DE1695411A1 - Substituted purine nucleosides and processes for their preparation - Google Patents

Description

The invention relates to a method for the production of new and valuable nucleosides. In particular, it relates to new nucleosides which are suitable as solo and for the production of other more complicated nucleosides and nucleotides. 2 ^1- methyl «nucleosides to the content.

The new invention-specific connections can be made through the following Structural formula to be reproduced »

109816/2197

YEAR 71T Al *. 2 Wr. 1 β * τ a evt 7n ** mim «* < ». t.

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HIGH ₂

(D

wherein R _a and R ^, which can be the same or different, stand for hydrogen, hydroxy, lower-alkyl, amine, alkylamine, alkylamine, halogen, mercapto or lower-alkyl mercapto.

The object of the present invention is to provide new 2,6-substituted purine-2 ¹ -methylene nucleosides which can be reacted to form a variety of different nucleosides and nucleotide compounds. When used as intermediate products, the compounds according to the invention can be used to produce various 2 * -Me thy! Nucleotides by reaction with phosphorus compounds. These nucleotides are of value for studying nucleic acid metabolism.

Other objects of the present invention are based on the * description.

BATH ORIGINAL

1 0 9 α 1 _L 6 Z 2 1 9 7

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Typical of the groups R _a and R _fe in the compounds of the invention, namely the compounds I, are hydrogen, alkyl, such as methyl, ethyl and propyl, and no, alkylaalno groups, le, for example, metbylasdno, diethylamino, Xthjlaadno, Dlithylaadno , Propjlasdno and Dipropylamine halogens, such as chlorine or Broa, Hercapto and iJicrJirircHpto, Mer.ryiiaercapto, Xthylneroapto and

The inventive connections become generally new. -wsSstufesveriahTOn yiergestellt · The first stage in this process, namely the step A ₄ is thereby made "un, OAQ a 2" 3f5 * Trl-0-8cyI-2 * "etliyl-D> rlbofuranosyl <halide of the following formula

(II)

Nc

R * O OR **
with a C3ilonaerouri-2 _f 6-subordinated Puriii in the distance!

(in)

HgCl

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with formation of 9- (2,3,5-Trt-0-aoyl-2-roethyl-D-ribofurano- ' syl) -2,6-substituted purine interstitial products from Fortsei

R ¹ OCR ₂

(IV)

where R ₀ and R _{fl represent} halogen, hydrogen, hydroxy, alkyl, acylamino or aoylalkylamino, R ¹ , R * and RV, which can be identical or different, represent acyl groups and X represent halogen. The reaction should be carried out in a temperature range from about 25 ° C. to about 150 ° C. and preferably between 100 ° C. and 140 ° C. for a period of time sufficient to complete the reaction. This period usually varies from about 15 minutes to about 5 hours .. The higher the reaction temperature range is "the quicker 1st implementation completed · The ^2,3,5-tri-0: * cyl-2-methyl" D-rlDofuranosyl halogenlde are new compounds «which by acylation of 2-C-methyl-D-ribono-y-laoton under BiI-

BATH ORIGINAL "* ■ _ 109816/2197 '

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dung of

which by means of a Dialkylborana to obtain 2,3 »S-Tri-O-aoyl-α-C-methyl- (α, fl J-D-rlbofuranose reduced becomes * being the latter compound forming 1 »2, j5, S-Tetwi-O-aoyl-2-C-iaethyX- (α, fl) -D-ribofuranoee further acylated and by means of a halogenation exchange reaction in a suitable solvent into the ribofuranosyl halide converted can be produced.

Reaction stage A in the preparation of the invention mSBen connections goes as follows:

R ¹ OCH ₀

R "0

If I

(H)

(HI)

The compounds of the formula I ¹ according to the invention in which R _a i and / or R _b f, which can be identical or different,

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for hydrogen * halogen, hydroxy, alkyl, amine and lower-alkyl-substituted amine "are obtained by means of a basic Solvoljra reaction of the intermediate compounds" namely the 9- (2,3,5-Trl-0 "aeyl" 2-methyl-D- ribofuranoeyl) -2,6-substituted purines (Fonoel IV ¹ ).

The reaction goes as follows:

R ¹ O

fit

(IV ¹ )

basieohe
Solvolyee

HIGH ₂

HO OH

(I ¹ )

In formula IV *, Rt and / nder H. _t mean hydrogen «

c ι

Hydroxy alkyl · "acylamino, Acylalk ^ l% mlno and halogen" while in Fornel I ¹ R _fc i and / or R _b represents hydrogen t "lower alkyl" hydroxy "Aeino, niedrlg ^ alkyl substltulertes amino and halogen are ·

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Another feature of the present invention are compounds of the formula I ** In which R _a "and / or R _b " stand for alkylamino and dialkylamino "by means of an andnolyte reaction of the interconnections, and" rarely the 9- (2,3 # 5- Trl-0- ^ wjyl-2-ethyl-1> -lbofuranoyl) -2,6-subtitled purines in which the 2,6-purines are substituted in either one or both positions with a halogen (formula IV "), manufactured"

The reaction proceeds as follows t

R ¹ OCH ₂

HH (R),

or

Aminolysis

HIGH ₂

Zn of the formula XV "means R _Q ir and / or R ^ w halogen, R in the andnolyeereagentlen stands for a lower alleyl group, while \ m and R _b « In the formula I ", which can be the same or different, alkylamino or palkylamino mean.

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Oemäfl another feature of the present invention, compounds of the formula I ¹ "" in which R _& «i and / or R _b i» i stand for mercapto or lower-alkyl-substituted mercapto "by means of a meroaptolysis reaction, where R is low in the mercaptolye reagents -Aikyi and M is an alkali or alkaline earth metal * while R ₀ «t and R _d ni in the formula IV ¹ ", which can be the same or the same, mean halogen and R ', R "and R"', the can be the same or different, represent aoyl «produced ·

The conversion takes place as follows

R ¹ OCH ₂

Thiourea
or MSR

Mercaptolysis

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If thiourea is used as the mercaptolysis reagent, the alkyl blocking groups on the R ¹ , R "and R"'parts are not removed; the intermediate product obtained must be subjected to a basic solvolysis so that the compounds of the formula I * 'according to the invention can be obtained.

In formula IV ¹ "H _o « t »R _d » »* Ri R '# R" and Ε "' have the same meanings as in _{formula IV", while Rm and R b} nt in formula I ¹ ", the are same or different, stand for mercapto or lower alkyl mercapto-substltuiertes "In general, the process comprises reacting a erflndungsgemftSe hydrochloric & ereurl-2 * 6 ~ aubstituierten purines with a _2> 5,5-tri-0-acyl'2- methyl-D-ribofuranoeylhalogenld to form a 9- (2,3,5-tri-0-acyl-2-n »thyl-D-rlbofuranosyl) -2-6-8 substituted purines of the compounds according to the invention either aolvolysed, amolysed or mercaptolysed.

In particular, the compounds according to the invention In stage A by converting a Chlormerouri ~ 2,6-eubstitu-

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ated purines with a 2,3,5-tri-0-aoyl-2-methyl-D-ribofuranosyl halide, wherein the reaction is essentially stoohioaetrisohen amounts at a temperature between about 25 and about 150 ° C and preferably between about 100 and 140 ⁴ C is carried out »obtained. At this stage, the reaction is carried out in a suitable solvent. The choice of solvent is not important as long as it is inert and boils between about 25 and 150 ° C. Examples of such solvents are benzene, dibufcyl ether, cyelohexane, toluene, xylene and the like. The solvents to be used are toluene and xylene. The reaction is usually complete after about 15 minutes to about 5 hours, depending on the reaction temperature chosen. After the intermediates have been obtained in stage A, these compounds are either solvolyzed, aminolyzed or mercaptolyzed in step B, depending on the desired 2,6-substituents in the purine components of the compounds.

in case of a solvolysis, the reaction is in Qegenwart a basic catalyst in a suitable solvent in a temperature range of approx your 5 * C to approx clock 150 ⁹ C, preferably approx & hr 65 * C to ungefihr 9O * C WSH * rend a Beaktionszeit of about 15 Performed for up to about 5 hours. The lungs' reaction time depends

BAD ORIEiNAL - ¹⁰ "109816/2197

of the temperature and the catalyst used and the solvent used from · Examples of basic catalysts are Alkall- and Brdalkallbasen and their corresponding alky late and solutions of Amnoniak * Ami n × n and substituted amines. Examples of solvents are the C ₁ ^ alcohols. Methanol is preferably used as the solvent. *

In the case of aainolysis, the reaction is carried out in the presence of ammonia or a monoalkyl or Dielkylaaln in a temperature range from about 25 to about 150 ° C and preferably about 85 to about 110 ° C for a reaction time of about 15 minutes to about 5 hours. Examples of amines are methylamine, Dlmethylaadn, Xthylamin, Diäthylamln, Propylasdn and Dlpropylamln · a

In the case of mercaptolysis, the reaction in counter wa of thiourea or a metal salt of a lower alkyl mercaptan In a temperature range of approximately 25 * C to about 1 * yO * C and preferably about 65 to about 90 * C durohgeftflirt, with the reaction time about 15 minutes to about 5 hours. Examples of alkali or alkaline earth salts of alkyl mercaptans are

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Sodium roethylraercaptan, sodium ethyln »rcaptan, sodium isopropyl mercaptan, KaliuwBethylnierceptan and Calcium " methyl mercaptan.

In the following, representative examples of new inventions Compounds to which the invention

* should not be restricted, given:

9- (2-methyl-D-ribofuranoeyl) -2-raethylpurine 9- (2-methyl-D-ribofuranosyl) -6-roethylpurine 9 * (2-methyl-D-ribofuranoeyl) -2,6-dinethylpurine 9- (2-methyl-D-ribofuranosyl) -2-ethyIpurine 9- (2-Ethyl-D-ribofuranosyl) -6-ethyl ipurine 9- (2-M3 t) »yl-D-ribofuranosy 1) -2,6-diethylpurine 9 · (2-methyl-D-ribofuranosyl) -2-propyIpurine 9- (2-methyl-D-ribofuranosy1) -6-propyIpurine

* 9- (2-methyl-D-ribofuranoeyl) -2,6 «dipropylpurine 9 * (2-methyl-D-ribofuranosyl) -2-atainopurine 9 "(2-methyl-D-ribofuranoay1) -6-aminopurine 9. (2-Methyl-D-ribofuranosyl) -2,6-diaminopurine 9- (2-methyl-D-ribofuranosyl) -2-methylaj binopurine 9- (2-methyl-D-ri bofuranoay 1) -6πββ thylaBiinopurine 9- (2-methyl-D-ribofuranosyl) -2,6- <3% β thyla binopurine 9- (2-methyl-D-ribo furanoayl) -2-kthyla «inopurine 9- (2-Metliy 1 -D-ribofuranosyl) -6-Kthylaninopurine

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9- (2-Methyl-D-rlbofuranoeyl) -2 «6-diethylaminopurine 9- (2-Methyl-D-ribofuranosyl) -2-hydrojqr {wrin 9- (2-Methy1-D-ribofuranosy1) -6-hydroxypurine 9 "(2-methyl-D-ribofuranosyl) -2,6-dihydroxypurin 9- (2-methyl-D-ribofuranoeyX) -2Hoethyl-6-aninopurine 9- (2-methyl-D-idl" for "noeyl) -2-methyl-6-methyl-6-methyl-purln 9- (2-methyl-D * rll »furano8yl) -2-i-methyl-6-methylpurin 9- (2-methyl-D-ribofur» no8yl) -2-amino-6- » ethyl minopurin 9- (2-methyl-D-ribofuranoeyl) -2-ethyl-6-hydpoxypurin 9 · (2-methyl-D-rilx> fiiranoeyX) -2-hydroxy-6-a * thylpurin 9- (2-methyl -D-ritr ^ furanosyl) -2- »alno-6-hydroxy purine 9- (2-methyl-D-ribofuranosyl) -2-hydroxy-6-aailnopurine 9 ·» (2-.Methyl-D-ribofuranosyl) - 2 »aethylamlno-6-hydroxypirin 9- (2 * .Methyl-D-ribofuranosyl) -2-hydroxy-6-n» thy lamlnopurine 9 " (2-methyl-D-ribofuranoeyl) -2-thy lamlnopurine 9 - (2-Methyl-D-riboAiranosyl) -6-dlBtthylÄiBinopurine

9- (2-Hethyl-D-ribofuranoeyl) -2-HWthyl * mino-6-dimethy 1-andnopurin

9- (2-methyl-D-ribofurftnosyl) -2-nercaptopurin 9 * (2 * methyl-D-ribofuranosyl) -6-B-rcftptopurine 9- (2-methyl-D-ribofuranoeyl) -2,6 «dimtroaptopurin 9- (2-methyl-D-ribofuranoeyl) -2- "" thyl-6-roercaptopurine 9 * (2-methyl-D-ribofur * no * yl) -6-ethyl-6-mercaptopurine

9 * (2-methyl-D-ribofuranoyl) ^ -etrqapto-o-methylmeroaptopurine

9- (2-methyl-D-ribofuranoeyl) -2 _f ö ^ dlohlorpurin

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9 * (2-methyl-D-rlbofur «noeyl) -2-chloropurine 9- (2-methyl-D-ribofuranosyl) -2-bvo * purln

9 »(2-methyl-D-rtbofuranoayl) -6-ehlorpurine

01 · compounds according to the invention have a wide range of uses · »» * :! t often. Si · are in the Χβββ »<* i · RibonuclelnaaYire (RHS) -3ynthee ·, for example, the synthesis of unholy RNA, in Ehrlloh-Asoite cells and ΚΒ-Ζ · 1-len do inhibit. In in vitro tests, the birth rate of KB cells is suppressed, as is the case with the incorporation of byoxanthin into acid-insoluble BNS. The compounds are therefore suitable as anti-metabolic products, as cell growth inhibitors and also for studies of metabolic systems, taking into account their cell growth-suppressing effect, the compounds also have favorable oytotoxic properties.

Duroh treatment with Phoepborsiuredexnvaten according to known Methods convert the compounds of the invention into nuoleotides be transformed. Ale "oil" they are for formulation of media for the selective) · Breeding of animal Oewebexella suitable. These nucleotides can also be used to study the

BATH ORIGINAL

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Nucleins & ure metabolism can be used.

The following examples illustrate the invention without it to restrict.

example 1

Preparation of 2,3,5-tri-u "b" nxoyl-2-methyl-D-rl "x> for Änoeylchlorld

This example shows the synthesis of a new starting material, which is used for the preparation of the compound according to the invention.

A solution of 5 g (30 * 8 mmol) 2-C-Methy1-D-ribono-p-lactone In 100 ml of dry pyridine it is cooled to approximately 5 * 0 and treated with 17 ml of benzoyl chloride. The mix will Heated to 65 to 70 ° C for 4 hours and kept at room temperature for 16 hours. The reaction will be deleted with 2 ml of water for 23 minutes to decompose any sediments Benzoyl chloride stirred, whereupon the pyridine was eroded reduced pressure is removed · The thick residue is dissolved in 100 ml of chloroform, whereupon the chloroform old three 50 ml servings of 1Q1 / 1 hydrochloric acid «two 50 tbsp servings a lOjf-lgen sodium carbonate solution and two 30 al-portions Water is washed. The dried chloroform «

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solution is concentrated, whereupon the residue is dissolved in ether is dissolved »The ether solution is concentrated to 250 ml; after several hours of cooling down to 5 * 0, 8.8 g (60 *) ao ^ -Trl-O-benzoyl ^ -C-Bethyl-D-rlbo-y-laoton, F. 138-l4O * C * at.

A solution of 7 β (1 ** 7 «mol) 2,3,5-tri-0-ben * ojrl-2-C-methyl-D-rlbono - ^ - laoton In 50 tablespoons of dry tetrahydrofuran is cooled under nitrogen and with 58.8 «1 1« - dlsekundtra «Ieoaaylboran treated * The reaction solution is kept at room temperature for 16 hours. Well the careful addition of 6 sü. Water becomes the nisefaung Refluxed for 0.5 hours. The mixture is Cooled to about 5 ºC, whereupon 11 ½ “1 of a 30 ºC Hydrogen peroxide can be added, the pH value by adding about 7 ml of 3N-Hatrluehydroxyd swisohen 7 and 8 is held. The mixture is made with six 50 ml servings Chlorofo "extracts" the extracts with several servings of haters to be washed. The remaining peroxides are removed by washing the chloroform solution removed with a 30% iron (II) sulphate solution. In the Concentration of the Chlorofomsohloht fall 7.8 g of the crude product in the form of a syrup. The product is chromatographed on 200 g of silica gel in benzene / ethyl acetate

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(4: 1) cleaned. Fractions are obtained from the SSuXe which contain 2.5 g (37 #) 2.5 # 5 ⁱ -Trl-0 "'benawyl-2-C-iaethyl- (a and B) -D-ribofuranose.

A solution of 4.2 g (8.8 mmol) 2,3,5-tri-Q-oenzoyl-2-C-methyl- (a, fi) -D-ribofuranose (the small amount of 3,5-Di-O benzoyl-2-C-methyl- (a, fl) -D-rlbofuranoee contains) In 80 al dry Pyrldln is cooled and with 8.0 ml (68 oMol) Benzotrichloride treated. Dl · mix is for 4 hours to 90 ° C and then cooled to about 5 * 0.

A small amount of water is added before the mixture

For 0.5 hours to decompose excess benxoyl

Chloride is stirred. The reaction mixture is concentrated,

whereupon the residue was dissolved in chloroform · The chloroform solution is washed with three 50 πα portions of a 10 £ strength hydrochloric acid, bicarbonate solution "three 50 ml portions of a saturated Natriumbicar- (and three 50 ml portions of water. Di · dried Ghloroforosohlcht is concentrated , resulting in 5 * 1 g of an oil, adding 50 ml of Xther results in 2.16 g

(420) 1,2,3 » 5-Tetra-0-ben» oy1-2-C-raethyl-fl-D-rlbofuranoee,

F. 155-156 * 0. When the filtrates are concentrated, 2.9 g fall

(57 $) an essentially pure l * 2,; 5,5-tetrm-O-bensQyl-2-C-raetnyl-a-D-ribofuranose In the form of an oil

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To 100 el of a saturated ventilation of chlorine fiber in Xtber there are 2 al acetyl chloride and 1 «$ C (2.6« mol)

given.

Dl «Solution HlTd svel hour ·» long at glass temperature «• hold, whereupon the Xther removes under reduced pressure «Lvd · fOnf 25 al-Portlon ·» «in the troelcan ··! Toluene« trdm oaoheinander under v «ndnd« rt «m pressure from du itad« ntf «rnt. The BHolftand is applied in trookm-xtter and Eohnell «it cold, saturated 8atriu« bloarbonatlO «une and EehlieBUoh old cold water. Well the drying the solution is consolidated, with a return from

is obtained

Example IA

\ Herateilung of 2 _# 3 # 5 Tri ^ -ben "oyl-2Heethyl-D-ribofuranosyl · brosld '.

Bine solution au * 1.5 g (2.6 rttel) 1,2,3,5-Tetra-0-benxoyla ^ C-eethyl-a-D-ritKJfuranoee, soft gaseous Example 1 has been provided 1st »In 7 * 5 al acetic acid old 0 * 25 si Aoetylbroeld and 7.5 wl of a 32 pound solution (Oewloht / Oewicht) von Bosüaserstofff Treated in acetic acid · The mixture is held at 25 * 0 for 24 hours. Then the mixture is concentrated and a part of dry toluene under different

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tem pressure distilled off the residue to remove excess Remove hydrogen bromide and acetic acid · The residue is dissolved in dry ether and sohneil with cold saturated sodium bicarbonate solution and finally with cold Water washed. After this. Drying, the ether solution is concentrated, leaving a residue of 2,3,5-tri-O-benssoyl-2-C »methyl-ß-D-ribofuranosyl bromide is obtained.

Example 2

Preparation of 9- (2,3,5-tri-0-beiizoyl-2-methyl-D-ribofuranosyl) -2-acetamido-6-hydroxypurine

About 25 ml of xylene are distilled off from a suspension of 5 * 95 g (0.014 hol) of chloromercuric-2-acetamido-6-hydroxypurine in 173 oil of xylene to remove the last traces of water. The suspension is cooled to 25 ° C., whereupon 2, 2, .5 "TrI-O-benzoyl-2-methyi-D-ribofuranosyl chloride, which is obtained from 8.1 g (0.014 mol) l, 2.5 _# 5 -Tetra «0-benzoyl-2-methyl-D« ribofuranoBe prepared in 25 ml of dry xylene must be added * The mixture is stirred and heated to a temperature of about 50 to about 100 ° C. The solid changes from a granular form After refluxing for an hour, the hot mixture is filtered to remove undissolved solids by leaching the solids with three 50 ml portions of boiling water

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Chloroform is further removed from the public product * with the oil-free starting chloro-mercurides and inorganic salts remaining. The original filtrate is diluted with two volumes of petroleum ether, whereupon the solid which separates out is dissolved in the chloroform solution obtained above Washed water. The dry ChloroforBchioht is concentrated «whereby 9- (2,3 * 5-Tri-O-Denzoyl-S-methyl-D-ribofuranoayl) -i
is obtained.

Example 3

Production τοη 9 * (2 «>« 5 * Tri-> 0 "> benzoyl-2-methyl * D-> ribofuranoayl)« 6 ^ N> Biethylbenzaaidopm ^> in ■

Vngefsnr ISfO B1 xylene is distilled off from a suspension of 9 * 5 g (19 * 5 "mol) of chloromeroitri ~ 6" N "methylbenr ^ injdopurine in 500 μl of xylene. The mixture is cooled, whereupon a solution of 2,3,5-tri-0-denxoyl-2-methyl-D-ribofuranosyl chloride (from 8 * 2 g (14.1 dMol) l _v 2 _# 3 «5« Vetra- O-benzo3rl * 2-laethyl-D-ribofuranoae) in 50 μl of dry xylene is added. The reaction mixture is stirred and refluxed for 20 minutes. The hot mixture is filtered «wob«! 3 g of unreacted starting OhlorBerouripurine are recovered · The piled is concentrated to dryness, whereupon

BATH ORIGINAL -20 - 109816/2197

the oil obtained as a residue is washed in 300 ml of chloroform with two 80 ml portions of a 30% strength potassium iodide solution and two 80 ml portions of water. The Olrüokstand obtained after removal of the chloroform is filled on a short column packed with 140 g of washed with acid alumina 1st "In benzene-chloroform: initialed ohromatogra- λ (9: 1). The fractions are pooled and concentrated; 9- (2,3 * 5-tri-0-benioyl-2-methyl-D-rlbofuranosyl) -6-N-methyl-benzamidopurine is obtained.

Example 4

Preparation of 9- (2 _# 3,5- ^ rl-0-benzoyl «2-methyl-D-ribofuranosyl) -6-chloropurine

Approximately 100 ml of xylene are aue a suspension of 6.55 "g (16.8 mmol) Chlorinerouri-6-ohlorpurin in 460 ml 3QrIoI door removal of the last traces of water removed by distillation Sine solution of 9 # 05 g (l6 _# 8 mHol) 2.3 "5 ~ Trl" 0-benzoyl-2 "* methyl ~ D-ribofuranoeyl bromide in 40 ml troubled xylene is added to the stirred suspension at 25 ° C. The mixture is kept in the furnace for two hours the hot mixture is filtered to remove insoluble material. The piltrate is concentrated to 150 ml and diluted with 300 ml of petroleum ether. The mixture is kept at 5 ° C. for one hour and filtered. The solid is mixed with three 20 ml

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Fortionen Petrollther washed and dried. The raw pro The product is dissolved in 300 ml of hot chloroform and mixed with two 80 ml portlons of a JOjt-igen potassium iodide solution and two Washed 80 ml portions of water. The dried (MgSO ^) Chloroform is concentrated, whereby 9- (2,3 * 5-Trl-0-benzoyl-2-ethyl-D-ribofuranosyl) -6-chloropurine is obtained. The product is chromatographed on a short aluminum tube purified in chloroform.

Example 5

Preparation of 9- (2,3,5-tri-0-benzoyl-2-methyl-D-. ribofuranosyl) -2,6-dibenzaeidopurine

Approximately 100 ml of xylene are obtained from a suspension of 5.01 g (8.43 mmol) Chloia »2,6-dibenxamldopurln in 370 ml Xylene is evaporated to remove the last traces of water. The suspension is cooled to room temperature * whereupon a solution of 4.55 g (8.43 mmol) 2,3 * 5-Arl-0-bensoyl-2-mebhyl-D-ribofuranosyl-broeid in 37 ml of dry xylene is added; the suspension is stirred during the addition. The mixture is refluxed for two hours and then filtered whole. UnlSellcne material is thereby obtained removed · The filtrate is diluted with 400 ml petroleum ether and Cooled in a Slsbad · The Feetatoff is removed and dried. The product falls as a complex with

BAD QRIQ1NAU 109816/2197

The mercury (II) halide of the product is dissolved in 100 ml of chloroform and washed with two 40 ml portions of a 50% potassium iodide solution and two 40 ml portions of water. The dried (MgSO ^) chloroforal solution is concentrated under reduced pressure, whereby 9- (2,5 # 5-Trl-0-benzoyl-2-pethyl-D-ribofuranoayl) -2j 6-dihenza-type dopurine is found. i

Example 6

Preparation of 9- (2,3,5-Trl-0-benzoyl-2-ethyl-D-rlbofuranoayl) -6-methylpurin

A suspension of 3.7 g (10 sffol) of chloro-oil-6-ethylpurine [Daroll and Lowy, J.Ae.Chee.Soo, 23b 1 ^ 50 (1951)] in 200% of xylene is made by distilling off about 50% m xylene dried · The cooled suspension is achieved by *, 9 * g (10 nmol) of 2,3,5-Trl-0-benxoyl-2- 'ethyl-I> -rlbofüranoeylohlorid "In JO al of dry xylene, treated. The mixture is stirred and refluxed for two hours after which it is filtered to remove insoluble material. The piltrate is diluted with 4 volumes of Petrolfither * and the mixture is filtered in an ice bath after cooling for two hours. The solid is dissolved in 200 ml of chloroform and washed with two JO ml portions of a 20% aqueous 1Eallum iodide solution

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is dried (anhydrous MgSO ^) and a »residue from amorphous 9- (2,3,5 - ^^^ - ben * oyl-2-methyl-D-ribofuranoeyl) - 6-ethylpurine concentrated"

Example 7

Preparation of 9- (2,3,5-tri-0-benxoyl-2-methyl-D- ribofuranosyl) -6-benxami <lopurine

A suspension of 2.82 g (5 * 95 mol) of powdered chlonaerouri-e-benxamidopurine in 200 ml of xylene is dried by distilling off 100 ml of xylene. The mixture is cooled, whereupon a solution of 2.3 * 5- Tri-0-benzoyl-2-methyl-D-ribofuranosyl-chloride [prepared from 3.45 g (5 * 95 BaMoI) 1,2,3 * 5-tetra-0-benzoyl-2 "methyl-D-ribofuranose] in 30 ml of dry xylene is added. The mixture is stirred and held at the backflow for 80 minutes. The hot mixture is filtered and the solid is washed with 25 ml of hot xylene ml of petroleum ether is diluted, whereupon the mixture is filtered after storage for 20 hours at 5 ° C. The solid is dissolved in 300 ml of chloroform *, whereupon the solution is mixed with twelve 20 ml portions of a 30% ± efine potassium iodide solution and two 20 ml portions of water is washed. When the dried chloroform solution is concentrated, an amorphous product is obtained, which is dissolved in 70 g of aluminum oxide Ethyl-

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acetate-chloroform (1: 4) is chromatographed. "The fractions which, after thin-film analysis of aluminum oxide in ethyl acetate-chloroform (1: 4) only give one spot (R _f * 0.65), are combined! After concentration of the solvent, 9- (2,3,5 * tri-0-benioyl-2-methyl-D-rlbofuranosjl) "6-benza" dopurin is obtained as an amorphous solid * '

Example 8

Preparation of 9- (2-methyl-D-rlbofuranoeyl) -6-dinaethylaminopurine

A suspension of 1.0 g (1.57 "Hol) 9- (2,?, 5-Trl-0-benzoyl-2-ethyl-D-rlbofuranosyl) -6-chloropurine, welohee gemXS at » game 4 has been made in 25 «1 methanol, the 6.5 g Containing dimethylamine is kept in a sealed container for 10 hours Tube heated to lOO'C. The solution is published under ver concentrated under reduced pressure, whereupon the residue in 25 el Water is dissolved. The water solution is with. five 8 Bl servings Benzene washed and then added 2 g Doweac II-X8, a strongly basic anion exchange resin alt a styrene-divinylbenzene-polymerleate matrix, the quaternary ammonium group has, treated * The average size of the Ion exchange is such that it is through a Sieve with a clear Masohen world of 0.15 · »0, ^ 0 mn

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(50-100 mesh) go through it. The Bars, is from de: · »Dow Chemical Company, Midland, Michigan 1576 "7th Edition, Heroic Index" Merck ft Co; "Ine. Rahway, N.J.) The Harx is filtered and aged three 25 al portions WmMer washed The filtrate is concentrated to dryness, where 9- (2-Itethyl-D-ribofii «u» eyl) -6 ^ 1ieethylaeinopurin is obtained.

Example 9

Division of 9- (2-methyl-D-rlbofurano «yl) -2,6-dlaainopurln

A mixture of 1.2 g (1.37 *>!) 9- (2.5 »5-tri-0-benzoyl-2-i» thyl-D-riboi ^ raj ^ eyl) -2.6Hub * a "idopurln which ge <- is prepared vAB Beiapiel 5, in 12« 1 dry methanol kit is a Löeung from 97 ag (4.2 Alfol) of sodium in methanol w treated 12 al "The Mieohung is three hours at RüokfluB held, whereupon the solution obtained is concentrated under modified pressure. The ROokatand is dissolved in 24 al Waeaer, whereupon the pH is adjusted to approximately 6.5. The aqueous solution is extracted from five 10 ml portions of Chlorofora after removal of methylbenioate and concentrated under reduced pressure, whereby a residue is obtained which contains 9- (2-methyl-D-ribofuranoeyl) -2,6-diamlnopurln.

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Example 10

Preparation of 9- {2-methyl-D-rlbofuranosyl) -purine-6-thol

A suspension of 1.25 8 (1 * 96 µmoles) benzoyl-2 »niethyl-D-rlbofuranosyl) -6-chlorophenyln, which according to Example 4 is prepared * and 307 mg (4.0 mmol) of thiourea in 3 ml of ethanol is refluxed for 40 minutes. A clear solution is obtained after 5 minutes after 15 minutes it becomes yellow «whereupon shortly thereafter colorless« Crystals from 9- (2,3,5-tri-0-benzoyl-2-ethyl-D-ri1x> furanosyl) -purine-6-thiol crystallize out of the solution

A suspension of 400 mg (0.64 njMol) 9- (2,3,5-Trl-0-benzoyl-2-methyl-D-ribofurano3yl) -purine-6-tholol in 3.5 »1 dry methanol is treated with eisiey solution that consists of 19 »5 mg sodium and 3.5 ml dry methanol prepared will. Complete dissolution occurs immediately. The solution is refluxed for three hours. Ban will the solution concentrated by distillation under reduced pressure, whereupon the residue was dissolved in 6 ml of water and the pH of the solution is adjusted to 9 with acetic acid5 the aqueous mixture is added with four 1.5 ml fortions Methylene chloride extinguished. The water layer is through Distillation concentrated to a volume of 4 ml, whereupon the pH is adjusted to 4 using acetic acid.

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concentration of the solution; yields a residue which is 9- (2-Methy1-D-ribofuranosyl} -purine-6-thlol contains

Example 11

Preparation of 9- (2-methyl-D-ribofuranosyl) -6-n-methylamino-purine

Blue mixture of 1 g (1.6 mol) 9- (2.3 "5-tri-0-benzoyl-2-methyl-D ~ ribofurauM> eyl) -6-chloropurine and 8 g methylamine in 25 g dry methanol is heated to 100 * 0 in a sealed tube for 10 hours. The solution is concentrated to dryness under reduced pressure and the residue is dissolved in 25 ml of water. The water solution is washed with two 5 ml portions of benzene. The aqueous layer is stirred with 5.5 g of moist Dowex II-X8 (cf. Example 8) for a * 5 hours, during which time the pH of the solution is from 7 increases to 9. The resin is removed and washed with three 15 ral portions of water. The filtrate and the washing solutions are concentrated to a residue which contains 9- (2-methyl-D »rtbofui ⁱ auoeyl) -6-methylaminopurine.

Example 12

Preparation of 9- (2-methyl-D-.ribofuranosyl) -purine

A solution of 1 g (1.6 mmol) of 9- (2,3,5-tri-0-benzoyl-2- »ethyl-

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D-ribofuranosyl) ~ 6 «> chlorpuPin in 17 ml of Dloxan is mixed with 80 mg (2.0 nmol) of magnesium oxide and 0.5 g of a catalyst which consists of 5% palladium» which is deposited on activated carbon » for 8 hours in one Shaken hydrogen atmosphere at 25 ° C. The mixture is filtered and concentrated by distillation under reduced pressure to a residue which contains 9- (2,3,5-Trl-0-benzoyl-2-methyl-D-rlbofuranosyl) -purin.

A solution of 400 mg 25 mg (1 mg-atom) sodium and 8 ml dry methanol is prepared. The pale yellow solution is kept at the RUokfluS for three hours and then concentrated to dryness under reduced pressure. The residue is dissolved in 15 ml of water, whereupon the pH is adjusted to 6.5 % using acetic acid. The solution is extracted with four 5 ml portions of chloroform and the water phase is concentrated to Trookne under reduced pressure; a residue is obtained which contains 9- (2 · methyl-0-ribofuranoeyl) -purine.

A suspension of 800 mg (1.2 mmol) 9- (2,3,5 2-Bethyl-D-ribofur * noeyl) -2-aoeta * ido-6-hydro3typurln in 8 ml

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dry methanol is neatly treated with a solution that consists of 105 mg (4.5 mg-atom) sodium and 8 ml dry »methanol is made, whereupon the mixture lasts for xwel hours RUokflufl is held. The mixture is concentrated to dryness «- The residue is dissolved in 35 ml of water, whereupon the pI value by adding acetic acid to 7 elnge- ™ will provide. The clear solution is made with three 8 ml portions Washed chloroform, whereupon tile aqueous layer to one Concentrated residue from 9- (2-Mofchyl-D-r! BofuranosyL) -guanine will,

Example 13 Manufacture of 9- (2-Mo thy 1-D-r L bofurmnosy1 > -6 -ohlorpurln

A solution of 479 mg (0.98 mmol) 9- (2 _a 3 »5-tri-0-benzoyl-2-methjrl-D <-ribofuranosyl) '- 6-chloropurine _> which is prepared according to Example h » in 20 ml of cold methanol containing 2 g of anhydrous ammonia is kept at 5 ° C. for 20 hours. The solution is concentrated under reduced pressure and at a temperature of less than 20 ° C. The residue was recrystallized from methanol, 9- (2-methyl-D-rlbofuranosyl) -6-chloropurine being obtained.

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example

Preparation of 9 "(2-methyl« D-ribofuranosyl) -6-mefchylafliinopurine

About 150 ml of 3QrIoI n & x-aen distilled off from a suspension of 9 * 5 β (19 * 5 "mol) chlorine" reuri-6- (N-methyll "ttzamido) ~ purine in 500 ml xylene. The mixture is cooled, | whereupon a solution of 2,3 # 5-tri-0-benzoyl-2-methy3-D-ribofura »osr? .- chloride (from 8.2 g (14, 1 mmol) _{1,2 #} 3it5-Tetra-O -benaoj1-i-methyl-β-D-ribofuranose) in 50 ral dry xylene is added. The reaction mixture is stirred and refluxed for 30 minutes. The hot mixture is filtered, recovering 3 g of unreacted starting Glorpiereuripurfn. The piltrai viva is concentrated to dryness, whereupon the oil residue is washed 100 ml of chloroform with two 1 K) ml portions of a 5% potassium iodide solution and two 100 ml portions of water. The oil residue obtained after removal of the chloroform is chromatographed in benzene-chloroform (19) in a short column filled with 140 g of aluminum oxide washed with acid. The fractions * which only contain product are combined and concentrated! 9- (2.5 # 5-tri-0-benzQyl-.2-methyl-D-ribofuranosy 1) -6- (N-methylbenzamido) -purine is obtained in the form of a glass.

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A suspension of 3.9 g (5.45 mmol) of 9- (2,3,5-tri-0-bensoyl-2-methy1-D-ribofuranoayl) -6 «(N-raethy lbensamido) -purine In 40 ml of dry methanol, nil; dealt with a solution, which consists of 175 »8 (7.6 mg-atoms) sodium in 40 ml dry Methanol is produced «whereupon the solution takes 3.5 hours is refluxed for a long time. The methanol is removed and the residue is dissolved in 76 ml of water with acetic acid is neutralized (pH 7.0) and washed with three 10 oil portions of chloroform. The aqueous layer becomes by distillation tu a residue of 9- (2-methyl-D-ribofuranosyl) -6-ethylaminopurine concentrated.

Example 15

Preparation of 9- (2-methyl-D-ribofuranosyl) -6-iltnylandnopurine

* A solution is prepared from 2.0 g (3.2 mmol) of 9- (2,3,5-tri-0-benxoyl-2-i "thyl-D-ribofuranoeyl) -6-chloropurine _t which genH8 Example 4 , in 30 ml of ethanol, which contains 12 ml of ethylamine, is heated in a closed tube for 10 hours at 100 ° C. After removing the solvent, the residue is dissolved in 60 ml of water and extracted with three 15 ml portions of ether. The aqueous Schioht (pH 6.5) is stirred for one hour Jang with 2.5 & Dowex II-X8 (see Example 8) The resin is removed and with four 10 ml portions -

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Water washed. This combines · piltrate and dl · washing solutions become a residue of 9- (2-Hethyl-D-ribofuranosy 1) -6-ethyl-aminopurine concentrated,

Example 16

Preparation of 9- (2-methyl-D-rlbofuranosyl) -6-methylthiopurine

A boiling mixture of 605 mg (1.9 "mol) 9- (2-M * methyl-D-ribofuranosyl) -6-chloropurine, which is prepared according to Example 14, in 30 ml of anhydrous methanol is treated with a solution which is prepared by using 20 ml of O, ln-sodium methylate in methanol with methyl mercaptan. After refluxing for 30 minutes, the solution is cooled and concentrated to dryness. The residue is then dissolved in hot water 9- (2-Methyl-D-ribofuranosyl) -6 methyl-thiopurine separates out on cooling.

Example 17 Production of 9- (2-methyl- "U" 2 ^> ibofurano8yl5 "6-a" ethylpurine

A mixture of 590 ng (0.8 mmol)
2-8iethyl-D-rlbofuranos3rl) -6 * 5i # th3rlpurin, welehes ssßwäB B ·! · BpLiI 6 produced wlM * wan. - ml of dry ethanol is treated with a solution - a & m 2 * w $ (lm ~ atom) of sodium and 10 iul of trocttnem methtsisi imvgfi & tmllt wivd · i # Mieahung

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Held "IXD 4 hours * ■ reflux and ansefalieeend sur dryness focused · The residue is gelöet in JO nl water and old acid neutralized (pH 7). If the vaesere is concentrated to a small volume and cooled * then 9- (2-methyl-D-ribofui-ano8yl) ^ - methyl purine precipitates out "

Example 18 Production τοη 2 ^f -Htthy: Ladenosin

A mixture of 1.48 g (2.08 acol) 9- (2 * 3 * 5-tri-0-benroyl-2 «B» t ^ l-ß-l) -ribofuranoeyl) -6-benza «Ido- purine, irelehes genXfi Example 7 is prepared, and 15 ml of dry methanol is treated with a solution of sodium methoxide which is prepared from 70 mg (3 alfol) of Hatriua and 5% methanol. After 45 minutes of reflux, the mixture begins to dissolve, whereupon the oil is dissolved in 50 ml of corn . The pH is adjusted to 6.8 with a few drops of acidic acid. The solution is extracted with three 30 ml portions of ether, whereupon the Weeserschioht is filtered and concentrated to about 5%. The solid matter obtained is recrystallized from 7 Bl warning water * whereby 360 ng (59J *>S'-methyladenosine are obtained.

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Claims (6)

March 18, 1970 10 425 / M 73 721 patent claims 1. Compounds of the general formula HIGH OH where R _a and R _b , which can be identical or different, denote hydrogen, hydroxy, lower alkyl, amino, lower alkylamino, lower dialkylamino, halogen, mercapto or lower alkyl mercapto. 2. Process for the preparation of compounds according to claim 1, characterized in that in a stage A a compound the formula R ¹ OCH ₂ (II) -35 - 109816/2197 wherein R ', R "and R"', which can be the same or different, Represent acyl groups and X represents a halogen, with a compound of the formula (III) HgCl wherein R ₀ and / or R ^, which can be the same or different, stand for halogen, hydrogen, hydroxy * lower-alkyl, acylamino or lower-alkyl'amino, with formation of the intermediate compound of the formula R ¹ OCSl (IV) wherein R ₀ , R _d , R ', R ⁿ and R ^{HI have} the meanings given above, is treated and this compound IV in stage B 109816/2197 a) a basic solvolysis, if R _Q and B ^, which can be identical or different, in the compound XV are hydrogen, hydroxy, alkyl, acylamino, aoylalkylanlno or halogen, or b) aminolysis or mercaptolysis, if R ₀ and / or R ^, which can be identical or different, are halogen in the compound IV. 3. Process according to claim 2, characterized in that stage B is a solvolysis and basic catalysts and C ₁ - to C ^ alcohols are used as the solvolysis medium, with alkali or alkaline earth hydroxides or alkylates, solutions of ammonia or amines as catalysts , be used 4. The method according to claim 2, characterized in that stage B is an amolysis and the aelnolye agent is lower Alkyl or dialkylamines are used 5. The method naoh claim 2, characterized in that stage B is a meroaptolysis and as a meroaptolye agent Thiourea or alkali metal salts of lower alkyl mercaptans be used ORIGINAL INSPECTED 109818/2197 10 425 6. The method according to claim 2, 'characterized in that step A at a temperature of about 25 to about 150 ⁰ C during a tent span of about 15 minutes to about 5 hours durohgefährt is the basic Solvolyee at a temperature of about 5 to about 150 ⁰ C for a period of about 15 minutes to about 5 hours, the aainolysis is carried out at a temperature of about 25 ° C to about 150 ⁰ C for a period of about 15 minutes to about 5 hours and the meroaptolysis is carried out at one Temperature of about 65 to about 90 ^° C. for a period of time from about 15 minutes to about 5 hours. 7 »A process for the preparation of 2 * -methyladenosine, characterized * that 2,3,5-tri-0-benzoyl-2 * -methyl-D-ribofuranosylohlorid with Cnlorraerouri-o-benzaniidopurine in the presence of xylene for a period of approximately for 40 min under reflux and is for the recovery of 9- (2,3,5-Trl-0-benzoyl-2 '-methyl-D-ribofuranoeyl) -6-benzamidopurln at about 5 ⁰ C ansohliessend held for about 20 hours and the 9- (2,3,5-Trl-0-bensu> yl-2 ^t -methyl »D-ribofuranoayl) -6-benxa» idopurine is treated with sodium ethoxide in methanol ^{for about 2 hours to form 2 1 -methyladenosine} . .38. 109816/2197