KR920005743B1 - Process for the preparation of fluoropurine nucleic acid derivatives - Google Patents

Abstract

A method for preparing fluorinated purine nucleic acids of formula (I) comprises a deamino-substitution reaction of a purine nucleic acid of formula (II) by use of tetrafluoro sodium borate and a cpd. of formula t-BuSNOn (where n = 1 or 2) in the presence of acetonitrile. In the formulas, R= triacetyl ribose or thyl; X= methylamine, H or F; Y=OH or F; Z=H or Br; X'= methylamine, H or amine; Y'=OH or amine. Pref. the molar ratio of (II): tetrafluoro sodium borate: t-BuSNOn is 1:2:2. The cpds. (I) have antivirial, antibacterial and anticancer activities.

Description

Method for preparing fluorinated purine nucleic acid

The present invention relates to a new and advanced process for preparing fluorinated purinenucleic acid represented by general formula (I), which are important organic compounds or compounds related thereto that exhibit antiviral, anticancer and antibacterial properties.

(In the formula, X represents -NHMe, -H, -F group, Y represents -F, -OH group, Z represents -H, -Br group, R represents ethyl group or triacetylribose group.)

Briefly describing the preparation method of the present invention, the fluorinated purinenucleic acid of general formula (I) is prepared by converting an amine group to a fluorine group through the deamination reaction of the purinenucleic acid represented by the following general formula (II).

(Wherein X 'represents -NHMe, -H and -NH ₂ groups, Y' represents -NH and -OH groups, and Z and R are the same as in general formula (I).)

Known methods for the preparation of purine nucleic acid derivatives of the general formula (I) known to date have been introduced in various literatures.

1) Method using tetrafluoroboric acid

48% -HBF ₄ was added to triacetyl adenosine and NaNO ₂ was added at -20 ° C to obtain fluorinated purine nucleic acid (JA Montgomery and K. Hewson, J. Org. Chem., 34, 1396 (1969)). However, this method is not practical due to the disadvantage that the reaction is performed at low temperature under strong acid conditions and the yield is very low (3.3% yield).

2) Method using hydrogen fluoride

Triacetylribo-2 and 6-diaminopurine were reacted with anhydrous HF / pyridine and t-butylnitrite (t-BuONO) at −20 ° C. to produce triacetyl-2-fluoroadenosine in 48% yield [ MJ Robins and B. Uznanski, Can. J. Chem., 59, 2068 (1981). This method is known to be difficult to separate in the final step due to the disadvantage of using hydrogen fluoride, which is relatively difficult to handle but has a relatively good yield. In addition, there is a disadvantage that you must use a stainless steel or plastic container without using a candle.

The present invention aims to provide a new and advanced method for producing fluorinated purine nucleic acid derivatives in higher yields by improving the problems raised in conventional manufacturing methods and having mild reaction conditions. According to the present invention, purinucleic acid having a primary amine group of general formula (II) is subjected to deamino-substituted reaction in sodium tetrafluoroboron (NaBF ₄ ) and a compound of general formula (III) below in an organic solvent, A method for preparing the purine derivatives of I) is provided.

t-BuSNO _n (III)

(Where n is an integer of 1 or 2)

In more detail, the preparation method of the present invention is first dissolved in purified acetonitrile of purine nucleic acid and sodium tetrafluoroboron in general formula (II), and then a compound of general formula (III), that is, t-butylthionitrite Fluorinated purinenucleic acid of general formula (I) is prepared using (t-BuSNO) or t-butylthionite (t-BuSNO ₂ ).

In this reaction, the molar ratio of purinenucleic acid: tetrafluoroboronate of the general formula (II) to the compound of the general formula (III) is preferably about 1: 2: 2.

Since the production method of the present invention uses NaBF ₄ which is stable and easy to handle and uses thioniterate, which is an excellent nitrification reagent, the reaction conditions are milder than those of the known methods, and the separation of the target product in the final step is easy, and thus the yield is good. It turned out to be. The production method of the present invention is represented by the following scheme.

The following examples illustrate the invention in more detail but are not intended to limit the scope thereof.

Example 1

Preparation of (2 ', 3', 5'-tri-O-acetyl) -6-fluoronebrarin

i) When t-butyl thionite (t-BuSNO) is used

(2 ', 3', 5'-tri-O-acetyl) atenosine (197mg, 0.5mmol) and sodium tetrafluoroboron (110mg, 1mmol) were dissolved in purified acetonitrile (4ml) and then t Butyl thionite (119 mg, 1 mmol) is slowly added and stirred at room temperature.

After stirring for about 20 hours, the reaction solution was extracted with dichloromethane (20ml × 3), and the target product was separated and purified through chromatography. (123mg, 62% yield).

¹ H NMR (CDCl ₃ ): δ 2.1 (t, 9H), 4.4 (m, 3H), 5.6 (t, 1H), 5.9 (t, 1H) 6.3 (d, 1H), 8.2 (S, 1H), 8.7 (S, 1 H).

Ii) When t-butylthionitrate (t-BuSNO ₂ ) is used

(2 ', 3', 5'-tri-O-acetyl) adenosine (197mg, 0.5mmol) and sodium tetrafluoroborate (110mg, 1mmol) were dissolved in purified acetonitrile (4ml) and then t-butyl Thionitrate (135 mg, 1 mmol) is slowly added, followed by stirring at room temperature for about 20 hours. After the reaction mixture was extracted with dichloromethane, the desired product was separated and purified through silica chromatography (about 26% yield).

Example 2

Preparation of (2 ', 3', 5'-tri-O-acetyl) -2-fluoro inosine

i) When t-butyl thionite (t-BuSNO) is used

(2 ', 3', 5'-tri-O-acetyl) guanosine (0.5 mmol) and NaBF ₄ (1 mmol) were dissolved in purified acetonitrile (4 ml), and then t-BuSNO (1 mmol) was slowly added thereto. Add. After stirring for about 48 hours at room temperature, the reaction mixture was extracted with dichloromethane (30ml × 3) to give the desired product in about 30% yield through silica gel chromatography.

IR (neat) 1760, 1570, 1220 cm ⁻¹ ;

¹ H NMR (CDCl ₃ : 2.1 (t, 9H), 44 (m, 3H), 5.6 (t, 1H), 6.0 (t, 1H), 8.0 (s, 1H).

Ii) When using t-butyl thionite (t-BuSNO ₂ )

In i), instead of t-BuSNO, t-BuSNO ₂ was used to stir at room temperature for about 15 hours, and the target product was obtained in about 48% yield through the same purification process as i).

Example 3

Preparation of (2 ', 3', 5'-tri-O-acetyl) -2-fluoro-8-bromoinosine

(2 ', 3', 5'-tri-O-acetyl) -8-bromo guanosine (0.5 mmol) and NaBF ₄ (1 mmol) were dissolved in purified acetonitrile (4 ml), followed by t-BuSNO Slowly add ₂ (1 mmol). After stirring at room temperature for about 10 hours, the target product was obtained by chromatography using about 56% yield.

¹ H NMR (CDCl ₃ : 2.1 (t, 9H), 4.5-6.1 (m, 5H), 9.3 (brs, 1H).

Example 4

Preparation of 9-ethyl-6-fluoro-2-methylaminopurine

6-amino-9-ethyl-2-methylaminopurine (98 mg, 0.5 mmol) and NaBF ₄ (1 mmol) are dissolved in purified acetonitrile (4 ml), and then t-BuSNO ₂ (1 mmol) is slowly added. After stirring for about 2 hours at room temperature, the desired product was separated and purified through silica column chromatography.

mp = 175 ° C. (decomp.)

¹ H NMR (DMSO-d ₆ ): 1.5 (t, 3H), 3.5 (d, 3H), 4.3 (q, 2H), 7.6 (brs, 1H), 8.2 (s, 1H).

Claims (3)

The defluorination of the fluorinated purine nucleic acid of general formula (I), characterized in that the depurification reaction is carried out in the presence of acetonitrile using sodium tetrafluoroboron and the compound of general formula (III) to the purine nucleic acid of general formula (II). Manufacturing method.

(Wherein R represents a triacetyl ribose or ethyl group, X represents a methylamine, hydrogen or fluorine group, Y represents a hydroxy or fluorine group and Z represents hydrogen or bromine.)

(Wherein R represents triacetyl ribose or an ethyl group, X 'represents methylamine, hydrogen or amine group, Y' represents hydroxy or amine group and Z represents hydrogen or bromine.) t-BuSNO _n (III) (Where n is an integer of 1 or 2) The compound of claim 1, wherein when R is a triacetyl ribose group, Y is fluorine when X is methylamine, Y is fluorine when X is hydrogen, and Y is hydroxy group when X is fluorine. The method for producing the fluorinated nucleic acid of (I). The fluorinated purine nucleic acid of formula (I) according to claim 1, wherein the molar ratio of the compound of formula (II) purine nucleic acid: sodium tetrafluoroboron: compound of formula (III) is 1: 2: 2. Manufacturing method.