Quinoline catalyzed synthesis of pyridazinone pharmaceutical intermediates

Valuable pyridazinone intermediates to pharmaceutically useful compounds can be prepared in surprisingly high yields by the quinoline catalyzed reaction of the corresponding monohydrazone with an appropriately substituted acetic acid ester. In an especially preferred embodiment, p,p'-dichlorobenzil monohydrazone and methyl acetoacetate are reacted in a xylene solvent in the presence of quinoline to afford 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one, which can then be reacted with ethylene carbonate in the presence of potassium carbonate to afford the antihypertensive agent, 4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one.

TECHNICAL FIELD OF THE INVENTION 
The present invention provides an improved process for the synthesis of 
pyridazinones which are valuable intermediates to pharmaceutically useful 
compounds, said process comprising the quinoline catalyzed reaction of the 
corresponding monohydrazone with an appropriately substituted acetic acid 
ester. 
BACKGROUND OF THE PRIOR ART 
Substituted pyridazinone compounds having various substituents have 
heretofore been prepared and proposed for use in a wide range of different 
ultimate applications. Thus, for example, U.S. Pat. Nos. 3,657,242; 
3,689,652; 3,746,712; 3,812,256; 3,822,260; 3,876,786; 3,876,787; 
3,931,177; and 3,975,388 disclose a variety of pharmacologically active 
4,5-dihydropyridazinones. As a chemical class, those compounds comprise 
dihydro (saturated) ketopyridazines. 
Representative of another class of related compounds are the pyridaz-3-one 
compounds disclosed in U.S. Pat. No. 2,839,532. The aforesaid patent is 
directed to 4,5-unsaturated pyridaz-3-one (or 3-ketopyridazine) compounds 
having a cyano, acetyl, carboxyl, carbethoxy or benzoyl group in the 
4-position optionally substituted in the 5,6- positions by lower alkyl, 
phenyl or substituted phenyl residues. These compounds are disclosed as 
being useful as medicaments, particularly, analgesics, anesthetics, 
antibacterials or disinfectants. 
U.S. Pat. No. 3,491,096 and British Pat. No. 840,522 are directed to other 
previously investigated pyridazone compounds. The aforementioned British 
patent pertains to 2-hydroxymethyl-6-phenyl-3-pyridazone and the analgesic 
utility thereof. U.S. Pat. No. 3,491,096 describes 
2-pyridylalkylated-6-phenylpyridaz-3-one compounds possessing sedative, 
analgesic and antispasmodic properties, with occasional hypotensive 
effects being observed. 
Copending Powers et al U.S. Patent Application Ser. No. 11,416, filed Feb. 
12, 1979, now U.S. Pat. No. 4,238,490 and assigned to the assignee hereof, 
describes novel pyridazin(2H)-3-ones of the general formula 
##STR1## 
and pharmaceutically acceptable nontoxic salts thereof wherein 
R.sub.1 is hydrogen, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 
carbamylmethyl, C.sub.1 -C.sub.6 carboxyalkyl, C.sub.1 -C.sub.6 
alkoxycarbonyl(C.sub.1 -C.sub.6)alkyl, C.sub.1 -C.sub.6 alkoxy(C.sub.1 
-C.sub.6)alkyl; or the group 
##STR2## 
where a is 1 to 4, inclusive, R.sub.2 is hydrogen or C.sub.1 -C.sub.4 
alkyl and R.sub.3 is amino, methylthio, C.sub.1 -C.sub.6 alkylamino, 
C.sub.1 -C.sub.6 alkylimino, C.sub.1 -C.sub.6 acylamino, C.sub.1 -C.sub.6 
alkoxycarbonylamino, morpholinyl, piperazinyl, (C.sub.1 -C.sub.6 
alkoxycarbonyl)piperazinyl, piperidinyl, pyrrolidinyl, glucuronyl or 
glucopyranosyl; or the group 
##STR3## 
where R.sub.4 is hydrogen, C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.6 
carboxyalkyl, phenyl, phenyl(C.sub.1 -C.sub.6)alkyl, or R.sub.4 represents 
the group 
##STR4## 
where b is 0 to 4, inclusive, R.sub.5 is hydrogen, C.sub.1 -C.sub.4 alkyl, 
methylthioethyl, benzyl, NH.sub.2, or benzyloxycarbamyl, and R.sub.6 is 
hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl or 
##STR5## 
R.sub.7 is acetyl, cyano, phenylsulfonyl, (C.sub.1 -C.sub.4)alkylhydrazono, 
naphthyl, phenyl or phenyl substituted with at least one substituent 
selected from the group consisting of halogen, C.sub.1 -C.sub.6 alkylamino 
and C.sub.1 -C.sub.4 alkoxy; and 
X.sub.c and Y.sub.c are the same or different and are independently 
selected from the group consisting of halogen, C.sub.1 -C.sub.4 alkyl and 
C.sub.1 -C.sub.4 alkoxy where c is 0, 1 or 2; 
subject to the provisos that when R.sub.7 is acetyl, phenyl or cyano, 
R.sub.1 is other than hydrogen; and when R.sub.7 is cyano, R.sub.1 is 
C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.6 carboxyalkyl or the group 
##STR6## 
where 
R.sub.4 is C.sub.1 -C.sub.6 carboxyalkyl and X.sub.c and 
Y.sub.c are halo, with c being at least 1; 
and the enol tautomeric derivatives and metabolites thereof. Said compounds 
are useful therapeutic antihypertensive agents, as described in the 
aforesaid U.S. Application Ser. No. 11,416, now U.S. Pat. No. 4,238,490 
said application being hereby incorporated by reference in its entirety 
and relied upon. 
As used throughout the instant specification and claims, the expressions 
"alkyl" and "alkoxy" are inclusive of straight and branched chain 
carbon-carbon linkages, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, 
isobutyl, sec-butyl, tert-butyl, isohexyl, etc. The expression "acyl" 
includes, e.g., formyl, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl 
and the like. The term "halo" includes chlorine, fluorine, bromine and 
iodine. The expression "pharmaceutically acceptable nontoxic salts," as 
used herein, is intended to include those salts capable of being formed 
with the compounds of formula (I) without materially altering the chemical 
structure or pharmacological properties of the parent compounds. 
Representative of acids for reaction with sufficiently basic pyridazinone 
derivatives include hydrochloric, hydrobromic, hydroiodic, nitric, 
phosphoric, citric, etc. Alkali metal salts of carboxylic acid derivatives 
of formula (I) may be obtained by reaction with suitable bases, e.g., 
sodium hydroxide, potassium hydroxide, etc. Alkaline earth metal salts may 
be similarly obtained. Additionally, compounds of formula (I) containing 
amino acid residues, i.e., an .alpha.-amino acyl group, may be obtained as 
their hydrate salts such as mono- or di-hydrobromide, hydrochloride, etc., 
hydrate and such inorganic and organic acid addition salts of certain of 
the compounds of formula (I) and amino acid residues or derivatives may 
advantageously be employed to, for instance, alter solubility properties 
or augment bioavailability. 
As will be apparent to those skilled in the art, the keto compounds of 
formula (I) wherein R.sub.1 is hydrogen may be present in the enol 
tautomeric form. It is also noted that certain of the R.sub.1 substituents 
at the 2-position, e.g., hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, 
alkoxyalkyl, alkylaminoalkyl, glucuronyl, etc., constitute possible enolic 
derivatives and/or metabolites of compounds within the scope of the 
present invention. 
U.S. Application Ser. No. 11,416 now U.S. Pat. No. 4,238,490 teaches that 
the subject pyridazinones, i.e., substituted keto-pyridazine compounds of 
formula (I), may be prepared by various alternative methods theretofore 
employed in the synthesis of other pyridazinone compounds (e.g., in U.S. 
Pat. No. 2,839,532) or modifications thereof to obtain the R.sub.1, 
R.sub.7, X.sub.c or Y.sub.c substituents thereon as defined above. In 
general, one method for the preparation of pyridazin(2H)-3-ones comprises 
reacting an appropriately substituted monohydrazone, with the 
appropriately substituted acetic acid ester or reacting the appropriately 
substituted benzil and appropriately substituted hydrazide under 
cyclization conditions, e.g., in the presence of suitable solvents, such 
as xylene, acetonitrile, methanol, benzene, etc., and alkaline condensing 
agents, such as hydroxides, alcoholates, hydrides, alkali or alkaline 
earth metals, tertiary amines, etc., to effect ring closure. The foregoing 
general reaction scheme may be depicted as follows 
##STR7## 
wherein R is typically an alkyl group and R.sub.7 is not here restricted 
by the provisos set forth earlier. As will be apparent from the foregoing 
description of the formula (I) substituents, the formula (Ia) products are 
in some instances pharmacologically active compounds of formula (I), while 
in other instances the formula (Ia) products are intermediates which can 
be converted by subsequent reactions to the compounds of formula (I). 
The monohydrazone reactants may be prepared by the reaction of an 
appropriate substituted benzil with hydrazine hydrate. Suitable benzil 
starting materials may be obtained commercially or prepared by known 
methods, for example, cyanide ion catalyzed benzoin condensation followed 
by oxidation. The pyridazin(2H)-3-one compounds thus prepared may be 
utilized following suitable recrystallization/purification as 
intermediates for the preparation of further 2-substituted derivatives in 
accordance with the above R.sub.1 definition. 
Exemplary of preferred compounds for use in the antihypertensive 
compositions and methods of U.S. Ser. No. 11,416 now U.S. Pat. No. 
4,238,490 are compounds of the above general formula (I) wherein, 
correspondingly, R.sub.1 represents C.sub.1 -C.sub.4 hydroxyalkyl 
(especially, hydroxyethyl), esters thereof, e.g., acetate, butyrate, 
propanoate, formate, hemisuccinate, octadecanoate, benzoate, etc.; amino 
acid esters thereof corresponding to the 
##STR8## 
group defined hereinabove wherein R.sub.4 represents 
##STR9## 
e.g., lysine, glycine, methionine, phenylalanine, etc.; or where R.sub.1 
is C.sub.1 -C.sub.4 carbamylmethyl, e.g., .alpha.-acetamido; aminoalkyl, 
e.g., aminomethyl, aminoethyl, etc.; C.sub.1 -C.sub.6 alkylaminoethyl, 
e.g., dimethylaminoethyl; glucopyranosyl; glucuronyl; 1-morpholinylethyl; 
1-piperidinylethyl; 1-pyrrolidinylethyl and acetamidoethyl; and wherein 
R.sub.7 represents acetyl and X.sub.c and Y.sub.c are para-halo, 
preferably para-chloro. An especially preferred antihypertensive agent 
provided by U.S. Ser. No. 11,416 is 
4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one. 
According to the methods described in Ser. No. 11,416, that compound is 
prepared by first reacting ethanol and sodium to form sodium ethoxide, 
then adding ethyl acetoacetate and p,p'-dichlorobenzil monohydrazone, to 
afford 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one in 20% yield. 
That intermediate is then reacted with ethylene carbonate and potassium 
hydroxide in dimethylformamide to afford the desired final product. The 
intermediate 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one can be 
used to prepare other antihypertensive compounds of Ser. No. 11,416 as 
well. See, for example, Examples 9, 10 and 11 therein. However, the poor 
yields heretofore obtained in the preparation of that key intermediate 
have been a serious problem standing in the way of commercialization of 
the final antihypertensive products such as 
4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one. 
In view of the foregoing, it is apparent that a serious need exists for an 
improved process for the preparation of the antihypertensive agents of 
formula (I) and intermediates thereto. 
SUMMARY OF THE INVENTION 
It is therefore a primary object of the present invention to provide an 
improved process for the preparation of the antihypertensive agents of 
formula (I) and intermediates thereto. More particularly, it is a primary 
object of the present invention to provide an improved process for the 
preparation of compounds of formula (Ia) in substantially higher yields 
than heretofore possible, thus affording a commercially viable route to 
the formula (I) antihypertensives. 
These and similar objects are accomplished according to the present 
invention by the quinoline catalyzed reaction of a monohydrazone of 
formula (II) above with an appropriately substituted acetic acid ester of 
formula (III) above in a suitable solvent, at elevated temperature, to 
afford the corresponding compound of formula (Ia). 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
Preferred monohydrazones of formula (II) for use in the instant process are 
those wherein X.sub.c and Y.sub.c are para-halo, a particularly preferred 
monohydrazone starting material being p,p'-dichlorobenzil monohydrazone. 
In formula (III), R.sub.7 is preferably acetyl and R is preferably lower 
alkyl. Accordingly, preferred starting materials of formula (III) are 
ethyl acetoacetate and methyl acetoacetate, with the latter being 
especially preferred. The solvent of choice is xylene, particularly when 
p,p'-dichlorobenzil monohydrazone and methyl acetoacetate are employed as 
the reactants. However, other suitable organic solvents will be apparent 
to those skilled in the art. 
It has surprisingly been found that quinoline is vastly superior to the 
sodium alkoxide condensing agents typically used in the prior art. Also, 
quinoline has been found to be a much more effective catalyst than 
pyridine. Thus, only 20% yields of 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one are reported in U.S. 
Ser. No. 11,416 when using a sodium ethoxide reagent to effect ring 
closure. Similarly, it has more recently been found that use of pyridine 
as the condensing agent affords the desired 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one in less than 35% 
yield. In contrast, yields of up to 76% of the aforesaid key intermediate 
have been obtained when using quinoline to catalyze the reaction. It has 
also surprisingly been found that, with quinoline, yields of up to 76% are 
obtained using only half as much catalyst as required in the case of 
pyridine. In fact, a ratio of 1 g quinoline per 7.1 g monohydrazone (1.0 
mole quinoline/3.16 moles monohydrazone) has afforded yields comparable to 
those obtained with 1 g quinoline/3.5 g monohydrazone, and considerably 
superior to those obtained with 1 g pyridine/3.4 g monohydrazone. 
The process of the present invention is most advantageously conducted under 
carefully controlled reaction conditions, especially as concerns time and 
temperature. Obviously, precise time and temperature ranges will vary with 
the particular reactants employed. In the preferred embodiment of the 
instant process, wherein methyl acetoacetate and p,p'-dichlorobenzil 
monohydrazone are reacted in the presence of quinoline in a xylene solvent 
to afford the desired 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one, 
the xylene is heated to about 120.degree. C. before the monohydrazone is 
added; the monohydrazone-xylene mixture is heated rapidly to about 
125.degree.-130.degree. C.; and the methyl acetoacetate and quinoline are 
then added as rapidly as possible, while maintaining the temperature at 
about 125.degree.-130.degree. C. The total reaction time is generally of 
the order of 2.5 to 3.0 hours. Stripping of the solvent is not necessary 
prior to isolation of the product. 
The condensation of a methyl acetoacetate molecule with p,p'-dichlorobenzil 
monohydrazone may go in either of two directions, as depicted below. 
##STR10## 
The formation of the desired pyridazinone key intermediate is favored at 
temperatures above 110.degree. C. The undesired reverse addition product, 
3-(4,4'-dichlorobenzilmonoazino)-1-methoxy-1,3-butanedione, is favored at 
lower temperatures and may even constitute the major reaction product 
under improper reaction conditions. It is also important that the methanol 
(and water) by-products be removed from the reaction zone as they are 
formed. Because the monohydrazone degrades at elevated temperatures, the 
initial reaction with elimination of the methanol by-product should be 
carried out rapidly. Presence of p-chlorobenzoic acid, hydrazine or 
methanol in the monohydrazone feedstock reduces yields. Therefore, the 
monohydrazone starting material should be of high quality. To obtain the 
desired degree of purity, the monohydrazone starting material [which has 
typically been prepared by (1) a classical benzoin condensation in which 
p-chlorobenzaldehyde in the presence of potassium cyanide is converted to 
p,p'-dichlorobenzoin in refluxing methanol and water solvents; followed by 
(2) oxidation of the dichlorobenzoin to the dichlorobenzil using 
concentrated nitric acid in glacial acetic acid solvent; followed by (3) 
conversion of the dichlorobenzil to the monohydrazone by reaction with 
hydrazine hydrate in isopropanol at reflux temperature] is recrystallyzed 
from isopropanol prior to its use in the cyclization process of the 
present invention. 
In a particularly preferred embodiment of the present invention which 
provides 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one, the 
following procedure has been utilized: 
The reactor is preheated by refluxing xylene (about 140.degree. C.). 
Sufficient xylene is distilled and removed to ensure that any moisture 
present in the reactor and in the xylene has been eliminated. The xylene 
is then cooled to about 130.degree. C., and solid p,p'-dichlorobenzil 
monohydrazone is added. The mixture is quickly heated, then methyl 
acetoacetate and quinoline are added. Immediately thereafter, a 
methanol-xylene emulsion distilling at about 138.degree. C. (pot 
temperature) is removed. (The time which elapses from the beginning of the 
monohydrazone addition through the heat-up stage, the methyl acetoacetate 
and quinoline addition to the beginning of the methanol distillation is 
generally less than 10 minutes.) The mixture is held at reflux temperature 
for about 2 hours, during which time approximately 90% of the theoretical 
amount of methanol and water are removed by distillation. During the 
methanol-water distillation and very early in the run, a light brown 
precipitate, which is the desired 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one, begins to form in the 
hot xylene solution. 
The reverse addition product precipitates as a flocculent material and is 
much more soluble, generally dropping out of solution when the temperature 
goes below 40.degree. C. If the content of desired product is in excess of 
about 65%, then the xylene solution can be cooled to about 20.degree. C. 
without crystallizing out the reverse addition product. On the other hand, 
if the content of desired product is less than about 55%, the filter 
collection of product should be done at about 40.degree. C. Otherwise, 
when the temperature drops below 40.degree. C., a precipitate which is a 
mixture of desired compound and the reverse addition product is obtained. 
After the methanol-water has been removed, approximately half of the 
reaction xylene is then removed by distillation over an approximately one 
hour period. The mixture is then generally cooled to room temperature and 
the crystallized 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one is 
removed by filtration, washed with methanol and dried. Following this 
procedure, yields of about 75% can be expected, with the product being 
more than 98% pure 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one. 
It has been observed that the desired 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one has low solubility in 
xylene. The uncyclized reverse addition product has high solubility in 
xylene. However, it is very important that very little of the uncyclized 
reverse addition product become cyclized because the solubility 
characteristics of the desired pyridazin-3-one and of the cyclized reverse 
addition product are very similar. Consequently, the heating time after 
the water and methanol have been removed should be limited to minimize 
dehydration of the reverse addition product to its cyclized version. 
Because 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one is the 
immediate precursor to the desired antihypertensive agent 
4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one, a 
high degree of purity of the precursor is required. Therefore, the 
crystalline product obtained by the instant process as described above is 
recrystallized from ethyl acetate. The recrystallization comprises 
dissolving the 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one in hot 
ethyl acetate, filtering, removing a portion of the solvent by 
distillation and collecting the desired 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one by filtration at about 
20.degree. C. 
The preferred product of the instant process, i.e., 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one, after purification as 
described supra, can then be converted to the antihypertensive agent 
4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one, 
preferably by reaction with ethylene carbonate in dimethylformamide 
solvent in the presence of trace quantities of potassium carbonate at 
about 85.degree. C., followed by crystallization from ethyl acetate. 
Without further elaboration, it is believed that one of ordinary skill in 
the art can, using the preceding description, utilize the present 
invention to its fullest extent. Consequently, the preferred specific 
embodiments set forth below are to be construed as merely illustrative and 
not limitative of the remainder of the specification and claims in any way 
whatsoever.

In the Examples which follow, it is to be noted that Examples 1-3 are 
illustrative of starting material preparations; Examples 4 and 5 are 
comparative examples of the procedures used and yields obtained 
previously; Examples 6-9 are illustrative of the improved process of the 
present invention; and Example 10 is illustrative of methods for 
converting a product of the instant process into an antihypertensive agent 
of formula (I). 
EXAMPLE 1 
A 20 gallon (approximately 76.9 liter) reaction vessel was charged with 
22.7 kg of p-chlorobenzaldehyde and the solids were blanketed with 
nitrogen. 12.6 Liters of methanol were added, and the resultant mixture 
was agitated and heated. When the temperature reached 50.degree. C., the 
solids had dissolved and 6.0 liters of distilled water were added. Heating 
was continued until the temperature reached 79.degree. C., at which time 
544 g of potassium cyanide dissolved in 1.3 liters of water were added. 
The methanol began refluxing vigorously and the solution turned a bright 
orange color. The exothermic reaction was essentially complete within 30 
minutes, but heating was continued at methanol reflux temperature for an 
additional hour. 
The reaction product was cooled to 50.degree. C., 20 liters of cold water 
were added, and the mixture was agitated. Then the orange colored organic 
layer was allowed to settle and the water-methanol upper layer was removed 
under nitrogen. The organic layer was washed twice more with 8 liter 
portions of water, the final wash being carried out at 60.degree. C. to 
prevent solidification of the organic layer. There was thus obtained the 
desired p,p'-dichlorobenzoin. 
EXAMPLE 2 
To the washed p,p'-dichlorobenzoin obtained in Example 1 were added 21.3 
liters of glacial acetic acid. The mixture was agitated and heated to 
97.degree. C., then 13.7 kg of concentrated nitric acid were added over a 
one hour period. The reaction mixture was heated at 97.degree.-100.degree. 
C. for an additional six hours, an additional six liters of glacial acetic 
acid being added during the oxidation period to maintain fluidity of the 
thickening slurry. 
After the oxidation was completed, the reaction mixture was cooled to 
25.degree. C. and transferred to a filter crock. The bright yellow-colored 
product was thoroughly washed with water. The washed product was divided 
into four portions, and each portion was returned to the reaction vessel 
and stirred with 10 gallons (approximately 38.5 liters) of an 
approximately 5% bicarbonate solution to neutralize any residual acids and 
to remove p-chlorobenzoic acid by-product. 
The bicarbonate washed p,p'-dichlorobenzil was returned to the crock 
filter, washed thoroughly with water and dried overnight at 120.degree. C. 
The weight of dried p,p'-dichlorobenzil was 17.5 kg, a 77% yield based on 
the amount of p-chlorobenzaldehyde charged in Example 1. 
EXAMPLE 3 
A 20 gallon (76.9 liter) reaction vessel was charged with 5.0 kg of 
p,p'-dichlorobenzil and 37 liters of isopropyl alcohol. The mixture was 
agitated and heated to 85.degree. C., then 1.03 kg of 85% hydrazine 
hydrate were added. Within twenty minutes, the slurry became a clear 
solution. An additional 200 g of hydrazine hydrate were then added. Within 
30 minutes after the second hydrazine addition, the desired 
p,p'-dichlorobenzil monohydrazone began to precipitate and to form a thick 
slurry. The slurry was stirred for one additional hour at 
85.degree.-90.degree. C., then was cooled to 25.degree. C. The 
monohydrazone was transferred to a filter crock and washed with isopropyl 
alcohol. The washed monohydrazone was returned to the reaction vessel, 25 
liters of isopropyl alcohol were added and the mixture was heated to 
80.degree. C. with agitation. The reaction mixture was then cooled to 
25.degree. C., transferred to the filter crock, washed with isopropyl 
alcohol and dried overnight at 65.degree. C. The total weight of dry 
p,p'-dichlorobenzil monohydrazone was 14.86 kg, an 81% yield based on the 
p,p'-dichlorobenzil. 
EXAMPLE 4 
Ethanol, dried by distilling from Mg-I.sub.2, was added to a dry flask 
(N.sub.2 atmosphere) containing clean sodium (1.1 equivalent). After the 
sodium had reacted, ethyl acetoacetate (7 ml) was added dropwise to the 
cold (0.degree.-5.degree. C.) alkoxide solution. p,p'-Dichlorobenzil 
monohydrazone (15 g) was added through a powder addition funnel. After 
heating the reaction mixture at reflux for three hours, it was cooled and 
poured into 1 N HCl. The resulting precipitate was separated by filtration 
and washed with water. The resulting product was recrystallized from 
ethanol-acetonitrile to give 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one melting at 
269.degree.-271.degree. C., in 20% yield. 
Analysis--calculated for C.sub.18 H.sub.12 Cl.sub.2 N.sub.2 O.sub.2 (%): C, 
60.20; H, 3.34; N, 7.80. Found (%): C, 60.02; H, 3.33; N, 7.91. 
EXAMPLE 5 
A 20 gallon (76.9 liter) reaction vessel was charged with 34.2 liters of 
xylene and 13.76 kg of p,p'-dichlorobenzil monohydrazone. The mixture was 
heated up to 60.degree. C. over a 20 minute period and 4.125 liters of 
pyridine were then added. Heating was continued for an additional 30 
minutes, during which time the reaction temperature climbed to 110.degree. 
C. 6.0 Kg of methyl acetoacetate diluted with 5.5 liters of xylene were 
then added. Water began to distill immediately. Over the next 5 hours, 
1.25 liters of water were removed by azeotropic distillation. The 
temperature was then raised and 28.5 liters of pyridine and xylene were 
removed by distillation. 
The reaction mixture was cooled to 40.degree. C. and the solids were 
collected by filtration and washed, first with xylene and then with 
petroleum ether. The crude product was dried at 75.degree. C. for 6 hours. 
There were thus obtained 5.845 kg of crude 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one melting at 
262.degree.-270.degree. C. (34.7% yield based on monohydrazone charged). 
The crude product was slurried in methanol to remove a red-brown colored 
solid which was soluble in the methanol. Total reaction time to convert 
the monohydrazone to the pyridazin-3-one was 10 hours, with an additional 
one hour for methanol wash and an additional 12 hours for drying time. 
EXAMPLE 6 
A flask fitted with a stirrer, Deans Stark trap, condenser, thermometer and 
addition funnel, was charged with xylene and p,p'-dichlorobenzil 
monohydrazone. The mixture was heated with stirring to 105.degree. C. and 
then charged with methyl acetoacetate, followed immediately with 
quinoline. The mixture was refluxed for approximately two and one-half 
hours, then cooled to 45.degree.-50.degree. C., filtered, washed with 
methanol, dried and weighed. The product was 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one. The particulars for 
several runs are shown in the following table. 
TABLE I 
__________________________________________________________________________ 
Quantities of Starting Materials 
Weight 
Run Number 
Monohydrazone 
Methyl Acetoacetate 
Quinoline 
Xylene 
of Product 
Yield 
Melting Point 
__________________________________________________________________________ 
1 25.0 g 14 ml 7 ml 60 ml 
22.5 
g 70% 268-270.degree. C. 
2 25.0 g 14 ml 3.5 
ml 60 ml 
22.7 
g 74% 268-270.degree. C. 
3 100.0 
g 48 ml 14 ml 240 
ml 
89.0 
g 72.6% 
268-270.degree. C. 
4 200.0 
g 96 ml 28 ml 480 
ml 
167 g 68.4% 
269-270.degree. C. 
5* 876 g 416 ml 122 
ml 3725 
ml 
813 g 75.7% 
Not recorded 
__________________________________________________________________________ 
*In this run, xylene solvent was heated to 110.degree. C., then the 
monohydrazone was added. That mixture was heated to 124-125.degree. C., 
then methyl acetoacetate, followed by quinoline, was added. 
EXAMPLE 7 
A 5 liter flask fitted with a stirrer, Deans Stark trap, water cooled 
condenser, thermometer, and addition funnel was charged with 1200 ml of 
xylene. The xylene was heated to 120.degree. C. Then, 500 g of 
p,p'-dichlorobenzil monohydrazone were added and the resultant mixture was 
heated to 126.degree. C. 240 Ml of methyl acetoacetate and 70 ml of 
quinoline were added in sequence at such a rate as to maintain the 
reaction temperature between 126.degree. and 128.degree. C. (approximately 
8 minute addition time). The reaction mixture was then refluxed for 
approximately two and one-half hours at 137.degree. C. At the end of that 
time, the flask was cooled to 45.degree. C., and the solids were removed 
by filtration, washed with methanol, and dried. A yield of 348 g (57% 
yield) of the desired 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one, 
melting at 269.degree.-271.degree. C., was obtained. 
EXAMPLE 8 
A 20 gallon (76.9 liter) reaction vessel was preheated by refluxing xylene 
(140.degree. C.). Sufficient xylene was distilled and removed to ensure 
that moisture in the reactor and in the xylene was eliminated. The xylene 
was cooled to 130.degree. C. by shutting off the steam to the reactor and 
solid monohydrazone was added. The resultant mixture was quickly heated, 
then methyl acetoacetate and quinoline were added through a liquid feed 
tube. Immediately thereafter, a methanol-xylene emulsion distilling at 
138.degree. C. was removed. The time which elasped from the beginning of 
the monohydrazone addition, through the heat-up stage and the methyl 
acetoacetate and quinoline addition, to the beginning of the methanol 
distillation was less than 10 minutes. 
The mixture was held at the reflux temperature for about two hours, during 
which time approximately 90% of the theoretical amount of methanol and 
water were removed by distillation. Approximately half of the reaction 
xylene was then removed by distillation (time elapsed, approximately one 
hour). The reaction mixture was then cooled to room temperature and the 
crystalline 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one which 
formed was collected by filtration. The crystals were washed with methanol 
until the methanol filtrate was clear. The product was greater than 98% 
pure. The particulars for two runs are given in the following table. 
TABLE II 
______________________________________ 
Quantities of Starting Materials 
Run Methyl Weight 
Num- Mono- Aceto- Quino- 
Xy- Of 
ber hydrazone acetate line lene Product 
Yield 
______________________________________ 
A 3680 g 1766 ml 515 ml 
17 l 3480 g 75.6% 
B 5550 g 2644 ml 777 ml 
24 l 5129 g 75.4% 
______________________________________ 
EXAMPLE 9 
A 12 liter flask immersed in a heating mantle was charged with 6 l of 
xylene and heated to 100.degree. C. Then, 1409 g (4.81 mole) of 
p,p'-dichlorobenzil monohydrazone (m.p. 159.degree.-160.degree. C.) was 
rapidly added. A reaction flask head containing a stirrer was quickly 
attached to the flask and equipped with a dropping funnel and a Barrett 
type water trap with a condenser. The mixture was heated with rapid 
stirring and, when the pot temperature reached 120.degree. C., 675 ml 
(6.26 mole) of methyl acetoacetate (b.p. 169.degree.-170.degree. C., 
density=1.076) were added quickly from the dropping funnel, followed 
immediately by 197 ml of quinoline. Almost immediately following the 
quinoline addition, a methanol-xylene emulsion began to distill (at 
128.degree. C.) into the Barrett water trap. Total time elapsed between 
the monohydrazone addition and the methanol-xylene azeotrope distillation 
was 10 minutes. 
The temperature rose to 136.degree.-139.degree. C. and the methanol-xylene 
azeotrope, followed by the water-xylene azeotrope, distilled. The 
methanol-water lower layer was removed from the water trap. Distillation 
was continued for a total of three hours, during which time 260 ml (90% of 
theoretical) methanol-water were removed. During this time, a brown 
precipitate, which was the crude product, continued to form. After the 
methanol-water removal, approximately half (2750 ml) of the remaining 
xylene was removed by distillation. 
The reaction mixture was cooled to 30.degree. C. and the crude product was 
collected by filtration. The filter cake was washed, first with 200 ml of 
cold xylene, then with about 1500 ml of methanol until the methanol 
filtrate was clear. The product on air drying weighed 1312 g (76% yield) 
and melted at 268.degree.-270.degree. C. 
The 1312 g of crude 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one 
were placed in a 20 gallon (76.9 liter) glass-lined steel reactor and 
47.55 l of ethyl acetate were added. The temperature was raised to reflux 
(75.degree. C.) and the mixture was stirred until the pyridazin-3-one had 
completely dissolved. The hot solution was then pressured through a fine 
cartridge filter to remove insolubles and into a second reactor. Then, 
35.6 l (75%) of the ethyl acetate were removed by distillation. The slurry 
in the reactor was cooled to 22.degree. C. and the product was collected 
on a filter. The filter cake was washed with two 250 ml portions of cold 
ethyl acetate, and the product was dried to constant weight in a vacuum 
oven at 90.degree. C. (10 hours). The final weight of purified 
4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one was 1128 g (86% 
recovery), assaying 99.7% pure. 
EXAMPLE 10 
4-Acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one (3.1 g), ethylene 
carbonate (2.0 g), and potassium hydroxide (powdered) were dissolved in 
dimethylformamide (50 ml) and the flask placed in an oil bath 
(110.degree.-120.degree. C.) until CO.sub.2 evolution ceased (ca. 3.5 
hours). The reaction mixture was poured into water (400 ml) and chilled at 
5.degree. C. for 1 hour. The resulting precipitate was separated by 
filtration and recrystallized from methanol (85 ml) to afford 
4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one 
(68 percent yield) as pale yellow crystals, m.p. 191.degree.-193.degree. 
C. 
Analysis--calculated for C.sub.20 H.sub.16 Cl.sub.2 N.sub.2 O.sub.3 (%): C, 
59.56; H, 4.00; N, 6.95. Found (%): C, 59.44; H, 3.94; N, 6.71. 
While the invention has been described in terms of various preferred 
embodiments, the skilled artisan will appreciate that various 
modifications, substitutions, omissions and additions may be made without 
departing from the spirit thereof. Accordingly, it is intended that the 
scope of the present invention be limited solely by the scope of the 
following claims.