Hydrochloric Acid → Cytosine

where R1 is H, R3, R4, 2′-deoxyribosyl, R4 is alkyl or aryl, X is N or C, wherein if X in the analogue of formula I is N, then R5 is no substituent and if X in the analogue of formula I and/or II is C or if X in the analogue of formula II is N, then R5 and R6 are independently alkyl, aryl, hydroxyalkyl, aminoalkyl, hydroxyl, carboxyl, amino group, alkoxyl, aryloxyl, aminoalkyl, aminoaryl, thio group, sulfonyl, sulfinyl or halogen, wherein cytosine and aromatic or alkyl aldehyde in the quantity of 4-6 eq are added to anhydrous methanol or ethanol, NaBH4 or BH3×TMS are introduced to the mixture in the amount of at least 1.1 eq relative to the aldehyde in order to reduce the obtained imine, the reducing agent is then neutralized with hydrochloric acid and the mixture is evaporated, poured into water and extracted with ethyl acetate or butanol to obtain a mixture of alcohol and modified cytosine in ethyl acetate or butanol; next, the separated organic layer is evaporated to dryness to obtain the pure product or extracted with aqueous solution of an inorganic acid to obtain an aqueous solution of cytosine hydrochloride or other modified cytosine salt, depending on the acid used, where the resulting salt is free of alcohol; the solution is then neutralized with a hydroxide or other hydroxyl group donor and again extracted with ethyl acetate or butanol; the organic layer is evaporated to obtain pure product which is then subjected to freeze drying. Preferably, when aromatic aldehyde is used, magnesium is added to anhydrous methanol or ethanol in the amount of at least 4 eq relative to cytosine and heated until complete dissolution of magnesium filings; next, at least 2 mmol of cytosine is added, followed by the aromatic aldehyde in the amount of 4-6 eq, minimum of 4 eq relative to cytosine; next, the reaction mixture is placed in temperature in the range of 45-65° C. for at least 3 hours, and later, a reducing agent, preferably NaBH4, is added to the cooled mixture in the amount of at least 1 eq relative to aldehyde; the mixture is then kept at room temperature for at least 15 minutes, followed by addition of inorganic acid solution; next, the mixture is evaporated, water is added again and the mixture is extracted with ethyl acetate to isolate the product; the separated organic layer containing the product and the aromatic alcohol is evaporated to obtain pure product or extracted with an aqueous solution of inorganic acid to obtain an aqueous solution of modified cytosine hydrochloride or other modified cytosine salt, depending on the acid used, where the resulting salt is free of alcohol; the solution is then neutralized with a hydroxide or other hydroxyl group donor and again extracted with ethyl acetate; the organic layer is evaporated to obtain pure product.

1. customthe mixture is evaporated
2. additionpoured into water
3. extractionextracted with ethyl acetate or butanol
4. customto obtain
5. customnext, the separated organic layer is evaporated to dryness
6. customto obtain the pure product
7. extractionextracted with aqueous solution of an inorganic acid

ORD record

ord-5b55f43ec62b404aa71078ffed501b96

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040490B2