DE1668467A1 - Chemical processes and products - Google Patents

Description

NBRCK * CO., IHC.

126 East Llnooln Avenue »Rahway, New Jersey 07065, V.St.A.

Chemical processes and products

According to the invention, phosphanil acid amides are prepared by reducing the corresponding nitrobenzene phosphonamide. The nitrobenzene phosphonamides can be obtained from the phosphonic acid dihalide be prepared by reacting the dihalide with an amine ^ The PhosphQnsäuredihalogenid can be prepared from the corresponding phosphonic acid by reaction with a halogenating agent. They phosphanilic acid amides are considered antibacterial

109841/1970

10871 *

Hittel usable.

The present invention thus relates to new, in the core substituted phosphanilic acids, 'as antibacterial Ilittel are useful

The present invention relates to compounds of structural formula ait

H ₂ H

and a process for the preparation of such compounds, where E ₁ and R _{2 are} hydrogen, halogen, alkyl and haloalkyl, R- is hydrogen or fluorine, when Rj and R _{2 are} hydrogen, Q is the radical 0 or NH, R ^ is hydrogen, lower alkyl, phenyl, Lower alkylamino, phenylamino or 4- (2 ~ Heterocyclosulfamoyl) - pheayl and the alkali metal salts thereof and ZV / assers1; off, lower alkyl, 4- {2-Heterocyclo3ulfaiaoyl) -phenyl nnö di ^ alkali metal salts thereof can be acidified, where Z eir can be alkali, if Q has the meaning 0

- 2 -

109841/1970

These connections are made by reducing the corresponding Hitroben?! Olpho3phciiainids to the desired Phosphanilic acid amide produced.

These compounds are useful against a variety of bacteria, particularly Salmonella schottmuelleri.

Preferred embodiments of the present invention are described below. In accordance with the main embodiments of the invention, a nitrobenzene phosphonaiaid is reduced to the corresponding phosphorus-nilsäursamiä «Dag? Jlitrobenzolphosphonainid can be prepared from the corresponding Piiosphonaäuredihalogetiiä, which is then converted into the desired amide by reaction with an amine. The Biosptonsäujredihalogenid can be aergesteiit from the corresponding Phosphonsäinre by reaction with a halogenating agent. . '

In other embodiments of the invention, the so horge »told Hitrobenzo3.paosp; iouamide in the following In practice the other .'tmidoderivate are converted will. These connections then advertise equally the corresponding Phasphanileüureamidderivaten reduced.

109841/1970 ^p ^ d op ^ inal

In the main embodiment of the present invention, the phosphonic acid halide, for example 4-nitrobenzene phosphonic acid dichloride or dibromide, is produced by reacting the corresponding phosphonic acid with a halogenating agent, such as phosphorus pentaulfuride or phosphorus pentfebromide. If the aromatic nucleus bears 2-fluoro or 2,6-difluoro substituents, the corresponding substituted halobenzene phosphonic acid can be prepared in accordance with the procedures described in patent ... are described. The azido compounds are prepared by the nitrobenzene phosphonic acid dihalide, suitably the dichloride, with the desired amine, for example a lower alkylamine such as jithylamine, propylamine or butylamine, or an aromatic amine such as aniline or substituted derivatives such as nitroaniline, methoxyaniline or chloroaniline also sulfamoylanilines, in particular heterocyelosuXfarooylaniline * such as sulfadiaain _% sulfanoxazole, sulfathiazine and sulfamerazine, oingosohloasen Bind, is implemented. This reaction can be carried out in a suitable organic solvent, bromobenzene, chloroform or pyridine being one of the solvents in the list.

109841/1970

1888467

per KoI dihalide is preferred, except when pyridine is used as the solvent or the Iftassitaung is carried out with o-phenylenediamine. The reaction is carried out in a temperature range from about ⁰ ° C. to about the reflux temperature of the solvent, which depends on the reactivity and volatility of the amine used. After the reaction has ended, the solvent is removed under reduced pressure «the residue is washed with water and recrystallized from a suitable solvent, for example chloroform».

In a modification of this embodiment, it can do so formed phosphondiamide in the? corresponding phospbanamic acid or their metal salts are converted miscible organic 'solvents' suitably an ether, such as dioxane, added and with exactly 1 equivalent of an aqueous solution of a suitable base, for example an alkali metal hydroxide such as sodium hydroxide for a period of about 1 to about 3 hours heated. It is desirable that small amounts of water . be added at intervals of, for example, 15 minutes during the reaction »until the added V / as-

- 5 109841/1970

serine close to the originally used solution amittölaonge is about the same · The solvents are avoided at » Removed tem pressure and the residue is extracted with water »from the dae Hatrluraaalz of the corresponding Phosphonamic acid can be isolated, for example the sodium salt of N-Phenyl ™ P- (4 * -nitrobeiiaol) -phosphonamic acid ·

The connections that can be produced by this method of operation include

the sodium salt of tf- / C4 ~ (PyriMdiaylaulf04Bayl} -pb6nylJ7-P- (4 * -nitrobenzolj-phosphonaaic acid,

the sodium salt of H ~ / f4- (Kethylpyrifflidinylsulfamoj <l) -pheny I _- J ¹ P- (4 ^f -nitrobenzene) -phosphonamic acid,

the sodium salt of Ii ~ _i / 74- (Diiiiethylp; TpiiaidinylsulfaiDoyl) -phenylJZp- (4'-nitrobenaol) -phoaphonaaic acid,

the sodium salt of N-ZT4- (Thiazolylsulfamöyl) -phenyl_y-P- (4 * -nitrobenzene) -phosphonamic acid ,

the sodium salt of lf- / 74- {öhino3calinyleulfamoyl) -phenyl ^^ - (4 * -nitrobenzene) -phosphonamic acid,

the sodium salt of N- ^ r4- (Diniethylisoxazolsulfamoyl) -phenyl_7 "P- (4 ^f -nitrobe azole) -phosphonamic acid

and the alkali metal salts thereof.

109841/1 970

The corresponding aminobenzene derivative is then made by reduction Enjoy one of the following working methods obtain.

In a further embodiment of the present process, the nitrobenzene phosphonic acid dihalide is reacted with a lower alkylene diamine, such as ethylene diamine, propylene diamine or butylene diamine. In this reaction, a solution of the dihalide in a suitable organic solvent, for example an iither such as dioxane, is added dropwise to an exactly equimolar amount of the diamino in a similar solvent. The reaction is carried out at ambient temperature and is complete in about 1 to about 3 hours. The reaction mixture is then cooled to about 0 to about 5 ⁰ C, filtered and the B ¹ Utrat is evaporated to result in a solid residue which is then washed with a weak aqueous base, said aqueous Natriumbicarhonat is particularly suitable. The residue is extracted with acetone, washed with 1 / aseer and recrystallized from a lower alkanol, suitably ethanol, to give the corresponding U-aminoalkyl-P- (4-nitrobenzene) -phophonamic acid in the form of its inner salt.

109841/1970

This phosphonic acid is described by below Procedures for the corresponding 4-aminobenzene phosphonaiididic acid reduced·

In a further modification of the invention o-phenylenediamine or the derivatives substituted in the core of which with the Nltrobeneolphosphonsäureäihalogenid in a moderately high-boiling organic solvent that is inert to the reaction. Although the Choice of solvent is not critical, the use of a solvent ml.t a reflux temperature e:? wishes that is high enough to keep that in the course dissociate the aminhylrohalides formed in the reaction » and is low enough to sieve the amides formed do not decompose. In addition, it is preferred to use a solvent in which you can considerably reduce amides in the cold are less soluble than in the heat, which simplifies the isolation of the reaction products will. Finally, it is desirable to use a solvent in which hydrohalic acids are not very are soluble. These are criteria for a solvent best met by bromb ^ nzol. However, everyone can Solvents are used »most of these Criteria met.

109841/1970

In a further codification of this embodiment the diazaphosphine can be cleaved, for example by alkanolysis, suitably reduced by ethanolysis, whereby the corresponding 3J- (2-aminophenyl) -P- (4-nitrobenzene) phosphonemidic acid alkyl ester results «Likewise, by using other alkanols, such as Ethanol, propanol or butanol, the corresponding ethyl, Propyl or butyl derivative can be obtained instead of the methyl derivative.

In this procedure, the diazaphosphole is in one large excess of an alkanol, suitably a Medrigalkanol, for example of methanol or ethanol ^ taken up and refluxed for 1 to: about 3 hours « Concentrating the solution; gives the desired Alkyl derivative as a crystalline precipitate. This alkyl derivative can easily be done by tjnsetzimg with a Ketallbaae into the metal salt, more suitably the alkali metal salt, the corresponding phos; ohonäinidic acid converted v; earth? i. The Alk & liiaeiallfdze are preferably by Dictionary iait äem enisptee henüeri Aikälih ^ droxyd; how Matrium- or Käliümlydro :: yd, uiiter BildUrig des chendsn Bitriüid- bdei Ke.lL. umalzelt lier ^ elitellt.

10 114 ii 1 1V £ ORIGINAL SNSFECTED

10871

In the preferred operation of the Phosphonamidsäurealkylester is dissolved in a water-miscible organic solvent and appropriate ethers, such as dioxane or tetrahydrofuran and in the presence of an equivalent lienge heated from aqueous alkali to reflux · The product is then isolated · In the preferred Ieolierungsweise the Reaktionsmisehung is evaporated to dryness, stirred with water, filtered and the pure product is precipitated from the precipitate by adding a lower alkanol, a suitable solution for ethanol.

If production via free acid is desired, then the aqueous solution of iletallsalsses with a little excess shot, for example 5 to 15 5 », of aqueous inorganic Acid, partially η-hydrochloric acid, treated, whereby the free acid is precipitated, which is isolated by centrifugation or by filtration what will depend on the grain size of the precipitated phosphonamic acid depends "

however, it is not intended to extend the scope of the present Invention only to the alkali metal ala restrict, since the production of the corresponding derivatives from other Iletallbaswn is possible »

- 10 -

ORiGiNAL IKC

All of the aforementioned Hitrobenssolderivate can by means of the reduction process described below the corresponding Asinophenylphosphonamiaen or -phosphouaFideäureaalzen bsw »-estern be reduced ·

In the preferred procedure, this reduction is carried out by hydrogenation, suitably in the equivalent of a catalyst. Carriers are used and the hydrogenation is carried out under weakly acidic conditions, for example at pH 4 ^ is 6, while "weakly basic conditions, ie pH 7 to 9" are suitable when using Bsnuy-Niokel. The Hitrobenaolphosphcraanjid wild in a suitable solvent, such as a lower alkanol, preferably ethanol or ethanol, or in an ether that is miscible with Wasrjar, such as Bioxai., aTifgonomn-en, or Ef tal; / aator, is added and the hydrogenation is wiped off when it is ⁽ 2 amperes) 15 and 35 ⁰ O b-ji a pressure between 1.41 and 4.22 hg / cm ² (20 mrl 60 psi) aurc ". The hydrogenation mixture is filtered through the product ch evaporation of the Mltrata isolated.

109841/1970

The following examples are intended to further illustrate the invention, but not to limit it.

B ei B _1n J) ₁₁ i, jg. I. ,, J ₁ ,

To 100 of a solution saturated at ⁰ ° C Mt methylamine chloroform solution are slowly ml 2.8 g p-NitrobenzolphosphonsLLuredichlorid given _s to give a clear solution results, which is evaporated under reduced Druok to dryness. The residue is washed wit water and the undissolved residue is recrystallized from chloroform, the U, egg ^! -DiiDet} iyl ~ P "- {4'-aitroben2ol) -phosphondiainide with an F» 159 to 161 ⁰ C results.

According to the above work, when using the P-iTitrobenzolphosphonsäujeditroinids instead of the dichloride get the same product.

Similarly, if ethyl amine, butylamine or propylamine is avoided, the corresponding n _? 3ff ''diethyl> P (4 x -nit3-obenzol) -phosphondiamid, N, H ^r ~ P dibutyl -phosphondiainid and W, N (4 ^{-tiitroaen2ol!):} -Dipropyl PC ^ ¹ -nitrober.i ; ol) -phosphondiaiDid received u

- 12 1 0 9 8 A 1/1 9 7 0 B ^AD o « ^{G! NAL}

For S ₁ ρ i e I ₁ 2

548 mg of NjlT-DiJoethyl-P - ^ '- nitrobenzene ^ phosphonamide dissolved in 25 ml of methanol and hydrogenated in the presence of 200 mg of Kaney-Kickel at a pressure of 2.8 kg / cm (40 psi). After the hydrogenation, the reaction mixture is filtered, concentrated and triturated with iither to give a solid residue which is recrystallized from ethanol to give the ΙΙ, ϊί'-dimethyl-P- (4 * -aininobenjsol) -phoephone, mid with an S ¹ = 152 to 154 ⁰ C results.

According to the above procedure, but starting from the corresponding "'H' Mathy · -, 2i, H 'dipropyl and $, $' - Dtbutyl-P {4'-nitrobenzene} ~ pho3phonairiid instead of the H ₉ Ii '-v) iiseth5 ^ir lP ~ {4 * «Eitrofcenzene) -phosphonamids, wii? D the corresponding H, H * -dialkyl-P- (4 * -aminobensol) -phosphon-

araid received, (

B e i s ρ 1 e 1 3

700 "i £ 1,3-dihydro-2- (4'-Kitro.> Enaol) -2" H-1,3,2-benzodiarsaphoephol are suspended ^{in 25 ml of moxan in the presence of 300 mg of activated charcoal with 5 C} A palladium and hydrogenated at a pressure of 2.8 t kg / om ² (40 psi) at 25 ⁰ g.

- 13 109141/197 0 _BAD

10871 **

After the hydrogenation has ended, the reaction mixture is diluted with a further 250 ml of dioxane, the mixture is stirred for 5 hours and filtered and the product is isolated from the solution by concentration, the 1,3-bihydro-2- (4'-aminobenzene) - 2-H-1,3, 2-benzodiazapbospbol results with a 1 a 263 ⁰ O (Zera.).

Example 4

5 g of 1,3-dihydro-2- (4 * -nitrobenzene) -2-H-1, 3,2-benJBQ.diazaphoaphol are taken up in 200 ml of methanol and heated to reflux for 5 hours. The reaction mixture is cooled and the solvent is removed under reduced pressure, yielding crystalline H- (2-aesi-rophenyl) -P- (4'-nitrobimzol * i -phosphonamic acid methyl ether.

According to the above procedure, 3 © but using of ethanol, propane © "., ode:? Butanol instead of Hethanol, V7 is the corresponding If- (2-aminopiienyl) -P- (4 * -nitrobenzene) -phosphonamic acid lithium 3 eater, propyleeter and butyl ester.

- 14 *

109841/1970

10871 Λς

B e i play 5

996 mg of lf- (2-ainoplienyl) -P- (4 ^t -ni "troben20l) -phospliOTiamiüBäuremethylester are suspended in 25 ml of ethanol in the presence of 400 mg of Raney-Niekel and with a bridge of 2.81 kg / cm ² (40 After the hydrogenation has ended, the reaction mixture is filtered, the filtrate is evaporated and the residue is recrystallized from! •! ethanol, the N- (2-aminoplienyl) -P- (4'-aminobenzene} - Phosphonamidsäuremethyles t er with a P = 152 to 153 ⁰ O results.

According to the above procedure, but starting from ΪΤ- (2-aminophenyl) -P ~ (4 '-nitrobenzolj-phosphonamic acid ethyl ester, -butyl ester or propyl ester instead of the N- (2-aminophenyl) -P- (4 * -nitrobenzene) -phosphkonainidsäuremethylesters, the corresponding N- (2-aminophenyl) -P «(4 * -aminobenzene) -phosphonamic acid alkyl ester obtained "

B is τ ie 1

1.6 g N- (2-aminophenyl) -P- (4'-r'itrobenzene) -phosphonamide acid methyl ester are heated for 10 minutes in 20 ml of Sloxan with 5 ml of 2N aqueous sodium hydroxide. the Solution is brought to dryness under reduced pressure.

- 15 109841/1970

10871 4h

evaporates, the residue is stirred with water and filtered, the piltrate is concentrated to about 2 ml and 10 ml of ethanol are added, yellow needles of the sodium salt of N- (2-aminophenyl) -P- (4 ^f -nitrobenzene) -phosphonamic acid result as a hydrate with an F «8O ⁰ O, which loses water on further heating and then ^{decomposes at about 250 0} C ·

Be is P ₁ ie, 1. ,,,. J ₁

2.7 g of sodium as the N- (2-aminophenyl) -P- (4'-nitrobenzene) Phosphonamic acid in 50 ml of 80 tiger aqueous Methanol and added at 2.81 kg / cm (40 psi) in Hydrogenated presence of 2 g Haney nickel. After Hydrogenation, the reaction mixture is filtered, the filtrate is evaporated to dryness and taken up in water and ethanol is added to form the sodium salt of N- (2-aminophenyl) -P- (4'-aminobenzene) -phosphonamic acid to fell.

240 mg of this sodium salt are dissolved in 2 ml of Vfasser and ^{cooled to 5 0} O and 0.8 ml of 1N HOl are added to the N- (2-aminophenyl) -P- (4 ^l -aminobenzene) -phosphonamic acid with a F = 118 to 123 ⁰ C,

- 16 109841/1970

which resolidifies and decomposed at 215 to 22O ⁰ C.

Example 8

0.5 g (8.4 mmol) of ethylenediamine are dissolved in 15 ml of dioxane, to which 1 g (4 »2 mol) of 4-uritrobenzene-g of phosphonic acid dichloride in 10 ml of dioxane are added dropwise. The addition is carried out in the course of 1 hour with vigorous Eühren * Then the Reaktionsmisehung is kept for 12 hours at 5 ⁰ C, it is filtered and the Filtx-at is eingedaspft, wherein there is a light yellow powder which was washed with aqueous sodium bicarbonate, Rait Acetone is extracted, washed with water and recrystallized from methanol, whereby the U- (2 ~ amines ethyl) -P- (4 * -a ^ robeazol'-phosphonamic acid {inner gIh) with a temperature of 257 to 259 ° 0 ( Zerß _tt ) results. '

the above procedure, but using 1,2-di-dinopropyl and 1 _t 2-j3iaminobutane instead of ethyl end ißiniB, the corresponding inner salt of 1ϊ- {2-aminopropyl) «? { 4'-nitrobenzene) -phosphonamic acid is obtained and the 3ff- (2-A «inobui; yl) -]? - {4 ^l -nitrobenzene) - phoephonaiaid ßäure obtained *

109841/1970 bad

Be i S ₁ ρ ie I ₁₁₁₁₁ ff

200 m ^ N- (2-aminoethyl) -P-4'-nitrobeiizole) -pho3phoiian »iä ~ acid are dissolved in 25 ml of methanol and in the presence hydrogenated by 0.5 g of Raney nickel at 2.81 kg / cm (40 psi). After the hydrogenation, the reaction mixture is filtered and the piltrate is evaporated, whereby the H-C2-Aaiinoä thyl) -P- (4 '«aminoberzol ^ -phosphonamic acid yields,

According to the above procedure, but starting from the H-AüJiaopropyl- {4 '-nitrober zol> -phosphonamideäare and the ΪΓ-aminobutyl-P- (4 · -nil robe azole) -phoephoisaiEiäsäare instead of the N-aminoethyl- (4'- * nitrobenzene) -p] iosphonaiaidic acid, the corresponding l-A-aminoalkyl-P- {4 * -aiainobenzene) -phosphonamic acid is obtained.

3 4 s 4-Nitrobenzolphösphcndiß: Ilid be 2 hours in 15 ml of dioxane containing 4 ml 2,5it aqueous Hatriuahydroxyä, erhitst, vobei tfähr-md this period and after 15 Hinuten 5 ^ al ^ asac isii are given, they insgesami ; 20 ml of water have been added. The solvents are removed when the pressure is prevented

- 18 -

109841/1970 bad okoh

Hiickeiand is stirred with water and removed by filtration of äem unreacted starting material. The filtrate is heated with activated charcoal, filtered, concentrated to about 10 a? L and poured into a; Ice bath cooled, with the U-sodium as egg N-'Phenyl-P- (4'-nitrobenzene) -phosphonamic acid results as a crystalline precipitate.

B e P ie I 11

1.9 g of nitrous oxide as the H ~ pratvayi-p- (4'-nitrobenzene) -pboaphoiiaaidic acid were taken up in 30 ml of water and at 2.81 cg / cm (40 psi) in the presence of 1 g of Eaney-Sickel Hydrogenated for 3 1/2 hours. The hydrogenation mixture is filtered and the filtrate is evaporated, resulting in a syrup which crystallizes on addition of Diosan, the Hatriuia salt of the IF marriage 7I-P- {4 '-an = ino "benzene; -phosphonaridic acid as Heaihy.lrat with a Έ = 1i5 ° 0 'sintering) and 25O ⁰ C (Ζ <3Γ8.? results.

According to the above operation \ rird the same product obtained when anstells before Ransy nickel as a catalyst platinum or palladium on üxtit ^r:; is used ohle ".

- 19 -

108841/1970 bad original

Example .1.2

10 g of sulfadiazine and 5 g of 4-Nitrobenzolphosphonyldichlorid be taken up in 30 ml of pyridine and heated for 15 Hinuten at 100 ⁰ C. The hot solution is then poured into 200 ml v / water and the precipitate is filtered off, washed with water and triturated with hot 90% aqueous acetone, the K, M "'- bis- / 74- (2-pyrimidinylsulfamoyl ) «Phenyl ^ -P- (4'-nitrobenzene) -phosphonamide with an F« 260 to 275 ⁰ C (decomp.) Results,

2.9 g of the bis-phenylphosphonamids in 18 ml of 1N aqueous sodium hydroxide are received and 1 1/2 hours, heated to 30 ⁰ C. It ts'erden 100 ml of water and then 11 ml of 1N acetic acid were added vräßrige. After 2 hours, the sulfadiazine precipitate is removed by filtration, a further 2 ml of acetic acid are added and the solution is ^{cooled to 0} ° C. for 3 hours. The precipitate produced in this way is removed by filtration. separates and air-dried, resulting in the sodium salt of 1- / 4- (2-Pyriiiiidinylsulfamoyl) -pheny ^ -P- (4 - nitrobenzolj-phosphanamidic acid)

467 mg of the sodium salsa are dissolved in 20 ml of vaseer

- 20 -

109841/1970

10871 _f

and 1 ml of 1N aqueous sodium hydroxide is added. Eb 0.2 g of Baney Nickel is added and the mixture is ^{hydrogenated at 2.81 kg / cm 2} (40 psi) for 2 hours. The catalyst is separated off by filtration and the filtrate is evaporated under reduced pressure until crystallization is observed. Then ethanol is added, whereby the disodium sala of the N-

Pyrimidinylsulf axnoyl) -phenyl J7-P- (4'-aainobenzene) -phosphonamic acid results.

The sodium salt is dissolved in cold water and mixed with Treated acetic acid, a precipitate of ET- / "" 4- (2-pyrimidinylsulfamoyl) -phenyl J7-P- (4'-aminobenzene) ■ phoaphonamic acid results.

According to the above procedure, but using sulfaiaerazine, sulfaiaethaain, sulfathiazole, sulfa ~ quinoxaline and sulfisoxassol instead of sulfa ~ adiazine, the H ~ _< / ~ 4- (methyl-2-pyri] aidinylsulfamoyl) ~ phenyl_7-P- ( 4 ^f -aminobenzene) -phosphonamic acid, N ~ / "4- (dimethyl-2-pyrimidinylsulfamoyl) -« phenylJ ⁷ -P- {4 ^l -aminobenzene) -phosphonamide acid, H- / ~ 4 ^l - {2-0! Hiazolylsulfainoyl ) -phenylJ ^ -P- (4'-aminobenzene) -phosphonamic acid, N- ^ 4- (2-quinoxalinylsulfamoylJ-phenylJ ^ -I'-C ^ '- arainobenzeneJ-phosphonamic acid

- 21 -

109841/1970

10871

ft

and the N- / 4- (DimethylisoxazolylsulfaBJoyl) -phenyl7 - P- (4 ' -aminobenzene) -phosphonamic acid obtained.

Example 13

A mixture of 4.4 g of 2-fluoro-4-nitrobenzenesophosphonic acid and 4 g of phosphorus pentachloride are heated on the steam bath until the reaction subsides. The phosphorus oxychloride thus formed is distilled off under reduced pressure. Then, the 2 ~ I ^l ~ 4-luor nitrobenzolphosphonyldi ~ chloride is distilled 80 ⁰ G and an estimated pressure of 1 mm at a leinparatur of about! "

Example 14

To 100 ml of a solution of 12 * 8 g (0.05 Kel) 2-! Luor-4-nitrobenzolphosphonsäuredichlorid in 10 ml bromobenzene is at 15 ⁰ O a solution of 5 »4 g o-ihenylendianin in 200 ml bromobenzene was added dropwise in Terlauf of 15 minutes with vigorous stirring. A white precipitate forms immediately. The mixture is then refluxed for 30 minutes. Hydrogen chloride develops and the solid dissolves in the refluxing brorabeneol. The opinion smell

- 22 -

109841/1970 originally inspected

is cooled and it shows that 1 _r 3-i) iliydro-2 -. (2 ^l fluoro-4 ¹ -nitrobenzene) -2-H-1,3, a-benzodiazaphoephol - ^ - oxide as a crystalline precipitate, the separated by saturation, washed with bromobeszol and petroleum ether and dried.

According to the above procedure, but starting from the corresponding 2,6-difluoro-4-nitrophosphonic acid dichloride , the corresponding 1,3-dihydro-2- (2 ¹ ^ ¹ -difluoro-4 ^f nitrobenzene) -2-H-1, 3,2-benzodiazaphosphole-2-oxide obtained.

-23-

109841/1970

Claims (1)

166846 10871 30 January 1968 Claims 1. Compounds of the formula in which R ₁ and R «are hydrogen or halogen, IU is hydrogen or, if R ₁ and R _{2 are} Y-carbon, fluorine, Q is the radical 0 or HH, R ^ is hydrogen, lower alkyl, phenyl, lower alkylamino, phenylemino, (pyrimidinylsulfamoyl) phenyl, (Dimethylisoxazolyisulfamoyl) -phenyl, (thiazolylsulfamoyl) -phenyl, (methylpyrimidinyleulfamoyl) -phenyl and the alkali metal salts thereof and Z is hydrogen, lower alkyl, (pyrimidinylsulfamoyl) -phenyl, (dimethylisoxazolylsulfamoyl) -phenyl)} -phenyl, (Ihiazolyl-phenyl) -phenyl-methyl-phenyl, and the alkali metal salts thereof, where Z can be an alkali metal when Q is 0, and where the groups R ^, KH, P, Q and Z together represent the 2-H-1,3 »2-benzodiazophosphole group when Q is MH. - 24 109841/1970 2, 1,3-Dilaydro-2- (4
diaüiaphosphol-2-oxide, 3. 1 »3-Diliydro-2- (4 ^l -aDino-2 ^l -fluorobenzene) -2-.H - 1,3,2- 4 «1 ρ 3-33iliydro ~ 2 ~ (4 * -aipino-S · -f liaorbensBOl)» -2-H-1,3,2- 5 * 1,3-I »ihydro-2« (4 '-ettIno-2', 6 ^! -Difluorobensol) -2-H 1,3 * 2 « 6 * Natriinmaalz der li-Pi: 'enyl ~ P- (4' '- aininobenaol) -> pIios phonaric acid. 7 «HaUriumaalz der I-Pi5siiyl-'P- (4 ^l -ß3aino-2 ⁱ « fluor- 8 »MfatritUDfialz der Ii-Pi3Ai
b <3ßzo:.) - piiosplionaniida lure. 9 Sodium acid of IT-Ph 2ByI-P- (4 * -amlno-2 ', ti-difluoro- "benzene) -" phospho "affiida; iure. 108841/1970 _BA d 10. Disodium salt dex H - ^ - (2-Pyriiiidiiayl0ulf8jaoyijl · phenyl7-P- (4 * -aminobenzene> -phosphonamic acid 11. disodium salt of H ~ / 4- (2-pyri "idinylsiilia! Boyl] l · phenyl7-P- ^{(4-amino-1 t} 2 -fliaorbenzol) -pIio8phonamldBäurö * 12 »Dinatriuinsalz der iT- ^ 4- (2-Pyrieidinylsulfaiaoyl} - -P- (4 '-aiaino-3' -f l't 13. Disodium salt of vT- / 4- (2-PyrlJiidinylsiafaEaoyl) -pheny ^ -P- (4 * -aiaiirio-2 ', 6 ♦ -dif luorbenaol} -phosphonamic acid. 14ο Procedure for making connections with;
the! formula " ^Λ 2 Ο > - ~~ < HHR. wherein R ₁ and R _{2 are} hydrogen or halogen, R * is hydrogen or, if R ₁ and R _{2 are} hydrogen, fluorine and B * is hydrogen, lower alkyl phenyl, lower alkyl] aaino, - 26 - 109841/1870 Mean Phenylami.no, Pyrimidinyleulfanioylphenyl, Dimethyloxazolylsulfamoylphenyl, Ihiazolylaulfamoylphenyl, Metnylpyrimidinyleulfanoylphenyl and the alkali metal salts thereof, wherein the group represented by E ^, HH and P together form the 2-H-1,3,2-Ben5odiazaphospholgruppe if H ₁ or R "halogen or R ^ mean fluorine, characterized in that one is a compound of the formula where E ₁ , £ 2 ^un ^ ^ -x ^ - ^e have the meaning given above and X is halogen, with a / ^ in having the formula B ^ (SH ₂ ) _n , where R _{4 has} the meaning given above and η has the meaning 1 or 2, and then · adds water » 15 «Process for the preparation of compounds of the formula * 27 - 109841/1970 10871 HHR ₄ in which R ₁ and R _{2 are} hydrogen or halogen, Rj is hydrogen or, if R ₁ and R _{2 are} hydrogen, fluorine and R ^) hydrogen, lower alkyl, phenyl, lower alkylamino, phenylamino, pyrimidinylsulfamoylphenyl, dimethylisoxaolylsulfamoylphenyl, thiazolylsulfamoylphenyl, thiazolylsulfamoylphenyl and the alkamoylpyrimylphenyl, and the alkamoylpyrimidyls thereof are denoted , the group represented by R ^, HH and P together being able to form the 2-H-1,3,2-benzodiazophosphole group, characterized in that a compound prepared according to claim 14 is reacted with a reducing agent. 16. The method according to claim 15, characterized in that that the reducing agent is hydrogen in the presence of a noble metal catalyst. 17. The method according to claim 16, characterized in that that the precious metal is palladium. - 28 - 109841/1970 18, method according to claim 15 »daduroh characterized in that the reducing agent is hydrogen in the presence ' by Raney-Hickel. 19 · Process for the preparation of compounds of the formula in which R ₁ and Rg are hydrogen or halogen »B, hydrogen or, if R ₁ and Rp are hydrogen,» 71uor, R _{4 are} hydrogen, lower alkyl, phenyl »lower alkylamino, phenylamino» pyrimidinyleulphamoylphenyl »bimethyloxazolylsulphamoylphenyl, ihiazolylsulphainoylzanoylpyramylphenyl, ihiazolylsulphainoylphenyl, Ihiazolylsulfainoylphenyl of which and K denote an alkali metal »characterized» that a compound prepared according to the process of claim 14 »in which R ₁ » R ₂ and R _{5 have} the meaning given above »is reacted with 1 equivalent of an aqueous alkali metal base of the formula MOH. - 29 109841/1970 10871 3D 20. Process for the preparation of compounds of the formula characterized in that a compound prepared according to claim is reacted with a reducing agent. 21 · The method according to claim 20 »characterized in that the reducing agent is hydrogen; ± n presence of Raney nickel is. 22. Process for the preparation of compounds with the formula - wherein R ₁ and R _{2 are} hydrogen or halogen, R _{5 is} hydrogen - 30 -109841/1970 or, when H ₁ and Rg are hydrogen »mean fluorine and R 1 mean lower alkyl, characterized in that a compound according to claim 14» in which R *, HH and P together form the 2-H-1,3,2-benzodiazophosphole group »Reacts with a lower alkanol · - 31 - 1098 ^ 1/1970