DE1670014A1 - Process for the preparation of tricyclic organic compounds - Google Patents

Description

DR. I. K - MAAS DR. W. ο. PFEIFFER PATENTANWÄLTE MDNCHlN 23 UNGKERSra. 25 - TEL. 390236

American Gyanamid Company, Wayne, Iiew Jersey, V. St "A

Process for the preparation of tricyclic organic

links

Together mraenfasaung

The invention relates to the production of substituted diazepines, oxazepines and thiazepines. More particularly relates ä a process for the preparation of substituted 11 ~ Aminodiben5 £ b _t fJ [* 1,4] oxazepines or "thiazepines and substituted 11-Aminodibenz £ b _v fj £ i ₉ 4Jdia ze pine from appropriately substituted Diphenylthioharnstoffen by ring closure, the process products are because of their central nervous system (CNS) ~ <activity a] s tranquilizers Ur ₁ -Ji antiilepresoiva fcvie as analgesics.

There are no methods available according to the invention Dtazepine, oxazepine and thiazepine can be found through fol-Porwel represent:

009831/1860 ^ ^Q ^

· ■ · ■ ·· c. - ·

(D

where RJ and & 2 are hydrogen atoms, lower alkyl groups, lower alkoxy groups, nitro groups, halogen atoms or trifluoromethyl groups, R, a hydrogen atom or a lower alkyl radical, R, a hydrogen atom, a lower alkyl radical, a lower alkylene radical 6> (l ) i ~ lower alkylamino) ~ lower alkyl or a & ~ (hydroxy) -lower alkyl: or the group -Ir together an A- (lower alkyl) -1-piperazino radical 4- (hydroxy-lower alkyl) «1-piperaainoreotj 4 ~ (di-alkylamino-lower alkyl) -1 ~ piperazinorest, 1-? Iperidinoreet, 4 '- ^ orpholinorest or 2,2-polymethyler; «- hydrazinorest and Z saiiarstoff, sulfur or lower alkyl

Stinky means »

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The compounds of the invention are generally white crystalline contaminants which are only sparingly soluble in water but moderately soluble in organic solvents, for example kethanol, ethanol and the like. They are "basic substances which are usually soluble in aqueous mineral acids at room temperature" they form substantially insoluble Säureadditionssalse, for example hydrochlorides, sulfates, phosphates, citrates _{9 9} tartrates, maleates, fumarates and the like%. The compounds can erfindungsgemäSen

or generally administered orally / parenterally in the form of their salts

become and are effective central nervous system agents when administered. For oral administration, the new compounds according to the invention combined with the usual pharmaceutical carriers and, for example, in the form Clay tablets, capsules, coated tablets, liquids that are to be administered dropwise, emulsions. «, Suspensions and syrups as well in chocolate, candy «. Chewing gum and the like are used They can also be in the form of suppositories and as aqueous solutions for partial injection can be administered

The new process according to the invention consists in the cyclization of substituted thioureas (II) to compounds (2) according to the following reaction scheme:

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(η)

CD

There are R-, Rp ₉ R? » R * and Z as defined above. The use of phosphorus pentoxide in conjunction with phosphorus oxychloride is particularly advantageous for the conversion of II to I. An excess of the latter reagent can also serve as a convenient solvent. The cyclization reactions are generally carried out at temperatures between about 50 and i50 ⁰ C »The preferred! Ce .-. I $, perature is about 80 ~ 110 ⁰ C, the addition of other solvents which are inert under the reaction conditions, sum as benzene, Toluene, xylene, and the like can also be beneficial. After the cyclization has taken place, usually after heating for about 30 minutes to about 24 hours, the products (I) are generally grounded by treatment. the reaction solution with water and other

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ORIGINAL

final cleaning of the raw products by known. Measures received

The new thioureas (II) involved in this new process As starting materials for the compounds (I) can be used from substituted mphanyl esters, substituted diphenyl sulfides and substituted biphenylamines according to the following Reaction scheme be prepared?

(III)

"1

(IV)

(II)

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H ₁ , Hg »%» ^R 4 ^{and z are as} defined above. Treatment of the last-mentioned compounds with a mono- or diaraine yields the thioureas (U) ₀

The compounds obtainable by the process according to the invention have a physiological effect on the central nerve * system on, you show high activity as a tranquilliser non-toxic doses, and in some cases antidepressant bigens, at dose levels that are neither overt Stimulation still produce depression.

A suitable test for tranquilizer activity consists in this the reduction of spontaneous motor activity in animals with the help of an actophotometer (a photoelectric device for the quantitative measurement of locomotor activity) to eat. Graduated doses according to the invention Process produced active compounds are sent to group administered by mice * and the effective doping range for a significant reduction in motor activity (ei? hatred for tranquililian effects) in comparison to control groups is determined «The use of reduced motor activity as a hatred for tranquility activity was suggested by W * D, (Jr?

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A ^ C «Osterberg and GoE ₀ Rauh, Archives Internationales et de Therapy, Vol _? 134 _ff p. 198 (1961) and WJ. Kinnard and CJ. Described _Carr's Journal of Pharmacology and Experimental Therapeutice "Ed, 121 _P S. 354 (1957)."

The antidepressant properties of the rgemäßen Inventive by the method available compounds come to light when measuring their ability of animals γόη by administering Setrabenazinhexamat induced depression Λ counteract "graded doses of the active compounds according to the invention are the following to groups of Muse administered Thereupon the administration of a dose of tetrabenazine which is known to markedly suppress the research behavior of normal mice »The groups treated with antidepressant show normal behavior, while the control groups and groups treated with an agent ineffective as an antidepressant do not show this normal research behavior, but rather show the well-known deep depression induced by tetrabenazine. The results of the corrective values are used to determine effective dosage ranges *

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Some of the compounds obtainable according to the invention show furthermore, other important pharmaceutical properties, for example analgesic activity.

The following examples explain in detail the preparation of representative substituted 11-aminodibenz / ö * f // ic4 / -oxazepines and -thiazepines and substituted 11-aminadibenzfc h> -ff-l [i »4j diazepines according to this invention =

example 1
Production of 11 ~ (1-Plperidinvl) & ibenzfb _a fJ / t _P 4-joxazepine

The compound phenyl-o-phenoxythiccitrate and piperidine are heated to reflux temperature in ethanol, followed by removal of the solvent and crystallization from dilute ethanol. As a product wurd 2 ^f * -Phenoxypiperidin thiocarboxanilid vom'i \ 135 - hold 136 ° C ej.

1 _e 0 g of 2 ^t -phenoxypiperidine thiocarboxanilide are refluxed with about 1 g of phosphorus pentoxide in 5 ml of phosphorus oxychloride for 2 hours. After cooling to room temperature, the reaction mixture is diluted with ether. The precipitate obtained is washed several times with ether, with aqueous Potassium carbonate solution (preferably with cooling)

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IN QUESTION and dreiraal extracted with ether The ether solution is dried over anhydrous potassium carbonate and, after evaporation of the solvent a yellow Peststoff consisting of heptane to white crystals, F, 98 - 100 ⁰ C is Aiert to * krtstiiXli.

Example 2.
Manufacture of 11-aminodibenzfb "fI / i _o 4J oxszepin

According to the procedure of Example 1, by treating phenyl-o'phenoxythiocarbanilate with ammoniacal ether, the product 1 «(2-phenoxy) -phenylthiourea, from P _t 125 ■ - 127 ⁰ C after recrystallization from dilute methanoi is obtained»

Heating the i- (2 ~ phenoxy) -phenylthioureas prepared above with phosphorus pentoxyä in phosphorus oxychloride gives the crystalline product from P. 198-200 ⁰ C,

Example 3

Production of 11- (nB "itylaminoldiban'5 £. \ Ι, £ ΐΙΐ, 4J oxaaepine

16. ^ 6 g (0 ^ 075 mol) of 2-aminodiphenylä!; H «rhydrochloride by shaking with dilute ammonium hydroxide into the open air ßase transferred- The released Bas "" is with ether

extracted, and the essential solution vürd over sodium

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0AÖ ORIGINAL

sulfate dried. This solution is treated with a solution of 6.45 g (O375 O _P mol) in ether offset Phenoxythiccarbonylchlorid The resulting solution is stirred at ambient temperature about 21 hours with a magnetic "Filtration of white crystals of 2-Arain.odiphenylätherhydrochlorid be separated» By Removal of the solvent from the filtrate gives an amber-colored oil which, after recrystallization from hexane, yields 12.4 g of solid with a melting point of 95 ° -98 ° C.

A solution of 3 ₉ 21 g (10 mol) of the above prepared phenyl-o-phenoxythiocarbanilats and 1.46 g (20 mol) of n-butyl 'amine in 50 ml of ethanol is heated 50 minutes to reflux temperature. The solvent is removed and the residue crystallized on trituration with hexane, by recrystallization of the product 1-butyl-3 ~ (2-phenoxy) phenylthic urea, from ether-hexane gives crystals melting at 80 wdße -. 81 ⁰ O.

Following the procedure of Example 1, the 1-butyl-3 ~ (2-pheno3fy) -phenylthiourea prepared above is obtained by reaction with phosphorus pentoxide in phosphorus oxychloride Crystals with a melting point of 67 - 71 ° C after ^ crystallize out Heptane "

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example

Manufacture, yon _ι 11 "(4 ^ -Hetb.yl-1-pipeΓa zinyl) diben5s ^ bpf J / 1

s aazepine .

Following the procedure of Example 1, phenyl-e-phenoxythiocurbanilate is obtained with 1 molar equivalent of I-methylpiperazine 4 ~ methyl-2 * -phenoxy ~ 1 ~ piperazinthiocarbxanilid vice versa from dilute ethanol in the form of white crystals

from the F. 159 - 142 ° G is obtained

Following the procedure of Example 1, by reacting 4 = methyl = -2 ^s ~ phenoxypiperazinthiocarboxanilide with phosphorus pentoxide in phosphorus oxychloride, the above-mentioned product is obtained in the form of clay crystals with a temperature of 96 ° C = 97 ° C after recrystallization from heptane,

example 5

Producible ung of 11-t4- (B »H _f ydroxyathyl)» 1 ~ piperagjLnylJdibenz-

Following the procedure of Example 1 is phenyl-2- (pchlorphenoxy) thiocarbanilat with 1 ~ (ß-hydroxyethyl) piperazine to 2 * - (p-chlorophenoxy) -4f2 ' »hydroxyethyl) -1-piperazinthiocarboxanilid mp 155-158 ⁰ C reacted after recrystallization from ethyl acetate.

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The 2'- (p ~ chloroplienoxy) -4 ~ (2 '«hydroxy) prepared above ethyl) = i-pipereainthioaarbosanilid is combined with phosphorus pentoxide heated in phosphorus oxychloride. After dissolving The product in ether and treatment with hydrogen chloride is not obtained in 1 * - £ 4 - »(ß ~ hydroxyethyl) ■ 1 --pipfsrassi nyljdibens -

Am crystals from

«^ S K ₉ ^{= 1}

Production of 2- chlorine-1 LtI 4_-tn ethyl - 1 -piper a y, iny l) dibenz-

Following the procedure of Example 1, by reacting phenyl-2 - (p-chlorophenoxy) 1; hiOi2arbanilat with 1-methylpiperazine crystals of 2 ^s - (p-chlorophenoxy) -4 methyl-1-piperazinthioGarboxanilid rom i \ 145-147 ⁰ C obtained after recrystallization from acetone-hexane.

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If you look for the operation of example 1 2 ^! - (p ~ ChlorpheriOxy) ~ 4 "methyl ~ 1-piperazinthiooarboxanMd used as the starting material, the product obtained is brownish crystals of Pc 109 to 111 ° C.

Example,._?_.,

Horste.ll_ung__vfin_ 2-chloro-1.1 .- (4 "-methyl-.1.-giperazinyl) dibenzftj.fj £ i , $ , thiazepine

Following the procedure of Example 1, phenyl (p-chlorophenylthio) thiocarbanilate is obtained with 1 equivalent of 1-methylpiperazine to 4 -Methyl'2 '- (p'Chlorphenylthio) piperazinthiocarboxanilide hydrochloride implemented »

The conversion of the 4-methyl ~ 2 * ~ prepared above (p-'ChlorophenylthioJpiperazinthiocarboxanilide-hydrochloride with phosphorus pentoxide in phosphorus oxychloride according to the procedure from Example 1 gives white crystals of P, 114.5 up to 117 * 0 ° £ after recrystallization from heptane »

SAD GRlQiNAL

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- 14 - Example__8_.

Division of ^ irMejjhylrJJ ^ :( 4-Methyl-1 -piperazinyl) dibena-Cb, £ Γ1 ₈ 4] d ia ζ ejBin_

By using 2-araino »N-m3thyldiphenylamine with phenoxy thioearbonyl chloride following the procedure of Example 1 φ becomes Phenyl ™ 2- (N ~ methylanilino) thioearbanilate in the form of a Get oil *

Treatment of the phenyls prepared above ~ 2 ~ (N-methylanilino) thiocarbanilate3Diit 1-methylpiperazine after the procedure of Example 1 gives crystals of 4 ~ Methyl-2 '■ »(N-methylanilino) -" 1 -piperazinthiocarböxanilid vom P "131-132 ° C after recrystallization from heptane-ethyl acetate.

^ Following the procedure of Example 1, 4- ~ methyl ~ 2'-N-methylanilino-i-piperazine-thiocarboxanilide is reacted with phosphorus pentoxide in phosphorus oxychloride au crystals of P. 119 = - 120 ⁰ C after Umkriatallisleren from heptane.

example
Yon production JJ ~ (4 _< '' Ior p uo lino) Dibeng / b, fJ (n 1 "4 ^ thiai2epi

Hydrochloric!

The Umeetzung of 2-aminodiphenyl sulfide with phenoxythiocarbonyl chloride according to the procedure of Example 1 Working lie · fert white crystals, melting at 86 to 88 ⁰ C after recrystallization

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from ivttianol.

The working procedure of Example 1 is repeated to convert phenyl 2- (phenylthioHhiocarlranilat with morpholine in propanol to crystals of 2 "- (phenylthio) -4-morpholinthiocur ⁱ boxanilid Fo 83-84 ° C after recrystallization from ethanol-heptane

A solution of 3oo rag 2 '· - {Phenylthio) -4-morpholinothio ^ carboxanilide in 2 ml of PhosphoxOXj'Chlorid, which contains a drop of dimethylformamide, is heated to reflux temperature for 5 hours * After isolation of the product in the V / ice cream-colored crystals, P. 250 are - 26O ⁰ C after recrystallization from ethyl acetate-methanol obtained *

Beis |> iel_10_
Production of 11- ( Dimethylaminoäthylamino) dibenz ^ b, fJ-

L * 4Jj> xazegin ^

The procedure of Example 1 is followed by reaction of phenyl-o-phenoxythiocarbanilate with linsym «.- dimethylethylenediamine in ethanol i- (2 ~ dimethylaminoethyl) -3- (2-

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PhsnoxjO-phenylihiourea obtained as a colorless oil. i) Ui. ³ eh heating of l- (2 ~ dimethylaminoethyl) ~ 3 = (2 ~ phenoxy)

yOxy

phenylthiourea with phosphorus chloride in the presence of v-.m dimethylformamide at reflux temperature gives 11 4> i methylaminoethylamino) dibenz [b, fJ / Y, 4J-oxszepin from F, 82-84 ⁰ C,

Balap.iel -. 1L ..

Preparation of 2-chloro ~ 1i ~ M5HUmethylaminoethyl) methyl- _amino3-dibenzfb ₈ f - '/ U

According to the procedure of Example 1, 2 ~ (p-chlorophenylthie> thiocarbanilate is reacted with trimethylethylenediamine ^to 1 ~ £ 2- (p "OhIophenylthio) phenyl] -3-methyl-3-dimethylaminoethy 1-thiourestaff, which as the hydrochloride salt of F. 16 ? - 168 ^d C is isolated.

The 1- ^ 2- (p-chlorophenylthio) -phenyiJ prepared above 3-methyl-3 * ÄimethylaminoäthylthiourstoffhydrochloΓid is heated with phosphorus pentoxide in phosphorus oxychloride. By Dissolving the product obtained in ether and treating with hydrogen chloride gives 2-chloro-i1 ~ £ (3-dimethyl ~ -

i ^ D ORIGINAL 009831/1860

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äthyi} msthylaainoj ~ άί \) βη?, [κ _ν ΐ] [ 1 »4 ^ thiasepinhydro

rid from Fc 196 - 197 ⁰ C *

Example 12

Hers.t?.! -'- MJBg τοπ. .2 -. Chlorine ~ 11

Phenyl-2 '(p-chlorophenoxy) i; hioear1) anilat r / ii ^j: 1 - (3-Diaethylaminopropyl) piperazine according to the Arbeitsv / Qiü'i; fon instance i to obtain an oil "the ethereal by treatment ϊάϊΛ hydrogen chloride in the dihydrochloride is transferred, it is after recrystallization from methanol

thioiarbQxanilid-dihydroehlorid from F, 208-210 ⁰ C obtained.

Following the procedure τοπ Example 1 v / ird by heating the % Y above prepared ^2f ~ (p-chlorophenoxy) ~ 4- (3-dimethylaminopropyl) -1-piperaiinthiocarboxanilid-dihydrochloride

/ oxy with phosphorus pentoxide in PhoephorxJhlorid 2-chloro-11-

ssepin manufactured

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1 ~ (4HBorpholinyI) dlbengfb, f7

thi azepine

By the procedure of Example 1 is phenyl "is 2" (p-chlorophenylthio) thioear "banilat with morpholine au 2 * - (p * Chlorphenylfchio) -4" rflarphöiin-thiocarboxanilid from P. 65 "67 ⁰ C

By heating the above prepared 2 " ^e ~ (p = chlorophenylthio) -4" iaorpholinthioöarboxanilid with Phesphorpentoxyd in phosphorus oxychloride, 2 ~ chloro ~ 11- (4-morpholinylidibenssfbpf]; 1,4J thiazepine as crystals ^ om P. 148 ^ 150 ⁰ C.

Example 14 Preparation of 2 ~ chloro-11- (i ~ piperidinylamino) dibenz-

fb, f JTi «43thiazepine

Following the procedure of fellspiel 1 , msn uses phenyl-2- (p-chlorophenylthio) thiqoebanilate with N-aminoplperidine

16700U

to 1 -Al · - ρ-Chlorplienylthio) -phenyl] -3 "(1 -piperidino) thiourea from Po 158.5-16O ⁰ G after recrystallization from ethanol ZUp

By heating the 1 ~ [2- (p «Qhlor ~ phenylthio) phenyl] ~ 3- (1-piperidino) thiourea ^ with phosphorus pentoxide in phosphorus oxychloride, mr-n 2-chloro-11- (1 = piperidinylamino) diben ^ is obtained i> _t fJ / "i _i 4jthiazepin as crystals' from Ρ" ~ 153 154- ⁰ C.

Example. Ig ₁

Manufacture of 1 1- (B »gyaroa: yath.Ylamino) dlbeHgA) _t f7f 1.4 * 1

oxazepine.

After the procedure of Example 1, phenyl ~ 2-phenoxythiocarbanilate is converted to 1- (β = -hydroxyethyl) -3- with ethanolamine

(2 * -phenoxy) pheny! Thiourea implemented. Ä

By heating the I- (S-hydroxyethyl) -3- (2 ^f -phenoxyjphenylthiourine sulfate with phosphorus pentoxide in phosphorus oxychloride), 11- (β-hydroxyethylamino) abenz / ii, fJ (I, 4joxazepine as crystals of P. 136 139 ⁰ C.

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Example 16

Manufacture _im von 11 ~ («- DlmjBthy laming pro pyl ^ d ibenzfb, £. J / i« 4?

(Bxazepine

Following the procedure of Example 1, by reacting 2-phenoxythiocarbanilate with α-dimethyl ainopropylamine, 1 - (3 "dimethylaminoprcpyl)" 3- (2-phenoxy) phenoxy thiourea rom JP. 113-114 ⁰ C produced after recrystallization from ethanol-heptane.

By heating the 1- (3-diraethylaniino "prepared above" propyl) -3- (2-phenoxy) = phenyl-thioureas with phosphorus pentoxide in phosphorus oxychloride the product is obtained in Form of crystals from F * 108 - 109 ° C «

Example 17

Manufacture of 11-All. vl aiainodlbenz / "b, f3 / i« 4Jo xage pin-HydrO "

chloride

Following the procedure of Example 1, the reaction of phenyl-2-phenoxythiocarbanilate with AXlylamine is obtained as the product 1-Allyl-3- (2-phenoxy) phenylthiourea in the form of an oil.

Heating the 1-ally1-3- (2-phenoxy) phenyl-

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■ thioureas with Phcsphorpenioxyd in Phosphoroxychloria Ιΐβ-ated as a product I1-Allylaminodibenzib, £? [I ₉ 4 j ~ _t oxazepine its Hydroohlorid in the form of crystals -ron Tom Fo 220Ό (Zera.) Is obtained = "

Example_18

lh , flT [Vgil pacaaepin

the working method of example 1 we ^ d phenyl = 2 - "(p-fluoro * · phenoxy) thioearbanilate with 1-methylpiperaain to 2 ^a - (p-pluophenoxy-4-methyl-1-piperazinthiocarboxanilid converted"

By heating the 2 ⁵ "(p-fluorophenoxy) -4-methyl-1-piperazinthiocarboxanilide prepared as above with phosphorus pentoxide in phosphorus oxychloride, the product is obtained as crystals of P. 84-86 ⁰ C,

Example 19

fferatellunp of 2-bromo-11 ~ (4-methyl-1-piperaginy l ) dibenz ~ Tb, f? M, 4! oxazepine

Following the procedure of Example 1 ', phenyl 2- (p-bromophenoxy) thiocarbanilate is reacted with 1-methylpiperazine to give 2' ~ (p-bromophenoxyJ ^ -methyl-i-piperazinthiacarboxanilide.

ORIQtNAL INSPECTED

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Of the above prepared by heating 2 '■ = (phenoxy) -4-methyl-1-pipera "inthiocarboxanilids obtained with phosphorus pentoxide in Phoaphoroxychlorid the product as crystals, melting at 95-99 ⁰ C ₀

Example ^ 20
Manufacture _y_on _2 ^ Hetbyl ~ 1 1 - ■ (4 ~ methyl - 1 "P _M iperazin.vl) dibenz ~

According to the procedure of example t, phenyl ~ 2- (p -5olyloxy) * l; hiocarbanilate with 1-methylpiperazine to form 2 '- (p ~

around.

Of the above prepared by heating 2 * - (p-tolyloxy) = - 4-iaethyl-1-piperazinthiocarboxanllids Phospharpentoxyd with phosphorus oxychloride in the product is obtained as crystals ΙΌ 130-131 ⁰ C.

Example 21 Preparation of 8-chloro-1i «(4 ~ meth.vl-1-piperazinyl) dibenz ~

/b.f It1.4loxazepine

Following the procedure of Example 1, phenyl 5-chloro-2-phenoxythiooarbanilate is etched with 1-methylpiperazine to give 5 * - "chloro-2" phenoxy-4-methyl-i-piperazinthiocarboxanilide.

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By heating the 5 '"chloro-2" -phenoxy * 4-methyl-i- ^ piperazinthiocarboxanilids with phosphorus pentoxide in phosphorus oxychloride, the product is obtained as crystals from P. 165 - 166 ^e G.

Example 22
Production τοη 6 »chlorine-11 ° (4-methyl-1-pi perazinyl) dibeng"

Following the procedure in Example 1, phenyl = 3-chloro-2-phenoxythioearbanilate is reacted with 1-methylpiperazine to give 3'-ChIOr- ^2f -phenoxy-4-methyl-1 * piperas5inthiocarboxanilide.

By heating the 3 ^t- chloro-2'-phenoxy 4-methyl-1-piperazinthioearboxanilide prepared above with phosphorus pentoxide in phosphorus oxychloride, the product is obtained as crystals of P. 83-87 ° C.

Example 23

Manufacture of 4- ° chlorine "11- (4" m ethyl ~ l "piperazinyl) dibenz" -

fb, fj ^ 1 "43 oxazepine

Following the procedure of Example 1, phenyl ~ 2 ~ (o ~ chlorophenoxy) thiocarbanilate with 1-methylpiperazine to form 2 '- (o-chlorophenoxy) -4 «methyl« 1'-piperazinthiocarboxanilide around.

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By heating the 2 ¹ - (o chlorophen oxy) -4-fliethy 1-1i-piperazinthiocarbo ^ anilids mil; Phosphorus pentoxide in phosphorus oxychloride is obtained the product as crystals, P _3173-174 C ⁰

Example 24

Manufacture fi_Yon. 1 1 - (4 ~ He thyl-1 _r piperazinxl) _-; 8-tgifluoromethyldibenz Γ b, t) [y ₉ 4 * , ^ hiagegin-Mhydrqghlorid

Following the procedure of Example 1, 5-trifluoro-methyl-2- (phenylthio) thioearbanilate is reacted with 1-methylpipej-azine to give 5 '"trifluoromethyl-2 ⁹ - (phenylthio-4-methyl-1" piperazinthiocarboxanilide,

The above prepared 5 ^I -trifluoromethyl "2 '* phenj ^ lthio =' 4-methyl-1 ~ piperazinthioearboxanilid is heated with phosphorus pentoxide in Phorphosoxychlorid, by dissolving the obtained product in ether and treating in hydrogen chloride to obtain 1 ^ - (4-methyl ^ II * - _; rap-! Nyl) - 8 «-trifluorraethyldibenzfbffJ {1, / - JtiLvasepisi'dihydrochlorid as crystals ■ romJP, 192 ⁰ G (Zers-i _n

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- 25 Example 25

According to the procedure of Example 1, mg η Phsayl-2- (p-

iojthiooaybanilat old piperidine so 2 ¹ ^ Cp-

; ih Brwärmen des Yorsnsh-saä hergesteirrce-n S * - ■ {p-i5efhox, v- ^ pnen> x-) hi &eäi>; - c3caniläclBt a: lt .rhoeniioi'psntcxyd in

iä one obtains <Jaü product as KrisiiiO 'Ie from 116-117 ⁰ C ₁

Hero telly ng νοη 2 - Hitrö = 11- (4 - methyl -i-pinerasinylidibens-

Aub 1-methylpiperazine and Shiophosgea produced 1-methyl-

will
4-piperaiaiRthiocarbonylchloride / with o-aminophenisl au 1-methyl-

^ tati Dlessa product is treated with 4-Chlornitrobenaol in dimethylacetamide in the presence of £ aliumcarbonat »give 4 ~ methyl ~ 2 '- Cp-nitrophenoxy) plperazin-thioca3 £ ^c l3OXSBilid get" wiyd *

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~ 26 -

Hash of the procedure of Example 1 is carried out by reacting the above Xi'h < 4-methyI ~ 2 ^! «(P-nitropbenoxy) piperazine * thiouarüoxanilids with phosphorus pentoxide in phosphoroxy-

Chloride 2-Nitro-1- (4 »aethyl-1» piperazinyl) = dibenzfl), f 3 ^ 1. ₀ .4y

O3iä £ .epir _; iu Jiorsi -of crystals toe ί ¹ , 189 - 191 ⁰ C after recruiting bus Hes: an received,

009831/1860

Claims (1)

in which R 1 and Hp are hydrogen atoms, lower alkyl groups, lower alkoxy groups, nitro groups, halogen atoms or trifluoroethy] groups, H, a hydrogen atom or a lower alkyl radical, R, a a, ubric, aiioai , small lower alkyl radical , a lower mkenyl radical, a Cj lower alkylamino) = lower alkyl radical or a (J ~ (hydroxy) lower alkyl radical or the Srappe -IJ 'aysannnen ^U 4 is a 4- (M ed era Iky 1) -i-piperazino _r, 4- (hydroxy ^ -i-piperazinoreBti- A ^ (dialkylamino} -i-piperazino "i-Pipfca idinosrfcsto-4- ^ morpholino or 2 _S 2-Polyraethylene hydrazino radical and Z is an oxygen atom, a _t 5chv "Fe3.atom or a ffiisderalkylau"bs1; ituiertea Stiekstsffatom tedsaten ₀ thereby 009831/1860 INSPECTED 16700U ^ iil · ϊ- that u'an Qinen Th-i toff uev Fo vioriii ILi ll _o »R _vs R ,, and Z as defined above; are, with: Phosphorus pentoxide or Phosphorus oxychloride heat and the Pr od η kt ge ν; ί η nt, 2. ~ The method according to claim 1 _; characterized by the fact that the thiourea 4-methyl- ^2r: -phenox.vpipera ^ in ^ hiocarbox anilid - ^ r turns U2id to 's 1 - (4 - Mo thyl-i-piper-a ^ i ny J ) diba η a, f3 ^ 1 _, 4j oxaaepin converts " is method according to claim T-. characterized in that .ia = than thiourea '2 ^K - (p - 0hlorpheno3cy) - = 4-iaethjfi - 1 -piperazinthiooiirboxan ^ 3 id itt and KU 2-ChlOA'-11 - (4 "ta6t« yl - 1 "piperazinyl)' 009831/1860 4. = Procedure according to iUispraäte I _2, characterized in that wan as! Hii ο urn st off 4- ^ ethyl ~ 2 ^t - (p - ohlo5? Pli.ßsjlthio) piper · ' and to 2-Cfel62 ⁵ --- 11 = {4- A method according to claim 1 "characterized by the fact that one a is shiourea 1 - (2-Bimethylarainoäthyl) -3- (2-phenoxy) -phehylthioharnatöff Tsrwendet and jsu Ii - (dimethyl-amino ~ äthyl) dibenss ^ b, f1 [i ^ josaaepin converts ο 003831/1880