DE2441484A1 - PROCESS FOR THE PREPARATION OF N HIGH 6-SUBSTITUTED ADENOSINE NUCLEOTIDES - Google Patents

Description

SCHERING AG

Intellectual Property

Berlin, August 27, 1974

Process for the production of

N -substituted adenosine nucleotides

Addition to patent application P 21 51 013 · 4

Subject of the main patent (patent application P 21 51 Ο13 4) is a process for the production of N -substituted adenosines

of the general formula I.

R.

wherein
R ₁ and

Each for itself a hydrogen atom or an alkyl, Aralkyl, aryl or heterocyclic group or R-, a hydrogen atom and Rp a hydroxy, amino or an optionally terminally substituted alkyl group or R-, and Rp together including the N-atom preferably consists of a heterocyclic ring

609811/0792

Board of Directors: Dr. Christian Brunn · Hans-Jürgen Hamann · Dr. Heinz Hannsa

Karl Otto Mittelstenscheid Dr. Gerhard Raspe ■ Dr. Hoist jokes! Deputy: Dr. Herbert Asmis

Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Company headquarters: Berlin and Bergkamen Commercial register: AG Charlottenburg 93 HRB 283 and AG Kamen HRS 0061

Postal address: SCHERING AG D-1 Berlin 65 PO Box 65 0311 Postal check account: Beriln-West 11 75-101, bank code 10010010 Berliner Commerzbank AG, Berlin, account no. 108 7006 CO, bank code 100 400 00 Berliner Discontö-Bank AG, Berlin, account no. 241/5008, bank loan number 100 700 00 Berliner Handels-Gesellschaft - Frankfurter Bank -, Berlin, account no. 14-362. Bankleltzah! 10020200

83 OE IV 2 ^ 20

SCHERING AG

Intellectual Property

-Z-

4-, 5- »6- or 7-members represent, R ₅ , a hydrogen atom or a free or silylated one

Amino group and

Z denotes a free or protected sugar residue, characterized in that a 6-trialkylsilyloxy-purine derivative is used of the general formula II

(II),

in which alkyl is in each case the same lower alkyl radical, preferably the methyl radical, R ^{1 is} a hydrogen atom or a trialkylsilylamino group and Z ^{1 is} a silylated, acylated or acetal-protected sugar radical, with ammonia or an amine of the formula HNR-, Rp or optionally one Salt of the amine using the amine salt or a Lewis acid as a catalyst, reacted and then optionally removing the protective groups on the sugar.

8098 11/0792

SCHERINGAG

Intellectual Property

As sugar protection groups are according to the "procedure of the main patent the trimethylsilyl groups are particularly suitable because they can be easily removed. You get those on the sugar residue silylated starting compounds of the general formula II, if one uses free adenosine or guanosine, for example with hexamethyldisilazane (HMDS) in the presence of trimethylchiοsilane or Ammonium salts and, if appropriate, in the presence of a tertiary base such as pyridine. The 6-trimethylsilyloxy group and the Protecting groups are then introduced at the same time.

In a further development of the process of the main patent, it has now been found that compounds of the general formula II acylated by phosphoric acid can also be converted to the compounds of the general formula I by the process of the main patent. The phosphoric acid can be bonded to the sugar radicals Z and Z ^{1 of} the general formulas I and II via one or two hydroxyl groups, it being possible for the bond to take place via two hydroxyl groups on one molecule or via two molecules. '

When binding via 2 hydroxyl groups of the same molecule, for example, a cyclic monophosphate of the general is formed formula

60981 1/0792

SCHERING AG

Intellectual Property

2UU84

CH,

O = P- I
OH

0 OH

When binding via 2 hydroxyl groups of different molecules, a di- or bridged via 3,5-position is created. Polynucleotide:

HIGH,

I!

CH ₂ -OPO

A.

oe (h)

OH OH

= P- I 6 0 9 8 11/0792

SCHERING AG

Intellectual Property

- 5 - *

The residues of ribose and in particular come as sugar residues Deoxyribose in question.

The connections are for the most part already known to them have anti-proliferative and heart disease-active effectiveness.

The invention thus relates to a further development of the method for the preparation of N -substituted adenosines of the general formula I.

(D,

R ₁ and R ₂ each represent a hydrogen atom or an alkyl, aralkyl, aryl or heterocyclic group, or R _{1 is} a hydrogen atom and Rp is a hydroxy, amino or an optionally terminally substituted alkyl group, or R- and Rp together including the N atom represent a heterocyclic ring preferably composed of 4-, 5-6 or 7-members,

SCHERING AG

Intellectual Property

a hydrogen atom or an amino group and Z denotes a free or protected sugar residue by reacting a 6-trialkylsilyloxy-purine derivative general formula II

(II)

Alkyl in each case denotes the same lower alkyl radical, preferably the methyl radical, R ^{1 is} a hydrogen atom or a trialkylsilylamino group and Z ^{1 is} a silylated, acylated or acetal-protected sugar radical,

with ammonia or an amine of the formula HNR, Rp or optionally a salt of the amine, preferably using the amine salt or a Lewis acid as a catalyst according to

Main patent (patent application P 21 51 013.4),

characterized in that for the preparation of compounds of the above formula I in which Z is a sugar residue with one above one or two hydroxyl groups of the same molecule or bound via two hydroxyl groups of different molecules

609811/0792 _ ₇ _

SCHERING AG

Intellectual Property

Represents phosphoric acid radical, starting from compounds of the general formula II in which Z ^{1 has} the same meaning as in formula I and the free hydroxyl groups of the sugar and the phosphoric acid ester are additionally silylated.

It is not necessary for the reaction according to the invention to isolate the starting compounds of the general formula II. The 6-trialkylsilyloxyadenosine irucleotides formed in situ can be converted directly to the corresponding adenosine nucleotides in the reaction solution with ammonia or an amine will.

The type of implementation depends on the compound HNE-.Rp and the catalyst. Treatment of the silyl compound of. General formula II with primary or secondary amines is preferably carried out at 0 to 180 ^° C. When using salts of primary and secondary amines, the amine salt also serves as a catalyst.

Propylamine, butylamine, aniline, p-anisidine, benzylamine, homoveratrylamine, tryptamine, Ν, Ν-dimethylethylenediamine, ⁿ ~ Dopami hydrochloride methylamine, ethylamine, etc: as the primary amines which may be mentioned

6098 11/0792

SCHERING AG

Intellectual Property

2UH84

The following are preferred as secondary amines: Dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine, hexamethyleneimine, N-methyl-piperazine, etc.

Silylating agents and primary and secondary amines can can be used at the same time.

The reaction with ammonia is carried out under increased NH ₅ pressure of about 3O-5O atm. The reaction is complete after 20 "to 80 hours at 0 to 180 ^° C. In the case of silylation with hexamethyldisilazane, which releases ammonia anyway, the silylation and reaction with ammonia can be carried out in one step.

A particularly suitable solvent for the reaction is excess amine HNR.Rp, but indifferent ones can also be used Solvents such as toluene, xylene, anisole, dioxane, glyme, pyridine or for the less soluble silyl compounds preferably dimethylformamide or suIfolan.

Lewis acids, in particular metal oxides, metal salts, and salts of amines are suitable as catalysts. The metal salts are optionally with excess amine HNR-jRp in the Reaction used.

. 60981 1/0792

SCHERINGAG

Intellectual Property

2UH84

The catalysts are used in amounts from 0.001 mol to 5 mol based on the nucleotide, but preferably in amounts of 0.05 to 1 mol, used in the reaction.

The most effective were found to be acidic aluminum oxide, mercury-II-chloride, Mercury-II-acetate as well as zinc-II-chloride, tin-IV-chloride, Titanium IV chloride and boron trifluoride etherate, which are found in Combination with excess amine can be used, and Salts of amines such as ammonium sulfate, tryptamine hydrochloride, Dopamine hydrochloride, pyridinium chloride, etc.

It is surprising that in the Umsetzurgmit amines at temperatures up to 180 ⁰ C, the Phosphorsaureesterbindung is not cleaved.

- 10 -

6 0 9 8 11/0792

SCHERING AG

Intellectual Property

- 10 -

244H84

example

Έ -Benzyladenosine-5'-monophosphoric acid A suspension of 117.65 S (0.3 mol) inosine-5'-monophosphoric acid disodium salt in 188.7 ml (0.9 mol) hexamethyldisilazane and 113.7 ml (0.9 Mol) trimethylchlorosilane was refluxed at a bath temperature of 145 ° C. for 12 hours. The suspension was then mixed with 200 ml of 1,2-dichloroethane (abs.) And filtered with exclusion of moisture. The residue obtained after evaporation of the filtrate was carried out at after addition of 62.9 ml (0.3 mol) of hexamethyldisilazane and 163.7 ^m l (1.5 mol) of benzylamine and 3.96 g (0.03 mole) of ammonium sulfate 27 hours 145 ° C bath temperature stirred. The resulting hexamethyldisiloxane (b.p. 101 ⁰ C) was distilled off over a Yigre _u x-column (10 cm). 600 ml of methanol were added to the brown reaction mixture and the mixture was stirred at room temperature for 16 hours. The precipitated benzylamine salt of IT -benzyladenosine-5'-monophosphoric acid was filtered off, washed with ethanol and dried. After the concentrated filtrate was crystallized from ethanol, the substance was filtered off and dried, 146.8 g of benzylamine salt were obtained. Ion exchange chromatography in water / water over a DOWEX column (type 50 WX2, H shape; 2.5 x 120 cm), concentration of the fractions and crystallization from ethanol / water gave 93.5% (71%) of colorless-crystalline N benzyladenosine -5'-monophosphoric acid with a melting point of 173-175 ° C.

609811/0792 _ΊΊ

Claims (1)

SCHERING AG Intellectual Property - 11 -. Claim. Further training of the process for the production of N -substituted adenosines of the general I formula I. (I) wherein - ..; ,. · R-, and Ep each for itself a hydrogen atom or an alkyl, Aralkyl, aryl or heterocyclic group or R-, a hydrogen atom and Rp a hydroxy-, amino- ode :: an optionally terminally substituted alkyl group or -R-, and Rg together including the N-atom preferably consists of a heterocyclic ring 4-, 5-, 6- or 7-limbs represent R-7 is a hydrogen atom or an amino group and Z denotes a free or protected sugar residue by reacting a 6-trialkylsilyloxy-purine derivative general formula II - 12 - 609811/0792 SCHERING AG Intellectual Property 2UH84 ^ Alkyl
i ^ -alkyl
^ Al Alkyl in each case denotes the same lower alkyl radical, preferably the methyl radical, B ^{1 is} a hydrogen atom or a trialkylsilylamino group and Z ^{1 is} a silylated, acylated or acetal-protected sugar radical, with "ammonia or" an amine of the formula HNR ₁ R ₂ or optionally a salt of the amine, preferably using the amine salt or a Lewis acid as a catalyst according to Main patent (patent application P 21 51 013 «4-) characterized in that for the preparation of compounds of the above formula I in which Z is a sugar residue with one above one or two hydroxyl groups of the same molecule or bound via two hydroxyl groups of different molecules Phosphoric acid residue represents, of compounds of the general - 13 - 609811/0792 Board of Directors: Dr. Christian Bruhn · Hans-Jürgen Hamann · Dr. Heinz Hannse · Postal address: SCHERING AG · D-1 Berlin 65 · P.O. Box 65 0311 Kar Otto MlttoMenscheld Dr. Gerhard Raspe Dr. Horst Witzel Postscheck account: Berlin-West 11 75-101, bank number 10010010 btelly .. Dr. Herbert Asrnis Berliner Commerzbank AG, Berlin, account no. 108 700600. Bank code 10040000 Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppen Berliner Disconto-Bank AG, Berlin, account no. 241/5008, bank code 100 700 Company headquarters: Berlin and Bergkamen Berliner Handc-Is-Gesellschaft - Frankfurter Bank -, Borlln, Commercial register: AG Charlottenburg 93 HRB 283 and AG Kamen HRB 0061 account no. Ί4-302, bank code 100 20200 S3 DE IV 245JD SCHERINGAG Intellectual Property 2UU84 Formula II starts in which Z ^{1 has} the same meaning as in formula I and the free hydroxyl groups of the sugar and the phosphoric acid ester are additionally silylated. 609811/0792 Board of Directors: Or. Christian Brunn · Hans-Jürgen Hamann ■ Dr. Heinz Kannt postal address: SCHERING AG D-1 Berlin 65 Postfach 65 0311. Karl Otto Mittelstenscheld Dr. Gerhard Raspe Dr. Horst Wltzel Postscheck account: Berlin-West 1175-101. Bank code 10010010 Deputy: Dr. Herbert Asmls Berliner Commerzbank AG, Berlin, account no. 108 7006 00, bank code 10040000 Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppon Berliner Disconto-Bank AG, Berlin, account no. 241/5008, bank code 100 700 Company headquarters: Berlin and Bergkamen. . Berlin trading company - Frankfurter Bank, Berlin, Commercial register: AQ Charlottenburg S3 HRB 283 and AQ Kamen HRB 0061 account no. 14-362, bank code 100 20200 13 DE IV 2dS3O