Methanol → Mitomycin C

HRID 1461502

Reaktionsgleichung

Reaktionsgleichung von HRID 1461502
[CH3:1][C:2]1[C:22](=O)[C:20](=[O:21])[C:5]2[C@@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C@@:7]3([O:13][CH3:14])[C@H:11]4[NH:12][C@H:10]4[CH2:9][N:8]3[C:4]=2[C:3]=1[OH:24].CO.P(=O)(O)(O)O.[N+:32](=C(C1C=CC=CC=1)C1C=CC=CC=1)=[N-]>C(Cl)Cl.O>[CH3:1][C:2]1[C:3](=[O:24])[C:4]2[N:8]3[C@@:7]([O:13][CH3:14])([C@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C:5]=2[C:20](=[O:21])[C:22]=1[NH2:32])[C@H:11]1[NH:12][C@H:10]1[CH2:9]3

Komponenten

7

Edukt 4

HCID 887Methanol2×HCID 1004Phosphoric AcidHCID 612301,1'-(Diazomethylene)bis(benzene)7×HCID 117273937-demethylmitomycin A5×

Produkt 1

HCID 5746Mitomycin C

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 6344DichloromethaneLösungsmittel4×

Versuchsvorschrift

We turn now to the case where drying (i.e., water removal) is not carried out, i.e., in the case where aqueous solution of basic 7-salt oxide-9a-methoxymitosane is treated directly with acid. The acid is preferably aqueous phosphoric acid and is admixed to provide a pH of 4.7 to 6.5, very preferably from 5 to 6, to produce aqueous solution of 7-hydroxy-9a-methoxymitosane. The reaction of this with diazodiphenylmethane proceeds as follows. The diazodiphenylmethane is admixed. The solvent in which the diazodiphenylmethane is dissolved and/or which is otherwise admixed is a solvent or solvent combination in which both the 7-hydroxy-9a-methoxymitosane and diazodiphenylmethane are soluble and preferably is the combination of methylene chloride and methanol in a volume ratio of methylene chloride to methanol ranging, for example, from 0.5:1 to 3:1. The reaction between 7-hydroxy-9a-methoxymitosane proceeds despite the presence of water apparently as an extractive alkylation where the organic solvent extracts the 7-hydroxy-9a-methoxymitosane from the water phase for reaction in organic solvent phase (preferably methylene chloride). The alkylation reaction to produce 7-(diphenylmethyl)oxy-9a-methoxymitosane proceeds, for example, at a temperature ranging from 0° C. to 30° C. for 1 to 10 hours using an excess of diazodiphenylmethane, e.g., 2 to 5 equivalents of diazodiphenylmethane. During the alkylation reaction, acid, preferably aqueous phosphoric acid, is preferably added periodically as may be necessary to maintain the pH in the range of 4.7 to 6.5, very preferably 5 to 6. When the alkylation reaction is completed, organic phase is separated and substantially pure 7-(diphenylmethyl)oxy-9a-methoxymitosane is recovered, e.g., by drying to remove water and evaporating to remove organic solvent and recovering product from the residue by chromatography on Al2O3 or SiO2. Additional product can be obtained by vigorously mixing the aqueous phase with diazodiphenylmethane in solvent for it and 7 -hydroxy-9a-methoxymitosane, preferably methylene chloride, and reacting, preferably at 15° C. to 25° C. for 10 to 20 hours, and recovering additional product, e.g., by chromatography. Yields from mitomycin C, including product obtained from workup of the aqueous phase, of 40 to 60% have been obtained. These yields are unexpected in view of the Sami, et al article referred to above. The resulting purified 7-(diphenylmethyl)oxy-b 9a-methoxymitosane can be reacted with amines wherein the amino or substituted amino group from the amine displaces the 7-(diphenylmethyl)oxy group to produce the corresponding 7-amino or 7-substituted amino compounds which are known antitumor agents. In other words, 7-(diphenylmethyl)oxy-9a-methoxymitosane is reacted with RNH or RNH2 to produce 7-RN- or 7-RNH-9a-methoxymitosanes respectively where R is aliphatic or cycloaliphatic or aromatic group, which is substituted or unsubstituted, or where R forms a heterocyclic group with N. For example, 7-(diphenylmethyl)oxy-9a-methoxymitosane is reacted with p-nitrophenyldithioethylamine, e.g., as the hydrochloride acid addition salt, in triethylamine/methanol at 0° C. to 30° C. to produce 7-[2-(4-nitrophenyldithio)ethylamino9a-methoxymitosane which is taught as an antitumor agent in Vyas et al, U.S. Pat. No. 4,691,023.

Aufarbeitung

  1. customThe alkylation reaction
  2. customto produce 7-(diphenylmethyl)oxy-9a-methoxymitosane proceeds
  3. customranging from 0° C. to 30° C. for 1 to 10 hours
  4. additionis preferably added periodically
  5. temperatureto maintain the pH in the range of 4.7 to 6.5, very preferably 5 to 6
  6. customWhen the alkylation reaction
  7. customorganic phase is separated
  8. customsubstantially pure 7-(diphenylmethyl)oxy-9a-methoxymitosane is recovered
  9. custome.g., by drying
  10. customto remove water
  11. customevaporating
  12. customto remove organic solvent
  13. customrecovering product from the residue by chromatography on Al2O3 or SiO2
  14. customAdditional product can be obtained
  15. customrecovering additional product, e.g.

Quellen und Nachweise

ORD-Eintrag
ord-1d9d2a4e91d542a8ab26f15c602c220d
Quelldatensatz
uspto-grants-1991_12
Patentnummer
US05075454

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