Synthesis of N-(2-(Methylamino)ethyl) Derivatives of 2H-Phthalazin-1-ones

Abstract A series of new alkyl, tosyl, acetyl, and tert-butoxycarbonyl derivatives of 2-(2-aminoethyl)-phthalazinones were efficiently synthesized by reaction of lactams with N-Boc-, N-acetyl-, or N,O-ditosyl derivatives of N-methylethanolamine in the presence of MeONa or under Mitsunobu reaction conditions. Selected compounds were converted into corresponding 2-[2-(methylamino)ethyl]phthalazinones in good yields. GRAPHICAL ABSTRACT

Especially interesting group of 2H-pyridazin-3-one derivatives are compounds substituted at the lactam nitrogen atom by x-aminoalkyl group. These type of compounds can exhibit analgesic as well as nonsteroidal anti-inflammatory activity Va-c. [8][9][10][11] In our previous articles we have described methodologies for the synthesis of novel (dimethylamino)methyl-and 2-(dimethylamino)ethyl-derivatives of phthalazinones and pyridopyridazinones (Scheme 1). [11,12] The synthetic methods applied in the preparation of these compounds were based on the Mannich reaction and on the reaction of lactams 1 with 2-chloro-N,N-dimethylethanamine.

RESULTS AND DISCUSSION
In this article, we present methods for the preparation of 2-(N-methylamino)ethyl-derivatives of phthalazinones. Starting lactams 1 were synthesized from the appropriate 3-hydroxyisoindolinones or ketoacids upon reaction with hydrazine monohydrate, according to previously described methods. [11][12][13][14] Our preliminary studies have shown that preparation of 2-(x-aminoalkyl) phthalazinones by reaction of corresponding 2-halogenethylamines 4 (Scheme 2) with lactams 1 is not effective. If primary or secondary x-halogenalkylamines 4a,b were used to react with phthalazinones 1, the outcomes were rather poor. [15]  N-Alkylated products 5 were formed in trace amounts only, if at all. The formation of compounds 5 was observed by NMR spectroscopy and they were not isolated in individual form. Therefore, practical application of the x-halogenalkylamines as alkylating agents is limited and determined by the degree of substitution of amine nitrogen atom. In practice, this methodology plays a significant role in preparation of 2-(N,N-dialkylamino)ethyl-lactam derivatives type 3, [11] solely (Scheme 1). Based on these results, we focused on the synthesis of selected N-(2-aminoethyl)-phthalazinone derivatives substituted on the amine nitrogen atom by alkyl, tosyl, acetyl, and tert-butoxycarbonyl group. These derivatives can be effortlessly converted into the desired secondary amines (N-methylamines). [16,17] Easily accessible derivatives of 2-(methylamino)ethanol, types 6, 7, and 8 ( Fig. 2), [18][19][20] were used as x-aminoethylating agents.
stage benzenesulfonamides 9 were hydrolyzed to corresponding amines 10 by heating with concentrated H 2 SO 4 (110 C). Desired amines were obtained in 56-78% yields. The structures of compounds 9 and 10 were determined by infrared (IR), 1 H NMR, and elemental analysis or mass spectroscopy (Table 1). Unexpectedly, synthesis of amine 10d via hydrolysis of appropriate N-tosyl derivative with H 2 SO 4 ended in failure. For this reason, the synthesis of amine 10d was carried out using the Mitsunobu reaction [21,22] as a key step, followed by deprotecion of the amine group. Alkylation of phthalazinone 1 with N-Boc-protected 2-(metylamino)ethanol using standard Mitsunobu conditions (TPP, DEAD) gave carbamic acid derivatives 11e in satisfactory yields (Scheme 3). Cleavage of the Boc protecting group of compound 11e with hydrochloric acid at rt gave the secondary amine 10d in 55% yield. This protocol was successfully applied to  preparation of N-(tert-butoxycarbonyl) derivatives 11b,d and N-acetyl analogs 11a,c using N-(2-hydroxyethyl)-N-methylacetamide as a starting material, too. Therefore, presented methods for synthesis of N-methylaminoethyl derivatives of phthalazinones are complementary to one another but application of Mitsunobu methodology allows the reaction to be carried out under milder conditions.

EXPERIMENTAL
The melting points were determined on a Boetius hot-stage apparatus and are uncorrected. 1 H NMR spectra were recorded at 200 MHz and 13 C NMR spectra at 50 MHz on a Varian Gemini 200 BB spectrometer with tetramethylsilane (TMS) as an internal reference. IR spectra were recorded on a Nexus FT-IR spectrometer. Mass spectra analyses were performed on a MAT95-Finnigan mass spectrometer. The analytical thin-layer chromatography tests (TLC) were carried out on Merck silica gel plates (Kiselgel 60 F 254 , layer thickness 0.2 mm) and the spots were visualized using an ultraviolet lamp.
The FTIR spectra of the benzenesulfonamides 9 displayed characteristic absorption of the C=O in the region 1640-1650 cm À1 . Besides, bands of SO 2 between 1150 and 1340 cm À1 were observed. The 1 H NMR spectra of amides 9 showed the presence of two singlets at 2.31-2.34 ppm and 2.91-2.93 ppm corresponding to methyl group of 4-toluenesulfonyl moiety and N-Me protons, respectively. The signals of the ethylene bridge were displayed as two triplets at 4.36-4.50 and 3.51-3.59 ppm. The Mitsunobu reaction was carried out under argon. DEAD (0.0102 mol, solution in toluene c % 40%) was slowly added to a stirred solution of TPP (0.0102 mol) in dry THF (10 ml) at À10 C. Then a solution of phthalazinone 1 (0.0068 mol) in THF (44 ml) was added dropwise. The whole lot was mixed for 15 min at À10 C and next the appropriate derivative of N-methylethanolamine 7 or 8 (0.00748 mol) in THF (5 ml) was added at À10 C. The mixture was stirred during 2 h at À10 C, after which time the reaction mixture was warmed to ambient temperature and stirred in this condition for 20 h. All volatile materials were removed under reduced pressure, ethyl ether (20 ml) was added to the residue, and the whole lot was stirred for 0.5 h at ambient temperature. The separate white solid was collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The residue was subjected to column chromatography to give the pure product 11.
1 H NMR spectra of compounds 11 showed doubled singlets of methyl groups connected with nitrogen atoms and derived from acetyl or tert-butoxycarbonyl moieties. This fact may indicate that amides 11 coexist as mixtures of rotamers. [23] N-Methyl-N-   (20%, 36 ml). The mixture was stirred for 30 h at room temperature. Next reaction mixture was alkalized with 20% aqueous solution of NaOH and extracted with CH 2 Cl 2 (3 Â 50 ml). The combined extracts were dried over MgSO 4 and concentrated under vacuum. The amine was isolated by column chromatography.
In the case of amines 10 FTIR spectra showed NH bands at %3320 cm À1 and strong C = O bands at 1652 cm À1 . In the 1 H NMR spectra of amines 10 (Scheme 3) the signals of the 2-(methylamino)ethyl moiety were displayed as two triplets at %4.42 and %3.11 ppm corresponding to CH 2 protons of ethylene chain, whereas the protons of NMe and NH groups exhibited as two singlets between 1.52 and 2.51 ppm.

SUPPORTING INFORMATION
Full experimental details, 1 H and 13 C NMR, and IR spectra can be accessed on the publisher's website.