PROCESS FOR THE PREPARATION OF N-TRIAZINYLAMMONIUM SALTS Field of the invention

The invention describes processes for the preparation of N-triazinylammonium salts. State of the art

N-Triazinylammonium salts found extensive application in organic synthesis, especially as coupling reagents useful in the preparation of nucleic acids, peptides, amides, esters, carboxylic acid anhydrides, aminoaldehydes, aminoalcohols, or are reagents useful for protection of functional groups. The most of the known process of preparation of N-triazinylammonium salts are based on the reaction between appropriate chlorotriazine and amine. In J.Org. Chem., 63, 4248-4255 (1998) the reaction of 2-chloro-4,6-dimethoxy-1 ,3,5-triazine or 2-chloro-4,6-diphenoxy-1 ,3,5-triazine with tertiary amines was described. The synthesis of N-triazinyltrimethylammonium salts by reaction of trimethylamine with chloro derivatives of 2,4-dialkylamino-1 ,3,5-triazines, 2-alkylamino-4-methoxy- 1 ,3,5-triazines, 2-alkylamino-4-alkylthio-1 ,3,5-triazines were described in Chem. Heterocyclic Compds, 13, 802-805 (1977) and with 2-chloro-4,6-dimethoxy-1 ,3,5- triazine in Chem. Heterocyclic Compds, 38, 177-182 (2002). Synthesis of 4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)morpholinium chloride from 2- chloro-4,6-dimethoxy-1 ,3,5-triazine and N-methylmorpholine was described in Tetrahedron 55, 13159-13170 (1999).

Several processes of preparation of N-triazinylammonium salts were described in the patent literature. Application WO 2001096282A1 presents the reaction between piperazine and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine. USA patent 6 458 948 B1 and Japanese patent 34634/1972 describe the synthesis of N- triazinylammonium perchlorates and tetrafluoroborates by the treatment of appropriate N-triazinylammonium chlorides with sodium perchlorate or sodium tetrafluoroborate respectively. All mentioned procedures lead to unstable N- triazinylammonium chlorides, or at least, require operations involving the use of this easily demetylating compounds. In the letter case, the success of chloride anion exchange procedure to tetrafluoroborate or perchlorate anion depends on the location of the equilibrium in the mixture of salts formed in reaction. It is

assumed, that formation of expected product is favored, but it has never been confirmed. Moreover, in the case of less favorable equilibrium the mixture of products is formed in the reaction and demethylation of N-triazinylammonium salts should be expected until all chloride anion is consumed. Detailed description of the invention

The process presented in this invention is free of the above said drawbacks.

According to the invention, N-triazinylammonium salts are prepared directly from the readily accessible and stable 2-halogeno-4,6-disubstituted-1 ,3,5-triazines and appropriate ammonium salts in organic solvent in the presence of hydrochloride acceptor.

Possible substituents of the 1 ,3,5-triazine, as above defined , can be for example: alcoxy-, benzyloxy- or benzoxy-groups.

More particularly according to the invention, the halogeno substituted 1 ,3,5-triazine are treated with appropriate ammonium salts, advantageously in acetonitrile solution at 0-10 ⁰ C in the presence of hydrochloride acceptor used in some excess.

As halogeno substituted 1 ,3,5-triazine, as above defined, chloro substituted triazine are preferred.

According to the invention as ammonium salts the salts of tertiary amines are preferred, in particular, for example, λ/-methylmorpholinium, N- methylpiperydinium, quinuclidinium.

As the HCI acceptors can be used hydroxides, carbonates hydrogen carbonates of alkali metals or alkaline earth metals, preferably sodium hydrogen carbonate, potassium hydrogen carbonate or cesium carbonate, or alternatively derivatives of silver, the HCI acceptor is preferably used in the form of suspension in the solvent used as reaction medium.

As it is said above, and it will be even more clear from the following examples, the process according to the invention is convenient, uses readily available and not expensive substrates, and can be applied to the broad range of triazines. Example I.

A vigorously stirred suspension of N-methylmorpholine tetrafluoroborate (1.89 g;

10 mmol) and finely powdered sodium bicarbonate (1.26 g; 15 mmol) in

acetonitrile (30 ml_) was cooled to 10° C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 20 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 2.47 g N-methyl-N-(4,6-dimethoxy-1 ,3,5- triazin-2-yl)morpholinium tetrafluoroborate. Mp = 199-200 ⁰ C. ¹ H-NMR (CD ₃ CN): 3.39 (s, 3H, CH ₃ -N-); 3.71 (t, 2H, J = 8.5 Hz, -N-CH ₂ -CIH-O-); 3.75 (t, 2H, J = 10 Hz, -N-CH-CH ₂ -O-); 3.99 (m, 2H, N-CH ₂ -CH ₂ -O-); 4.1 1 (s, 6H, CH ₃ -O-); 4.46 (dd, 2H, J ₁ = 10 Hz, J ₂ = 2 Hz, N-CH ₆ -C) [ppm]. ¹³ C-NMR (CD ₃ CN): 56.89 (CH ₃ -N ); 57.82 (CH ₃ -O); 61.10 (CH ₂ ); 62.77 (CH ₂ ); 171 23 (N-C-N); 175.01 (N-C-N) [ppm].

IR (KBr) ?: 1636vs; 1540vs; 1488vs; 1392vs; 1072vs (broad); 944vs; 864s; 788vs; 712vs [cm ^"1 ]. Analysis for Cio H ₁₇ BF ₄ N ₄ O ₃ (328.08) Calculated: %C 36,61 ; %H 5,22; Found: %C 36,44; %H 5,46.

Example II.

A vigorously stirred suspension of quinuclidine tetrafluoroborate (1 ,99 g, 10 mmol) and finely powdered sodium bicarbonate (1.26 g; 15 mmol) in acetonitrile (30 ml_) was cooled to 1 O ⁰ C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 24 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 2,36 g (70 %) N-(4,6-dimethoxy-2,4,6-triazin-2-yl)-quinuclidinium tetrafluoroborate, mp =1 15-1 17°C,

¹ H-NMR (CD ₃ CN): 2.05, 2.1 1 (dd AB system, 6H, J ₁ = 1 1 , Hz J ₂ = 8 Hz, J ₃ = 3.3 Hz, N-C-CH ₂ -); 2.27 (hept. 1 H, J = 3.3 Hz, C-H); 3.86, 3.91 (d AB system, 6H, J ₁ = 1 1 Hz, J ₂ = 8 Hz, J ₃ = 8 Hz, N-CH ₂ -); 4.09 (s, 6H, 0-CH ₃ ) [ppm]. ¹³ C-NMR (CD ₃ CN): 24.1 , 24.37 (CH-CH ₂ -C); 57.40 (CH ₃ -O); 57.45 (N-CH ₂ ); 173.4 (N-C-N); 174.5 (N-C-N) [ppm].

Analysis for: C ₁₂ H ₁₉ BF ₄ N ₄ O ₂ (338.12). Calculated: %C 42,63; %H 5,66;

Found: %C 42,38, %H 6,12.

Example III.

A vigorously stirred suspension of N-methylpiperidine tetrafluoroborate (1 ,87 g, 10 mmol), finely powdered potassium bicarbonate (1.50 g; 15 mmol) and cesium carbonate (100 mg) in acetonitrile (30 ml_) was cooled to 5 ⁰ C and 2-chloro-4,6- dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 14 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 2,24 g (72 %) N-methyl-N-(4,6-dimethoxy-2,4,6-triazin-2-yl)-piperidinium tetrafluoroborate, mp =1 1 1 -1 13 ^* 0,

¹ H-NMR (CD ₃ CN): 1 .50-2.00 (m, 6H, CB ₂ ); 3.31 (s, 3H, N-CH ₃ ); 3.56 (dt, 2H, J ₁ = 12 Hz, J ₂ = 3 Hz, N-CH-C); 4.10 (s, 6H, 0-CH ₃ ); 4.41 (broad d, 2H, J = 12 Hz, N- CH-C) [ppm]. ¹³ C-NMR (CD ₃ CN): 21.3, 22.0 (C-CH ₂ -C); 55.5 (CH ₃ -N ); 57.7 (CH ₃ -O); 62.5 (N- CH ₂ ); 171.8 (N-C-N); 175.1 (N-C-N) [ppm]. Analysis for C ₁₁ H ₁₉ BF ₄ N ₄ O ₂ (326.10) calculated: %C 40.52, %H 5.87; found: %C 40.31 , %H 5.64. Example IV.

A vigorously stirred suspension of 1 ,4-diazabicyclo-[2,2,2]-octanium tetrafluoroborate (1 ,99 g, 10 mmol), finely powdered potassium bicarbonate (1.50 g; 15 mmol) and cesium carbonate (100 mg) in acetonitrile (30 ml_) was cooled to 5 ⁰ C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 10 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 2.61 g (77 %) N-(4,6-dimethoxy-2,4,6-triazin-2-yl)-1 ,4- diazabicyclooctanium tetrafluoroborate, mp =262 - 265 °C, ¹ H-NMR (D ₂ O): 3.88 (AB system, 6H, -N-(CH ₂ ) ₃ -); 3.99 (AB system, 6H, C-N ⁺ - (CH ₂ ) ₃ -); 4.08 (s, 3H, CH ₃ -O-); 4.15 (s, 3H, CH ₃ -O-) [ppm]. Analysis for:: Cu Hi ₈ BF ₄ N ₅ O ₂

Calculated: 38,96 % C, 5,35 % H, 20,65 % N; Found: 38.61 % C , 5.28 % H, 20.35% N.

Example V.

A vigorously stirred suspension of N-methylmorpholinium p-toluenosulphonate (2,73g, 10 mmol), finely powdered sodium bicarbonate (1 .26 g; 15 mmol) and cesium carbonate (100 mg) in acetonitrile (30 ml_) was cooled to 0 ⁰ C and 2- chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 20 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 3,17 g (77 %) N-methyl-N-(4,6-dimethoxy-2,4,6-triazin-2-yl)-morpholinium p- toluenosulphonate, mp =59-60°C.

¹ H-NMR (D ₂ O): 2.31 (s, 3H, CH ₃ -C ₆ H ₄ -); 3.14(d, 2H, -N-CH ₂ -CH ₂ -O-); 3.48 (s, 3H, CiH ₃ -N-); 3.84 (d, 2H, -N-CH ₂ -CH ₂ -O-); 3.98 (d, 2H, -N-CH ₂ -CH ₂ -O-); .4.04 (s, 3H, CiH ₃ -O-); 4.31 (s, 3H, CH ₃ -O-); 4.41 (d, 2H, -N-CH ₂ -CiH ₂ -O-); 7.35 (d, 2H, CH ₃ - CeH ₄ -); 7.67 (d, 2H, CH ₃ -CeJH ₄ -) [ppm]. Analysis for:: Ci ₇ H ₂₄ N ₄ O ₆ S

Calculated: %C 49,50; %H 5,87; %N 13,58; %S 7,77 Found: %C 48;67, %H 5;54, %N 13;61 ; %S 7,63 Example Vl.

A vigorously stirred suspension of quinuclidinium p-toluenosulphonate (2,84 g, 10 mmol) and finely powdered potassium bicarbonate (1.10 g; 1 1 mmol) in acetonitrile (30 ml_) was cooled to 0 ⁰ C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 18 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 2,95 g (70 %) N-(4,6-dimethoxy-2,4,6-triazin-2- yl)-quinuclidinium p-toluenosulphonate as a pale yellow oil. ¹ H-NMR (CD ₃ CN): 1.76 (q, 6H, -CH ₂ -CH ₂ -CH-); 1.85 (AB system, 1 H, -CH ₂ -CH ₂ - CiH-); 2.33 (s, 3H ₅ CH ₃ -C ₆ H ₄ -); 3.13 (q, 6H, -N-CH ₂ -CH ₂ -CH-); 4.02 (s, 6H, CH ₃ -O- ); 7.39 (d, 2H, CH ₃ -C ₆ H ₄ -); 7.69 (d, 2H, CH ₃ -C ₆ H ₄ -) [ppm]. Analysis for:: CIgH ₂₆ N ₄ OsS

Calculated: %C 54,01 ; %H 6,20; %N 13,26; %S 7,59 Found: %C 54,04; %H 6;16, %N 13;38, %S 7,22.

Example VII.

A vigorously stirred suspension of N-methylmorpholinium methanosulphonate (1 ,97 g, l O mmol) and finely powdered potassium bicarbonate (1.10 g; 1 1 mmol) in acetonitrile (30 ml_) was cooled to 0 ⁰ C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 15 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 1.85 g (60 %) N-methyl-N-(4,6-dimethoxy- 2,4,6-triazin-2-yl)-morpholinium methanosulphonate, mp =96-98°C. ¹ H-NMR (CD ₃ CN): 2.44 (s, 3H, CH ₃ -S-)3.39 (s, 3H, CH ₃ -N-); 3.72 (AB system, 4H, -N-CH ₂ -CH ₂ -O-); 3.85 (d, 2H, -N-CH ₂ -CJH ₂ -O-); 4.06 (s, 6H, CJH ₃ -O-); 4.65 (d, 2H, - N-CH ₂ -CH ₂ -O-) [ppm]. Analysis for: C ₁₁ H ₂₀ N ₄ O ₆ S:

Calculated: %C 39,28 %H 5,99 %N 16,66 %S 9,53,

Found: %C 39;45 %H 6;14 %N 16;20 %S 8,61.

Example VIII.

A vigorously stirred suspension of quinuclidinium methanosulphonate (2,07 g, 10 mmol) and finely powdered potassium bicarbonate (1.10 g; 1 1 mmol) in acetonitrile (30 ml_) was cooled to 0 ⁰ C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 15 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 1.75 g (51 %) N-(4,6-dimethoxy-2,4,6-triazin-2- yl)-quinuclidinium methanosulphonate, mp =144-146 ⁰ C.

¹ H-NMR (CD ₃ CN): 1.86 (q, 6H, -CH ₂ -CH ₂ -CH-); 1.95 (ukl. AB, 1 H, -CH ₂ -CH ₂ -CH-); 3.105 (q, 6H, -N-CH ₂ -CH ₂ -CH-);3.16 (s, 3H, CH ₃ -S-) 3.98 (s, 6H, CH ₃ -O-) [ppm]. Example IX. A vigorously stirred suspension of N-methylmorpholinium amidosulphonate (1 ,98 g, 10 mmol), finely powdered sodium bicarbonate (1.68 g; 20 mmol) and cesium carbonate (100 mg) in acetonitrile (30 ml_) was cooled to 0 ⁰ C and 2-chloro-4,6-

dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 30 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 2.38 g (70 %) N-methyl-N-(4,6-dimethoxy-2,4,6-triazin-2-yl)-morpholinium amidosulphonate, mp =97-99°C.

¹ H-NMR (CD ₃ CN): 3.45 (s, 3H, CH ₃ -N-); 3.77 (AB system, 4H, -N-CH ₂ -CH ₂ -O-); 3.91 (d, 2H, -N-CH ₂ -CH ₂ -O-); 4.15 (s, 3H, CiH ₃ -O-); 4.22 (s, 3H, CH ₃ -O-); 4.55 (d, 2H, -N-CH ₂ -CH ₂ -O-) [ppm]. Example X.

A vigorously stirred suspension of quinuclidinium amidosulphonate (2,08 g, 10 mmol), finely powdered sodium bicarbonate (1 ,68 g; 20 mmol) and cesium carbonate (100 mg) in acetonitrile (30 ml_) was cooled to 0 ⁰ C and 2-chloro-4,6- dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 30 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 1.46 g (50 %) N-(4,6-dimethoxy-2,4,6-triazin-2-yl)-quinuclidinium amidosulphonate, mp =265- 267 ⁰ C. ¹ H-NMR (CD ₃ CN): 1.77 (q, 6H, -CH ₂ -CH ₂ -CH-); 2.08 (AB system, 1 H, -CH ₂ -CH ₂ - CH-); 3.15 (q, 6H, -N-CiH ₂ -CH ₂ -CH-); 4.02 (s, 3H, CiH ₃ -O-); 4.22 (s, 3H, CiH ₃ -O-) [ppm]. Example Xl. A vigorously stirred suspension of N-methylmorpholinium 10-camphorsulphonate (3,34 g, 10 mmol) and finely powdered sodium bicarbonate (1.26 g; 15 mmol) in acetonitrile (30 ml_) was cooled to 10 ⁰ C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 12 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 3,24 g (70 %) N-methyl-N-(4,6-dimethoxy- 2,4,6-triazin-2-yl)-morpholinium 10-camphorsulphonate, mp=127-129°C,

¹ H-NMR (CD ₃ CN): 0.78 (s, 3H, CH ₃ -C-); 1.08 (s, 3H, CH ₃ -C-);1.26-1.45 (m, 2H, - CH ₂ -); 1.76 (m, 1 H, -CH ₂ -CH-CH ₂ -); 2.20-2.30 (m, CH ₂ -);2.51 (m, 1 H, -CH ₂ -S-) 2.98 (m, 1 H, -CH ₂ -S-); 3.39 (s, 3H, CH ₃ -N-); 3.69 (AB system, 4H, -N-CH ₂ -CH ₂ -O- ); 3.98(d, 2H, -N-CH ₂ -CJH ₂ -O-); 4.41 (s, 6H, CH ₃ -O-); 4.46 (d, 2H, -N-CH ₂ -CH ₂ -O-) [ppm].

Analysis for: C ₂₀ H ₃₂ N ₄ O ₇ S

Calculated: %C 50,83 % H 6,83 % N 1 1 ,86 % S 6,79 Found: % C 48.84 % H 6.83 % N 13.18 % S 5.48.

Example XII. A vigorously stirred suspension of quinuclidinium 10-camhorsulphonate (3,44 g, 10 mmol) and finely powdered sodium bicarbonate (1 ,26 g; 15 mmol) in acetonitrile (30 ml_) was cooled to 5 ⁰ C and 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.75 g; 10 mmol) was added. The stirring was continued until all CDMT was consumed (usually 14 hrs). Then, the precipitate was filtered off, the filtrate was concentrated to VA of the volume and left to crystallization. The product was filtered, washed and dried, yielding 4.35 g (90 %) N-(4,6-dimethoxy-2,4,6-triazin-2- yl)-quinuclidinium 10-camphorsulphonate, mp =128-130°C.

¹ H-NMR (CD ₃ CN): 0.78 (s, 3H, CH ₃ -C-); 1.08 (s, 3H, CH ₃ -C-);1.26-1.45 (m, 2H, - CiH ₂ -); 1.76 (m, 1 H, -CH ₂ -CH-CH ₂ -); 1.96 (q, 6H, -CH ₂ -CiH ₂ -CH-); 1.99 (m, 1 H, - CH ₂ -CH ₂ -CH-); 2.20-2.30 (m, -CH ₂ -); 2.51 (m, 1 H, -CH ₂ -S-) 2.98 (m, 1 H, -CH ₂ -S-); 3.25 (q, 6H, -N-CH ₂ -CH ₂ -CH-); 4.12 (s, 6H, CH ₃ -O-) [ppm]. Analysis for: C ₂₂ H ₃₄ N ₄ OeS

Calculated: % C 54,75 % H 7,10 % N 1 1 ,61 % S 6,64 Found: % C 65.60 % H 6.91 % N 1 1.89 % S 6.20. Example XIII.

A vigorously stirred suspension of 1 ,4-diazabicyclo-[2,2,2]-octanium tetrafluoroborate (3.00 g, 15 mmol), finely powdered potassium bicarbonate (3.00 g; 30 mmol) and cesium carbonate (25 mg) in acetonitrile (20 ml_) was cooled to 0 ⁰ C and 2-chloro-4,6-dibenzyloxy-1 ,3,5-triazine (4,916 g; 15 mmol) was added. The stirring was continued until all 2-chloro-4,6-dibenzyloxy-1 ,3,5-triazine was consumed (usually 3.5 hrs). Then, the precipitate was filtered. The precipitate was washed with acetonitrile (3x15 ml_) and the combined filtrates were concentrated

to dryness. The remaining residue was washed with boiling ether (3x30ml_) and left VA of the volume and left to crystallization. The crystalline precipitate was filtered and washed with ether yielding 5,799 g (80 %) N-(4,6-dibenzyloxy-2,4,6- triazin-2-yl)- 1 ,4-diazabicyclo-[2,2,2]-octanium tetrafluoroborate, mp=157-160°C. ¹ H-NMR (CD ₃ CN) δ= 3,39 (s, 6H, -CH ₂ -); 3,76 (s, 6H, -CH ₂ -); 5,598 (s, 4H, C ₆ H ₅ - CH ₂ -O); 7,428-7,505 (m, 1 OH, -CeJH ₅ ) [ppm]. ¹⁹ F-NMR (CD ₃ CN) δ= -151 ,80 (s, BF ₄ ^" ) [ppm].