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1. WO2006095359 - SYNTHESIS OF 2-DEOXY-2, 2-DI FLUORO-D-RIBO FURANOSE-3, 5 DI(4-METHY/4-NITRO-CHLORO)BENZOATE AND ITS CONVERSION TO GEMCITABINE HYDROCHLORIDE THEREOF

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[ EN ]

CLAIMS
1. A process for the synthesis of hereto unreported novel intermediates VIZ 2-deoxy-2,2-difiuoro-D-ribofuranose-3,5-di (aroyl) derivative of formula - VbI, where is R=CH31CI1NO2 as described earlier, and its conversion to gemcitabine HCI of formual - I.
2. A claim, as claimed in claim 1 , wherein the dibenzoate of formula - Vb is prepared by reacting 2-deoxy-2,2-di f!uoro-1-oxo ribose of formula -VII with aroyl chloride in an organic solvent in the presence of an organic base as an acid scavenging agent and a promoter at a temperature of 0 - 1000 C.
3. A claim, as claimed in claim 2, wherein the acid chloride used are A- methyl benzoyl chloride, 4-nitro benzoyl chloride and 4-chloro benzoyl chloride.
4. A claim, as claimed in claim 2, wherein the reaction is conducted in ethyl acetate, isopropyl acetate, butyl acetate.
5. A claim, as claimed in claim 2, wherein the organic base used is pyridine, α-picoline, β-picoline, γ-picoline a mixture of picolines etc.
6. A claim, as claimed in claim 2, wherein the promoter used is 4-dimethyl amino pyridine.
7. A claim, as claimed in claim2, wherein the reaction is conducted at a temperature of 50 - 70° C, preferably 60 - 65° C.
8. A claim, as claimed in claim 2, wherein the aroyl derivative of formula - Vb, where R is as given earlier, is isolated in pure form (98 - 99 % HPLC) by crystallizing from a mixture of toluene/hexane, or heptane or petroleum ether.

9. A claim, as claimed in claim 1 , wherein the aroyl derivative of formula - Vb, where R is as described earlier, is converted to gemcitabine HCI of formula - i by
a) reducing the product of formula - Vb, to give a product of formula - Via, where R is as described earlier,
b) converting the product of formula - Via to a product of formula - VIb, were R is as described earlier
c) coupling the .product of formula - VIb with disilylated product of formula - Xl
d) hydrolyzing and
e) purifying
10. A claim, as claimed in claim 9a, wherein the reduction is carried out using VITRIDE in toluene, THF, dioxane, monoglyme, diglyme, etc at - 30 to +300 C.
11. A claim, as claimed in claim 9b, wherein product of formula - Via is converted to a product of formula - VIb, by reacting with alkyl or aryl sulphonyl chloride wherein alkyl/aryl sulphonyl chloride is methane sulphonyl chloride.benzene sulphonyl chloride. p-toluene sulphonyl chloride in dichloro methane or ethyl acetate in the presence of a acid scavenging agent like tri ethyl amine or diiso propyl ethyl amine or N-methyl morpholine at 0 - 50° C.
12. A claim, as claimed in claim 9c, wherein the product of formula - VIb is coupled with the silylated product of formula - Xl in a solvent like toluene, fluoro benzene di chloro ethane, ethylacetate and acetonitrile using tri methyl silyl tri .fluoro methane sulfonate at 60 - 65° C for a duration of 8 to 24 hours.
13. A claim, as claimed in claim 9d, wherein the product formed after coupling of products of formula - VIb and Xl respectively was treated with ammonia or dimethyl amine or diethylamine in anhydrous alcohols like methanol, ethanol, l-propanol or 2-propanol at 0 - 5° C.
14. - A claim, as claimed in claim 9d, wherein ,,-|he hydrolyzed product was purified by,
a) isolation of the crude gemcitabin HCI in aqueous isopropanolic hydrochloric acid
b) leaching the crude product with water
c) crystallizing the water leached product in aqueous organic solvents like ethanol, 2-propanol or acetonitrile or acetone.