Process for the manufacture of 1,4-diaminophthaiazine
[ Apr. 15, 1975 PROCESS FOR THE MANUFACTURE OF 1,4-DIAMINOPHTHAIAZINE [75] Inventor: Klaus-Dieter Steffen,  
 Troisdorf-Oberlar, Germany [73] Assignee: Dynamit Nobel AG, Troisdorf (Bez Koln), Germany 22 Filed: Oct. 4, 1972 211 Appl. No.: 295,036  
 [30] Foreign Application Priority Data Oct. 28, 1971 Germany 2153693 [52] US. Cl. 260/250 P; 260/DIG. 2  
 [51] Int. Cl C07d 51/06 [58] Field of Search 260/250 P, 250 A [56] v References Cited UNITED STATES PATENTS 3,813,384 5/1974 Vogelsang et al. 260/250 P FOREIGN PATENTS OR APPLICATIONS 4,211,070 6/1967 Japan 260/250 P 543,569 7/1957 Canada 260/250 P 743,204 1/1956 United Kingdom 260/250 P 1,064,303 4/1967 United Kingdom 260/250 P OTHER PUBLICATIONS Noller, Chemistry of Organic Compounds, W. B. Saunders, Philadelphia, 1965, pp. 275-276, QD. 253.N65.  
 Simpson, ed., Condensed Pyridazine and Pyrazine Rings, lnterscience, 1953, p. 69, OD. 401.559. Armarego, .1. Appl. Chem. LL, Feb. 1961, pp. 70-72. Di Stefano, et al., Chemical Abstract, 68:78226b, (1968).  
 Primary Examiner-Alton D. Rollins Assistant E.raminerRalph D. McCloud Attorney, Agent, or FirmBurgess, Dinldage &amp; Sprung [57] ABSTRACT In a process for the manufacture of 1,4- diaminophthalazine by the reaction of phthalonitrile with hydrazine, the improvement which comprises carrying out the reaction in the presence of sulfur or sulfides of alkaline metals or ammonium, preferably in the additional presence of a solvent of the reactants and a non-solvent of 1,4-diaminophthalazim.  
 6 Claims, No Drawings PROCESS FOR THE MANUFACTURE OF Similarly, by the term non-solvent of 1,4-  
  1,4-DIAMINOPHTHAIAZINE diaminophthalazine is meant that the solvent does not dissolve more than grams of l,4-diaminophthalazine BACKGROUND OF THE INVENTION g per 100 cc of solvent, determined at C. L Field of the Invention i DESCRIPTION OF THE PREFERRED This invention relates to a one-step process for the EMBODIMENTS preparation of 1,4-diaminophthalazine. More particu- I the r tical p f rmanc of the p ocess, the pr larly, this invention relates to the preparation Of 1,4- cedure is generally first to dissolve hydrazine and diaminophthalazine from phthalonitrile and hydrazine. l0 phthalonitrile in the solvent and then to add the sulfur More especially, this invention is directed to the prepuor sulfides to this solution. The reaction is exothermic ration of l,4-diaminophthalazine from phthalonitrile and vigorous, with the formation of NH;, and H 8; it is wherein the l p t l llline is recovered in therefore desirable, after the reaction has started, to  
 high yields with good purity. cool the reaction vessel, and after the reaction has 2- Discussion of the Prior Art 15 progressed to heat it to 160C, preferably to 120C, in  
  Y li4-(llamlh0phlhfllilllhe is meant, as the term is order to assure a complete reaction. The end of the reused herein the helelhbelow Compounds in ZICCOF- action is indicated by the cessation of the formation of dance with the following three formula5- NH;, and H- S. The duration of the reaction depends on Pounds in equlllbllum with one allolhefi the size of the batch and the temperature that develops.  
  NIH I |lli Iil l l l l i F l blH H NH Pyridazine derivatives, including 1,4- In general, most of the phthalonitrile reacts within diaminophthalazine, have a generally increasing imporabout one hour. It is entirely contemplated. however. tance in drug synthesis. as revealed by J. Druey, Anto heat the reaction components to the stated temperagew. Chemie 70 (l958)5. Particularly, the hytures for a period of several hours in order to make the drazinophthalazines are used as blood pressure reducreaction as complete as possible without the formation ing agents. of appreciable amounts of by-products. After the reaclt is already known that 1,4-diaminophthalazine can tion has ended, the solution is cooled, preferably to be prepared from phthalonitrile and hydrazine hydrate temperatures below 0C, whereupon the 1,4- in solution in methanol, such as disclosed by L. Di diaminophthalazine is precipitated.  
 Stefano and Castle in lletefocycllc C 5 The hydrazine is used preferably in the form of the (1968) 111. In the process described 1n that article, the hydrate pure hydrazine can aIso be disadvantage is that the yield of is entirely unsatisused in the same manipulative procedum 40 factory and IS an obstacle to large scale manufacture of The molar mm) of phthalommle to hydrazme to SUL the product fur or sulfides can vary within wide limits. lt can be be- SUMMARY OF THE INVENTION tween l:l:0.l and 1:521. However, it is preferable to select from a range between 1:1.6:0.2 and 124:0.8. If the proportion of hydrazine is increased, the sulfur is also to be increased. The higher the hydrazine and sulfur proportions are, the purer will be the reaction product.  
  Broadly, this invention contemplates an improvement in a process for the preparation of 1,4- diaminophthalazine by reaction of phthalonitrile with hydrazine, which improvement comprises carrying out the reaction in the presence of sulfur or the sulfides or The solvent is to be one in which the phthalonitrile polysulfides of alkaline metals or ammonium. and the hydrazine are Soluble and the In a ti l l d i bl b dim thi invendiaminophthalazine that forms is poorly soluble or intion contemplates carrying out the above-described soluble. Furthermore, the solvent, of course, must not process in the presence of a solvent of the reactants and e c ith the reaction components. These requireanon-solvent of the 1,4-diaminophthalazine. Generally ments e fi ed by alkyl Substituted amides Wl&#39;llCll s ki h ti can b i d out i th presare fluid at room temperature, among others. The alkyl ence of sulfur or the alkaline metal sulfides or polysulg p involved is inly 1 to C4 lkyls, preferably the tides, employing a molar ratio of phthalonitrile to hyme hyl group and the ethyl group. By amides are meant drazine to sulfur within the range of 11:110.! to 15:1. h he ci mides of aliphatic carboxylic acids and Temperatures between and 160C are suitable. ni r g nous. heterocyclic compounds in which the Preferably the temperature is between 100 and 130C. amide group I5 =1 component of the ting. Examples of B using thi h d, i ld f more th are b- 60 suitable solvents, accordingly, are: dimethylformamide tained. Additionally, the product that is synthesized is n t ylformamide, dimethylacetamide and diethylof high purity and can easily be separated from the acetamlde. -methylpip n n N-m hylpyrroh on other reaction components and by-products. N-ethylpyrrolidone, N-butylpyrrolidone. The use of N- As indicated above, the process is preferably carried methylpyrrolidone is preferred. out in the presence of a solvent of the reactants, phthal- 65 onitrile and hydrazine. By this is meant at least 5 grams of phthalonitrile or hydrazine must be soluble in cc of solvent. Preferably, at least 10 grams of phthalonitrile or hydrazine are soluble in 100 cc of solvent, all The crude reaction product obtained by the method measured at the reaction temperature. of the invention is many times of an orange to red color Other suitable solvents are: dioxane, tetrahydrofuran, benzene, methanol, ethanol, butanol or acetone or mixtures of these solvents with one another.  
 EXAMPLES l to 3 64.1 g of phthalonitrile (0.5 mole) is dissolved together with the amount of hydrazine hydrate (100%) and sulfur given in the table in 300 ml of N- methylpyrrolidone. and carefully heated. The reaction is energetic and is accompanied by the formation of NH and H 8. After the development of gas has subsided. the solution is slowly heated up to 120C. After a total reaction time of five hours, the solution is chilled overnight in a chest freezer, the precipitated crystals are filtered out, washed well with benzene and dried.  
  The following table gives, in Column 4, the yields of crude 1,4-diaminophthalazine, and in Column 5 the purity thereof. determined and estimated by the thin-layer chromatography method.  
 Ex. Hydrazinc Sulfur Crude yield Purity of H. -O (q) (q) of theory crude prod.  
 (L6 mole) (0.3 mole) (1.2 mole) (0.2 mole) (0.8 mole) (0.1 mole) The crude products were then recrystallized from water with the addition of active charcoal and then had a purity of better than 99%.  
  From the above, it is seen that carrying out the reaction in the presence of sulfur there is produced 1,4- diaminophthalazine in high purity,.i.e., a purity of at least Additionally, the yield of crude product based upon the maximum amount allowed by theory is in excess of 90%, i.e., well above the 40% provided by prior art processes. The use of a solvent such as N methylpyrrolidone enables the ready separation of the 1,4-diaminophthalazine from the reaction medium.  
  1,4-diaminophthalazine reacts with hydrazine under formation of l,4-dihydrazinophthalazine according to Austrian Patent Publication 177,422. 1,4- dihydrazinophthalazine is a hypotensive agent and is known under the trade name of Dihydralazine.  
 I claim:  
  1. In a process for the preparation of 1,4- diaminophthalazine by reaction of phthalonitrile with hydrazine, the improvement which comprises the steps of carrying out the process in the presence of elemental sulfur, a sulfide or polysulfide of an alkaline metal or ammonium.  
  2. An improvement according to claim 1 wherein the sulfur is present such that the molar ratio of phthalonitrile to hydrazine to sulfur is in the range of 1:l:0.l to 1:521.  
  3. An improvement according to claim 1 wherein the molar ratio of phthalonitrile to hydrazine to sulfur is within the range of 1:l.6:0.2 to 114:0.8.  
  4. An improvement according to claim 1 wherein the solvent is selected from the group consisting of dimethylformamide, diethylformamide. dimethylacetamide, diethylacetamide, N-methylpiperidone, N- methylpyrrolidone, N-ethylpyrrolidone, N- butylpyrrolidone, dioxane, tetrahydrofuran, benzene, methanol, ethanol, butanol, acetone. and mixtures of these solvents with one another.  
  5. An improvement according to claim 4 wherein the reaction is carried out at a temperature between 60 and 160C.  
 6. An improvement according to claim 5 wherein the temperature is between and C.