichloroacetic acid gives the desired chloramphenicol (32.6.7).

The other synthesis begins with cinnamic alcohol, which is reacted with hypobromous acid to make 2-bromo-1-phenyl-1,3-propandiol (32.6.8), the hydroxyl group of which is protected as a ketal by reacting it with acetone, giving 5-bromo-2,2-dimethyl-4-phenyl- 1,3-dioxane (32.6.9). Reacting the resulting bromide with ammonia gives an isomeric mixture of D,L-threo-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane, which upon treatment with D-tartaric acid, separation of the resulting salts, and subsequent alkaline hydrolysis of the selected salt gives D-(?)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane (32.6.10). Acylating this with the methyl ester of dichloroacetic acid gives D-(?)-threo-5-dichloroacetamido-2,2-dimethyl-4-phenyl-1,3-dioxane (32.6.11). The phenyl ring is then nitrated, during which the 1,3-dioxane ring is cleaved off, giving dinitrate of D-(?)-threo-2- dichloroacetamido-1-(4-nitrophenyl)-1,3-propandiol (32.6.12). Reducing the nitro group in this compound with bivalent iron sulfate gives the desired chloramphenicol (32.6.7).

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Yield:56-75-7 13 %Chromat.

Reaction Conditions:

with Novozym 435 in acetonitrile at 30; pH=7; for 24 h;aq. phosphate buffer;Enzymatic reaction;regioselective reaction;

Steps:

Effect of the buffer pH in the hydrolysis reaction of diacetylated derivative 4e

A suspension of diester 4e (100 mg, 0.15 M) and CAL-B (ratio 1:1 in weight respect to 4e) in a mixture of phosphate buffer 100 mM pH 7.0/MeCN (several proportions), was shaken at 30 °C and 250 rpm. The reaction was stopped after 24 hours, and the enzyme filtered off. The organic solvent was evaporated and the residue extracted with EtOAc (3 x 10 mL). Finally the solvent was evaporated under reduced pressure, and the reaction crude analysed by HPLC (Table S1).

References:

Bizerra, Ayla M.C.;Montenegro, Tasso G.C.;Lemos, Telma L.G.;De Oliveira, Maria C.F.;De Mattos, Marcos C.;Lavandera, Iván;Gotor-Fernández, Vicente;De Gonzalo, Gonzalo;Gotor, Vicente [Tetrahedron,2011,vol. 67,# 16,p. 2858 - 2862] Location in patent:supporting information; experimental part

L-Phenylalanine, N-(dichloroacetyl)-β-hydroxy-4-nitro-, ethyl ester, (βR)- (9CI)

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555-16-8
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References

116-54-1 Synthesis

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Benzoic acid, 2-[(4-methylphenyl)methoxy]-, methyl ester

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116-54-1 Synthesis

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2-Oxazolidinone, 4-(hydroxymethyl)-5-(4-nitrophenyl)-, (4R,5R)-

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References

Chloramphenicol Related Search:

Ethyl acetate Ethanol Acetamide N,N-Dimethylacetamide Thioacetamide 1-Hydroxyethylidene-1,1-diphosphonic acid 3-Diethylaminophenol 4-Nitrobenzoic acid Methylparaben 2-HYDROXYACETAMIDE