Process for the preparation of acyl-2 hexahydro-1, 2,3,4,6,7,11b-2h pyrazino (2,1-a) isoquinolène-4 and intermediaries.

aEG presented a 'concerned an method for preparing' EIT acyl 2 hexahydro 1>3, 4, 6, 7, 11b 2b-to-pyrazinc. (2 1 .,-) isoqoincléinones and 4 -.

More particularly, the present invention_> has, ; P-it-a pure§||of NOy? calf DRP 'pêdé for preparing' compounds of formula

3 wherein R represents a lower alkyl group, cycloalkyl having 3 to

•5 carbon atoms, phenyl or substituted phenyl.

The acÿl-to-2 hëxahydro-to-1v3, 4, .6, ?, 11b 2h hexahydropyrazino (2.1-) of formula I isoquinolêinones and 4 above are well-known products are described in the German patents no. 1 295 - 720 and no. 2,362 539 as potent yearthe I thelmintic or as intermediates in the preparation of products with anthelmintic activity.

The compound of formula I above wherein R is cyclohexyl I received the common name International "praziqantel" and it has been indicated as having a broad spectrum anthelmintic activity with ELLEN-to-3 tee against all species of schistosomes pathogens and howneûestedes ' - CExperientia 1s77, 103sî.

N * 2 362,539 no. 2,441 251 and German patents describe a method that may be used 'for' the. preparation of compounds of general formula law above, said method being characterized in that the treated 3, 1 * oxo 4 hejcahydro L, 2.3 * 5, 7, 11b 2w hexahydropyrazino (2, 1 - 3 ℮ tetrahydroisoquinoline of formula

THE II

with the R-GOQH * dede.ses could with a functional derivatives, or although

1 '- treated, a ooaposéormule of f -'

wherein the dotted line indicates that there may be a double bond at 8.7,

. According to the German Patent no. 2,504 250, the starting material III shows the I 'disadvantage that it is accessible only with very low yields from i' isoquinoline, chloride of R-c0c1 and cyanides..

The same patent is directed to a method characterized in that the treated a compound of formula

V

under firm mono-addition salts, with the chloride R c0c1 in the presence of a based low which ' is more weakly basic than the product obtained, and subsequently converting the compound obtained into the compound III above by action of a-acetyl halide.

The compounds III SAL are then transformed into compounds of formula I according to the method above n-German Patent^I 2,352 53S.

■the compound of formula V is in turn prepared by catalytic hydrogenation of the compound: of. formula

preferably using the Ni Raney nickel as catalyst CHelv. Chem. WTA.

1S39, 22, Β 72 - 503) ·, followed by hydrolysis. This hydrogenation has cepéndent, already for 150 to 200 mg amounts, a. -operation à'à' high temperature and unq ^ b.? egelap, jtres high (at hands 150 - up 25q atmospheres), which ^ ocnstitue: TFG disadvantage industrially ., especially - when the amounts are even more important.

German Patent no. 2,457 971 describes another method for preparing the compounds of formula I above which comprises cyclizing a compound of the formula

or a functional derivative thereof on the carboxyls.

The compounds VII are however prepared from the product V above that requests, for obtaining same, temperatures and pressures.

" the same patent, can also cyclizing a compound of the formula

where e is a halogen or a hydroxyl group, but this procedure is not the preferred relative to that which comprises cyclizing the product VII below.

In any case:, all methods which lead to the products, of formula. I with yields suitable, comprise, upstream, or a hydrogenation at pressures and temperatures are achieved, in pre-'serres catalysts such as Raney-the MI, running in delicate, either other methods which include, by example ., the card user gas hydrofluoric or intermediates Si-containing expensive. '•

It has now been found that the compounds of general formula I above may be -. - prepared with high yields. glpbaux by the method of the present invention which utilizes novel intermediates and chemical reactions facilesa implementing, whose transposition - to L'échelis: - industrial_; is; aiséè.

Thus, . one of. kay's aspect, the present invention relates to

. a method for, the 'preparation of acyl-to-2 hexahydrc-a 1" 3.4, e, 7, 11b 2h hexahydropyrazino HAIs isequinolMédheS' XtV ' -¹ ? - die ' formulated ii DL above, said method being caiactérise in EEP is treated acyl-4 piperazine derivatives of formula dioxo 2.6

r-CO N. the m the RX

with an alkylating agent of formula

/ *% V.^CY^XX

x-aù represented chlorine, bromine, iodine or a nucleofugal leaving group, in the presence of a condensing agent in an inert organic solvent alkali ; a selectively reduced imidic carbonyls of the compound thus obtained of formula

by a complex metal hydride in the presence of a metal chloride catalyst. cuCl or selected from₂ , COCl to₂ , NiCl₂ , CrCl_3<FeCl_3>SnCl₇ , SrCl₂ , FlnEl ^, LMTF_2>HgCX_2< et - is cyclized to the compound thus obtained of formula

10' IN; NR XII.

by the action of a strong organic or mineral acid at a temperature of between 0. and 25 °c.

According to another aspect, the present invention provides, a T # anan.t; rívetted." intermédisires, novel acyl-4oxo-to-6 pipéraiinesphénéthyï L

wherein R is as defined above and wherein Y is 0 or K, the OH.

'The steric configuration of 1' hydroxyl in position 2 compounds. XII as above does not matter in the method of the present invention because the cyclization goes through a carbocation which destroys the asymmetric center in 2 and final products are obtained in near quantitative yield.

The term " lower alkyl * ', as used herein, refers to a saturated aliphatic hydrocarbon radical straight or branched chain containing up to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, isobutyl, dry-cutyle, tert-butyl and the like.

The term "substituted phenyl", as used herein, denotes a phenyl group mono - or di-substituted by an atom or a radical which is inert under the reaction conditions above, such as a halogen such as fluorine, chlorine or bromine, a free hydroxy group or etherified with lower alkyl as defined above, a free amino group or mono - or disubstituted by lower alkyl. - as-defined above, mercapto tMoéthérifié could free with a lower alkyl group as defined above, a cyano group, " trifiuorométhylthio or a trifluoromethoxy group.

The reaction between the compound of^: start of formula IX above and the reagent of formula X is an alkylation carried out in the presence of a condensing agent such as alkali; 1' sodium hydride, an alkali alcoholate and similairesLe nucleofugic group indicated by X in, the formula X above, is preferably the group methanesulfonyloxy Cmésyloxy] or P-toluènesulfonyioxy (tcsyloxy], but benzenesulfonyloxy groups, β-naphtalènesulfonyloxy and the like can be also used. Alkylating agents. particularly preferred are phenethyl bromide and iodide phenethyl, .

According to a preferred mode of operation, is heated there and then reaction mixture during 2 to & hours; alder temperature between 50 to 100 °c.

in a solvent. inert organic such as a-pyrrolidone, dioxane at the dimsthbxyétbane. At the end of the reaction, the resulting product is_;

, isolated according to the conventional technique and it can be purified or used directly for the next step.

The acyl-to-4 dioxo 2.6 phénéthyï-to-1 piperazine of formula XI is then reduced with a metal hydride complex, as hydride of an alkali metal and an alkaline earth metal such as sodium borohydride, the lithium borohydride or lithium hydride ' and aluminum or other metal hydrates complexes such as potassium borohydride and tri-dry. butyl chloride in the presence of a metal catalyst, reaction is carried out usually in an inert solvent such as an ether, such as diethylether diathyliqu-th, the tétrahydrofprenne, dioxane or dimethoxyethane at a temperature between - -70 °c and the boiling temperature of the solvent employed, when using sodium borohydride, the reaction may be conducted in solution aqueous. or hydroalcoholic at a temperature near room temperature,

According to a preferred mode of operation, it is carried out with an excess of borohydride. sodium in an alcoholic solvent such as methanol or ethanol - has, at a temperature of 25 °c 0° and using catalyst of cupric chloride CCuSl ^ ii. After having destroyed the excess reducing agent, the compound thus obtained, the acyl-to-4 hydroxy 2 axoglial-to-6 phénphén.éthyl and 1 pipérezine of formula XII, is isolated according to conventional methods and purified or used as such for the cyclization.

The cyclization is effected by treatment with a mineral acid or strong organic ' such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and the like has a temperature between 3° and 25^has C., 5 °c to 0° of preferably. The final product of formula 1 above is isolated by pouring the reaction mixture into ice water and by extraction with a suitable solvent.

The acyi-to-4 dioxo 2.6 piperazines of formula IX used as starting compounds in the method of the present invention are products known dansrdansr.ia literature or readily prepared from imino -

üiacétonitriiehslogénure by reaction with an acid, by treatment ulté -

- '* I-

wetted the n-acyl iminodiacëtonitrile thus obtained with 1' hydroxylamine and diazotization according to: 1, ℮ ·. following scheme.

described in J mal, share. Perkins Brailler I-, 1372, 1009.

The. acyl 4 dioxc above 2.5 piperazines of formula IX - used as compound s.de can also be prepared starting by reacting an n-acyl-iminodiacetic acid or - corresponding with the diamide of formamide. while removing water that forms by ' path azeotropic according to the following scheme

R C0-N-<

hM₂ the COOH

hM₂coch

0

" THE NH₂ C0 H- ' R-CO N-THE NH

0

X

as described in the Belgian Patent n° s24 586.

The following examples illustrate the invention without however

the limit.

i) The n - - iminodiacetonitrile (cyclonexylcarbonvl)

Is mixed under vigorous stirring 50 grams (0.52 mol) of d! iminodiacitonitrile, ISO-grams (0.78 moles) of potassium carbonate ., 150 ml .'d ' water and 400 ml of dichloromethane - / after. cooling of the reaction mixture to 0 °c, is added, dropwise, SSs, 5 grams (0.65 mol) cyclohexylcsrbonyle chloride. Allowed to return to room temperature by maintaining 1' stirring, 2 hours. By-settle upon the organic phase, the aqueous phase is extracted twice with dich-to-iorométhane. The organic phases combined, dried on sodium sulfate is -, leave an oily residue after evaporation. By trituration with cyclohexane, crystals are recovered EEP the L? is recrystallized in Is cyclohexane derivatives. White crystals, f=52 °c, yield: · j55%.

b) (the O/cIohsxylcarbonyrj-substituted bis (hyriroxyimino)~-2, piperazine■sec.

■has a mixture bone ls, 4 grams [0.23 moles) die hydrochloride hybroxylamine and 7i.42 grams [0.07 moles) of potassium carbonate in the DS · in 30 ml of methanol and 20 ml of water, added a 14.4 grams [0.07 moles) of n - (cyclohexylca'cyclohexylca' rbanyll-to-iminbdiacétonitrile, reflux, under an inert atmosphere, during 2 hr 30, after cooling, crystals are filtered. Suspending the crystals in a mixture of ethanol and 50 ml 1o0 ml water and reflux during 1 hour. Is filtered hot crystals is recrystallized in a mixture of water and ethanol. White crystals, F. > 26q °C " yield: 64 H

c.) (Cyclohexylcarbonyl) piperazin -4 dioxo 2.5

Suspended is 6 grams [0,023 moles) of - [cyclohexylcarbonyl) of bis - (hydroxyimino)~4 -2.6 piperazine in a mixture of 20 ml of water and 20 ml of acetic acid. After cooling of the reaction medium between 0° and 5 °c, is added, dropwise, under an inert atmosphere, a solution of 5 grams (0,068 moles) of sodium nitrite in 25 ml of water. Dropping in room temperature 24 hours. The evaporation dry leaves a residue that is purified by filtration on a bed of silica (eluent: dichloromethane/methanol 3/1). The resulting crystals are recrystallized in ethanol. White crystals, f=180 ^ ϋ, yield; s3%.

Similarly, by reacting 1' iminodiacétonicrile with

cyclopropylcarbonyl chloride, cyclobutylcarbonyl chloride in DS, cyclopentylcarbonyla chloride, chloride cycloheptylcarbonyle and, respectively, cyclooctylcarbonyle chloride, by processing the resulting products by hydroxylamine hydrochloride and subjecting webs dicximes diazotized according to the procedure described above, is obtained (cyclopropylcarbonyl) piperazine -4 dioxo 2.5, the -4 (cyclobutyicarbonyl) dioxo 2.5 piperazine, (cyclopentylcarbonyl) the -4 dicxo-to-216 piperazine, has the -4 (cycloheptylcsrbonyl) dioxo 2.6 piperazine and, respectively, the -4 (cyclooctylcarbonyl.) diaxo-to-2.6 piperazine.

EXAMPLE: 1

a) (Cycchsxvlcarbcny 1 1) -4 Gioxo-to-2.6 phenethyl-1 piperazine

15 Grams is dissolved (0,067 moles), of 4 - (cyclohexylcarbonyl). dioxo 2.6 piperazine in 200 ml of dimethylformamide -. 4 Adds On. gms (0,073 mol). -, of sodium methoxide and left for 1 hour at room temperature.

The reaction medium is added, drop to drop, under atmospnèrs inert, a solution of 19 g-[0,081 moles) of (iodo 2 ethyl) benzene in 50 ml of dimethylformamide and year to 60 °c during 5 hours door -. Evaporated to dry,

•vacuum, and resumes the mth residue of a mixture of water et.de diohlorométhane.. the-'phase organic decanted is sécbee on if Officer Kate dry sodium, the L'■evapo ' intake of the solvent leaves a residue - oil is purified by chromatography. on silica column Céluant; toluene/ethyl acetate 7/3). The resulting crystals crystallize again in cyclohexane. White crystals, F.=OS °C, yield: 85%.

p) {CyclQhexylcarbonyl) -^has hydroxy 2 an OXC-s-piperazin ohénéthyl and 1

15.2 Grams is dissolved (0,046 moles) of (cyclohexylcarbonyl) dioxo 2.6 -4 phênéthyl-a 1. in 500 ml of ethanol piperazine. Under an inert atmosphere, to 0 °c, added 6.7 grams 10.0503 moles) of cupric chloride dihydrate and dropping penoant 1 hour at 0 °c, portionwise, added to the reaction medium, maintained at 0 °c, 5.5 grams (0.23 moles) boro ' sodium hydride and dropping. 45 min th 0 °c. The excess reductant is de truittruit.par adding acetone.

Insoluble salts are filtered and. the filtrate evaporated to dry -. The residue, obtained is treated with a mixture of water and diohlorométhane. The concentrated organic phase, in the dry - dry sodium sulfate and evaporated to dry.

_e residue obtained is purified by filtration on a bed: silica (eluent:

acetate D'ethyl). Beige crystals, f=134^S C., yield: 73%.

the c -); Cyclohexylcarbonyl) hexahydro 1, 3, 4, 6, 7, 11b -2 2h hexahydropyrazino (2.1-) - isequinoléinone and 4 the RPRAZIQANTEL)

Added a little, 12.25 grams (0,037 mol) AEs (cyclohexylcarbc-to-nylî-to-4 nydrcxy and 2 oxo 6 a-phênéthyl-a 1 s-piperazine. 150 ml acid chlorhycric 12 previously cooled to 0 °c n-and dropping during a ' night at room temperature. The reaction medium is poured into iced water ee.et extracted with at dicnlcrométhane. The organic phase dried over sodium sulfate dry, dry and evaporated, leaving an oil which crystallizes slowly at rest. The crystals of praziquantel crystallize again resulting in a mixture of petroleum ether and acetone. White crystals,

F≈ 138 - 1^0 °C, t-yield 35% overall yield of. - praziqantel from iminodiacetonitrile, starting compound of the~ion is prepared, EC is 35%, ■•

EXAMPLE 2 "

0.06 Is dissolved? mole of■(. C. yclopropylcar&onyl) piperazine derivatives in 2 cc 2.6 -4 diûxociméthylacétamide ml. Added 0,g73 mole of méthylste this. the mixture is allowed sodium and 1 hour at room temperature. The reaction medium is added, drop by drop, under an inert atmosphere, a solution of 0,081 mole-FTC syloxy and 2; in 50 ml of ethyllbenzene dimithylacétamide and door to OS⁰ C. for 4 hours. Evaporated to dry under reduced pressure, the residue is taken up by a mixture of water and methylene chloride and is.

the dry. organic phase 'settled' on sodium sulfate. dry. The solvent evaporated and the residue is dissolved consisting of the - (çyclopropyicarbonyl) ^ dioxc above 2.5 phênéthyl-to-1 crude piperazine derivatives, in 600 ml of ethanol. Is apertured has the solution thus obtained, to 0 °c and atmosphere. iperte, 0,059 months manganese chloride and dropping one hour at 0 °c. In portions, is added to the reaction medium, held to 0 °, 0.23 mole sodium borchydrure and thereafter the mixture ' reaction 45 minutes to 0 °c.

The excess reducing agent is destroyed by adding acetone. Insoluble salts are filtered, evaporated to dry - filtrate and treating the residue of a mixture of water and methylene chloride. Drying the organic phase decanted on dry sodium sulfate, evaporated dry sputtering. The residue is purified by filtration through a bed of silica and added a strip product thus obtained, consisting of (cyelopropÿlcarbanyl) -4 hydroxy 2 oxo 6 phenethyl-1 piperazine derivatives, th 150 ml hydrochloric acid previously cooled to 0 °c.

After one night at room temperature, the reaction medium is poured into ice water and extracted with dichloraméthane. The organic phase is dried over anhydrous sodium sulfate, is evaporated. This provides the (cyclopropylcarbonyl) -2. hexahydro 1, 3, 4, 6, 7, 11b 2h hexahydropyrazino (2.1-] isoqui-to-π℮2℮1ποη℮ and 4 j-f * 148 - 149⁰ C., yield: 57%.

The same, so, of the (cyclobutylcarbonyl) piperazin -4 dioxc and 2.6, that the [cyclopentylcarbonyl3-to-4 dioxo 2.6 piperazine derivatives, the (cycloheptylcarbonyl) piperazine and -4 dicxo and 2.6, respectively, of the (cyclooctylcarbonyl} piperazin - 4 dioxo 2.6, is cbtient

the -2•(cyclcbutylcsrbonyl) hexahydro 1, 3, 4, 6, 7, 11b 2h-to-pyrazina (2.1-] isoquinoléisoquinolé.inone and 4; f=153 - 156⁰ C.; 55% yield;

the (cycIopsntylcarbonylj-to-2 hexahydro 1, 3, 4, 6, 7, 11b 2:00 hexahydropyrazino (2.1-) ispquihQléinone and 4 j-f=127 - 128⁰ C. J. yield 60%;

the. (cycloheptyicarbûnyll-to-2 hexahydro 1, 3, 4 ,S, 7, 11b 2h hexahydropyrazino (2.1-) isoquinolinone and 4 ; S8 and 91 °F. - 57% yield j-O

and respectively,

the -2 (cyclcoctylcarbonyl) hexahydro 1, 3, 4, 5, 7, 11b 2h hexahydropyrazino (2.1-) isoquinoléincne and 4; F. ≈ 107 and 108° j-yield 55' c/o.

EXAMPLE ' 3

NC dissolved 7.6 grams (0,050 moles) of acétyl-to-4 dioxo 2.5 piperazin-Cans 200 ml of dimethoxyethane. Added 3.2 gm (0,050 moles) of sodium mêthylate stored characteristics during 1 hour of dropping temperature! ambient.

At nllieûvréaçticnhêl.■ônajDute, /^:gfiutte to drop,, under an inert atmosphere, a solution of 13 grams (0,070 moles) of (bromo 2-ethyl) benzene in 50 ml dimethoxyethane and - j is heated to 85 °c during 5 - hours. It is evaporated to dry, vacuum, and the residue is taken up by a mixture of water and - dichioreméthâtte. The organic phase is dried on elutriated dry sodium sulfate.

The oily residue obtained is purified by ' column chromatography de - silica (eluent: toluene/ethyl acetate 7/33. This provides the acetyl-to-4 oicxc-to-2 ,S phenethyl-1 piperazine derivatives which, after recrystallization in. an ethyl acetate/iscpropanol, melts at 130 °c.

The product obtained is dissolved in 500 ml of ethanol. Added to 0 °c, under inert atmosphere, 7.15 gm (0,055 moles) of COCl to ^ soandonne during 1 hour and at this temperature. Added a little at

- awarded through reaction, th 0 °c, 9.5 grams (0.25 moles) of sodium brorhydrure~and left for 45 minutes at the R th 0 °c. Destroyed by 1 'acetone 1' excess reducing aces, insoluble salts are filtered and evaporation of the filtrate to dry. the residue obtained is treated with a mixture of water and dichloromethane. The organic phase is decanted, dried over sodium sulfate and evaporated dry - dry. The residue obtained is purified by filtration on silica bed Céluant ethyl acetate), added a the product thus " obtained. to. 150 ml of hydrochloric acid 12 previously cooled n-th 0 °c.

and dropping overnight at room temperature. The reaction medium is poured into ice water and extracted with dichlorcméthane. The organic phase is dried on sodium sulfate - the dry, dry and evaporated, obtained ' thereby. I'i' ac.etyi-to-2 hexahydro 1, 3, 4, 6, 7, 11b 2h hexahydropyrazino (2.1 - a) isoqu'isoqu' inoiéincne above 4, which, after recrystallization from, a mixture of petroleum ether and acetone, 140 and 141° to bottom. Overall yield :. A SC %, EXAMPLE 4 -. '

. "

Is dissolved 12 grams (0.05, 5 moles) of benzoÿl-to-4 dioxo 2 ,S piperazine derivatives in 200 a-ml to the dimethylformamide. Added 3.5 grams (0, 0S5 Privacy moles) of sodium methylate and is left for 1 hour at room temperature.

At the reaction medium is added, drop I-drop, under inert atmosphere, .

a solution of 15 grams (0,080 moles) of.. (méthânesulfonyl and 2 ethyl) benzene in 50 ml dimethylformamide and this is brought to 70 °c during 5 hours. Evaporated dry cautious, vacuum, and the residue is taken up by a mixture of water and of dichlorcméthane. The organic phase decanted is dried-on sodium sulfate dry. Evaporation of the sclvant leaves residue oil. that. is.

perse purified silica column chromatography Céluant :■toluene/ethyl acetate 7/3}. This provides benzoyl 4 dioxo 2 ,6phénéthyl-to-1 piperazine, after recristalllsation " in a mixture ethyl acetate/cyolohéxane * D, melts at 102^C. C•

Is dissolved 16.1 grams (gm, 050 moles) of the product obtained in

60Û ml of ethanol. Under inert atmosphere, to 0 °c, added 8.94 grams (0,055 moles) of ferric chloride and dropping. 1 during time, 0 to^I C added by small amounts, to the reaction medium maintained at 0 °c, 9.5 grams (0.25 moles) of sodium borohydride and dropping during 1 hour at 0 °c.

The excess reducing agent is destroyed by addition of acetone. Insoluble salts are filtered and the filtrate is evaporated to dry. The residue obtained is treated with a mixture of water and dichloromethane. The organic phase is decanted dried on a dry sodium sulphate die, and evaporated to dry. The residue is purified by filtration through a bed of silica (eluent: ethyl acetate}. Then added by small amounts 10.78 grams (0.0, 35 moles) of the product thus obtained to 150 ml hydrochloric acid 12 previously cooled to 0 °c n-dropping and overnight at room temperature. The reaction medium is poured into ice water and extracted with dichloromethane. The organic phase is dried on sodium sulfate dry, evaporated to dry. This provides benzoyl 2 hexahydro 1, 3, 4, 6, 7, 11b 2h hexahydropyrazino (2.1-) isoquinoléincne and 4, f * 1s0 -: îb2 °C; overall yield: 5b %.

5 cXEUPLE

Is dissolved under an inert atmosphere 15 grams (0,050 mol] para bromobenzyol-to-4 dioxo 2.6 in 300 ml of dimethyl formamide with piperazine derivatives. Added 3.25 grams (0,060 moles) of sodium methoxide and gives up 1 hr 30 at room temperature. The reaction medium, is added, dropwise, a solution of 21 grams (0,050 mol] of (iodo 2 ethyl) benzene in 50 ml of dimethyl formamide and door to 120° during 8 hours.

Is cooled and then pouring the reaction medium over 3q0q ml of ice water, extracted 3 times with ethyl acetate. The combined organic phases are washed with water to remove the dimethylformamide résiouel, dried on sodium sulfate and evaporated to dry. Le. oily residue obtained is crystallized from isopropyl ether, filtered and dried under vacuum to give the parabromo-benzoyl 4 diaxo-to-2.6 phenethyl-1 piperazine derivatives in the form of gray crystals 110 - 12 degrees Fahrenheit.

14 Grams is dissolved (0,035 mol) under an inert atmosphere of the thus obtained product in 500 ml of ethanol and cooling the assembly to 0°. Then added 8.5 grams (0,038 moles) of cupric chloride dihydrate and is maintained during 1 hour to 0°. Added by small portions 6.6 grams (0,175 mol) of NaBH ^ in maintenan ure'ure' tempér3feurw. 'îoférieute-to-a-5⁰ ' el ILO relinquishes the medium during 45 min. to 0°. Is tiétFuifensuite excess reductant by acetone, insoluble salts are filtered and then the filtrate is evaporated to dry.

The oily residue obtained is treated with a mixture of dichloromethane and water. The phase: organic-is decanted, dried over sodium sulfate and evaporated to dry..

•is purified. residue by filtration through a bed of silica (eluent ethyl acetate) and evaporation of th dry. Para bromine benzoyi and 4 hydroxy 2 oxo 6 phenethyl-1 piperazin isopropylioue ether crystallizes in the form of white crystals. F=136 - 6 DEGREES.

9 Added by small amounts, e grams [0,024 moles) of the product obtained above to 150 ml hydrochloric acid 12 n-cooled 0° and ha discontinues a overnight at room temperature.

The medium is poured into ice water and extracted to methylene chloride ". The organic phase is dried over sodium sulfate and evaporated to dry. The oily residue which crystallized slowly is recrystallized in a mixture hexana-acetone to give 6.6 g of benzoyl 2 parabromohexabytiro. 1, 3, 4, 5, 7, 11b 2H hexahydropyrazino (2, the) isoquinolinone and 4, f=204 - 206 degrees [Kôfler) yield from the parabromobenzoyl-to-4 dioxo 2.6=35% piperazine.