Formic Acid → Methyl Acetate

HRID 1271533Notes

Reaction equation

HRID 1271533 reaction equation
[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][NH:7][C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[CH:52](O)=O.ClCCl.C(Cl)(Cl)Cl>C(OCC)(=O)C.C(C(C)=O)C(C)C.C(C(C)=O)C.CC(C)=O.C(O)(C)C.C(O)C.CO.ClCCCl.C(Cl)(Cl)(Cl)Cl>[C:16]([O:18][CH3:3])(=[O:17])[CH3:15].[C:16]([O:18][CH:3]([CH3:4])[CH3:2])(=[O:17])[CH3:15].[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:52])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]

Participants

16

Reactant 4

HCID 284Formic AcidHCID 6212ChloroformHCID 6344DichloromethaneHCID 98106019-Deoxo-9a-aza-9a-homoerythromycin A

Product 3

HCID 6584Methyl AcetateHCID 7915Isopropyl AcetateHCID 447043Azithromycin

Reagents, catalysts & solvents 9

HCID 111,2-DichloroethaneSolventHCID 180AcetoneSolventHCID 702EthanolSolventHCID 887MethanolSolventHCID 3776IsopropanolSolventHCID 5943Carbon TetrachlorideSolventHCID 6569Methyl Ethyl KetoneSolventHCID 7909Methyl Isobutyl KetoneSolventHCID 8857Ethyl AcetateSolvent

Procedure

In accordance with the present invention, the crystalline hydrate of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II) obtained in step (a) is subjected to conventional Eschweiler-Clarke reductive N-methylation (Eschweiler and Clarke, Org. React., 5, 290(1945)), i.e., reacted with a formic acid-aqueous formaldehyde mixture in an organic solvent which may be a halogenized solvent such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; an alcohol such as methanol, ethanol and isopropanol; a ketone such as acetone, ethylmethylketone and isobutylmethylketone; and an ester such as methyl acetate, ethyl acetate and isopropyl acetate, to give azithromycin of formula (I) in a high yield of at least 90%. The amounts of formic acid and formaldehyde used are each independently in the range of 1 to 3 mole equivalents based on the amount of the crystalline hydrate of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II), and the reaction may be performed at a temperature ranging from room temperature to the boiling point of the solvent.

Sources & evidence

ORD record
ord-5d58b035f2bc445d8e8f577783787225
Source dataset
uspto-grants-2007_04
Patent number
US07205395B2

Reaction notes

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