US 2007.0128680A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0128680 A1 Lopes et al. (43) Pub. Date: Jun. 7, 2007

(54) HYDRAZINES AND DERVATIVES (30) Foreign Application Priority Data PRODUCTION PROCESS FROM HYDRAZINES AND DICARBOXYLIC ACID Nov. 25, 2003 (BR)...... PIO3O7864-7 (76) Inventors: Claudio Cerqueira Lopes, Del Publication Classification Castilho (BR); Rosangela Sabattini Capella Lopes, Rio de Janeiro (BR): (51) Int. Cl. Jari Nobrega Cardoso, Rio de Janeiro CI2O I/66 (2006.01) (BR); Jacqueline Alves da Silva, Rio C07D 237/28 (2006.01) de Janeiro (BR); Leticia Gomes Ferreira, Rio de Janeiro (BR) (52) U.S. Cl...... 435/8; 544/235; 564/148; 564/149 Correspondence Address: POWELL GOLDSTEIN LLP ONE ATLANTC CENTER (57) ABSTRACT FOURTEENTH FLOOR 1201 WEST PEACHTREE STREET NW ATLANTA, GA 30309-3488 (US) The present invention describes a process to form hydrazides from the reaction of a hydrazine and a dicar (21) Appl. No.: 10/595,943 boxylic, using a Lewis acid as a main reagent of the reaction. The reaction occurs in a safe reactional environment, ulti (22) PCT Filed: Nov. 25, 2004 lizing Smooth conditions, neither involving high tempera (86) PCT No.: PCT/BRO4/OO236 tures nor high pressures, producing the desired products with high yields, between 90-95%. The invention also S 371(c)(1), describes a kit for utilization of chemiluminescent sub (2), (4) Date: May 22, 2006 stances, comprised of two solutions. US 2007/0128680 A1 Jun. 7, 2007

HYDRAZINES AND DERVATIVES PRODUCTION 0005 There are many applications for chemiluminescent PROCESS FROM HYDRAZINES AND substances besides forensics. Recently, there has been a DCARBOXYLIC ACID demand and production increase, especially for entertain ment and in accidents preventions industries. A number of FIELD OF THE INVENTION accessories, such as bracelets, necklaces, earrings, plastic 0001. The present invention describes a new process that teeth frame, cups etc., are frequently used in events, resi favors the production of hydrazides from dicarboxylic acids, dences, night clubs, theaters, stadiums, music festivals, using a Lewis acid. More specifically, the present invention rodeos and many others, drawing the attention of the public is directed to the formation of phtalazides, for example with the intense chemiluminescence reaction glow. Safety luminol, using as Lewis acid a halide donator, more spe flares are used by scuba-divers in deep waters and poor cifically chloride, for example niobium pentachloride. The visibility, especially in the maintenance of underwater process provides a global yielding well above traditional industrial petrol plants maintenance, or by the police and fire techniques yielding, as well as easy execution, without the department in case of night accidents with intense fog or in need of drastic reactional conditions. unfavorable weather conditions on roads and large avenues or by the coast guard, helping night sailing on rivers, bays BACKGROUND OF THE INVENTION and near the coast. These are some examples of the many 0002. It is extremely desirable and convenient to have applications of the chemiluminescent Substances industrially secure methods for the reliable trace detection of substances produced by the process described on the present invention, in liquids, especially body fluids, where the presence of a specially the luminol. concentration as low as 10' M of a substance may be 0006 Luminol and its derivatives synthesis process potentially pathogenic. include, among other steps, the reaction of a dicarboxylic 0003 Classical methods of detection in liquids are based acid with a hydrazine. This stage is usually difficult to on reaction mechanisms where either the appearance of a accomplish, since drastic conditions are needed and the product or the disappearance of a reagent can be measured. yield is not significantly high. Some documents propose Greater importance is given to chemiluminescent com Solutions to this stage. pounds, capable of producing light when in favorable con 0007 British patent GB 1,100,911 is the first to describe ditions. the synthesis of phtalazine derivatives. Among the proposed 0004 The chemiluminescence is a method based on processes, it uses a mixture of a dicarboxylic acid and a certain Substances characteristic of emitting light when in hydrazine, the mixture being heated under reflux for 4 hours. presence of the compound to be analyzed. It has applications The solution is cooled and water and HCl are added until pH in forensics, diagnosis and quality control fields, being 7. The solid formed is recrystallized in hot water. capable of detecting traces of compounds. One example of 0008 American patent U.S. Pat. No. 4,226,992 performs a commonly used chemiluminescent Substance in criminal the formation of the phtalazide from a dicarboxylic acid and investigations is luminol, capable of detecting blood stains a hydrazine in methanol under reflux for 3 hours. After hidden in Suspicious locations, such as crime scenes. The cooling, the mixture is evaporated until dryness in a roto mechanism of action of luminol is based on the reaction evaporator, and the crystalline residue dried overnight at 80° below, where the addition of hydrogen peroxide is capable C. under vacuum. of oxidizing the luminol in a basic medium, generating light. 0009 American patent U.S. Pat. No. 4.226,993 describes However, the reaction below needs a catalyst, which will be the reaction of a phtalimide with a hydrazine, in ethanol for the iron (Fe) present on erythrocyte's hemoglobin of the 2 hours under reflux, followed by cooling and rest overnight. blood. Hence, when a basic luminol Solution is put in contact After evaporation in rotoevaporator under reduced pressure, with a hydrogen peroxide Solution with Fe, an intense glow the solid was dried at 110° C. for 8 hours under a pressure will be produced, confirming the presence of the compound. of 0.1 mmHg. The solid residue was stirred for 90 minutes

O O Oo O

H N1 N- e- N. O.". O re- | - 2 - + hv + N2 N n N n ) N O H H H+ NH O NH O NH2 O NH O US 2007/0128680 A1 Jun. 7, 2007

in HCl 10%, filtered and neutralized with KOH, and the DETAILED DESCRIPTION OF THE precipitated was filtered, dried and recrystallized in aqueous INVENTION dimethyl formamide 0020. The present invention presents innovative charac 0010. One document describing a technique similar to the teristics in an alternative process for hydrazide production, present inventions is American patent U.S. Pat. No. 6,489, based in the use of halide donors as catalysts, resulting in 326. It describes an extremely dangerous and complex reactions with better yields than the available methods. The production process of a hydrazide from the 3-nitro-phtalic present invention also provides a new process of luminol anhydride and hydrazine. In spite of presenting excellent synthesis which is cheaper and economically viable. yields, between 85 and 90%, the reaction involves a Ni 0021. The reaction described aims a production of a Raney catalyst, gas generation, such as N2 and H, and is hydrazide from the reaction of a dicarboxylic acid of a extremely exothermic, reaching temperatures of 285-90° C. general formula (I): 0011 Unlike all the processes described above, the present invention uses a halide donator, more specifically (RCH), (COOH), (I) chloride, even more specifically niobium pentachloride in wherein R1 can be hydrogen, alkyl, alkenyl, alkinyl, phenyl, dioxane, that promotes a Smooth reaction, easy controlled aromatic heterocyclic ring containing as heteroatom S. O and capable of generating 90-95% yield. and/or N. heterocyclic non-aromatic ring containing as het eroatom S. O and/or N. cycloalkyl containing from 3 to 8 0012 Niobium pentachloride is a known Lewis acid, carbon atoms, cycloalkenyl containing from 3 to 8 carbon used as a catalyst for cyclotrimetrization reactions, for atoms, cycloalkinyl containing from 3 to 8 carbon atoms; all example, reactions described in document WO 91/09066. the described groups can be further substituted and/or Regarding the synthesis of organic compounds, an important branched; document, though not relevant, is document U.S. Pat. No. 4.349,471, which describes the synthesis of sulfonic acid 0022 in varies from 1 to 2: halides and aromatic carboxylic acids halides. The referred 0023 with a hydrazine of general formula (II): reaction involves the use of a Lewis acid, for example niobium pentachloride. 0013 However, the reaction of the present invention is (II) completely different from the reactions described on the above mentioned documents, and therefore the use of a Lewis acid halide donator, more specifically chloride, for example niobium pentachloride, aiming hydrazides synthe sis from dicarboxylic acids and hydrazines have never been described before, being the present invention therefore new. wherein R2 and R3 are, independently, hydrogen, alkyl, alkenyl, alkinyl, phenyl, heterocyclic aromatics contain OBJECT OF THE INVENTION ing as heteroatom S. O and/or N. heterocyclic non 0014. It is an object of the present invention to provide an aromatics containing as heteroatom S. O and/or N. alternative process for the synthesis of hydrazides from cycloalkyl containing from 3 to 8 carbon atoms, cycloalk dicarboxylic acids and hydrazines. enyl containing from 3 to 8 carbon atoms, cycloalkinyl containing from 3 to 8 carbon atoms; 0015. It is an additional object of the present invention to provide a process for the synthesis of hydrazides in safe and 0024 in the presence of a chloride donor reagent. Smooth reactional conditions, without gas or heat liberation 0025 Additionally, the present invention aims the pro and having an excellent yield. duction of a hydrazide from the reaction of a dicarboxylic 0016. It is still an object of the invention to provide acid of general formula (III): economically more viable hydrazides synthesis. 0017. It is an object of the present invention to provide a (III) process of synthesis of hydrazides, where such process is O based on the use of a Lewis acid as a halide donator. More specifically, the process is based on the use of a Lewis acid 1s as a chloride donator. More specifically still, the Lewis acid is niobium pentachloride. A OH 0018. It is an additional object of the present invention to provide a preparation process of luminol based on the O production of a hydrazide, where the Lewis acid is a chloride donator, more specifically still, the Lewis acid is niobium pentachloride. wherein A can be an aromatic heterocyclic ring containing from 4 to 8 atoms, a non-aromatic ring containing from 4 to 0019. It is an additional object of the present invention to 8 atoms, an aromatic heterocyclic ring containing from 4 to provide a kit for the use of a chemiluminescent composition, 8 atoms, wherein the heteroatom is S, O and/or N, a more specifically luminol, where such kit provides a long non-aromatic heterocyclic ring containing from 4 to 8 lasting luminescence and easy application without the need atoms, wherein the heteroatom is S, O and/or N. all the of ultraviolet light. described groups can be further substituted and/or branched; US 2007/0128680 A1 Jun. 7, 2007

0026 ring A can further have 1 or more aromatic, non aromatic, aromatic heterocyclic, non-aromatic heterocy -continued clic rings and mixture thereof, coupled, wherein the O O heteroatom can be N, O, and/or S. NH NH 0027 X can be C or N: He 0028 Y can be C or N: NH NH 0029 with a hydrazine of general formula (II): NO O NH O

(II) 0036 Reagents of stage 1 are HSO and HNO, respon sible for the nitration of phthalic anhydride in smooth conditions. 0037. In stage 2, the inventive step is the use of niobium pentachloride in a suspension of 3-nitrophthalic acid in dioxane. After 30 minutes was added an aqueous hydrazine wherein R2 and R3 are, independently, hydrogen, alkyl, 40% solution obtaining the 5-nitro-2,3-dihidroftalizide-1,4- alkenyl, alkinyl, phenyl, heterocyclic aromatics contain dione intermediate. ing as heteroatom S. O and/or N. heterocyclic non 0038. In a three-necked 100 mL flask, equipped with aromatics containing as heteroatom S. O and/or N. magnetic stirrer, reflux condenser and dry argon flow, were cycloalkyl containing from 3 to 8 carbon atoms, cycloalk added 4.71 mmols of niobium pentachloride followed by the enyl containing from 3 to 8 carbon atoms, cycloalkinyl addition of 30.0 mL of dioxane and 1-nitro phthalic acid containing from 3 to 8 carbon atoms; (14.13 mmols). After few minutes under vigorous agitation, 0030) in the presence of a chloride donor reagent. a suspension is observed. Afterwards, it was added a 40% aqueous solution of hydrazine (37.68 mmols) in the mixture. 0031. The reaction occurs at room temperature, with In thirty minutes the temperature was raised slowly to excellent yielding. Additionally, it is possible to use a 45-50° C. and the reaction time was extended more four dicarboxylic acid of general formula (I) or (III) suspended in hours. The mixture was cooled and the solids obtained were an organic solvent. removed through filtration. The filtered was extracted with ethyl acetate (200.0 mL) and washed with a 5% solution of 0032. The Lewis acid halide donator is chosen from the sodium bicarbonate (60.0 mL), saturated solution of sodium groups comprising aluminum chloride, antimony trichloride, chloride (2x60.0 mL) and distilled water (3x60.0 mL). The antimony pentachloride, arsenic trichloride, arsenic pen organic phase was dried with anhydrous Sodium Sulphate tachloride, beryllium chloride, bismuth trichloride, boron and evaporated under vacuum and recrystallized in ethanol/ trifluoride, boron trichloride, cadmium chloride, copper distillated water resulting in luminol in a 90-95% yield. chloride (I), copper chloride (II), cobalt chloride, chromo trichloride, gallium chloride, iron chloride (III), mercury 0039 The niobium pentachloride in this process is con chloride (II), magnesium chloride, magnesium bromide, verted to niobium pentoxide. However, the formation of nickel chloride, niobium pentachloride, titanium dichloride, 1-nitro-phthalic acid chloride can be admitted from the titanium trichloride, titanium tetrachloride, tellurium tetra correspondent niobate through a nucleophilic attack by the chloride, uranium tetrachloride, Zirconium tetrachloride, chlorides generated in the reactional medium from the Zinc chloride and mixture of them. niobium pentachloride, to this reagent earning the property of chloride donor in this transformation. 0033 Suitable organic solvents for the dicarboxylic acid Suspension can be selected among solvents of the prior art. 0040. In the 3rd stage, a simple reduction reaction was capable of reducing the nitro group to amine group. In this 0034. The followings examples are only illustrative, not case, it can be used reducing agents like Sodium dithionite limiting the present invention. in acid medium followed by the addition of acetic acid. This reduction can also be promoted by the hydrogenation pro EXAMPLE 1. cess containing palladium over carbon (10%) in solvents like dioxane and acetic acid. The final product, luminol, is 0035. The synthesis of luminol as presented in this inven obtained in quantitative yield. tion has four stages as showed in the following scheme: EXAMPLE 2

O 0041 Additionally, the invention provides a kit compris O ing a solution of one chemiluminescent Substance obtained by the process described above, being the kit composed by 1 OH O -- He two separated Solutions, namely solution A and solution B. OH 0042 Solution A comprises an alkaline solution of lumi O nol, where the concentration of luminol ranges from 0.75 to NO O 7.0 g/L, preferably 5.0 g/L. Solution B comprises hydrogen peroxide in water, wherein the hydrogen peroxide concen US 2007/0128680 A1 Jun. 7, 2007 tration ranges from 1.0 to 5.0%, preferably 3.0%. The solution pH ranges from 8 to 14, preferably 13.6. Any alkalinizing agent can be used, with the proviso that the final (III) pH ranges between 8 and 14. It is known by alkalinizing O agent any Substance capable of generate hydroxyl ions when in Solution. The preferred alkalinizing agents are alkali 1s metals hydroxides, and its concentration can range from A OH 0.05M to 3.0M, preferably from 0.1M to 0.5M. 0043. The procedure requires the simultaneously appli r cation of solutions A and B in the local where the chemi luminescent reaction will occur. If the reaction occurs, an intense blue coloration will be observed, visible in dark wherein A can be an aromatic heterocyclic ring containing environment not being necessary the use of UV lamps. from 4 to 8 atoms, a non-aromatic ring containing from 4 to Otherwise no intense coloration will be observed. 8 atoms, an aromatic heterocyclic ring containing from 4 to 0044) The principal advantage of this kit is the durability 8 atoms, wherein the heteroatom is S, O and/or N, a of reagents present at Solutions A and B. Conventional kits non-aromatic heterocyclic ring containing from 4 to 8 are presented as a mixture of Solids generally containing atoms, wherein the heteroatom is S, O and/or N: luminol, Sodium carbonate, Sodium borate etc., which after all the described groups can be further substituted and/or solubilization in distilled water produce one solution to branched; obtain the chemiluminescent reaction which do not last longer that the solution here presented. The kit presented in ring A can further have 1 or more aromatic, non-aromatic, this invention has the advantage of providing a long-lasting aromatic heterocyclic, non-aromatic heterocyclic rings reaction and not requiring the use of UV light to observe the and mixtures thereof, coupled, wherein the heteroatom color appearance. It is due to the stability provided by the can be N, O, and/or S; alkaline medium to the hydrogen peroxide, slowing its degradation. X can be C or N: 1-20. (canceled) Y can be C or N: 21. Process to produce hydrazides and their derivatives, with a hydrazine of a general formula (II) characterized in that the reaction of a dicarboxylic acid having general formula (I): (RCH), (COOH), (I) (II) wherein R1 can be hydrogen, alkyl, alkenyl, alkinyl, phenyl, aromatic heterocyclic ring containing as het eroatom S. O and/or N. heterocyclic non-aromatic ring containing as heteroatom S. O and/or N. cycloalkyl containing from 3 to 8 carbon atoms, cycloalkenyl containing from 3 to 8 carbon atoms, cycloalkinyl wherein R2 and R3 are, independently, hydrogen, alkyl, containing from 3 to 8 carbon atoms; all the described alkenyl, alkinyl, phenyl, heterocyclic aromatics con groups can be further substituted and/or branched; taining as heteroatom S. O and/or N. heterocyclic non-aromatics containing as heteroatom S. O and/or N. in varies from 1 to 2: cycloalkyl containing from 3 to 8 carbon atoms, with a hydrazine of general formula (II) cycloalkenyl containing from 3 to 8 carbon atoms, cycloalkinyl containing from 3 to 8 carbon atoms; (II) in the presence of a Lewis acid. 23. Process, in accordance to claim 21, characterized in that the Lewis acid is halide donator. 24. Process, in accordance to claim 23, wherein the Lewis acid is an halide donator chosen from the group consisting of aluminum chloride, antimony trichloride, antimony pen tachloride, arsenic trichloride, arsenic pentachloride, beryl wherein R2 and R3 are, independently, hydrogen, alkyl, lium chloride, bismuth trichloride, boron trifluoride, boron alkenyl, alkinyl, phenyl, heterocyclic aromatics con trichloride, cadmium chloride, copper chloride (I), copper taining as heteroatom S. O and/or N. heterocyclic chloride (II), cobalt chloride, chromo trichloride, gallium non-aromatics containing as heteroatom S. O and/or N. chloride, iron chloride (III), mercury chloride (II), magne cycloalkyl containing from 3 to 8 carbon atoms, sium chloride, magnesium bromide, nickel chloride, nio cycloalkenyl containing from 3 to 8 carbon atoms, bium pentachloride, titanium dichloride, titanium trichlo cycloalkinyl containing from 3 to 8 carbon atoms; ride, titanium tetrachloride, tellurium tetrachloride, uranium in the presence of a Lewis acid. tetrachloride, zirconium tetrachloride, zinc chloride and 22. Process to produce hydrazides and their derivatives, mixture of them. characterized in that the reaction of a dicarboxylic acid 25. Process, in accordance to claim 24, characterized in having general formula (III): that the halide donator Lewis acid is niobium pentachloride. US 2007/0128680 A1 Jun. 7, 2007

26. Process, in accordance to claim 21, characterized in sium chloride, magnesium bromide, nickel chloride, nio that the dicarboxylic acid is Suspended in an organic solvent. bium pentachloride, titanium dichloride, titanium trichlo 27. Process, in accordance to claim 26, characterized in ride, titanium tetrachloride, tellurium tetrachloride, uranium that the organic solvent is an aprotic polar organic solvent. tetrachloride, zirconium tetrachloride, zinc chloride and 28. Process, in accordance to claim 27, characterized in mixture of them. that the solvent is chosen from the group consisting of 33. Process, in accordance to claim 32, characterized in dioxane, acetone, methylpyrrolidone, dimethylsulfoxide, that the halide donator Lewis acid is niobium pentachloride. N,N-dimethylformamide and mixture of them. 34. Process, in accordance to claim 22, characterized in 29. Process, in accordance to claim 21, characterized in that the dicarboxylic acid is Suspended in an organic solvent. that the hydrazine is soluble in water or in the reaction 35. Process, in accordance to claim 34, characterized in solvent. that the organic solvent is an aprotic polar organic solvent. 30. Process, in accordance to claim 29, characterized by the reaction of 1-nitro-phtalic acid with hydrazine in the 36. Process, in accordance to claim 35, characterized in presence of niobium pentachloride. that the solvent is chosen from the group consisting of 31. Process, in accordance to claim 30, characterized in dioxane, acetone, methylpyrrolidone, dimethylsulfoxide, that the Lewis acid is halide donator. N,N-dimethylformamide and mixture of them. 32. Process, in accordance to claim 31, wherein the Lewis 37. Process, in accordance to claims 22, characterized in acid is an halide donator chosen from the group consisting that the hydrazine is soluble in water or in the reaction of aluminum chloride, antimony trichloride, antimony pen solvent. tachloride, arsenic trichloride, arsenic pentachloride, beryl 38. Process, in accordance to claim 37, characterized by lium chloride, bismuth trichloride, boron trifluoride, boron the reaction of 1-nitro-phtalic acid with hydrazine in the trichloride, cadmium chloride, copper chloride (I), copper presence of niobium pentachloride. chloride (II), cobalt chloride, chromo trichloride, gallium chloride, iron chloride (III), mercury chloride (II), magne