DE1090224B - Process for the preparation of substituted 3, 5-dioxo-tetrahydro-1, 2, 6-thiadiazine-1, 1-dioxydes - Google Patents

Description

GERMAN

INTERNAT. KL. C 07 d

PATENT OFFICE

INTERPRETATION PAPER 1090 224

G24259IVb / 12p

REGISTRATION DAY: 3rd A P R I L 1 9 5 8

NOTICE
THE REGISTRATION
AND ISSUE OF THE
DISPLAY:

OCTOBER 6, 1966

The invention relates to a process for the preparation of substituted S.S-dioxo-tetrahydro-l ^ .G-thiadiazine-1,1-dioxydes of the general formula Process for the preparation

of substituted 3,5-dioxo-tetrahydro-1 _r 2 _r 6-thiadiazine-1,1-dioxydes

R ₃ -Ch:

, co-n;

xo-n;

: so ₂

¹ K.

wherein R _{1 is} an aryl or aralkyl radical optionally substituted by halogen atoms, nitro groups, alkoxy or alkyl mercapto groups, R _{2 is} a hydrogen atom, an aryl or aralkyl radical optionally substituted by halogen atoms, nitro groups, alkoxy or alkyl mercapto groups or a methyl group, or an alkyl, alkenyl radical - Or cycloalkyl radical and R _{3 is} a hydrogen atom, an alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylmercaptoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl or cycloalkenyl radical or an aryl which is optionally substituted in the nucleus by halogen atoms, nitro or alkoxy groups or a methyl radical -, araikyl or aralkenyl radical, a 2,5-endomethylene - Δ ³ - cyclohexenyl, 2,5 - endomethylene - cyclohexyl, 2,5 - endomethylene - cyclohexyl - methyl, phenoxyalkyl, phenylmercaptoalkyl, phenylsulfinylalkyl or phenylsulfonylalkyl radical or a heterocyclic radical, which optionally has an oxy or mercaptoalkyl or an alkylene bridge is linked to the carbon atom in the 4-position of the S ^ -dioxo-tetrahydro-l ^ ö-thiadiazine-ll-dioxydringes, as well as their salts with inorganic and organic bases. It has surprisingly been found that the new compounds mentioned have valuable pharmacological properties, in particular a very marked anti-inflammatory, as well as antipyretic and analgesic activity and are suitable, for example, for the treatment of rheumatic diseases.

In aqueous solutions of alkali salts of the aforementioned 3,5-dioxo-tetrahydro-1,2,6-thiadiazine-1,1-dioxyde are various compounds, in particular also pharmacologically valuable substances of low water solubility, z. B. ^ Dimethylazaino-l-phenyl-Z ^ -dimethylpyrazolon- (5), much more easily soluble than in pure water. The salts mentioned can therefore also be used as Find solubilizers use. In addition, compounds of the general formula I and their salts as intermediate products for the production of medicinal products, pesticides or other technical products important connections are used.

Applicant: J. R. Geigy A.-G., Basel (Switzerland)

Representative: Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger, patent attorneys,

Munich 2, Bräuhausstr. 4th

Claimed priority: Switzerland of April 4, 1957

Dr. Helmut Teufel, Biberach / Riß, has been named as the inventor

The compounds mentioned are prepared by adding a sulfamide of the general formula

HN '

HN.

SO ₂

or an N-acyl derivative of such either a) with a malonic acid of the general formula

r ₃ -ch:

COOH

COOH

in the presence of an acidic condensing agent or

b) with a dihalide of a malonic acid of the formula II in the presence or absence of a basic condensing agent or

c) with a mixed anhydride of a malonic acid of the formula II and an aliphatic monocarboxylic acid in the presence of a basic condensing agent

reacts, and optionally then compounds of the formula I obtained in this way in which R _{2 is} an alkenyl

009 610/415

3 4

radical and / or R _{3 is} an alkenyl, alkynyl or cyclo- The following examples are intended to facilitate the preparation of the

represents alkenyl radical, explain in more detail by means of catalytically activated compounds mentioned above. Parts of be-hydrogen to compounds of the general formula I mean parts by weight therein; these relate to volumes whose substituents R ₂ and R ₃ do not share a multiple ^{bond like g-to cm 3} . The temperatures are given in Celsius or a reduced number of multiple bonds 5 degrees, contained, hydrogenated, and / or the compounds obtained

fertilize the general formula I in a known per se

Way in their salts with inorganic or organic 4.28 parts of sulfanilide are in 50 parts by volume of abso-

Bases transferred. lutem benzene dissolved in the heat; to do this one drips

When converting free malonic acids of the general io with stirring at about 50 ° 3.38 parts of allylmalonic acid formula with sulfamides can form acidic condensate dichloride in the course of half an hour. One stirs sationsmittel z. B. polyphosphoric acid or inorganic the mixture for a total of 14 hours at about 70 ° and Acid halides such as phosphorus trichloride or phosphorus shakes the benzene reaction oxychloride after cooling, in excess without further dilution solution with 1 η sodium hydroxide solution. By acidifying the The crude 4-allyl-2,6-diphenylnated is medium or in theoretical amounts in the presence of halogen-alkaline extract Hydrocarbons, such as chloroform or ethylene-3,5-dioxo-tetrahydro-l, 2,6-thiadiazine-l, l -dioxyd auschlorid, find use as a solvent. Malon-like. The pure compound melts after the acid dihalide and mixed anhydrides of malon- crystallize from methanol at 141 to 142 °; Yield: acid with z. B. acetic acid can be in the presence of 70% of theory.

tertiary organic bases, such as pyridine, dimethylaniline 20 According to the process indicated, in yields or triethylamine, for example in the presence of a between 60 and 82 ° / ₀ also the following 3,5-dioxo-tetra-ether, such as diethyl or diisopropyl ether, or in jtiydro-l, 2,6-thiadiazin-l, l-dioxyde are obtained: presence of aromatic hydrocarbons, such as

Benzene, toluene or xylene, as a solvent at tempe- 2,6-diphenyl- F. 240 to 241 °

React temperatures from about 0 to 100 ° C with sulfamides. 25 (decomposition)

Malonic acid dihalides react at slightly higher 4-methyl-2,6-diphenyl temperatures from 226 to 228 °

Temperatures from about 20 to about 120 ° C, also in 4-ethyl-2,6-diphenyl- F. 151 to 152 °

Absence of basic condensing agents with 4-n-propyl-2,6-diphenyl- mp 154 to 155 °

Sulfamides. 4-iso-propyl-2,6-diphenyl- mp. 243-244 °

The hydrogenation of compounds of the general 30 4-n-ButyI-2,6-diphenyl-F. 177 to 178.5 °

Formula I, in which R _{2 is} an alkenyl radical and / or R _{3 is} 4-n-amyl-2,6-diphenyl, melting point 158 to 159 °

represents an alkenyl, alkynyl or cycloalkenyl radical, 4-crotyl-2,6-diphenyl- M.p. 184 to 185 °

is z. B. carried out in ethanol as a solvent. You 4-propargyl-2,6-diphenyl- M.P. 163 to 164 °

can also be used in aqueous-alcoholic alkali lye as Lö- 4- (2 ', 5'-endomethylene-Zl ^s ' -cyclo-

solvents are carried out, z. B. palladium (35 hexenyl) -2,6-diphenyl- mp. 238-240 °

on calcium carbonate or on barium carbonate as Kata- (decomposition)

lysator can serve. 2,4,6 ^ triphenyl m.p. 229-230 °

The substituted 3,5-dioxo-tetrahydro-1,2,6-thiadi- 4-allyl-2-benzyl-6-phenyl-mp. 134.5 to 135.5 °

Azine-l, l-dioxides form with inorganic and organic 4-allyl-2,6-dibenzyl F. 132.5 to 133.5 °

niche bases water-soluble salts. An exception 40 2-phenyl-6-p-tolyl- mp 232 °

represent compounds which, as a result of substitution by 4-allyl-2-phenyl-6-p-tolyl- F. 143 to 144 °

basic groups are already present as internal salts. Aqueous 4-allyl-2-phenyl-6-p-nitro-phenyl- .. mp 153 to 154 ° rige solutions of alkali salts of suitable 2,6-disub-4-allyl-2-phenyl-6-m-nitro-phenyl- .. F. 159 to 160 °

Substituted compounds react almost neutrally, those 2,4-diphenyl-6-p-tolyl- F. 233 to 234 °

of 2,4,6-trisubstituted compounds only weakly 45 2,4-diphenyl-6-m-nitrophenyl melting point 214 to 215 °

alkaline, so that they can also be administered parenterally 4-phenyl-2,6-dibenzyl- F. 167 to 168 °

permit. Such alkali salts can be obtained from suitable 4-benzyl-2,6-diphenyl-F. 216 to 216.5 °

solvents by gentle evaporation (e.g. Ge 2,4-diphenyl-6-cyclohexyl- F. 191 to 192 °

freeze-drying of an aqueous solution under vermin- 4-cyclohexyl-2,6-diphenyl- F. 247 to 248 °

dertem pressure) or by failures, e.g. B. by zu- 50 4-Cyclohexyl-2,6-dibenzyl- F. 143 to 144 °

Put together a concentrated solution of sodium 2-phenyl-4,6-dicyclohexyl-F. 182 to 183 °

methylate in methanol and a concentrated solution 4- (2 ', 5'-endomethylene-cyclohexyl) -

a substituted S.S-dioxo-tetrahydro-l ^ o-thiadi- 2,6-diphenyl- mp. 253 to 254 °

azine-l, l-dioxyds in a halogenated hydrocarbon 4- (2 ', 5'-endornethylenecyclohexyl) -

substance or an ether of suitable boiling point and 55 methyl-2,6-diphenyl- F. 252 to 254 °

optionally subsequent concentration under vermin-2-n-butyl-4-allyl-6-phenyl-mp 67 to 68 °

dertem pressure in mostly fine crystalline, durable and 2,4-diphenyl- F. 192 to 193 °

obtained in a readily water-soluble form .. (decomposition)

The aryl-substituted 4-ethoxyethyl-2,6-diphenyl- F. 141 to 142 ° required as starting materials

Sulphamides are, for example, by reacting 60 4-methyl-2-cyclohexyl-6-phenyl-F. 194 ° to 195 °

Sodium salts of formarylides with sulfuryl chloride 4-allyl-2-cyclohexyl-6-phenyl- F. 93.5 to 94.5 °

and further reaction of the resulting N-chloro 4 - (^ ² '-cyclopentenyl) -2,6-diphenyl- .. F. 230 to 231 ° sulfonylformarylide with ammonia or with alipha- 4 - (<d ² ' -cyclopentenyl) -2,6-dibenzyl- .. mp 158-159 °

tables, cycloaliphatic, aromatic or aralipha- 4-methyl-2-phenyl- F. 163 to 164 °

primary amines available. To starting materials 65 4- (zI ² '-cyclopentenyl) -2-phenyl- mp. 166 to 167 °

■ with the same radicals R ₁ and R ₂ leads to the action of

■ Sulfuryl chloride to excess arylamines, given example 2

if in pyridine solution, as well as the conversion of chlorine

sulfonic acid phenyl ester with reactive, primary To a solution of 5.0 parts [2,5-endomethylene

■ amines, such as B. benzyl anun. 70 cyclohexyl-methyl-malonic acid dichloride in 200 volume

share absolute ether with stirring and ice-crystalline product, which after recrystallizing from

cooling 5.0 parts of sulfanilide and 5.0 parts of dimethylaniline methanol melts at 177 to 178 °. With that accordingly

- 4-n-butyl ~ 2,6-diphenyl-3,5-dioxo-

Ether- - from two dropping funnels within 1 hour, tetrahydro-l ^ .ö-thiadiazine-l.l-dioxide, no melting occurs

dripped in slowly. The mixture is for 2 hours at 0 ° '5 point depression; Yield: about 20% of theory, and stirred for a further 6 hours at room temperature

and then kept overnight. Example 5 is decanted Ether, treats the solid reaction product with water

and ether, the reaction product dissolving in ether 15.8 parts of 2,6-diphenyl-3,5-dioxo-tetrahydro-1,2,6- and washes the combined ether solutions neutral, iö thiadiazin-l, l-dioxide (shown according to example 1 or 3) By shaking out the ethereal solution several times, a solution of 1.17 parts of sodium in 70 vomit η sodium hydroxide solution and acidification of the alkaline solution lumteile absolute methanol entered and under with hydrochloric acid the 4- (2 ', 5'-endomethylene-cyclo- easy heating on the water bath in solution hexyl-methyl) -2,6-diphenyl-3,5-dioxo-tetrahydro-1,2,6- brings. After cooling, it is obtained in solid form while stirring with thiadiazine-l, l-dioxide. 15 250 parts by volume of ether added. The sodium

The compound crystallizes from dichloroethane in the coloring salt of 2,6 - diphenyl - 3,5 - dioxo - tetrahydro - 1,2,6 -

loose needles, mp 252-254 ° (decomposition); Yield: thiadiazine-l, l-dioxide in fine, colorless crystals

50% of theory. the end; M.p. 199 to 201 ° (decomposition). The sodium salt can

Using the method described in this example with no detectable decomposition at room temperature

the following S.S-dioxo-tetrahydro-l ^ .o-thiadi- 20 will be kept; it dissolves easily in cold water

azin-l, l-dioxyde obtained: -. and gives a practically neutral, aqueous solution.

".", "^,. ■,, - ^ a AA 1 · λ Ana Acidification turns it into the free 2,6-diphenyl-

l "5; iÄ ^y V- I ' iS I' ⁵ Hi SS-dioxo-tetrahydro-l ^ .o-thiadiazm-ll-dioxyd aus-

4-n-Butyl-2,6-diphenyl- F. 177 to 178 ° precipitated -

. 25 According to the result of the titration, the sodium

Example of salt 0.99 ± 0.03 equivalents of alkali.

A mixture of 70 parts by volume of Phos is heated in a similar way from 4-allyl-2,6-diphenyl-3,5-diphoroxychloride, 22.4 parts of n-butyl-malonic acid and oxo-tetrahydra-l, 2,6-thiadiaziti-l, l-dioxide with a Lö-31 Share sulfanilide to 60 ° and stir the resulting solution of sodium methylate in chloroform the sodium suspension another 4 hours at 80 to 90 °. The main salt (brown color from 220 ° [decomposition]) and with methamenge of the excess phosphorus oxychloride becomes the potassium salt (melting point ab

distilled. With external cooling and stirring, 200 ° [decomposition]) was added. The salts are slightly water-

the residue with methanol and then sucked the soluble; at room temperature can be an aqueous

solid reaction product obtained. After converting the solution that contains 500 mg of des in one milliliter

crystallize from methanol to obtain the pure 4-n-sodium salt in dissolved form.

Butyl ^ jo-diphenyl-SS-dioxo-tetrahydro-l ^ .o-thiadiazine- .

1,1-dioxide in colorless needles; 176-178 °; From example 6

Booty: 45% of theory. In a mixture of 0.53 parts of morpholine and 15

In a corresponding manner, during the condensation, parts of methanol are converted into 1.58 parts of 2,6-diphenyl

of malonic acid with sulfanilide, 2,6-diphenyl-3,5-dioxo-40 3,5-dioxo-tetrahydro-1,2,6-thiadiazine-1,1-dioxide

tetrahydro-l, 2,6-thiadiazine-l, l-dioxide (mp 240 to 241 °), brief heating dissolved. After filtering, one obtains

with N-phenyl-N'-p-tolyl-sulfamide the 2-phenyl-6-p-tolyl- the morpholine salt of 2,6-diphenyl-3,5-dioxo-tetrahydro-

3,5-dioxo-tetrahydro-l, 2,6-thiadiazine-l, l-dioxide (F.232 °) l, 2,6-thiadiazine-l, l-dioxide by adding the filtrate

and with N-phenyl-N'-benzylsulfamide the 2-phenyl with ether in colorless, elongated prisms; F. 129 to

6-benzyl-3,5-dioxo-tetrahydro-1,2,6-thiadiazine-1,1-dioxide 45 130 °. The product is clearly soluble in cold water; the

(F. 147-148 ° C) in yields of 65-72% of the theoretical solution has a _pH value of about 6.5. After this

obtain. The result of the titration contains this in this way

Example 4 obtained salt one equivalent of the base.

When recrystallizing from dichloroethane, higher

A suspension of 4.08 parts of the disodium salt of the 50 melting products obtained due to their content

n-Butylmalonic acid in 20 parts by volume of absolute benzene in free 2,6-diphenyl-3,5-dioxo-tetrahydro-1,2,6-thia-

will be only partially water-soluble in the case of room diazine 1,1-dioxide within 10 minutes with stirring

temperature with a solution of 3.14 parts acetyl and after titration a content of only 0.5 to 0.8

chloride added in 10 parts by volume of benzene. Then contain equivalents of the base. When adding mor-

If you stir I ¹ Z for ₂ hours at a bath temperature of 55 pholine to the solvent, the salt can be counteracted

55 ° and then allowed to cool to 40 °. Recrystallize unchanged at this temperature,

rature are now 4.96 parts of sulfanilide and 4.85 parts. .

Dimethylaniline - dissolved together in a mixture Example 7

from 75 parts by volume of benzene and 10 parts by volume of dimethyl 3 parts of the 4-allyl-2,6-di- obtained according to Example 1

formamide - within 2 hours to the solution of the 60 phenyl -S ^ -dioxo-tetrahydro-l ^ .o-thiadiazin-l ,! -d-

mixed anhydride from n-butyl malonic acid and acetic oxide are in a small excess of about

acid was added dropwise. The bath temperature is then increased to dissolved O, 2N sodium hydroxide solution and

and finally boils with stirring for 5 hours with sion of 2 parts of palladium-calcium carbonate catalyst

Reflux. sator (with an approximately 1% palladium content) in

After cooling, the mixture is added with a rich 65 40 parts by volume of ethanol. The hydrogenation under

borrowed amount of ether and the ethereal solution normal pressure and at room temperature already results

one after the other with dilute hydrochloric acid, water and after 15 minutes the absorption of the calculated amount

washed with a sodium bicarbonate solution. Then hydrogen shakes. With subsequent several hours of shaking

If the ethereal solution is repeated several times with 2N sodium bicarbonate, no further hydrogen is absorbed. Man

lye and precipitates from the extract by acidification 70 separates from the catalyst, acidifies the solution with acidification

dilute hydrochloric acid and obtained in practically quantitative yield after further dilution with water the 4 - η - propyl - 2,6 - diphenyl - 3,5 - dioxo - tetrahydrol, 2,6-thiadiazine-l, l-dioxide.

After recrystallization from methanol, the substance melts at 154 ° to 155 °; the mixture with the starting compound shows a clear depression of the melting point.

In an analogous manner, using 4-crotyl-2,6-diphenyl-3,5-dioxo-tetrahydro-1,2,6-thiadiazine-1,1-dioxide instead of the 4-allyl compound, 4-n-butyl-2,6-diphenyl-3,5-dioxo-tetrahydro-1,2,6-thiadiazine-U-dioxide; 177 to 178.5 degrees.

Claims (1)

Claim: ^x 5 Process for the preparation of substituted 3,5-dioxo-tetrahydro-l, 2,6-thiadiazine-l, l -dioxydes of the general formula IVg GH ν co-n; co-n; wherein R _{1 is} an aryl or aralkyl radical optionally substituted by halogen atoms, nitro groups, alkoxy or alkyl mercapto groups, R _{2 is} a hydrogen atom, an aryl or aralkyl radical optionally substituted by halogen atoms, nitro groups, alkoxy or alkyl mercapto groups or a methyl group, or an alkyl, alkenyl radical - Or cycloalkyl radical and R _{3 is} a hydrogen atom, an alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylmercaptoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl or cycloalkenyl radical or an aryl which is optionally substituted in the nucleus by halogen atoms, nitro or alkoxy groups or a methyl radical -, aralkyl or aralkenyl radical, a 2,5-endomethylene A ³ - cyclohexenyl, 2,5 - endomethylene - cyclohexyl, 2,5 - endomethylene - cyclohexylmethyl, phenoxyalkyl, phenylmercaptoalkyl, phenylsulfinylalkyl or phenylsulfonylalkyl radical or a heterocyclic clic radical, which is optionally linked via an oxy- or mercaptoalkyl or an alkylene bridge to the carbon atom in the 4-position of the 3,5-dioxo-tetrahydro-1,2,6-thiadiazine-1,1-dioxide ring, and of their salts with inorganic or organic bases, characterized in that a sulfamide of the general formula ην; :so, 'R, or an N-acyl derivative of either
a) with a malonic acid of the general formula r ₃ -ch: XOOH COOH in the presence of an acidic condensing agent or b) with a dihalide of a malonic acid of the formula II in the presence or absence of a basic one Condensing agent or c) with a mixed anhydride of a malonic acid of the formula II and an aliphatic one Monocarboxylic acid in the presence of a basic condensing agent reacts, and optionally then compounds of the formula I obtained in this way in which R _{2 is} an alkenyl radical and / or R _{3 is} an alkenyl, alkynyl or cycloalkenyl radical, by means of catalytically activated hydrogen to give compounds of the general formula I, the substituents R ₂ and R thereof ₃ contain no multiple bonds or a reduced number of multiple bonds, hydrogenated and / or the compounds of the general formula I obtained are converted in a manner known per se into their salts with inorganic or organic bases. Considered publications:
U.S. Patent No. 2,473,042. © 009 610/415 9.60