13127-18-9

Usage

Uses

Used in Pharmaceutical Industry:
ERYTHROMYCIN OXIME is used as an intermediate for the synthesis of antibiotics, specifically Roxithromycin and Azithromycin, due to its chemical properties and its role in the production process of these medications. Its presence as a metabolite of Roxithromycin further emphasizes its importance in the development of antibacterial agents.
Used as a Major Metabolite:
In the pharmaceutical industry, ERYTHROMYCIN OXIME is utilized as the major metabolite of Roxithromycin, an antibiotic agent. This application highlights its significance in the study and understanding of the metabolic pathways and effects of Roxithromycin, which can contribute to the optimization of its therapeutic use and potential improvements in antibiotic treatments.

InChI:InChI=1/C37H68N2O13/c1-14-25-37(10,45)30(41)20(4)27(38-46)18(2)16-35(8,44)32(52-34-28(40)24(39(11)12)15-19(3)48-34)21(5)29(22(6)33(43)50-25)51-26-17-36(9,47-13)31(42)23(7)49-26/h18-26,28-32,34,40-42,44-46H,14-17H2,1-13H3/b38-27+/t18-,19-,20+,21+,22-,23+,24+,25-,26+,28-,29+,30-,31+,32-,34+,35-,36-,37-/m1/s1

Synthetic route

erythromycin (114-07-8) → (9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9)

Conditions	Yield
With hydroxylamine; acetic acid In isopropyl alcohol at 50℃; for 24h;	95%
With hydroxylamine hydrochloride; triethylamine In methanol Reflux;	93%
With hydroxylamine hydrochloride; potassium carbonate In methanol at 20℃; for 48h; Solvent; Reagent/catalyst; Temperature;	88.2%

erythromycin (114-07-8) → (9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) + 8,9-anhydropseudoerythromycin A 6,9-hemiketal (105882-69-7)

Conditions	Yield
With hydroxylamine hydrochloride; sodium acetate In methanol at 50℃; for 13h;

erythromycin A thiocyanate (7704-67-8) → (9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9)

Conditions	Yield
With hydroxylamine hydrochloride In dichloromethane at 20℃; for 1.5h; pH=7; Beckmann Rearrangement;
With hydroxylamine hydrochloride; ammonium bicarbonate; sodium iodide In methanol at 56 - 60℃; Reagent/catalyst;	89 g

erythromycin A oxime thiocyanate (1357466-70-6) → (9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9)

Conditions	Yield
With sodium hydroxide In dichloromethane; water at 38℃; Solvent; Temperature;

2-Methoxypropene (116-11-0) + (9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) + 1,1,1,3,3,3-hexamethyl-disilazane (999-97-3) → C44H84N2O14Si (119685-40-4)

Conditions	Yield
Stage #1: 2-Methoxypropene; (9-E)-deoxo-9-hydroximinoerythromycin A With Pyridine hydrobromide In dichloromethane at 7 - 17℃; for 2h; Stage #2: 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane for 1h; Stage #3: With sodium hydrogencarbonate In dichloromethane; water at 27 - 33℃; for 0.5h; Product distribution / selectivity;	96.9%

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-homoerythromycin A (342371-84-0)

Conditions	Yield
With sodium hydrogencarbonate; p-toluenesulfonyl chloride In water; acetone at 0 - 20℃; for 4h;	91.8%
With sodium hydrogencarbonate; p-toluenesulfonyl chloride In dichloromethane; water at 0 - 5℃; Product distribution / selectivity;
With sodium hydrogencarbonate; p-toluenesulfonyl chloride In dichloromethane at 20℃; for 1.5h;
With sodium hydrogencarbonate; methanesulfonyl chloride In water at 5℃; Temperature; Reagent/catalyst; Beckmann Rearrangement;

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → erythromycylamine (26116-56-3)

Conditions	Yield
With methanol; sodium tetrahydroborate at 20℃; for 8h; Reagent/catalyst; Temperature; Cooling with ice;	85.03%

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → 9-Deoxo-9a-aza-9a-homoerythromycin A (76801-85-9)

Conditions	Yield
Stage #1: (9-E)-deoxo-9-hydroximinoerythromycin A With calcium(II) bis(trifluoromethanesulfonyl)imide; tert-butylammonium hexafluorophosphate(V) In 1,2-dimethoxyethane; 1,2-dichloro-ethane at 80℃; for 5h; Stage #2: With sodium tetrahydroborate In methanol at 0 - 20℃; for 51h;	78%
Multi-step reaction with 2 steps 1: p-toluenesulfonyl chloride; sodium hydrogencarbonate / acetone; water / 4 h / 0 - 20 °C 2: sodium tetrahydroborate; methanol / 24 h / 0 - 20 °C View Scheme

1,1-diisopropoxycyclohexane (1132-95-2) + (9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → 9-{O-[1-(1-methylethoxy)-cyclohexyl]oxime}-erythromycin (129288-91-1)

Conditions	Yield
With pyridine hydrochloride In dichloromethane at 20℃; for 42h;	71%

L-N-Boc-Ala (15761-38-3) + (9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → C45H81N3O16

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h;	70%

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → C37H66N2O12

Conditions	Yield
Stage #1: (9-E)-deoxo-9-hydroximinoerythromycin A With sodium hydrogencarbonate; p-toluenesulfonyl chloride In dichloromethane; water at 0 - 5℃; for 3h; Stage #2: With acetic acid In dichloromethane; water for 0.25h; pH=5.3 - 5.5; Stage #3: With sodium hydroxide In water pH=12 - 12.5; Product distribution / selectivity;	70%

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) + N-(Benzyloxycarbonyl)glycine (1138-80-3) → C47H77N3O16

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h;	65%

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → erythromycin A 6,9-imino ether

Conditions	Yield
With sodium hydrogencarbonate; p-toluenesulfonyl chloride In water; acetone at -5 - 30℃; for 4.5h;	55.2%

N-tert-butoxycarbonyl-L-leucine (13139-15-6) + (9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → C48H87N3O16

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h;	53.1%

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) + 4-methoxybenzoic acid (100-09-4) → C45H74N2O15

Conditions	Yield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h;	51.2%

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → 9-deoxo-11-deoxy-9,11-epoxy-9-nitroso-3'-des-N-methylerythromycin A (121238-13-9)

Conditions	Yield
With N-Bromosuccinimide; sodium hydrogencarbonate In 1,2-dimethoxyethane; water for 2h; Ambient temperature;	42%

UDP-glucose (133-89-1) + (9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → 2'-[O-(β-D-glucopyranosyl)]erythromycin A oxime

Conditions	Yield
With magnesium(II) glycosylation by cell extract of Streptomyces hygroscopius ATCC 31080; pH 6.0-9.5;	50 mg

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) + epichlorohydrin (106-89-8) → erythromycin-9-[O-(2,3-epoxypropyl)]oxime (93488-70-1)

Conditions	Yield
With potassium carbonate In acetone for 7h; Heating;

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) + 2-(((benzyloxy)carbonyl)amino)ethyl 1-methanesulfonate (134307-72-5) → C47H79N3O15 (256420-10-7) + C47H79N3O15

Conditions	Yield
With potassium carbonate In acetone for 24h; Heating;

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) + N-(benzyloxycarbonyl)-3-amino-1-propyl methanesulfonate (174626-34-7) → C48H81N3O15 (883739-43-3) + C48H81N3O15

Conditions	Yield
With potassium carbonate In acetone for 24h; Heating;

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) + N-(benzyloxycarbonyl)-6-aminohexyl methanesulfonate (75937-26-7) → C51H87N3O15 + C51H87N3O15

Conditions	Yield
With potassium carbonate In acetone for 24h; Heating;

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → 6-(4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-14-ethyl-7,12,13-trihydroxy-4-(5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy)-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione 10-[O-(2-amino-ethyl)-oxime] (134833-89-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / acetone / 24 h / Heating 2: 100 percent / H2 / Pd/C / methanol / 20 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → 6-(4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-14-ethyl-7,12,13-trihydroxy-4-(5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy)-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione 10-[O-(3-amino-propyl)-oxime] (883739-48-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / acetone / 24 h / Heating 2: 100 percent / H2 / Pd/C / methanol / 20 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → 6-(4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-14-ethyl-7,12,13-trihydroxy-4-(5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy)-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione 10-[O-(6-amino-hexyl)-oxime] (883739-49-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / acetone / 24 h / Heating 2: 100 percent / H2 / Pd/C / methanol / 20 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → C50H86N6O18

Conditions	Yield
Multi-step reaction with 4 steps 1: K2CO3 / acetone / 24 h / Heating 2: 100 percent / H2 / Pd/C / methanol / 20 °C 3: CH2Cl2; dimethylformamide / 20 °C 4: HF-pyridine / tetrahydrofuran / 0 - 4 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → C51H88N6O18

Conditions	Yield
Multi-step reaction with 4 steps 1: K2CO3 / acetone / 24 h / Heating 2: 100 percent / H2 / Pd/C / methanol / 20 °C 3: CH2Cl2; dimethylformamide / 20 °C 4: HF-pyridine / tetrahydrofuran / 0 - 4 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → C54H94N6O18

Conditions	Yield
Multi-step reaction with 4 steps 1: K2CO3 / acetone / 24 h / Heating 2: 100 percent / H2 / Pd/C / methanol / 20 °C 3: CH2Cl2; dimethylformamide / 20 °C 4: HF-pyridine / tetrahydrofuran / 0 - 4 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → C56H100N6O18Si (883739-50-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: K2CO3 / acetone / 24 h / Heating 2: 100 percent / H2 / Pd/C / methanol / 20 °C 3: CH2Cl2; dimethylformamide / 20 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → C57H102N6O18Si (883739-51-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: K2CO3 / acetone / 24 h / Heating 2: 100 percent / H2 / Pd/C / methanol / 20 °C 3: CH2Cl2; dimethylformamide / 20 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → C60H108N6O18Si (883739-52-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: K2CO3 / acetone / 24 h / Heating 2: 100 percent / H2 / Pd/C / methanol / 20 °C 3: CH2Cl2; dimethylformamide / 20 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → 3-O-descladinosyl-3-OH-6-O-allyl-erythromycin A 9-oxime (722495-12-7) + 3-halide-4-methyl-thiophene

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 71 percent / pyridine hydrochloride / CH2Cl2 / 42 h / 20 °C 2.1: 90 percent / dimethylaminopyridine / pyridine / 3 h / 20 °C 3.1: 56 percent / potassium tert-butoxide / dimethylsulfoxide; tetrahydrofuran / 4 h 4.1: HCl / ethanol; H2O / 6 h / 50 °C 4.2: 72 percent / K2CO3 / methanol / 12 h / 50 °C View Scheme

(9-E)-deoxo-9-hydroximinoerythromycin A (13127-18-9) → (3R,4S,5S,6R,7R,9R,11S,12R,13S,14R)-6-((2S,3R,4S,6R)-4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-7-[(E)-3-(4-methyl-thiophen-3-yl)-allyloxy]-oxacyclotetradecane-2,10-dione 10-oxime

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 71 percent / pyridine hydrochloride / CH2Cl2 / 42 h / 20 °C 2.1: 90 percent / dimethylaminopyridine / pyridine / 3 h / 20 °C 3.1: 56 percent / potassium tert-butoxide / dimethylsulfoxide; tetrahydrofuran / 4 h 4.1: HCl / ethanol; H2O / 6 h / 50 °C 4.2: 72 percent / K2CO3 / methanol / 12 h / 50 °C 5.1: triethylamine / palladium (II) acetate; triphenylphosphine / acetonitrile / 16 h / Heating View Scheme

Upstream product

• 7704-67-8 erythromycin thiocyanate A 
• 1357466-70-6 erythromycin A oxime thiocyanate 
• 114-07-8 erythromycin 

Downstream Products

• 129288-91-1 9-{O-[1-(1-methylethoxy)-cyclohexyl]oxime}-erythromycin 
• 80214-83-1 roxithromycin 
• 81103-11-9 clarithromycin 
• 342371-84-0 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-homoerythromycin A 
• 83905-01-5 Zithromax(R) 
• 76801-85-9 9-Deoxo-9a-aza-9a-homoerythromycin A 
• 111247-89-3 C₄₃H₇₁IN₂O₁₅S*ClH 
• 99290-97-8 C₃₇H₆₆N₂O₁₂ 
• 76820-32-1 erythromycin A lactam 
• 111247-90-6 C₄₅H₇₅N₃O₁₆S*ClH 
• 722495-10-5 2',4-diacetyl-6-allyl-9-{O-[1-(1-methylethoxy)-cyclohexyl]oxime}-erythromycin 
• 197074-59-2 2',4-diacetyl-9-{O-[1-(1-methylethoxy)-cyclohexyl]oxime}-erythromycin 
• 883739-43-3 C₄₈H₈₁N₃O₁₅ 
• 256420-10-7 C₄₇H₇₉N₃O₁₅ 

Relevant academic research and scientific papers

Translactonization of erythromycin a during oximation: Mixture analysis and reaction monitoring by NMR

Oximation of erythromycin A with hydroxylamine hydrochloride and sodium acetate in methanol led to the formation of pseudoerythromycin A enol ether with erythromycin A oxime as analysed by detailed two-dimensional NMR spectroscopy in the mixture along with traces of 8,9-anhydroerythromycin A 6,9-hemiketal and erythromycin A 6,9:9,12-spiroketal. The formation of the degraded products was established by performing in situ 13C NMR spectroscopy. The analysis suggests that pseudoerythromycin A enol ether is formed by the translactonization of erythromycin A enol ether which forms as a result of acid degradation. Copyright

Synthesis and antimicrobial activity of erythromycin-A oxime analogs

A series of erythromycin-A oxime ether as well as esters have been synthesized. Ether derivatives were synthesized through the epoxy ether intermediate of erythromycin-9-oxime, followed by opening of the epoxy linkage through various amines, whereas esters have been prepared through DCC mediated protocol. These derivatives have been evaluated for antibacterial activity and found to be as active as erythromycin-A.

Synthesis of two and antibacterial activity of one novel oxime ether derivatives of erythromycin A

The synthesis of novel erythromycin A 9-O-(2-ethenesulfony-ethyl)-oxime and erythromycin A 9-O-(3-oxo-butyl)-oxime from erythromycin A (EA) by the Michael reaction is described and to describe the effects of transformation of ketone in position 9 of EA to an oxime ether. This transformation occurred in a single step without protecting of any functional moiety of erythromycin oxime and zero waste manner in good yield. The antibacterial screen of EA 9-O-(2-ethenesulfony-ethyl)-oxime is also reported.

Method for synthesizing azorithromycin by utilizing erythromycin thiocyanate oxime

The invention relates to a method for synthesizing azithromycin by utilizing erythromycin thiocyanate oxime. The method comprises the following process steps: removing thiocyanate radicals through erythromycin thiocyanate oxime dissociation, performing rearrangement reaction, performing continuous back extraction, performing continuous reduction reaction and separation, and performing azithromycin crystallizing. According to the invention, the thiocyanate radicals are removed before the rearrangement reaction and then the rearrangement is performed, the reduction reaction adopts a continuous reaction process, the reaction mode is changed, and the process is high in reaction efficiency, low in production cost, small in environmental pollution, high in product yield and good in product quality.

Synthetic method of isotope-labeled erythromycylamine

The invention discloses a synthetic method of isotope-labeled erythromycylamine, belongs to the field of drug metabolism, and provides a synthetic method which is reasonable in process design, strongin operability and high in yield, can efficiently convert isotope-labeled raw materials into labeled target products, and can realize industrial production of isotope-labeled erythromycylamine. The method takes 13CD3 labeled methyl iodide as a starting raw material, the isotope-labeled erythromycylamine is synthesized by six steps of reactions, optimal preparation steps and reaction conditions arescreened out through a large number of experiments, the whole process is reasonable in design and high in operability, the labeled raw materials can be efficiently converted into labeled target products, the chemical purity of the labeled erythromycylamine prepared through the method can reach 98.5% or above, and the labeled isotope abundance is larger than 98.5%.

Macrolide derivative and application thereof

The invention provides a macrolide derivative of a novel structure. Experiments show that the macrolide derivative has a good promoting effect on alimentary motility and is capable of enhancing intestine peristalsis, increasing defecation quantity and accelerating passing of intestinal content; on such basis, it is further discovered that the macrolide derivative is low in antibiotic activity and small in side effect and can be taken as a gastrointestinal motility promoting drug. Particularly, a compound III-3 screened with the optimal efficacy is subjected to further efficacy evaluation as well as acute toxicity and cardiotoxicity evaluation by domestic rabbits, beagles and marmosets. Experiments show that the compound III-3 is safe and capable of effectively promoting gastrointestinal motility, thereby being excellent in druggability.

Preparation method of erythromycin A oxime

The invention belongs to the technical field of medical chemistry and particularly relates to a preparation method of erythromycin A oxime. The method has the advantages of being simple in operation, high in yield and good in product purity and suitable for large-scale industrial production.

Method for synthesizing azithromycin

The invention relates to a method for synthesizing azithromycin. According to the invention, erythromycin thiocyanate is adopted as an initial raw material of an oximation reaction, such that erythromycin oxime thiocyanate is obtained; the next step of reaction is directly carried out; and through rearrangement, reduction and methylation reactions, azithromycin is obtained. The rearrangement and reduction reactions are carried out with a one-pot method. A reduction reaction product is not separated in a solid form, and is directly used in the methylation reaction. With the synthesizing method provided by the invention, a conversion process from erythromycin oxime thiocyanate to eythromycin oxime is eliminated, and steps that rearrangement and reduction products are separated in solid forms in an original process are also eliminated. The process is environment-friendly and simple, and has the advantages of high yield, low cost, low pollution and high product purity. The method is suitable for industrialized productions.

PROCESSES FOR PREPARING MACROLIDES AND KETOLIDES AND INTERMEDIATES THEREFOR

The invention described herein pertains to processes for the preparation of macrolide antibacterial agents. In particular, the invention pertains to processes for preparing macrolides and ketolides from erythromycin A.

Process for the preparation of clarithromycin

The present invention includes a process involving a one-pot reaction for preparing erythromycin 9-oxime salt comprising: (a) reacting erythromycin thiocyanate with an ammonium source to obtain erythromycin free base; (b) oximating the C-9 carbonyl of the erythromycin free base by reacting the erythromycin free base with triethylamine and hydroxyl amine hydrochloride to form erythromycin oxime; and (c) reacting the erythromycin oxime obtained in step (b) with an ammonium source to obtain the erythromycin 9-oxime salt. The present invention is also drawn to a one-pot reaction for preparing clarithromycin starting with the one-pot reaction for preparing erythromycin 9-oxime salt, further comprising after step (c): (d) silylating the hydroxy groups at the oxime group, and the 2′ and 4″ positions of the erythromycin 9-oxime salt to obtain a silylated derivative; (e) methylating the hydroxy group at the 6 position of the silylated derivative using at least one methylating agent in the presence of at least one inorganic base to obtain SMOP, wherein SMOP is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime; and (f) converting the SMOP into clarithromycin using at least one deoximating agent in the presence of aqueous ethanol.