2-(4-Methyl-2-phenylpiperazin-4-ium-1-yl)pyridine-3-carboxylate dihydrate

The title compound, C17H19N3O2·2H2O, is particularly useful in the preparation of mirtazapine, which is the active agent in a new class of antidepressants. It crystallized as a zwitterion with two molecules of water in the asymmetric unit. The crystal structure is dominated by a system of hydrogen bonds involving the positively charged N atom and both water molecules.

The title compound, C 17 H 19 N 3 O 2 Á2H 2 O, is particularly useful in the preparation of mirtazapine, which is the active agent in a new class of antidepressants. It crystallized as a zwitterion with two molecules of water in the asymmetric unit. The crystal structure is dominated by a system of hydrogen bonds involving the positively charged N atom and both water molecules.   Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) Àx þ 1 2 ; y þ 1 2 ; Àz þ 3 2 ; (ii) Àx þ 1 2 ; y À 1 2 ; Àz þ 3 2 ; (iii) x; y þ 1; z.

Comment
The title compound, C 17 H 19 N 3 O 2 ·2H 2 O, is particularly useful in the preparation of mirtazapine which is the active agent in a new class of antidepressants. It crystallized as a zwitterion with two molecues of water in the asymmetric unit (Fig 1). The central piperazine ring has a normal chair conformation. In the molecule, the dihedral angle is 81.20 between plane 1(C7 C8 C9 C10) and plane 2(C11 C12 C13 C14 C15 C16), the dihedral angle is 68.40 between plane 2(C11 C12 C13 C14 C15 C16) and plane 3(N1 C2 C3 C4 C5 C6)and the the dihedral angle is 36.90 between plane 1 and plane 3. Packing is dominated by a system of hydrogen bonds involving the positively charged nitrogen and both water molecules (

Experimental
To 162 g of 1-butanol were added 2-(4-methyl-2-phenylpiperazine-1-yl)pyridine-3-carbonitrile(54 g, 0.2 mol) and 60.93 g of potassium hydroxide. The mixture was heated to 125 − 135 centigrade degree. (Eiichi, et al., 2002a;Eiichi, et al., 2002b;Metzger, et al., 2004) After 7 h, the reaction mixture was cooled and the butanol removed from the mixture by vacuum distilation after which fresh water and toluene were added and the two phases were separated. The water solution was neutralized with hydrochloric acid to pH=6.5-7. The water was evaporated and toluene was added. The inorganic salt were filtered and toluene solution was evaporated to dryness. Yield:52 g(90%). (Singer et al., 2004) Colourless crystals suitable for X-ray analysis were obtained by slow evaporation of an methanol-toluene solution at room temperature over 30 days.

Refinement
All H atoms were positioned geometrically and refined as riding, with C-H = 0.93-0.98 Å and N-H=0.949 Å U iso (H) = 1.2 U eq (C).

Special details
Geometry. All e.s. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.