DD279248A1 - PROCESS FOR THE PREPARATION OF 2 ', 3'-DIDESOXYTHYMIDINE-5'-DIAMIDOPHOSPHATES - Google Patents

Abstract

The invention relates to a process for the preparation of 2,3-dideoxythymidine-5-diamidophosphates of the general formula I. Field of application of the invention are the chemical and pharmaceutical industries. According to the invention, the compounds of the formula I are prepared by converting 3,5-dideoxythymidine through phosphorylating agent into 3,5-dideoxythymidine-5-dichlorophosphate and reacting this with ammonia or amines. Formula I

Description

Il

H -ti ^ ' \ / CH>

Cl

transferred, this brings with ammonia or with methylamine, dimethylamine or morpholine to the reaction and the resulting compound I isolated in a conventional manner from the reaction mixture and purified.

2. The method according to claim 1, characterized in that is used as the phosphorylating agent Phosphcroxychlorid, wherein the molar ratio Didesoxythymidin / Phosphoroxychiorid as 1: 1 to 2.8.

3. The method according to claim 1 and 2, characterized in that the phosphorylation is carried out anhydrous and in the presence of trimethyl or triethyl phosphate.

4. The method according to claim 1, characterized in that reacting the compound II with an aqueous ammonia or amine solution in excess.

Field of application of the invention

The invention relates to a process for the preparation of 2 ', 3'-Dideosxythymidin-5'-diamidophosphates. Field of application of the invention is the chemical and pharmaceutical industry.

Characteristic of the known state of the art

It is known that Nukleosiddiamidophosphate can be prepared by reaction of the corresponding dichlorophosphates with ammonia or with amines (S. Bottka and I. Tomasz, Tetrahedron, 35 (1979) 2909-2912). 2 ', 3'-Didesoxythymidindii.midophosphate the general formula I are not known.

Object of the invention

It is the object of the invention to develop a process for the preparation of the novel 2 ', 3'-dideoxythymidine-5'-diamidophosphates of general formula I.

Explanation of the essence of the invention

According to the invention, the 2 ', 3'-dideoxythymidine-5'diamidophosphates of the general formula I,

> ι

-C "Ji'Mj

in which R has the already mentioned meaning, prepared by reacting 2 ', 3'-dideoxythymidine with a phosphorylation target, e.g. B. phosphorus oxychloride, which is preferably used in a molar ratio of 1: 1 to 2.8, to the 2 ', 3'-Didesoxythymidin-5'-dichlorophat of formula II and the latter reacts with ammonia, methylamine, dimethylamine or morpholine.

The inventive conversion of the 2 ', 3'-Didesoxythymidins in the corresponding Oichlorophosphat is generally carried out in such a way that in the mixture of the nucleoside with a trialkyl phosphate, preferably trimethyl or Triethylphosphai with the exclusion of water with cooling (preferably at O ⁰ C. to 3 ° C.) and vigorous stirring of freshly distilled phosphorus oxychloride. Subsequently, stirring is continued at the temperatures mentioned until the nucleoside used is no longer detectable by chromatography. After a total reaction time of about 5 hours, an aqueous ammonia or amine solution is then added to the resulting clear solution in excess and the mixture is concentrated to dryness in vacuo, wherein the bath temperature does not exceed 35 ⁰ C. The residue, which generally still contains small amounts of unreacted starting material and by-products formed, is dissolved in water, the solution is adjusted to a pH of 8.5 and added to an ion exchange column (Dowex 1x10, HCGvForm). The elution of the column is carried out with water. The fractions containing the final product are combined and concentrated to dryness in vacuo. The residue is rotary evaporated several times with water / methanol mixtures.

The compounds of general formula I are new. They represent a new mode of transport of 2 ', 3'-dideoxythymidine, which is of interest as a potential cytostatic and virostatic. The compounds furthermore serve as valuable synthesis intermediates for the preparation of nucleotide derivatives of the dideox / thymidine type. The invention is illustrated by the following example:

embodiment

2 ', 3'-Didesoxythymidine-5'-diamidate I (R = NH ₂ ! 113 mg (0.5 mmol) 2', 3'-dideoxythymidine are dissolved in 1.5 ml of freshly distilled and dried trimethyl phosphate with stirring 120 ml (1.32 mmol) of freshly distilled phosphorus oxychloride are added dropwise to the cooled solution while stirring at 0 ° C. After 5 hours, a mixture of 3.5 ml of concentrated aqueous ammonia / 2 ml of water is added to the reaction solution and the solution is rotated in a high vacuum The residue obtained is taken up in about 5 ml of water, the solution is adjusted to a pH of 8.5 with ammonia and placed on a Dowex 1 × 10 column (HCO ₃ -form, 80 g of ion exchanger, column 2 × 60 cm). The elution is carried out with water and from fractions 11 to 22 (8 ml each) 72 g of the pure substance are isolated.

Thin Layer Chromatography: (Merck Finished Plates, Kieselgel 60 F-254), R ₁ 0.52 (n-propanol / 25% aqueous ammonia / water 8: 2: 1, v / v / v);

UV spectroscopy: K _m3 , 268.5 nm (water).

Claims (1)

1. A process for the preparation of 2 ', 3'-dideoxythymidine-5'-diamidophosphates of the general formula I, in which R =NH ₂ , NHCH ₃ , N (CH ₃ I ₂ N ₂ O) , characterized in that 3 ', 5'-dideoxyvhymidine is converted by reaction with a phosphorylating agent in the presence of a trialkyl phosphate into the 3', 5 'Didesoxythymidine-5'-dichlorophosphate of the general formula II