The present invention relates to a process for preparing piperazic acid or derivatives thereof.

Piperazic acid (hexahydropyridazine-3-carboxylic acid) has been prepared by electrophilic hydrazination of a N-bromovalerylcarboximide compound using di-tert-butyl azodicarboxylate (Boc-N=N-Boc) as hydrazination agent followed by cyclization of the reaction product in the presence of lithium diisopropylamide. The synthesis has been described by K. J. Hale et al. in Tetrahedron 1996, 52 (3), 1047-1068.

The yield of the reaction described by K. J. Hale was 55-63% and thus is relatively low.

It has now been found that piperazic acid derivatives can be prepared in a greater yield compared to the yield obtained in the Hale process by treating a 2,5-dihalopentanoate with a hydrazodicarboxylic acid derivative whereby nucleophilic substitution at both of the halo atoms of the 2,5-dihalopentanoate occurs.

Accordingly, the object of the present invention is to provide a process for preparing piperazic acid derivatives of the general formula wherein R'is C, 20-alkyl and R2 is hydrogen, C, 6-alkyl, Cl 6-haloalkyl, C, 6-alkoxy, allyloxy, 2,2,2-trichloroethoxy, 2-iodoethoxy, optionally substituted phenyl, benzyloxy, 4-methoxy- benzyloxy or 2,4-dimethoxybenzyloxy, which process comprises reacting a 2,5-dihalopentanoate of the general formula CH2X-CH2-CH2-CH, X-COOR' (II), wherein X is Br or Cl and R'is as defined above,

in the presence of a base with a hydrazine derivative of the general formula R'CONH-NHCOR' (III), wherein R2 is as defined above.

As used herein, the term C, 20-alkyl refers to straight chain or branched alkyl groups having 1-20 carbon atoms.

Examples of straight chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, decyl, dodecyl, hexadecyl, heptadecyl and eicosyl. Preferred straight chain hydrocarbon groups are methyl and ethyl.

Examples of branched alkyl groups include: * alpha branched alkyls such as e. g. isopropyl, 1-methylpropyl, 1-methylbutyl, 1-methyl- pentyl, 1-methylhexyl, 1-ethylpropyl, 1-ethylhexyl, 1-propylpentyl, 1-ethylheptyl, 1-propyl- hexyl and 1-hexylundecyl ; beta branched alkyls such as e. g. 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethyl- butyl, 2-methylhexyl, 2-ethylpentyl, 2-methylheptyl, 2-ethylhexyl, and 2-propylpentyl; * polybranched alkyls such as e. g. 1,1-dimethylethyl (tert-butyl), 1,2-dimethylpropyl, 2,2-di- methylpropyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, 3,5,5-trimethylhexyl, 3,7-dimethyloctyl and 1,5,9-trimethyldecyl; or * other branched alkyls such as e. g. 3-methylbutyl, 3-methylpentyl, 4-methylpentyl, 3-methyl- hexyl, 4-methylhexyl, 5-methylhexyl, isodecyl, and isoheptadecyl.

Preferred branched chain alkyl groups are isopropyl and tert-butyl.

The alkyl groups are optionally substituted with one or more substituents selected from the group consisting of C, 6-alkoxy, amino, monoalkylamino, dialkylamino, cyano, halo, hydroxy, nitro, phenyl, substituted phenyl and the like. A preferred substituted alkyl group is the benzyl group.

As used herein, the term C, 6-haloalkyl refers to a straight or branched alkyl group substituted with one or more halo atoms such as e. g. trifluoromethyl.

As used herein, the term C, 6-alkoxy refers to C, 6-alkyl-O-groups having from 1 to 6 carbon atoms. Preferred alkoxy groups include e. g. methoxy, ethoxy, propoxy, isopropoxy, (n-) butoxy, tert-butoxy, sec-butoxy, (n-) pentyloxy, (n-) hexyloxy, 1,2-dimethylbutoxy, and the like.

The phenyl group is optionally substituted with one or more substituents selected from C, 6-alkyl, C, 4,-alkoxy, hydroxy, nitro, chloro, fluoro, trichloromethyl and trifluoromethyl.

As used herein, the term halo refers to fluorine, chlorine, bromine, and iodine.

The-COR2 moities may also be regarded as amino protective groups. The expression"amino protective group"is generally known in the art and relates to groups which are suitable for protecting an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions of the molecule. Examples of such groups are, in particular, C, 6-alkanoyl such as e. g. formyl, acetyl, propionyl, butyryl; C, 6-alkoxycarbonyl such as e. g. methoxycarbonyl, ethoxycarbonyl ; tert-butoxycarbonyl (Boc); Aryl-C, 6-alkoxycarbonyl such as e. g. benzyloxycarbonyl (also called"CBZ"or simply"Z"), 4-methoxybenzyloxycarbonyl or 2,4-dimethoxybenzyloxycarbonyl; and other known groups such as e. g. allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl.

The reaction of the 2,5-dihalopentanoate (II) with the hydrazine derivative (III) of the above process is effected in the presence of a base. Any base suitable to perform the nucleophilic disubstitution reaction will suffice. Examples for a suitable base are NaH, KH, LiH, n-butyl- lithium, tert-butyllithium, phenyllithium, lithium diisopropylamide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide sodium hexamethyldisilazide, NaOH or KOH. Preferred bases are NaH and n-butyllithium. The base is preferably added in an amount somewhat greater than the stoichiometric amount of two equivalents. The base may be added or prepared in situ.

The molar ratio of the 2,5-dihalopentanoate (II) to the hydrazine derivative (III) is preferably 1.0 to 1.2, a ratio of 1.03 to 1.1 being especially preferred.

The above process is suitably carried out in the presence of an aprotic solvent.

Examples of preferred aprotic solvents useful in the present invention include tetrahydrofuran, dimethylsulfoxide, N, N-dimethylpropyleneurea (DMPU), diethyl ether, methyl tert-butyl ether, diisopropyl ether, N, N-dimethylformamide, N-methylpyrrolidone, toluene or a mixture of two or more of the foregoing solvents.

Preferably, the above process is carried out at a temperature in the range of-30 to 40 °C, most preferably at room temperature.

The product, i. e. the compound of the general formula I may be recovered by known methods such as extraction, distillation or chromatography.

A preferred compound of the formula I is a compound wherein R'is ethyl and R2 is ethoxy. Said preferred compound can be prepared by adding diethyl hydrazodicarboxylate to a solution of ethyl 2,5-dibromopentanoate in the presence of NaH.

Compounds of the formula II which are preferably dibromo compounds can be prepared using methods known in the art, for example from 8-valerolactone as described by W. A. J. Starmans et al. in Tetrahedron 1998, 54, 4991-5004 or by bromination of 5-bromopentanoic acid as described by R. Merchant et al. in J. Am. Chem. Soc. 1927,49,1828-1831.

The compound of the formula III wherein R2 is hydrogen can easily be prepared by reacting hydrazine with formic acid C, >-alkyl ester. The compound of the formula III wherein R2 is methyl, ethoxy or phenyl is commercially available, for example at Aldrich or Fluka.

The compound of the formula III wherein R2 is other than hydrogen can be prepared by known methods such as e. g. described in the following references: L. A. Carpino and P. J. Crowely in Organic Syntheses. Coll. Vol. V, page 160; J. M. Mellor and R. N. Pathirana, J. Chem. Soc.

Perkin Trans. 1 1984, 753-759; H. Böshagen and J. Ullrich Chem. Ber. 1959,92,1478.

In an additional step, the-CO-R2 groups of the compound of formula I may be detached from the nitrogen atom by treatment with a base. Furthermore, under these conditions hydrolysis of the ester function (-COOR') occurs. This reaction is preferably carried out under heating to reflux in the presence of a base such as for example in the presence of a hydroxide of an alkali

metal, preferably in the presence of KOH. Piperazic acid is obtained in the form of its alkali metal salt which may be recovered by known methods, such as e. g. extraction. The aqueous solution obtained together with salts are purified by extraction of neutral and basic components with e. g. methylene chloride.

The alkali salt of piperazic acid may easily be converted into free piperazic acid by methods known in the art.

The alkali salt of piperazic acid may also be reacted in a further additional step with a chloroformate of the general formula R'OCOCI(V), wherein R3 is C, 6-alkyl, allyl, 2,2,2-trichloroethyl, 2-iodoethyl, benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, to give a compound of the general formula wherein R3 is as defined above, or an alkali salt thereof.

Preferably, this additional step is carried out by adding the chloroformate (V) to an aqueous solution of the salt of piperazic acid in the presence of a base as an acid acceptor. This kind of reaction is known in the art and for example described by C. E. Adams et al. in Synth. Commun.

1988,18 (18), 2225-2231. It may be carried out with the solution obtained by base treatment of the piperazic acid derivative (I) without isolating the alkali salt of piperazic acid (IV).

With regard to the chloroformates of the formula V, benzyl chloroformate is especially preferred.

The compounds of formula V are known and commercially available.

The amount of the chloroformate (V i is usually 0.7 to 1.4 mol based on 1 mol of the alkali salt of piperazic acid.

The reaction with the chloroformate (V) is usually conducted in an aqueous solvent, and an aprotic solvent such as one of those listed above can be added to the aqueous reaction solution.

The reaction temperature of this step is usually-10 to 50 °C, preferably 0 to 20 °C.

In a preferred work-up procedure, after completion of the reaction, the aqueous and the organic phase are separated, the aqueous phase is acidified to afford crystals of the desired N'-substituted piperazic acid.

The piperazic acid derivatives of formula I contain a center of asymmetry and can, therefore, exist in racemic or optically active form. Thus, the invention includes within its scope the resolution of racemates which can be carried out according to known methods.

The compounds of the general formula I are valuable intermediates for the preparation of pharmacologically active molecules.

The following examples are merely for illustrative purposes.

Example 1 Ethyl 2,5-dibromo-pentanoate To a solution of 6-valerolactone (417.2 g, 96% pure, 4.00 mol) and PBr3 (22.0 g, 0.08 mol) at 110-115 °C bromine (645.7 g, 99% pure, 4.00 mol) was added below the surface over a period of 2 hours, the second half of that amount being added more slowly. After a further 60 minutes the solution was cooled to 0-5 °C and added to cold ethanol containing 36.5 g (1.00 mol) of dry HCl gas. After stirring for 22 hours at room temperature the ethanol and water were removed by distillation under reduced pressure. (Azeotropic removal of water-ethanol using toluene or other suitable solvent is also possible.) The crude product was taken up in ether (2000 ml) and washed with saturated aqueous sodium bicarbonate solution (total 980 ml, 1.24 mol) to remove any

unreacted acids. After drying and removing the solvent in vacuo the crude ester (922.7 g, 69.6% pure, yield 55.8%) was fractionally distilled through a 60 cm Vigreux column with a reflux ratio of 3: 1, in order to separate some ethyl monobromopentanoate (yield 20.3%) which is recyclable and ethyl tribromopentanoate, and to collect 565.3 g (two main fractions, 95.1% and 92.1% pure) of ethyl 2,5-dibromopentanoate.

Boiling point: 97-98 °C/1. 8 mbar. Yield of distilled material: 49.1 %.

Example 2 Triethyl hexahydro-1, 2,3-pyridazinetricarboxylate To a suspension of NaH (36.0 g, 1.50 mol) in THF (600 ml) was added in 45 min a solution of diethyl hydrazodicarboxylate (117.45 g, 99% pure, 0.66 mol) in DMSO (600 ml) at room temperature. When hydrogen evolution ceased, a solution of ethyl 2,5-dibromopentanoate (181.8 g, 95.1% pure, 0.60 mol) in THF (750 ml) was added carefully over a period of 60 min while stirring vigorously at 20-30°C (cooling necessary). The mixture got quite thick during the addition but was readily stirrable at the end of the addition. After stirring for a further 2 hours the suspension was distributed between aqueous (1500 ml H20) KH2PO4 (57.6 g, 0.42 mol) and ethyl acetate (840 ml). The aqueous phase was extracted with ethyl acetate (2x840 ml) and the combined organic phases were washed with saturated NaHCO3 solution (410 ml, 0.51 mol, to remove any acid present) and then with water. After drying (300 g MgSO4) and removal of solvent under reduced pressure, crude triethyl hexahydro-l, 2,3-pyridazinetricarboxylate (174.15 g, 86.8% pure by GC, 0.50 mol), containing 4.5% diethyl hydrazodicarboxylate but essentially free from DMSO, was obtained in a yield of 83.3%.

Example 3 Potassium salt of piperazic acid To a solution of KOH (179.4 g, 85%, 2.84 mol) in n-butanol (1500 ml) under nitrogen was added triethyl hexahydro-1, 2,3-pyridazinetricarboxylate (172.1 g, 86.8% pure, 0.49 mol) in butanol (150 ml) and the solution was heated to reflux temperature for 14 hours. Precipitation of most of the solids occured in the early stages. After cooling to 95 °C, water (1500 ml) was added, and

further cooled to room temperature, and the phases were separated. The organic phase was again extracted with water (2x250 ml) and the combined aqueous extracts were back washed with methylene chloride (2x500 ml) to remove butanol. The pH of the aqueous phase was adjusted to 10-11 by the addition of 2 N HCl (185.5 g). [At this stage the potassium salt of piperazic acid was dissolved in the water containing K2CO3 and a little KCl].

Example 4 N'-benzyloxycarbonylpiperazic acid For the reprotection step, the aqueous solution obtained in the preceding example was cooled to 10-15 °C and was treated in two parallel streams, with 2 N NaOH (247 ml) and with a solution of benzyl chloroformate (79.9 g, 95% pure, 0.44 mol) in toluene (247 ml) over a period of 30 min, while maintaining the pH at 10-11 and agitating rapidly. The pH may be adjusted with additional 2 N HCl or with 2 N NaOH. After a further 2 hours stirring at 10 °C the phases were separated and the aqueous phase washed with toluene (2x250 ml). The aqueous phase was then carefully acidified with 6 N HCl (493.0 g, 2.70 mol) to pH 1-2. The N'-benzyloxycarbonylpiperazic acid precipitated. After stirring for 2 hours at 3 °C the crystals were filtered, washed with cold water (0-5 °C, 3x270 ml) followed by ether/hexane (1 : 1, 500 ml), and dried at 60 °C in vacuo for 24 h.

Colourless crystals of N'-Z-piperazic acid (105.9 g, yield 81. 1%) are obtained. mp: 144.5-147.5 °C.