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(19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0293970 A1
Villa et al.
(54) PROCESS FOR SYNTHESIS OF
4-4-DIAMINO-DIPHENYL-SULFONE
PCT Filed:
PCT No.:
(75) Inventors:
Marco Villa, Padova (IT); Carla De Faveri, Farra Di Soligo (IT); Riccardo Zanotti, San Giorgio delle Pertiche (PD) (IT); Francesco Ciarde?a, Padova (PD) (IT); Fabrizio Borin, SelVaZZano Dentro
Feb. 7, 2008
Publication Classi?cation
Int CL
(Padova) (IT)
Correspondence Address:
C07C 211/09
(2006.01)
(57)
ABSTRACT
_ _ _
11/630,760
US 2008/0293970 A1
intermediate obtained is deacetylated and reduced for hydro genation in presence of Raney-Nickel catalyst, knoWn cata lyst for this type of reaction. Either purity of the product or
yield of the process are not mentioned.
[0001]
[0010]
preparation of 4-4'-diamino-diphenyl-sulfone.
PRIOR ART
[0002] 4-4'-diamino-diphenyl-sulfone also knoWn as dap sone (DDS) is a Widely employed chemical entity, being used
both as hardening agent in the curing of epoxy resins and as therapeutic agent for treatment of bacterial infections in humans and animals, approved as antibiotic by Food an Drug Administration since 1963. As for its use in human medicine, dapsone is, in fact, an effective antibiotic used at the begin ning for treatment of leprosy and later on as suppressant of
the process for synthesis of diphenyl sulfones by oxidising With sodium hypochlorites 4,4'-di(acetylamino)diphenyl
sul?des in acetic acid solution at 85 C.
SUMMARY
mocyslis carinii pneumonia (PCP), an opportunistic disease in HIV infection, often diagnosed When the pathology is
severe, occurring very frequently in Women Where it seems to be the ?rst or the second AIDS-related illness. Therefore the
[0011]
e?icient, cost effective and With good yield and purity of the ?nal product for the synthesis of 4-4'-diamino-diphenyl-sul fone, particular attention has to be given to the starting mate
rials and reagents as Well as to the reaction conditions of the
[0003]
reported in 1938 in FR829926 among those of other diamino diphenyl-sulfone colorant intermediates. The product Was
either for purity and yield of the ?nal product, While costing
[0005] SU302338 describes a single step synthesis of DDS avoiding the step of condensation. The product is obtained
[0006] SU592822 improved the synthesis process of SU193497 alWays avoiding the step of condensation, but oxidising the starting material 4,4'nitro-diphenyl-sul?de With
diluted nitric acid in presence of FeCl3 and then reducing With
Fe in alkalinised aqueous medium With ammonium chloride
at 70-82 C.
trophenylsulfanyl)-phenylamine;
[0014] oxidation of the thioeter formed in the previous step With an oxidising system formed by Na2WO4 and
[0007]
compound.
[0008] In all the cases above mentioned the starting mate
rial Was a parasubstituted-diphenyl-sul?des or parasubsti
[0016]
tuted-diphenyl-sulfone.
[0009] In a more recent one, Chauhan P. M. S. et al. (Indian
Chem. J. 25, 1142-1145, 1986) describes a synthesis ofDDS departing from para substituted-phenyl compounds, Where a
parasubstituted-diphenyl-sul?de is an intermediate. The
Indian J. Pharm. Sci. 44, 14-15, 1982). The limiting step in a DDS synthesis process, industrially effective for purity and
yield, is related to the achievement of the para substituted
sul?de and obtaining the parasubstituted-diphenyl-sul?de intermediate subsequently oxidised KMnO4. The oxidised
US 2008/0293970 A1
[0018]
4-chloroacetanilide and sodium sul?de and the oxidising agent consists in a potent oxidising agent such as KMnO4. [0019] Also in US. Pat. No. 2,227,400 is described the
condition With diluted H2SO4 (i.e.) Without affecting the yield of the product.
accessible starting materials in solvents having an high boil ing point from 150 C. to 180 C., and preferably ciclohex anol (b.p. 160-161 C.), With a very poor yield of 50% (maxi mum yield obtained). This reaction is therefore
disadvantageous for an industrial process either for reaction
Second Step
[0032] The oxidation step can be carried out directly, With out protection, on 4-(4-nitrophenylsulfanyl)-phenylamine under acid conditions employing an environmental clean and mild oxidant such as hydrogen peroxide in combination With sodium tungstate as catalyst, but in order to obtain good yield and purity of the ?nal product, as for the purposes of the process, a protection of the amino group of the intermediate obtain in the previous step is preferentially carried out.
nyl)-phenylamine;
[0022] [0023] 20 step: oxidation of 4-amino, 4'nitro-diphenyl 3 step: reduction of 4-amino, 4'nitro-diphenyl
[0033] The Whole sequence (protection-oxidation-depro tection) is preferentially carried out Without isolation of the intermediate. [0034] Protection is realised by adding acetic anhydride or any suitable protecting group suitable for amino groups knoW by a person skilled in the art (see Green T. W., Protective
First Step
[0025] This step can be carried out under very different
3%, preferably 1% molar) previously dissolved in the suitable amount of Water, usually 4-5 preferably 4 times of the Weight
ratio. Then a solution of commercial and stable 35% hydro
conditions since the reactivity of both the reagents is quite relevant, being the substrate reactive toWard the oxygen. Therefore the reaction has to be preferentially perform under phase transfer conditions in organic solvents and Water and
gen peroxide 1.0-1.3 eq. preferably 1.05 eq. is sloWly added at temperatures from 50 to 85 C. in about 1-5 hours. Tempera tures comprised betWeen 80-85 C. are preferred.
hydrolysed separately.
[0037] More conveniently, the solvent can distilled or suck aWay of and the residue added With 21% HCl in Water (up to 8 liter/kg of substrate). The mixture is heated to re?ux While part of the solvent is distilled off concentrating the mixture to about 3-5 volumes With respect to the substrate. At the end the reaction can be diluted With Water and the product isolated by
?ltration at room temperature.
1.05), organic solvent and (15%) ofan alkali (1.05-1.15 eq. preferably 1.10) in Water preferentially in presence of phase transfer catalyst such as tetrabutyl ammonium hydrogensul
phate (5% molar) at a temperature betWeen 60 C. to re?ux. To better control the reaction heat, the substrate is preferen tially added in about tWo hours at 45 C. to re?ux of reaction mixture preferably at 80-85 C. After separation of the phases
[0038]
and Washings of the organic phase With diluted aqueous acid solution the product can be directly crystallised from the
Third Step
[0039] Final reduction is conveniently carried out With
Pd/C 0.5%, preferably, or Pt/C as catalyst in a mixture of methanol and Water preferentially in presence betWeen 0 and 2 eq., preferably betWeen 1 to 2, of an acid (such as for
[0028] Different inorganic base such as sodium hydroxide, sodium or potassium carbonate, potassium hydroxide are
US 2008/0293970 A1
lamine (10 g), oxalic acid (5.1 g) and sodium tungstate dihy
drate (0.26 g). the mixture is heated to 50 C. and hydrogen peroxide 35% (9 ml) is added. At the end of the addition the mixture is kept at 50+55 C. for ?ve hours. The mixture is treated With 30% ammonia (10 ml) and diluted With Water (140 ml), the cooled. The product is isolated at room tem
hydroxide.
[0040] Final puri?cation from organic solvents gives a product With high purity and yield to obtain a product suitable for pharmaceutical application. The solvents for this step can
be methanol, ethanol, isopropanol, ethylene glycol, ethyl acetate, methyl tert-butyl ether; methanol, isopropanol,
MTBE With alcoholic solvents and their mixture With Water are preferred choices.
phenylamine
[0047] A reactor ?ask is charge With 4,(4'-nitro-phenylsul
[0041]
Worse result.
[0042]
Preparation of 4-(4'-nitro-phenylsulfanyl)-pheny
lamine
[0043] A solution of 4-amino-benzenethiol (1.00 Kg, 7.99 mole) is dissolved under nitrogen in toluene (2 It) and sloWly
added under mechanical stirring to a reactor containing a
mixture of 4-1-chloro-4-nitro-benzene (1.32 Kg; 8.38 mole), toluene (2 It), 30% sodium hydroxide (1.17 Kg; 8.78 mole) and tetrabutyl-ammonium hydrogensulphate (68 g; 0.2 mole). During the addition the reaction temperature is main
tained at about 85 C.; the mixture is then kept at the same
Preparation of Dapsone
[0048] Charge an hydrogenation vessel With 4-(4'-nitro benzenesulfonyl)-phenylmanine (380 g; 1.36 mole), Water (220 ml), methanol (910 ml) and methansulfonic acid (187 kg; 1 .95 mole). Then charge under nitrogen, 5% palladium on charcoal (14.4 g; 0.0067 mole). After inertization, the mixture
is added With hydrogen under vigorous stirring up to 4 bar and
then heated to 50 C. The mixture is maintained under the above conditions for the least 4 hours. After reaction comple
temperature for about tWo hours. The mixture is added With toluene and the phases are separated at about 85 C. The
tion the reactor is purged With nitrogen several times and the catalyst ?ltered off. The ?lter is Washed With methanol (25 ml) and Water (200 ml) and the solution is concentrated under
vacuum beloW 50 C. to remove the organic solvent. A the
phenylamine
[0044] A reactor ?ask, maintained under nitrogen, is
charged With acetic acid (4 It) and 4,(4'-nitrophenylsulanyl) phenylamine (1 kg; 4.06 mole) The mixture is heated to
50-55 C., and added in one hour With acid anhydride (0.46
C., then cooled and the product isolated by ?ltration. [0049] After drying, 315 g of crude product is obtained. Product is crystallised from iso-propanol (1000 ml) and Water (700 ml) to give 302 g of pure product (80% yield; >90%
purity).
EXAMPLE 6
Kg; 4.47 mole). The acetic acid (3 1t) is charged and the
mixture heated under vigorous mechanical stirring to 85 C. Charge ?rst a solution of sodium tungstate dihydrate (13.4 g;
Preparation of Dapsone
[0050] In a hydrogenation vessel 4-(4'-Nitro -benzenesulfo
about 2 Kg). [0045] Charge under stirring 21% HCl (10 It.) and heat the
mixture under stirring to re?ux. After one hour, begin the distillation at atmospheric pressure of about 7 liters of solvent
Preparation of (4-acetyl)-(4-nitrobenzenesulfonyl)
phenylamine
[0046] A 250 ml three-necked round bottom ?ask is charge
175-181 c.
US 2008/0293970 A1
13CNMR(DMSO-d6)
IR (v/cmI)
1630-1590 bending-NH2 1338-1446-1106 Bending-S02 <900 CiH Finger print for aromatic protons MS (m/Z)
[0051] Further on the disadvantages before mentioned, it is also known that the synthesis processes for dapsone is limited by low yields and production of a number of by-products,
forming in some extent a remarkable industrial waste. At the purpose to recover these by-products a complex method to
convert these by-products is described (Sengupta, C. et al. 1982, ref. cit.), but this method is very dif?cult to implement
in an industrial process due to the need of many separations,
puri?cations and conversion reactions in dapsone. [0052] On the contrary, the process for synthesis of 4-4' diamino-diphenyl-sulfone described in the present applica tion has many advantages for the industrial application. In
fact all the three steps are performed at mild temperatures and in any cases below 100 C. in organic solvents commonly
vents respectively. [0053] The results herein described demonstrate that the process according to the present invention permit an ef?cient and cost effective synthesis of 4-4'-diamino-diphenyl-sul fone, thus ful?lling the purposes of the present invention.
Further implementation or adaptations as well as embodi ments readily apparent to those skilled in the art are to be
8. Process for synthesis of 4-4'-diamino-diphenyl-sulfone according to claim 1 wherein the hydrogenation is performed
in 1 to 4 hours at 50-60 C. in presence of 0.5% Pd/C catalyst
in a mixture of methanol and water.
9. Process for synthesis of 4-4'-diamino-diphenyl-sulfone according to claim 8 wherein the hydrogenation is performed
in presence of 1 and 2 eq. of an acid selected from the group