Process for 4-sulfonamidolphenyl hydrazines

4-Sulfonamidophenyl hydrazines are prepared by reaction between the hydrazine, optionally substituted, and the corresponding 4-substituted benzenesulfonamides, where the 4-substitution is an appropriate leaving group, in the presence of water and the absence of dimethyl sulfoxide as a solvent. The result is a product of unusually high purity.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention lies in the technology of synthetic processes for 
4-sulfonamidophenyl hydrazines. 
2. Description of the Prior Art 
The compound 4-sulfonamidophenyl hydrazine and its various derivatives and 
analogs are useful for a variety of purposes. Some of these compounds are 
intermediates in the production of substituted phenyl pyrazolones, which 
serve a wide range of utilities extending from magenta color formers used 
in color photography to non-steroidal antiinflammatory drugs (NSAIDs) used 
for the inhibition of prostaglandins in the control of inflammation 
arising from arthritis and other physiological conditions. Disclosure of 
the use of 4-sulfonamidophenyl hydrazines in the synthesis of magenta 
color formers appears in U.S. Pat. No. 3,839,325 to Hoffstadt, Walter F. 
(GAF Corporation), issued Oct. 1, 1974, while disclosure of the use of 
these compounds in the synthesis of NSAIDs appears in U.S. Pat. No. 
5,563,165 to Tally, John J., et al. (G. D. Searle & Co.), issued Oct. 8, 
1996. The NSAIDs formed from 4-sulfonamidophenyl hydrazines are 
particularly useful for the selective inhibition of COX-2 relative to 
COX-1, both of which are cyclooxygenase enzymes that play key roles in the 
biosynthesis of prostaglandins. 
The substituted phenyl pyrazolones that are used as COX-2 inhibitors and 
other therapeutic drugs often require administration in large doses over 
extended periods of time. It is therefore important that the drug and its 
intermediate be highly pure and capable of being synthesized free of 
impurities, in addition to being economical. 
The most cost-effective synthesis of the 4-sulfonamidophenyl hydrazine 
intermediate is one in which the starting material is 
4-chlorobenzenesulfonamide, since this material is both commercially 
available and readily prepared from the chlorosulfonation of chlorobenzene 
followed by reaction with ammonium hydroxide. A description of the 
conversion of 4-chlorobenzenesulfonamide (and its substituted analogs) to 
4-sulfonamidophenyl hydrazine (and its substituted analogs) appears in the 
Hoffstadt patent cited above. The Hoffstadt process calls for the use of 
dimethyl sulfoxide (DMSO) as an aprotic dipolar solvent to enhance the 
nucleophilic character of the hydrazine. Unfortunately, the hydrazine, in 
addition to reacting with the 4-chlorobenzenesulfonamide, also reduced the 
DMSO to dimethyl sulfide and other by-products, resulting in a critically 
impure product. 
A process that takes advantage of the low cost and availability of 
4-chlorobenzenesulfonamide and yet produces a high product yield with 
little or no impurities is therefore needed. 
SUMMARY OF THE INVENTION 
It has now been discovered that 4-sulfonamidophenyl hydrazines can be 
prepared from an appropriate hydrazine and the corresponding 
benzenesulfonamide substituted with a leaving group at the 4-position, to 
result in a product of high yield and high purity, by eliminating the use 
of dimethyl sulfoxide as solvent, and preferably by avoiding the use of 
all organic solvents, i.e., performing the reaction in a reaction medium 
that is devoid of solvents other than water. When water is present in the 
reaction medium, the reaction successfully proceeds at a rapid rate with 
little or no by-product formation. When the product is further converted 
to the more stable hydrochloride, it is readily purified by 
recrystallization. Thus, the invention permits use of a relatively 
inexpensive starting material and produces a product of high purity that 
permits recycling of the recrystallization solvent. 
These and other features, objects, and advantages of the invention are 
presented in detail in the description that follows. 
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS 
The 4-sulfonamidophenyl hydrazines whose preparation is the subject of this 
invention are those having the formula: 
##STR1## 
The corresponding 4-substituted benzenesulfonamides are those having the 
formula: 
##STR2## 
In Formulas I and II, the symbols R.sup.1 and R.sup.2 represent substituent 
groups, either individually in which case the sulfonamido nitrogen atom is 
an acyclic secondary or tertiary amine, or together in which R.sup.1 and 
R.sup.2 are combined to form a single divalent moiety and to form a 
nitrogen-containing heterocyclic with the sulfonamido nitrogen atom, the 
latter thereby forming a cyclic amine. 
When taken individually, R.sup.1 and R.sup.2 are either the same or 
different (and are thus referred to herein as being "independently 
selected") and are either hydrogen, alkyl, cycloalkyl, alkaryl, aralkyl or 
aryl. The term "alkyl" as used herein includes saturated groups, 
unsaturated groups, straight-chain groups and branched-chain groups. A 
preferred carbon atom range for the alkyl groups is 1 to 6 carbon atoms 
per group, with 1 to 3 carbon atoms preferred. Cycloalkyl groups are 
nonaromatic cyclic groups in which the ring atoms are all carbon atoms. 
Examples of cycloalkyl groups are cyclopentyl, cyclopentenyl, cyclohexyl, 
and cyclohexenyl. The term "aryl" includes any conjugated (aromatic) 
six-membered carbon atom ring or two or more such rings fused. The 
preferred aryl group is the phenyl group. A preferred subgenus for both 
R.sup.1 and R.sup.2 is hydrogen and alkyl, more preferably hydrogen and 
C.sub.1 -C.sub.3 alkyl, and most preferably hydrogen. 
When combined with the sulfonamido nitrogen to form a heterocyclic ring, 
the heterocyclic ring contains from 3 to 7 ring atoms in addition to the 
sulfonamido nitrogen, the ring atoms can be substituted or unsubstituted, 
the ring can be saturated or unsaturated, and the ring can contain the 
sulfonamido nitrogen as the sole heteroatom, or one or more additional 
heteroatoms such as S atom(s), (O) atoms, or further N atom(s). Examples 
of heterocyclic rings within this group are pyrrolydyl, pyrryl, 
pyrrolinyl, piperidyl, oxazolidyl, thiazolidyl, imidazolinyl, 
imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, and morpholinyl. 
The formula for the hydrazine used as a starting material is R.sup.3 
--NH--NR.sup.4 R.sup.5. In both the hydrazine formula and in Formula I, 
R.sup.3, R.sup.4 and R.sup.5 are either the same or different (and are 
thus referred to herein as being "independently selected") and are either 
H, alkyl, aryl, aralkyl, or alkaryl, with the limitation that the total 
number of carbon atoms in R.sup.3, R.sup.4 and R.sup.5 is seven or less. A 
preferred subgenus for R.sup.3, R.sup.4 and R.sup.5 is H, alkyl, and aryl, 
with H and alkyl more preferred. Compounds in which R.sup.3, R.sup.4 and 
R.sup.5 are each H are the most preferred. 
The symbol X in Formula II represents a leaving group active in an aromatic 
nucleophilic substitution. Such leaving groups are well known among 
synthesis chemists. Examples are F, NO.sub.2, OTs (p-toluenesulfonyl), 
phenylsulfenyl, chloro, bromo, iodo, aryloxy, alkylthio, and 
alkylsulfinyl. Preferred among these is chloro. 
Water can be present in the reaction medium either as water of hydration of 
the hydrazine monohydrate, or as free water. The amount of water included 
in the reaction medium is not critical to the invention, and can vary 
while still achieving beneficial results. Water is conveniently included 
by simply using hydrazine monohydrate in place of hydrazine, although 
water can be added separately. In hydrazine hydrate, the water of 
hydration constitutes 36% by weight (a hydrazine:water weight ratio of 
64:36). In preferred reaction media in accordance with this invention, the 
weight ratio of hydrazine to water is from about 15:85 to about 75:25. In 
reaction media that are more preferred, the weight ratio of hydrazine to 
water is from about 25:75 to about 64:36, and most preferably from about 
50:50 to about 64:36. 
The mole ratio of the hydrazine to the 4-substituted benzenesulfonamide can 
vary widely while still providing effective results. Since the cost of the 
hydrazine is low compared to the 4-substituted benzenesulfonamide and the 
reaction rate increases with the hydrazine concentration consistent with a 
second-order reaction, the hydrazine is preferably used in excess. The 
mole ratio of hydrazine to the 4-substituted benzenesulfonamide is 
preferably from about 2:1 to about 20:1, and more preferably from about 
5:1 to about 10:1. 
The reaction is best conducted at a temperature sufficiently high that all 
reactants are dissolved in the reaction medium, thus forming an entirely 
liquid reaction medium. The reaction is preferably performed at reflux, 
particularly when water is the only solvent present. When using hydrazine 
monohydrate as the source of both hydrazine and water (a hydrazine:water 
weight ratio of 64:36), the reflux temperature is approximately the 
boiling point of hydrazine monohydrate, which is 119.degree. C. The 
reaction can be performed at ambient pressure or at a higher pressure. 
Ambient (atmospheric) pressure is preferred. 
The reaction can be performed in a batchwise manner, a continuous manner, 
or a process that includes a combination of both batchwise and continuous 
segments. Batchwise reactions are preferred. The reaction residence time 
will vary depending on such factors as temperature, hydrazine:water ratio, 
and hydrazine:benzenesulfonamide ratio. The progress of the reaction is 
readily monitored by sampling and analysis such as chromatography or NMR. 
In general, and particularly in the preferred procedures and conditions 
described above, the reaction will be substantially complete in a period 
of time ranging from about twenty hours to about 50 hours. 
Recovery of the product from the reaction mixture is achieved by 
conventional techniques. A particularly convenient technique is to cool 
the reaction mixture to a temperature at which the product precipitates. 
In the system where water is the only solvent, effective recovery of the 
product can be achieved by cooling to a temperature of about 10.degree. C. 
or below, and preferably about 5.degree. C. or below, and adding 
additional water. The degree of cooling and amount of water added are 
preferably sufficient to precipitate at least about 95% of the free base. 
The precipitated free base is then recovered by filtration, 
centrifugation, decantation or any other conventional technique for 
separating solids from liquids. 
The free base product is readily converted to the hydrochloride by reaction 
with hydrogen chloride, preferably aqueous hydrochloric acid. Since the 
hydrochloride is more soluble in water than the free base, the solid 
product from the reaction to form the free base is preferably washed in a 
nonaqueous solvent prior to the reaction to form the hydrochloride. For 
this wash, it is preferred to use a nonaqueous solvent that dissolves the 
starting 4-substituted benzenesulfonamide in order to remove any residual 
amounts of this starting material before the hydrochloride reaction. A 
lower alkyl alcohol such as a C.sub.1 -C.sub.3 alkanol is an example of a 
solvent that can be used effectively for this purpose. Methanol and 
ethanol are preferred, with methanol the most preferred in terms of 
convenience and cost. 
In the hydrochloride reaction, the hydrochloric acid is preferably added as 
concentrated aqueous hydrochloric acid of at least about 25% by weight. 
Full strength hydrochloric acid at 37% by weight can be used, although 
additional water may be useful in dissolving the reaction materials. The 
hydrochlorination is preferably performed at an elevated temperature, 
particularly at least 50.degree. C., and most preferably within the range 
of about 65.degree. C. to about 90.degree. C. Recovery of the 
hydrochloride can be achieved by any conventional means. The preferred 
method in the context of this invention is by cooling the reaction mixture 
to a temperature at which the hydrochloride precipitates out. To enhance 
precipitation, the reaction mixture can contain an appropriate nonaqueous 
solvent. A convenient solvent is the same solvent used for the solvent 
wash of the free base prior to the hydrochlorination reaction. Thus, a 
C.sub.1 -C.sub.3 alkanol, preferably methanol or ethanol, is conveniently 
used. 
Recovery of the precipitated hydrochloride is achievable as well by 
conventional means, including filtration, centrifugation, and decanting. 
To improve the product purity, the recovered hydrochloride can be 
recrystallized from fresh solvent, or from recycled solvent.

The following examples are offered for purposes of illustration only. 
EXAMPLE 1 
This example illustrates a batch process for the preparation of 
4-sulfonamidophenyl hydrazine hydrochloride (unsubstituted at the amido N 
atom: R.sup.1 =R.sup.2 =H) from 4-chlorobenzenesulfonamide and hydrazine. 
A 2-liter glass reactor fitted with a reflux condenser, thermometer, 
heating mantle and magnetic stirrer was charged with 
4-chlorobenzenesulfonamide (500 g, 2.61 moles) and hydrazine monohydrate 
(1,000 g, 20.0 moles, 64% water by weight). The mixture was heated to 
reflux (121.degree. C.) over about 30 minutes and maintained at reflux for 
40 hours, at which time analysis by NMR indicated that 93% conversion of 
the 4-chlorobenzenesulfonamide had occurred. While the reaction mixture 
was maintained at a temperature of at least 90.degree. C., the reaction 
mixture was filtered into a 5-liter reactor equipped with a mechanical 
stirrer, thermometer, reflux condenser, and heating mantle, then diluted 
with water (1500 g) while maintaining a temperature of at least about 
80.degree. C. With continuous stirring, the diluted product was 
crystallized by cooling to 5.degree. C. over a two-hour period. 
The product mixture was filtered, leaving a filter cake of about 1,600 mL 
in volume (3.3 inches (8.4 cm) in depth and 28 square inches (181 square 
cm) in area). The filtration required about 2.5 minutes. Filtration was 
followed by a cold water displacement wash (2,500 g, 5 minutes) and a 
0.degree. C. methanol displacement wash (750 mL, 2.8 minutes). Titration 
of the filtrate from the methanol displacement wash with hydrochloric acid 
revealed that the filtrate contained only 0.06% hydrazine. 
The filter cake remaining after the displacement washes was added to 
methanol (1,700 mL) and 37% hydrochloric acid (2.75 g, 2.84 moles) to form 
a slurry. The addition caused an exotherm from 20.degree. C. to 34.degree. 
C. The slurry was then heated to 71.degree. C., and 300 mL of water was 
added to dissolve the hydrochloride product. The solution was then stirred 
for 15 minutes and cooled to -6.degree. C. over two hours, causing the 
hydrochloride to precipitate. The precipitate was filtered over about 20 
seconds, forming a filter cake 740 mL in volume and 1.6 inches (4.1 cm) in 
thickness. 
The hydrochloride filter cake was displacement washed with methanol at 
-10.degree. C. (650 mL), leaving a slightly off-white cake (525 g). The 
resulting cake was vacuum dried over two hours to a constant weight of 404 
g (1.806 moles). This corresponds to a 69.2% yield. The purity was 
determined by titration to be 99.0%, with less than 0.1% starting material 
remaining as indicated by NMR. 
The combined filtrates weighed 2,920 g, and contained 3.1% product (90 g), 
representing 15% of the theoretical yield. 
EXAMPLE 2 
This example illustrates a batch process for the preparation of 
4-sulfonamidophenyl hydrazine hydrochloride from 
4-chlorobenzenesulfonamide and hydrazine as in Example 1, with the 
hydrochloride stage performed in a succession of batches. Rather than 
using fresh methanol as the solvent for each batch of the hydrochloride 
stage, the solvent used was a recycled mixture of filtrate from the 
hydrochloride product filter cake (i.e., the mother liquor filtrate) and 
filtrate from the methanol wash, both from the preceding batch. The 
purpose was to determine whether the solvent could be recycled repeatedly 
without detriment to product yield and purity, since product purity was so 
high and the quantity of unreacted material in the solvent so low. 
The crude 4-sulfonamidophenyl hydrazine (i.e., the free base) was prepared 
in two batches, the first providing five 200-g portions of a wet filter 
cake, and the second providing three 200-g portions. These portions were 
used in succession, beginning with the five from the first batch. For the 
hydrochlorination stages, the solvent used for the first 200-g wet cake 
portion was 350 mL of methanol plus 90 mL water. A slurry of the free base 
filter cake and this methanol/water mixture was formed, and aqueous HCl 
(37%, 55 g) was added with agitation. A sample was taken from the slurry 
to check pH, and the sample was then returned to the slurry. Extra water 
was added as needed to dissolve the solids when heated to reflux, and the 
mixture was then refluxed until all solids dissolved. The resulting 
solution was then cooled to -5.degree. C., filtered, washed with methanol, 
and dried. 
For subsequent wet cake portions of free base, the filtrates (i.e., 
combined portions of both the mother liquor (recrystallization) filtrate 
and the methanol wash filtrate) were used in place of the methanol/water 
mixture. To avoid an accumulation of water in the reaction medium from the 
need for fresh HCl for each batch, a portion of the mother liquor was 
discarded. Otherwise the procedure was the same as that used with the 
first free base wet cake portion, with variations in the amounts added, as 
indicated in the table below, which lists the amounts used and the results 
for each batch. In this table, the abbreviation "MeOH" is used for 
methanol, the abbreviation "4-SAPH.multidot.HCI" is used for 
4-sulfonamidophenyl hydrazine hydrochloride, and the abbreviation "CBS" is 
used for 4-chlorobenzenesulfonamide. 
EXAMPLE 2 
Hydrochloride Stage Recycle--Materials and Results 
__________________________________________________________________________ 
Slurry Composition 
(2) (3) (4) Mother Liquor Filtrate Analysis 
Initial MeOH Charge or Fresh 37% (remainder: methanol) 
(1) 
Recycled Filtrates 
H.sub.2 O 
HCl (6) (7) (8) 
(9) 
Run from (11) and (12) Added Added (5) % % % Volume 
No. (mL) (mL) (g) pH Water 4-SAPH.HCl CBS (mL) 
__________________________________________________________________________ 
1 350 90 55 2 24.1 
4.2 0.17 
363 
2 410 10 55 2.5 24.8 4.7 0.17 368 
3 450 10 55 2.3 25.1 4.0 0.22 390 
4 410 20 55 2.2 26.7 4.5 0.29 475 
5 430 20 55 1.9 26.0 3.7 0.25 295 
6 450 10 55 1.8 27.7 3.5 0.12 460 
7 440 10 51.2 1.5 24.8 3.3 0.42 390 
8 440 10 48 1.6 26.5 3.8 0.29 390 
__________________________________________________________________________ 
Continuation: 
__________________________________________________________________________ 
Mother Liquor 
(10) Methanol Wash Discarded Product 4-SAPH.HCl 
Mother 
(11) 
(12) 
(13) (15) (17) 
Liquor Wash Filtrate Total (14) Wet (16) Purity by (18) 
Run Recycled Volume Volume Volume 4-SAPH.HCl Cake Dried titration 
Percent 
No. (mL) (mL) (mL) (mL) (g) (g) (g) (%) Recovery 
__________________________________________________________________________ 
1 210 125 200 153 5.35 188 
102.8 
100.6 
96 
2 190 125 260 178 7.19 155 115.5 100.6 95 
3 210 120 200 180 6.19 179 116.5 95 
4 240 120 190 235 9.09 162 112.7 100.5 93 
5 165 120 290 130 4.14 205 111.1 97 
6 280 100 180 180 5.42 153 102.4 100.6 96 
7 210 100 230 180 5.11 176 102.6 96 
8 0 100 205 595 19.44 196 103.6 100.1 84 
__________________________________________________________________________ 
While the CBS starting material was present in the filtrates at levels 
ranging from 0.17% to 0.42% as shown in the above table, no CBS was 
detected in the final product by NMR, which has a detection limit of about 
0.1%. Titration of the product yielded purities ranging from 100.1% to 
100.6% (column 17), indicating no deterioration of product quality. 
The foregoing is offered primarily for purposes of illustration. It will be 
readily apparent to those skilled in the art that the proportions, the 
operating conditions, the order and method of performing the procedural 
steps, and other system parameters described herein may be further 
modified or substituted in various ways without departing from the spirit 
and scope of the invention.