DD145537A5 - METHOD OF PREPARING A 4A, 9B-TRANSHEXAHYDRO-GAMMA-CARBOLIN COMPOUND - Google Patents

Description

Λ2 331 55

A process for preparing a 4a, 9b-trans-hexa ydro- h / '-carb olin-verb indung

Field of application of the invention: »

The invention relates to certain trans-2-substituted- / "- 5-aryl 2 _s 3 * ^z '- _l ^/ ia, 5,9b"he>: ahydro-1Ii ~ pyrido / 4,3 ~ bJ7-indoXdGrivato.

Characte ristics may be techni cal

Following the introduction of reserpine and Chlorpronazin in psychotherapeutic medicine in the early 195o ~ years, great efforts in the search for other tranquilizers or Tranquil were "Lantien with improved biological profiles made several of these are f '' carboline derivatives based on the art as derivatives of pyrido _j / ''! '~ j3 b are __ known indol / ~.

U.S. Patent No. 3,687,961 has disclosed 8-fluoro-2 /> - (4-fluorophenylanilino) -propyl_y-1,2,3,4-tetrahydro- _< | ^/> 'carboline described as a useful tranquilizer for warm-blooded animals. U.S. Patent 3,755,584 describes structurally related compounds with fluorine in the 6- or orders and .a specific p-substituted phenylalkyl moiety in the 2-position as compounds having similar activity.

- 2 ~ 6 * 3 B <8 ^ ^ β g

U.S. Patent No. 3,923,239 discloses hexahydro- / "carbolines of the formula a wherein R is a methyl or ethyl radical and R is a hydrogenatoBi, a methyl or ethyl radical The stereochemical arrangement of the hydrogen atoms attached to the carbon atoms in the 4a and 9b-5iellungen are not mentioned in this document. "However, it can be assumed that they are present in a cis arrangement, and because of the method of formation of Hexahydro-» l ^ -carboliax'inges from a 1 , 2,3,4-tetrahydro-carbarboline precursor compound by catalytic hydrogenation in the presence of platinum, a method well known in the art for introducing hydrogens in a cis configuration into a carbon-carbon double bond Compounds are neuroleptic agents, which are considered useful for the treatment of schizophrenia.

U.S. Patent 3,991,199 discloses hexahydropyrimido-3,3-b-7-indoles, as well as their pharmaceutically acceptable salts, useful as analgesics and sadativa, some of which are of tranqilizers, some of which are muscle relaxants of interest, and many of these compounds indicate hypotensive activity; the compounds described have the formula b _t wherein the hydrogen atoms bonded to the carbon atoms in the 4a and 9b positions are in a translocation relation to each other and where Y is H, X = -H, -Cl, -Br _t -CH -tert _t, -C H or -OCH ^, and when Y is ^a = CF, X is -H and R is hydrogen, 3-chloro-2 ~ ~ bute nyl, 2- Broiaailyl, benzyl _f sra sing methyl-substituted benzyl, methoxy or chloro; Phenethyl, 3-phenylpropyl; 3-phenylpropyl substituted by chlorine, brow or methoxy on the ring; furfuryl; 2 ~ ^r i'henyl; C 1 -C ₁ -alkyl; C 1 -C 6 alkenyl C 1 -C 6 alkynyl; cinnamyl; cinnamyl substituted by chlorine, bromine or methoxy on the pendent; 3-phenyl-2-propynyl; -C-C "-» cycloalkyl; C ^ -co-Cycloalkylinothyl; (Heethylcyl opr opyl) -idyl] (cis-2,3-β-ethylcyclopropyl) -methyl; C, _r -C _o -cycloalkenyl-ethyl; C _r -Cr.

~ 3 - ^ I tt ^ β fry

Cycloalkadienylmethyl; ; Methyl - (2,3 ~ Mniethylcycloprop-2 ~ en-1 ~ yl) exo - - Norcarylmethyl?; (? I cis-6-Dimethylendo-3-norcaren, - - yl) ~ methyl; (4-Methylbicyclο / _2.2,2> _ ^ oct-1-yl) methyl; (4-IIethylbicyclo _J / 2,2,2_ / oct-2-en-1-yl) -t-methyl; (Bicyclo / 2 ".2.2" 7hept-2-yl) "methyl; (bicyclo [2] 2,2_7hept-2-quin-5-yl) -diethyl; 1-adamantyl-ethyl or 2-adamantylmetfail;

Belgian Patent 845,368 (Derwent Kr. 00043Y), recently published, discloses 5-penyl-hexahydro-1-carbolines, many of which are optionally in the 2- and 4-positions by methyl or ethyl and in the 3-position by alkyl with 1 to 3 carbon atoms, allyl or propargyl substituted. These compounds are useful as antidepressant drugs.

In more recently published DE-Offenlegungsschrift 2,631,836 (Derwent Hr. O9738Y) structurally related octahydropyrido / 4 ¹ , 3 ¹ : 2.3 _m / -indolo ^ 1,7-ab _ / i_7 ~ benzazepine described can be derived from the formula given above, in which Y is an ethylene bridge between the two benzene rings, X ^{a is} a hydrogen atom and R ^{a is} a radical -CiH ₀ CK ₀ COCH ₀ or -CH ₀ CH ₀ COC-H, -

2 2 3 2 Δ ft ο

* These compounds are also said to be useful as analgesics and tranquilizers «

In U.S. Patent 4,001,263 are 5-aryl-1,2,3,4-tGtrahydro- f ~ described carbolintranquilizer of formula c, wherein. X and Z may be hydrogenato or fluorato, and the meanings of R may be the same as before for H «

Surprisingly that certain novel trans-2, 3 _f 'T, 4a, 5,9b-hexahydro-1l-pyrido / 4,3 ™ was nungefunden, b _ / - indole pronounced superior in Tranquilizeraktivität) compared to the corresponding 1,2 ,. Possess 3,4-tetrahydro - / "carbolines"

The invention is intended to provide a method for the preparation of intermediates that can be used for the production of four-part tranquilizers. These compounds which are valuable as tranquilizers are the enantiomers and racemic compounds of formula II, as well as the pharmaceutically acceptable salts thereof, wherein the hydrogen atoms bonded to the carbon atoms in the 4-a and 9b positions are in a trans-arrangement with each other, and wherein X and Y, which may be the same or different, represent a hydrogen atom or a fluorine atom, η = 3 or 4,

0 OH

M is one of the radicals -C- or -CH-, and Z represents a hydrogen atom, fluoratoGi or a methoxy radical

The manufacture and use of these tranquilizers are described in the same priority DD patent specification ΛΡ C07 D / 205 4? 9 and a further DD patent application which, like the present application from application A? CO? D / 205 ^ζ > ·? 9 resigned vmrde, described »

Reaction Scheme 1 illustrates the procedures used to synthesize 4a, 9b-trans-2-methyl-2,3,4- _t, a, 5,9b-hexahydro-1H-pyrido-4,3-b-indoles can be.

The second step of this reaction Schetaas represents the method according to the present invention. X and Y are the same or different and denote hydrogen or fluorine *

Sine's preferred meaning for R ₀ is benzyl for economic reasons, but Rp can also have other meanings, with dioss ebon-

_5- £ <£ 2 ^ ty? fa ^

if the above scheme can be used, as known to those skilled in the art, examples of such alternative meanings for R ₀ are benzyl radicals substituted on the benzene ring, z "B" as substituents of one or more in the form of methyl, methoxy, and Hitro ~ or phenyl radical, and the benzhydryl radical,

Reduction of the tetrahydro - ('' - carbolines of formula VIII to form the 4-a, SJb-trans-hexahydro-compound of formula IX is carried out in an ethereal solvent, usually tetrahydrofuran Borane / tetrahydrofuran complex (BH-THF) is commonly employed, and a 100 to 200 Fe molar excess of this complex is preferred. Although the reaction can be carried out at a temperature in the range of about -10 C to 80 C, For example, a solution of the starting material of formula VIII in tetrahydrofuran is added to an iced solution of BII.THF.After completion of the addition, the reaction mixture is heated to reflux and at this temperature for a period of about 1 to 2 hours or more The reaction is usually carried out in the presence of an inert gas such as nitrogen f performed. man, the reaction is virtually finished, the solvent is evaporated, the residue is un acidified with an excess of acid such as hydrochloric acid 2m to 12in. Sin preferred Ansäurungsraittel is a mixture of equal volumes of acetic acid and ^ m hydrochloric acid. The acidified mixture is usually heated to reflux for 1 to 2 hours or more. The desired product can then be isolated, for example, by evaporation of any residual ether solvent and portion of the acid mixture, and the precipitated product collected and washed by filtration become. In an alternative method of isolation of the product IX, the reaction mixture is filtered after refluxing with dom, the filtrate is cooled and added by adding.

Sodium hydroxide, potassium hydroxide or sodium carbonate made alkaline. The basic mixture is extracted with a water-immiscible organic solvent such as chloroform, methylene chloride or benzene, the extracts are evaporated and the residue is purified by column chromatography on silica gel, elution, sec _e . purified by ethyl acetate or mixtures of hexane / ethyl acetate j «

The reduction of the tetrahydro- ['' - carbolines by BH "oTHF followed by the acid treatment gives hexahydro- f- carbolines, in which the hydrogen atoms bound to the carbon atoms in the 4a and 9b positions are in the trans-type order, See, for example, U.S. Patent 3,991,199 *

The 2-benzyl compounds of the formula IX are then converted into the corresponding 2-y-compounds according to the process according to the invention. In general, this can be achieved by treating the compound of formula IX with a molar excess of a loweralkyl chloride orally star such as the methyl, ethyl, propyl or isobutyl ester in the presence of a suitable, reaction-inert, followed by alkaline hydrolysis. As the preferred chloroformate ester, the ethyl chloroformate is preferred because of its ready availability and efficacy. A suitable reaction-inert organic solvent means a solvent which substantially dissolves the reactants under reaction conditions without the formation of by-products. Examples of such solvents are aromatic hydrocarbons such as benzene, toluene and xylene, chlorinated hydrocarbons chloroform, and Dichloroethane, diethylanglycol diethyl ether and diciethyl sulfoxide ,. Especially before the solvent is toluene,

there

To the mixture of the starting material of the formula IX in this reaction-inert, organic solvent is added up to about 10 times the molar excess of Chloroforraiatesters, for economic reasons, a molar excess of about 3-fold to 5-fold is preferred- "The resulting Geraisch is then heated to a temperature of about SO C to 15Q C, typischsrweise to JRüclcflußteraperatur of the mixture, namely for periods of about 6 to '2h stood "odor long * usually, the'Rü'ck'flüßkochen from © round of The reaction mixture is then evaporated in vacuo and the residue is taken up in a mixture of alcohol-water, it becomes one-alka compound, eg sodium hydroxide or potassium hydroxide, in about 10-fold to 30-fold molar excess , based on the amount of starting material of the formula IX added, and the resulting mixture is usually over Fach The solvent is then evaporated off and the residue is partitioned between water and a water-immiscible organic solvent such as, for example, chloroform, ethylenediamine or ethyl ether, and the organic phase is evaporated to dryness. The residual product of formula X can be used further in the present state, or it can be further purified by a method known per se in the art such as, for example, column chromatography on kiosel gel.

In the following, the preparation of starting materials will be described; '2 ~ Bert2yl "5-phenyl-1 _v 2, 3 _f ^ -tetrahydro-J''~ carboline, after the Fischer see' indole synthesis using N, N-diphenylhydrazine. And N-Bensyl-A-piperidone obtained" The mono- or di-fluoro-substituted starting tetrahydrocarboxylines of the formula VIII in which at least one of the radicals X or Y is fluorine and R "is the benzyl radical are prepared from the corresponding compounds of the formula VIII in which Rp is a Hydrogen atom is, by reaction with a Bonzyllialogenid like

ο 9 1 ^

- O - 4 * β «a?

Benzylbroraid iö. made in equolar quantities. The compounds of the formula VIII ₉ R ₂ HH required for this purpose are prepared as described in US Pat. No. 4,001,263. The starting tetrahydro- / '' • carboline V are described in the same document

The other starting materials are either commercially available products, their production is described in detail in dear · chemical literature or they can be prepared in a conventional manner to the expert "For example, phenylhydrazine commercially available or they are #urch reduction of Phenyldiazoniurasalzes as specified won Viagner and Zook in "Synthetic Organic Chemistry", John Wiley & Sons, Hew York, NY _e, 1956, Chapter 26, made "the 1-substituted-4-piperidones are commercially available reagents or they are using the method of McSlvain and Rorig, J "Atn. ChenvSoQ ", 70 (1948), S 18 £ 6 _} . The requisite 3-benzoylpropionic acids and 4-butenoylbutyric acids are commercially available or, in accordance with a modification of the method of operation, are described as follows: "Organic Synthesis''' _F Coll _e Vol. 2 _f John VJiley 8c Sons, Nev, York, N * Y _#i 1943, S, BA is working »

Wio previously ECN haschriefcenj -. _'} Of the invention n.en basic compounds acid addition salts "The basic compounds who · ™ the converted to their Säuraadditioussalza by contacting dor base with an acid either in an aqueous or · a non-aqueous medium ,, In Similarly 'i / eisa results in the treatment of Säureadditi ~ ons sal ze with an equivalent amount of an aqueous base solution, for "B" Alkalimetallhydroxidön _s Al'kalitaetallcarbonaten and Al kai ims tal! bicarbonates or with an equivalent amount of a Matallkations which an insoluble Forming the precipitate with the acid anion, the recovery of the free base. The backbiidoton bases can be converted to these same or different acid addition salts.

Embodiments;

The invention will be explained in more detail with reference to the following examples.

example 1

dl-tr to 2-benzyl-2,3,4,4a, 5b-hexahydro-5-phenyl-1H-pyrido-

To e * iner stirred at ⁰ ° C. solution of O, 14O INOL borane fe in 150 ml »trahydrofuran in a vessel equipped with magnetic stirrer, thermometer, condenser and addition funnel, and maintained under a nitrogen atmosphere for three-necked flask, a solution of 23 _S 9 g = 0.071 Raol 2-Benzyl-5-phenyl-1,2,3,4-tetrahydropyrido _J / 4,3-b_7-indole in 460 ml of dry tetrahydrofuran. The addition was carried out at such a rate that the reaction temperature remained below 9 ° C. After completion of the addition, the resulting mixture was refluxed to reflux temperature and held at that temperature for 1 hour. The solvent was then evaporated in vacuo to give a white The solid obtained was suspended in 40 ml of dry tetrahydrofuran and initially heated slowly with 18 ml of a 1: 1 volume of acetic acid and 5N hydrochloric acid. The resulting suspension was refluxed for 1 hour and then cooled. Evaporation of the tetrahydrofuran and a part of the acetic acid gave the precipitate of a white solid, which was separated by filtration and washed with water. The solid was resuspended in tetrahydrofuran, filtered with ethyl ether and dried in air, yielding 6.7 g (63 %) of the desired trans isomer was obtained n; F. 256-260 ⁰ C.

Bas evaporation of the mother liquor yielded an additional 7 _t 2 g of the product, which was axled by a small amount of the cis isomorenes. "

"~ο ~ g ι 3 υ ι y

In the repetition of the zmvor procedure described but using the appropriately substituted 2 - benzyl-5-phenyl-1 _f 2.3 »4 ~ tetrahydropyrido / 4 _{J-3 b>} _ / -> indole as starting material, the following 4a, 9b-trans compounds similarly obtained in the form of their hydrochloride salts, formula d;

X Y X ¥ "

H js-fluorine H-fluoride

FH P ja-f luor

F jv-fluorine F jD-fluorine

dl ~ trans ~ 8 ~ fluoro-5- (p -fluorophenyl) -2 _s 3 _s 4, ^ a, 5 _> 9b-hexahydro-iH "

indole

Ä) To a solution of 5 _s og = 12 _s k mmol dl ~ trans-8- ~ fluoro-5- (p-iluorpheny 1) -2 «V ~ ~ hydr oxy-Λ ~ (ρ-fluoro phenyl) ~ butyl _i j7 ~ 2,3 »4,4a, 5, Sb-hexahydroiH-pyrido ^, 3-bJ7-indole in 40 ml of toluene were added 5 _S 3 mis 5?> 7 to oil of ethyl chloroformate." The resulting mixture was maleated cooked 'reflux overnight and then eiugedarapft to dryness, v; obei as a residue a rubber-ar ti ge s product obtained viurdöe 2u diesera gumraiartigen product were added 200 ml of a 9: 1 by volume mixture of ethanol / l / added ater "Machdera SiCH it guiatniartige product had dissolved, 15 g of potassium hydroxide were added, and the mixture thus obtained was heated under reflux overnight cooked the solvent was evaporated in vacuo, the residue vmd was distributed between water and chloroform and the organic extracts were Rait water gewä "rule _f dried over sodium sulfate and evaporated to dryness. The residual oil was dissolved in ethyl acetate At first, ethyl acetate was removed to remove by-products and then the desired product was slurried with a 1: 1 by volume mixture of ethyl acetate / ethanol.

The fractions containing the title compound were combined and evaporated to dryness to give 1.6 g (43 %) of a yellow gum-like product which crystallized on standing; F.115-117 C.

B) Alternatively, dl

4,4a 5j9 _i ^ ~ hexahydro-1H ~ pyrido _J / l 4,3-> __ _- / -indolhydrochlorid cooked in the presence of 'excess · ethyl chiorf ormiat or the corresponding methyl, isopropyl or n-Butylchlorformiatester under reflux, and then hydrolyzed according to the procedure described above

and worked up to get the connection mentioned in the headline «

Example ^

Using the appropriate starting materials in each case and using the procedures of Examples 2A and 233, the following products were obtained in a similar manner:

indole,

dl-trans

indole,

dl-trans

-indol _$

dl-trans

^ 3 "-bJ7

dl-trans-5- (ci ~ fluorophenyl) -S-fluoro-2, 3 »^ · t ^" ^a t5 »9b-hexahydro ~ 1 H" -pyrido

4 _f 3-bJ / indoles

 Λ \ -

Reaction Scheme 1

NR ₇ O) BH / Ether (2) H '

NO,

(ΤΣ)

(IX) O) Cl

(2) KOH ₁ CJ-i-OH /,% 1 * .2 3 2

N-H

NO

NR ¹

Z ^b

96th

4 σ

.- "Ν

V (CHJ _n - M

- ^Λ -5- "dl Ά; J ύ V

N-CH ₀ C _n Η _Γ 4α I 2 6 5

Claims (5)

Ö & 7 S <f 1 «Process for producing a 4a, 9b ° trans-hexahydrocarboline Compound of the all formula X wherein X and Y are the same or different and are hydrogen or fluorine, g © denotes that a 4a, 2b-trans-hexahydrocarbol ~ of the general formula IX, wherein X and Y are as are defined above,! L benzyl ,. benzhydryl, OH or by methyl, methoxy, nitro or phenyl substituted benzyl, Z is hydrogen, fluorine or methoxy and η 3 or h is »with a molar excess of a lower chlorofluorocarbonic acid ester in the presence of a / td / l $ r th organic; Solvent and then subjected to alkaline hydrolysis, 2 «Method according to item 1, characterized in that the Chlororkohlensäuroester is Chlororkohlensäureäthylester. 3 "procedure according to item 1 or 2 _S marked d a & c h "that the solvent is toluene and the reaction is carried out at the reflux temperature of the mixture» 4- »method according Pun Li 1 to 3" characterized in that _s is Bensyl Ep * 5 »Procedure according to points 1 to 4 dadu ν _s ch that the alkaline hydrolysis is carried out with sodium hydroxide or potassium hydroxide at HückfIrißtemperatur "