DE1917127A1 - Process for the production of indolyl aldehydes - Google Patents

Description

Process for the production of indoly-aldehydes

The invention relates to a new "process for the production of indolyl aldehydes and in particular a process for the production of Qt- (3-indolyl) aldehydes which have an aroyl or heteroaroyl radical at the V ₁ " position of the indole ring.

The aldehyde produced by the process according to the invention is represented structurally in the following way:

CH ₂ CHO

wherein R _{1 is} substituted or unsubstituted aroyl or substituted or unsubstituted heteroaroyl, R _{2 is} hydrogen or molecular alkyl, such as methyl, ethyl, propyl, butyl

909843/1754

BATH ORIGINAL

12 135 y.

or the like, and R- is alkoxy, alkyl, amino, monoalkylamino or dialkylamino.

Examples of the R * groups that may be present on the indolyl component are aroyl radicals such as benzoyl and naphthor yl, which are preferably substituted by at least one functional substituent «Among the preferred substituents» Tuents are halogen, alkyl, alkoxy, haloalkyl and the like. Most preferred is halogen-substituted aroyl and especially p-chlorobenzoyl and p-bromobenzoyl. The heteroaroyl groups can be 5- or 6-membered heterocycles which, as stated above, substituted or unsubstituted "Typical of such groups are those in which the hetero-Be" constituent is pyridyl, furyl, pyrryl, thiazoyl, pyrimidinyl and the like. These groups can be represented by factional groups, such as halogen, alkyl, haloalkyl, such as fluoromethyl, alkoxy and the like. However, silver-substituted hetero-beatand parts are preferred.

The compounds prepared in accordance with the invention are preferably those wherein R _{1 is} p-halobenzoyl, most preferably p-chlorobenzoyl, or 3- or 4-pyridinoyl; R ₁ is low molecular weight alkyl, most preferably methyl and R- is low molecular weight alkoxy or dialkylamino, most preferably methoxy or dimethylamines). In general, the compounds fertilize can be referred to as 1,2,5-trisubstituted indole-3-acetaldehydes, for which the following examples are:

1- (p-chlorobenzoyl) -2-methyl-5-methoxy-ii} dol ~ 3 ~ acetaldehyde, 1- (p-bromobenzoyl5-2-methyl-5-methoxy-indole ~ 3-acetaldehyde, 1- (3- "pyridinoyl) -2-methyl ^ 5-methoxy-indole-3-acetaldehyde, 1 ~ (4-pyridinoyl) "2 ~ methyl« 5 ^ aiethoxy- = indole-3-acetaldehyde,

^ 2 -909843/1754

1- (4-TbiaBoloyl) -2 ~ ethyl-5-amino-indole-3-acetaldehyde,

1 - (p-Ohl orbenBoyl) -2-ethyl-5-methyleaino-iiidol ~ 5> aoetald * hyiJ, 1- (3-Pyri4inoyl) -2- «ethyl-5-dimethylaiiina-indole-3-ac * taldehyde,

and i. (3-Pyridlnoyl) -2- »ethyl-5-ethboxy-tndol ->« ö «taldebyd

BeYoreugt among the aforementioned

1- (p-ChlorbenB03Tl) -2-ethyl ~ 5-ethoxy-yne <Jol-3-acetaldehyde, i-ip-Chlorbenioyl ^^ - methyl-S-dlmethylamino-indole ^ -aeetaldehyd,

? - (3-Pyridinoyl) -2- * ethyl-5 ^ inetbylajnino-IndOl-3-aoetaldehyde.

The process according to the invention includes the general addition implementation of indole compounds, such as the following formula

II

beeltsen, where R ₂ and R correspond to the definition given earlier, R ^ Vaeaeratoff or R ₁ let and Rc is hydroxy or Waeeervtoff. If R _{5 is} hydroxy, the compounds II can exist in the same way in the keto form, but for the sake of clarity they have been identified above in the enol form. If Re is hydrogen, let R ^ be hydrogen and if Rc is hydroxy (or keto), R _{4 is} preventive R ₁ .

Examples of compounds II, which of the invention Procedures accessible are the following:

- 3 -909843/1754

12 135 If

2-methy1-5-methoxy-yne oil _f
2 ~ Metbyl-5-dimethylamine-inäöl,

2 «xtäyl-5-ethoxy-indöl,
2-methyl ~ 5-ethboxy-indole,

1- (p-Brombenaoyl) -2-methyl-3-hydroxy-5-ae thoxy-indole, 1- (p ~ chlorobenzoyl) -

(3- °? Yridinoy 1) -2'Hötethyl-3'hydroxy-5 ^ methoxy- »indöl,

indole,

and the like.

In one embodiment of the invention, the Yei bonds II, in which It. and Re are hydrogen, are converted to the compounds Ϊ by way of the introduction of the aldehyde group in the 3 position of the compounds XI, whereupon the conversion of this group to an e ^ / ^ - spoxy acid benzitrate, acylation in the H ^ position and the formation of the Alöehyö group follows. The following Plieaoohema Aj, where R _{6 is} alkyl or aralfeyl, represents the following:

909843/1754

135

TL- ¹¹

.CHO

ΪΪΧ

.CH-CHC 00R <

CHCOOR

ν \ ^R 1

(») R ^ alkyl compounds I

(6)

R ₆ «aralkyl

.CH-GHOOOH

YIC

R-

909843/1754

12 135

fr

In step A ₁ above, the zndole is converted to a 3-aldehyde by direct introduction of an aldehyde group. This can be achieved by reacting the compounds II with carbon monoxide in the presence of an acid, aluminum chloride or aluminum chloride and copper (II) chloride. It is preferred that the copper (II) sulphide is used in catalytic amounts, while the aluminum chloride is preferably used in equivalent proportions with the indole. _{HCl 1} BF, RF and the like can be used as acids, but HCl is preferred. The implementation will. supported by heat, whereby it is preferred to work at moderately increased temperatures in the range of 25 to 60 ° C. The reaction can be carried out under anhydrous conditions and generally in the presence of an anhydrous solvent. Aromatic solvents such as benzene, toluene, Xylene and the like are suitable. As a result of the reaction, the aldehydes, compounds III, are obtained in solution and they can be separated off therefrom by methods known to those skilled in the art. It is preferred to convert the aldehyde to a sulphite via reaction with, for example, itodium sulphite -To convert adduct, in this way to precipitate the adduct, whereupon the aldehyde is restored therefrom by treating the adduct with sodium carbonate, preferably in aqueous solution.

The compounds III are prepared in a different way by reacting the compounds II with an amide of formic acid, preferably dimethylformamide, in the presence of a phosphorous oxyhalide, preferably the oxychloride. It will preferably stoichlometric amounts of the reagents are used, which lead to an economic utilization of the starting materials. The effect of the implementation is the introduction of the aldehyde group at the 3-position of the indole and the

909843/1764

BAP ORIGINAL

12 135 -a.

Recovery of the starting asain form which Euvor had used in the form of formic acid # amlds. The reaction is preferably carried out at moderately elevated temperatures, 25 to 60 ° C. generally being suitable. Preferred operating temperatures are in the range of 30 to 40 ° C. When either of the reactants is liquid, such as β.B. the preferred dimethylformamide, it is convenient to carry out the reaction without the use of an additional solvent medium; however, solvents can be employed if desired. The course of the Urneetsung can be followed by collecting the hydrogen chloride gas which is evolved as a result of the decomposition of the phosphorous oxyhalide. The resulting aldehyde is obtained in solution and can be separated therefrom by methods known to the person skilled in the art. The aldehyde _r is preferably converted into the biaulphite adduct as previously described.

In stage A ₂ , the aldehyde group is converted to a protected constituent with formation of the compounds IV, which is then followed in stage A- by an acylation. In this regard, a direct acylation of the compounds III can be carried out, but it is preferred in this embodiment of the invention to protect the aldehyde group prior to the acylation. The protection of the group is achieved by converting it into a QC ^ -Epoxy-propionstture or a derivative thereof, which further serves to introduce the additional carbon atom which is necessary for the appropriate subsequent conversion to indolyl-acetaldehyde, with a reaction is used, which is a Gi-monohalogenous acid or an ester thereof with the general formula

XCH ₂ CDOR ₆ in combination with an Aleali alkoxide, of which.

- 7 «AD OR {Qi _NAL

80 & 843/1784

12 135 g.

each is preferably used in stoichiometric amounts with the aldehyde; Here, X is halogen "such as chlorine or bromine and R ₆ iet hydrogen, alkyl, such as methyl, ethyl, isopropyl Pronrl _t, B * utyl, t-butyl and the like or ArftUqrl '· such as benzyl, substituted Bensyl and the like. Bie useful alkali alkoxides are the Uatrium- or potassium t ~ oxide, -propexide, tert ~ _f - »butoxide or the like * Bie Laset" Aung is preferably carried out at temperatures below EauateapaB door ^, most suitably in the range of -80 bie 0 ^Q © in a suitable solvent, in this context dermolecular alkenols and glycols, such as methanol, tert-butanol, ethylene glycol and the like, particularly suitable.

While the initial mixing of the reaction ingredients is preferably done below room temperature, aging at moderately elevated temperatures in the range of 40 to 75 ° 0 helps bring the reaction to completion and is preferred to work in this way. As a result, OCE reaction, the epoxy compounds are obtained (compounds IV) in solution and can extract it therefrom and separated by well known methods. Solvent extraction using ethers, halogenated hydrocarbons and the like is preferred.

Typical compounds IV and all the results obtained from stage A _2:

jl- {2-Metbyl-5 ~ methoxy-indolyl) - Qf-y ^ -epoxy-piOpionic acid,

tert-butyl-jÖ - (2-methyl-5 ~ dimethylamino-indolyl) - Ot-4-epoxypropionate, /

Me thy1-yÄ - (2 ~ methyl-5-methoxy-indolyl} -o (~ ß -epoxy-propionate,

Methyi ~ / 3- (2-meteyl ~ 5-methylamino-indolyl) ~ o (- / ^ ~ epoxyproiJionat, /

- 8 -30984 3/1764

BATHROOM OBlGlMAL

y3- (2-ffletbyl "5Hftethoxy-yneolyl) - <^ * / 5-epo3ey" propi

eyl β - (2 ~ methyl-S-dlmethylaminG-indolyl} - ok ~ / # - »epoxy proplon & t. ■ '·»' .-

and the same. . ...

The corresponding A-Monoohlor- or Moiiöbrott-acetic acid derivatives are used to make the above compounds IV used.

The compounds XV are converted in stage A- into their Rj-aeyl-Jöerivate; by treating with an acid halide containing the desired Ej acyl group. Isa is the most preferred way to convert the connections into an alkali rail! converted, such as by treatment with an alkali .halide, such as sodium or potassium halide. ttes metal salt * is then "halide treated" _{with a suitable acid containing the best R 1} . Furthermore, the heating is preferably carried out under anhydrous conditions using a suitable inert solvent such as dimethylformamide and hexamethylphosphoramide and the like.

la ata taeieteti is careful not to use the acid chlorides of the H ₁ "containing compound" in question, but the bromids are just as suitable. Typical acid chlorides are p-chlorobenzoyl chloride, 3-? Yridinoyl chloride, 4-3 ^ riäinoyl chloride _t Haphthoyl-'Chlori'd, ^ ίά8θ1-4 "· οβ ^ © η9 & υΓβ-οΜθΓΐά and the like · The use of such Compounds lead to the corresponding hydrogenated indolyl-epoxy compounds, compounds V, as identified above.

909843/1754

To level A *. belongs to the Utawa & älung 3er Bp «y» * er | iiaiuBgf5! 8 V au connections I by means of flyärolyee · Bi © the actual type of hydrolysis depends about® on the bustard ₉ w © Xelt.e äw? A Eg dar- ».

■ is set, where basic "hydrolysis feevereagt ■ Rg is hydrogen, and saicre hydrolysis is" bewMtig "R ^ alkyl or arallryl are sulfonic acids'"si egeeieli arciiatiaete © H> wi £ t acids Ie matching Weis® ice; Bydrolysis sedltiQ. veywe "aÄetv Sp are ssiell such acid in ^ wi®% aulfonsäure, A Xyiolsulfonsäure '' p-Ohlor = -« nd eulfdnaäure and the like in fa @ senicl © r @ Weie Bg Aralieyl iet that Hyis * olyae aur Bildtan lead gen VI via hydrolysis in the ester group instead of cleavage at the ^ - «carbonateQH of the Sndoly.l- ^ propioaat ^ o Β«

te train hydroXysierende acids sini in this Hiasüetit Si @ 'genwasseretoffsäuren as ChlortiagserstoffsäiLgi? e _f 3? @ @@ ιιμβ3 Γ' st of f acid, acetic acid "(kalsäur® miii case, the temperature of the Ejrdreiyse miss ig temperatures in the range of 35 Me 11Q ⁰ O suitable ^ are temperatures ₄ is Bersiek ¹ WOU 30 to 30 °

skillful * In addition, a sttaungavlttel fUv äas oedium can be used »such as eroffiBtiaehs and aliphatisch® lenwaeseratoffe, for which benzene» folvol, xylene, 'Hept © »," Hesaa and the like are examples.

If R ₆ . Is hydrogen or aralfcyl and the stage is carried out so that the compounds TI are obtained, their conversion to the compounds 1 is effected in the stage A ^ yoräSuga by means of basic hydrolysis "with the formation of an alkaline medium such as aqueous sodium aryl monkeyonate, potassium carbonate, sodium hydroxide, sodium ethoxide

- 10 ~.

809843 / 17S4

BATH

12 135 11

The like »Again, elevated temperatures are suitable and desirable, even if temperatures at or near room temperature are used. All the result of the hydrolysis, which is described for the stages A ₄ , Ας and A ₆ , receives the compounds I in solution and can use them from it »as described above, separate.

In another way, if R _{6 is} aralkyl, the conversion of the compounds VI by catalytic hydrogenation can be achieved, which leads to a reduction of the ester to acid. Suitable hydrogenation catalysts can be used as catalysts, which are usually used and, in particular, palladium, preferably on activated charcoal and Baneytfiekel. The hydrogenation is vorsugeweiee carried out in the presence of a solvent "such as a low molecular weight alkanol, such as methanol ₉ doors Xsopropanol and the like or other suitable Hydrierunge-Iiöeungetaittel" at temperature "which is generally range from below room temperature to au elevated temperatures" as well as bridges in the range of 1.05 to 5 "25 kg / cm" νoraugewoise 2.1 to 4.2 kg / cm. The compounds VX are obtained in solution and can be separated off therefrom by known processes, 2.B. can ma.n the mixture in a suitable. Dissolve solvents such as ethyl acetate, then absorb on silica gel * followed by elution and concentration of the eluate.

According to a further embodiment of the invention, the compounds XX, in which R _{5 is} hydroxy (or the keto form), are converted to the compounds X via the formation of the 3-ethynyl derivatives or the alkoxylated forms thereof, whereupon the direct conversion of aldehyde follows. The following flow chart B represents this conversion -

909843/1754

sad

12 155

B) R

OSOH

VIII

Therein &} mean alkyl, such as methyl, ethyl, propyl, butyl and the like. In the claims, R _? used to represent hydrogen and QE '.
7th

In Step B _1, the compounds II are "vat, compounds VII, is converted by way of reaction with an acetylene-Halogeronagnesium" dae in 3-ethynyl ~ Beri compound in a direct SubstitutionöreaktioYi. The reaction is carried out, for example, using Acetyien-magnesiumbrcmid and Yer-

- 12 -

909643/1754

12 135 13

Windings XI executed in a LüsungssiitteleyEtem, where R ^ 6IGiChR ₁ is presumably. Torsugsweiae are increased

used, where m®n suitable results at 35 ⁰ C foie 110 ° C @rziolt, work feei © der Bah © «! er lückfiusstem-

p®ratiar de® Systems is special® b © v © r »ägt« Among the usable iäeumgeaiittelö b @ £ ted © as sieve ether uni aromatic · 'cotelea hydrocarbons, such as pearethyl ether, bio-ethyl ether, bis-oxane, solid-hydrofuran, benzene-soluene land like. Ethers are WM most preferred. Until Änagangsffist @ riali®n, in atöohioisetrise & en Menfeen an® reasons of profitability vewsacäöt "Bais Ethisyl-Ssrivat - is received in IÖ - and is hardly cleaned after leaving the factory.

With regard to the acetylene magneaim-iferfelndiing it is the most it is preferable to use freshly produced materials »This can be achieved in a square way» by using example white ! .thyl-magneaiuebrotaid spit acetylene in a dry solution means eystea implements. Elevated temperatures lead to good ones Reaction results, where dl @ reflux temperature beeondera suitable 1st. Me reaction is usually within 1 to 3 hours complete and the acetylene magnreium bromide obtained can be used directly for the implementation of the compounds II be used*

Typical compounds obtained YII and;

1- (p-Obl orbeneoyl) «2 ~ ia © thyl ~ 3 ° & thiiiyl-5 - ethoxyind oil, 1 - (p ~ chlorobenz oyl 5 <> 2 ~ me thy l ~ 3-ätfeinyl-5 »d imethylaminoind oil,

1- (3-pyridinoyl) -2-1- {4-j-pyridinoyl) -2
and the same.

_ 13 -909843/1754

In the Anaohlusa to the Umwanfllmig sum Äthinyl- = S © i? 4vat, connections VII in stage B _g in the Vertoinflwagen I via a swioohenlieeende hydrotoorierangs ^ Stufβ, Ckitetios ä © s Hydrobariis to the llöefejri follows * Di © rung wiriüngnäckDSesigeicwelse under Veffwsnäg fett i | ®yaa äer ifesetsuisg with the ItMinyl ^ ertiaclii ^ geii from

Baa SiLboran is used in twectelssiger l © ia © "on i © ii ¥ eg © Implementation of an alkali 'isbsorbent' like Hatriua-s

liorhySrid isa a suitable solution sitt © öas "the entire Healctionseediusi-vrirS directly la salt the üthinsrl ^ connections used» read © raielt · good · results, if _ $ i © Hsrdroborierungs ^ Bs ^ ktiGn in Biglya © as SHsiaiag- raittelmeäium ^ iri "Si © reaction" is temperature vorauge ^ EIEE below RausiteiQperatur, v / obei ^ 0 10® are suitable to 1NC ° 0.. & structures Bie wesentlietie Tollstämöigkeit € © r ¥ issetsnag wirö at the low Xemper reached UNAE üanB.üb ersielt you An inevitable leaction, inü @ m © aa the reaction level, see building temperature © TOfese ?! causes «atf to age for a period of 1 to 3 hours * As a result of the reaction ias an intermediate * - product formed borohydride with the fern ©! YII _B

YII _a

R ₄

Bie stage Bg is completed, inolsm 'man the connections subjected to treatment with an oxidation system, as s Hydrogen peroxide in a basic hedium «Si® oxidation

■ - 14.,
90984371754

BATH ORIGINAL

12 135 AB

is preferably below room temperature, usually from -10 ° O to 10 °. C, keeping the pH on the basic side. Any suitable baee can be used for this purpose, but the alkali hydroxides and. especially barium hydroxide. The product, compounds X are obtained in the solution and are able to _t as described ttuvor be separated.

In another way, instead of the procedure via the unsubstituted ithinyi compounds via stage B _1, the compounds Irin stage B. can be converted into the corresponding alkoxylated thynyl derivatives, whereupon the reduction by vinyl ether in stage B. and the subsequent conversion the vinyl compound IX follows via step B ^.

The alkoxylated compounds VIXZ are formed in step B using the conditions which are explained _{in connection with step B 1.} Instead of using a simple magnesium acetylene halide, however, a magnesium alkoxyethylene halide is used in stage B *. Typical alkoxy groups are methoxy, ethoxy, propoxy, and the like. The chloride or bromide thereof can be used, but it is preferred that the Broaid bu be used. The most preferred compound is ethoxy, acetylene, iaagnesiUabromidr

In stage B ₄ , the compounds VIII are reduced by means of catalytic hydrogenation, using a Pallaaiutt-on activated carbon catalyst which has previously been poisoned with chloroline. The reaction is vorsugsweiee iie is a matching flydrierungs Lösungami-fctel, \ Alkanoleti the "methanol Fropa" nolt isopropanol and ciergieicüan bie at a Wasaerstoffdruclr of generally 1:05 5 _r 25 kg / cm and 2.6 to voreugoweise

909843/1754

3 * 15 kg / cm executed. You can implement it, if you wish be carried out at elevated temperatures. preferred to work at room temperature au. You're hyArlerung is stopped, robaid a fiquinolar amount of hydrogen aw £ ~ · has been taken to prevent the formation of undesirable product © eu avoid· . . . '

Typical obtained as a result of stage B «

1 "'(4-Eyrid inoy 1) ~ 2HBne thy 1
1 *> p-Chlörhenzoyl-2 ~ ethyl
and the same.

In stage B ^. the Ethoxy and Propoa ^ -äthyiea gen, which entepreähen the above Kthiny! -compounds th.

Bs belongs to the level Βς * the compounds IX of the acidic lyee KU subjugate which one in most preferred in the reaction mixture of stage Sg without 'purification, but Eugweise nachdeia the catalyst removed and that tel has been distilled off quickly 1st, reached. Äl @ acids nen p-toluenesulphonic acid, benzoleulphonic acid, p-fluorobenseneul « fonsfiure and the like can be used. Implementation viril supported by warming and it is preferable to work at sa & ssig elevated temperatures «values in the range from 35 to 110 ° 0 and preferably 50 to 60 ° C are suitable: Precaution « white, a solvent is also present, and the aromatic ones Hydrocarbons have been found to be satisfactory.

-. 16 909843/1754

SAD ORIGfHAL

12 135

Benaol is particularly preferred but also doluene, xylene and such can be used *

After completion of the reaction, usually within 2 to Q hours, the reaction mixture is allowed to cool .and separates compounds X from it, for example after the procedure described above «.

As mentioned above, in general Tile scheme B is the radical R ^ preferably equal to R ₁ , Sails, depending on "! Or desirably", R ^ can be hydrogen Another connection in the sequence carried out according to the method described above.;

The successfully prepared indole aldehydes also have a high degree of anti-desulfurization activity. They also have a useful degree of antipyretic activity. The compounds werclen in aweokmäesiger manner orally in Fora of! Tablets or capsules administered in Bosierungaaengen which 'tn a function of the special compound employed and the * As * t and severity ύ & τ infection and the reaction Aneprechbarkeit DLEA kömien vary patient. In general, you can bsvorssugten compounds in oral Bosierungsmengeti sswischeia 1 to 200 mg jje feg aur control -voia arthritiechen supply ■ stands are administered, the actual Menget as g '^ Ee gt ₅ of Teh above vfie ^ EIF given Paktorsß dependent. If large doses are required, periodic administration of several smaller amounts before the Sagee can be used. · ■ ■ "

XI, where R ^ Hydroxy-isti can be according to the »method of Piper and Stevens, Journal of Organic Chemistry»

- ■ 17 r>

9098A3 / 175A

12 155 1 *

(196S) produced from * Since decay, as it is written, begins with £ «mtito-anfehraiiil8f! Tire 'in tion with £ * / - chloropropionic acid. The condensed product is oyolized and the "group" wm MiM r @ dtä8i @ rt ", Di®s®g is then methylated around the 5-DiftethylatBin8-" bind "fig. l obtained by treating nlt GhlortGOhlensMure-tlthyleater and. a strong Baae > such as sodium or potassium hydroxide «- An can be carried out under Yerwniusig you 5- & ίΚ3Γΐ», s «.B ltettoyl- oäe'r S-alkoxy-, aB» Metboay-aiattoraiiilsäisrej, m® the corresponding Veybinäiu ΪΪ feersustelleiu

Compounds ΪΪ, in which R _{K is} alkoxy and inäbesonäeE · ©! Fetlaosy is amino, are known. The higher alkoxy derivatives are analogous to those of the known compounds. The 5 ^ diethyl compound is obtained from the Hethylisrsn der S'-Amiiio ^ prebonding with, for example, stethyl iodide and felitaaicarbonat. The other dialkylamino compounds are made using the appropriate alkyl compounds.

example

a) A stream of carbon monoxide is passed in for 8 hours as a stirred solution of Q ₉ 1 MqI 5-methoxy-g-methylindole in 75 ml of dry benzene oil, which contains anhydrous aluminum chloride and 3 " O g Kunfer (II) chloride. contains, at 35 to 40 ° Ö.ein, gieeat after standing at room temperature, the mixture Geesthacht on Sis "subjecting iia or, see phase steam distillation, zn to the benzene

,. r 10 909843/1754

BAD ORlQVNAL

12 155 13

echütttlt dtn Rücketand old an excess of a saturated Dissolve sodium sulphite for 12 hours at room temperature, filter off the bisulphite adduct and wash with ethanol and Ither.

After drying, the bisulphite adduct is mentioned at 50 ° C old aqueous matrix, cooled and the lower coal filtered. The crude aldehyde is made from a mixture of and methanol uncrystallized

Xan receives the corresponding aldehyde «if you carry out the above reaction using 5-bimethylamino -2-methylindole or $ "Aminomethyl" 2 "methylindole instead of the 5-methoxy compound executes.

b) Su 12.3 parts of dimethylformamide, which has been dried over potassium hydroxide and distilled over lime, is added dropwise with cooling in a bath 0.12 hol phosphorus ox; chi orid ISUt eetrit the vegetable 0.1 Hol J5 ™ Hetfe © Ky-2-iaethylindol au, er «· warms the stirred mixture to 50 and 60 ° 0, passes through a Sticketoffetrom in order to remove the developed hydrogen chloride. drift, which is caught in a measured amount of a & tandardbaee. The mixture is cooled to room temperature and poured into an excess of 20% sodium acetate solution. The crude aldehyde is mixed with a mixture of X thy lather: Ethylene chloride (1t1) extracted. Separate the organic Bubble off, dry over magnesium sulfate, concentrate in vacuo a temperature equal to or below 40 ° C, shakes the bridge with an excess of a saturated sodium bisulfite solution for 12 hours at room temperature and cleans further, as described in section a).

909843/1754

ic

Example 2

tert -butyl - / $ ~ (5 "methoxy" 2- methylindolyl) "Ot, / S -epoxypropionate

A solution of 0.1 mol of tert-butyl-OU-chloroacetate and 0.1 mol of 5-methoxy-2-methylindole-3-aldehyde, which is cooled in an ice bath, is added dropwise over the course of 3 Hours 0.1 mol of a freshly prepared solution of sodium tert «· = * butoxide in tert.» Butane oil, the mixture is allowed to age for 2 hours in a bath and overnight at room temperature and then heated for 6 hours on a water bath 50 ° C, add ice water and gradually acidify the mixture with acetic acid. The product is extracted with ethyl ether: Methylenchlorifl (1s1), the ether ^ Kethylenehloriö extract is then with 5 #igem sodium bicarbonate, water and sehliesslieta. with saturated Natriumchloriä-LSsung extracted »Hseh äem drying over anhydrous magnesium sulfate, obtains the product by removal of the solvent" The Rücketand ~ stage is used for the acylation, which is described in Example 3. FIG.

B e 1 s ρ 1 e 1 3

tert. -Butyl- = / * ^ £ Tp ~ chlorobenzoyl- (5-methoxy-2-methylind - ^Ä .epoxypropionat

0.1 mol of tert-butyl-yrt "(5-methoxy ~ 2-methylindolyl5- 0 -epoxypropionate is dissolved in 100 ml of dry dimethylformamide, and a suspension of sodium hydride in UI is added at 10 to 15 ° C. over a period of 30 minutes with stirring , lets the Oemioch age for 30 minutes at 10 to 15 ° C. and keeps it at this temperature during the addition of 0.1 mol of p-chlorobenzoyl chloride.After the addition, the mixture is stirred at 10 to 15 ° C. for 1 hour Mix in egg water containing 0.3 mol of ice

~ 20 909843/1754

12 135 ^

contains vinegar, extract the precipitate with ether: methylene chloride (1: 1) »wash the extract with water and saturated Saline solution and dry over anhydrous magnesium sulfate After filtering the desiccant, the solution is in vacuo at a temperature equal to or less than 40 ° C «ur Dry «concentrated. The residue can be used for example 4 will"

The corresponding acyl compound is obtained if, instead of p-chlorobenzoyl chloride in the above process, 3-pyridinoyl chloride, 4-pyridinoyl chloride or Tfeiazol-4-carboxylic acid chloride is used. In a corresponding manner, the 2- and 5-positions of the xndole ring and the tert-butyl group the side chain in the case of 2 «methyl by ethyl or propyl, in the case of 5-methoxy by dimethylamino, ethoxy or amino and in the case of tert-butyl by methyl, ethyl or propyl be replaced in order to obtain the corresponding acyl-containing indole ·.

Example 4

t ~ (p ^ chlorobenzoyl) »5« methoxy ~ 2 ~ methylindole-3 ~ acetaldehyde

0.1 mol of tert-butyl ~ / 3 ~ ^ -p ~ chlorobensoyl- (5-methoxyotHaethylindolylJT- öi, / f -epoxypropionat in 200 ml of rinsed toluene, add 0.5 g of p-toluenesulphonic acid in 50 ml of toluene, heat the mixture at 50 to 60 ° C. until about 0.2 mol of gaseous products have evolved, keep the toluene solution at 60 ° up to 100 ° C and extracted with dilute (1 #) sodium bicarbonate solution until the solution is neutral and finally with saturated sodium chloride solution. The toluene phase will dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to dryness. Bas product, 1- (p «= 0hlorbeneoyl) -

- 21 ", 909843/1754 Bao

12 135

5Methoxy ~ 2 ~ methylindole ~ 3 »acetalehyde is _{recrystallized from t®rt e} ~ butanol, ϊρ. 118-120 ° E.

Example 5

Benzyl- fl - (methoxy-2 <-methyli & dolyl ) ■ » pt ^ l

a) A solution of 0.1 mol B «m« yl <-Ot ~ ehlorae © tat unä 0 _e t mol 5 ~ methoxy ~ 2-HBethylindole <»3" ald®bydft which is in a slso & d gg® ~ cool " adds dropwise während.einer -Seltsparae of 3 hours, a freshly prepared solution of HAT r ^ umethoxia in methanol to "the mix can be 2 hours in elmm lie.fea" i and then flattens About age at Baum temperature "

The solvent is quickly distilled off and the residue according to the procedure given in Example 3 and »as described there» »ur dry © ingeengt ·

b) jP "/ T ^ p ^ GhlotToens oyl- (5" -m © thQxy "'2-BiethylinäolylJ7 ^e * ⁰ Io / epoxypropionic acid .' /

To 495 ml of glacial acetic acid added to Beneoyl indoly-5 ml ätöngentrierte hydrochloric acid and 0.1 mol of the obtained in step a)! Ester ζμ ₉ heats the air for 5 hours at 80 ° 0, then cools the Gfemischi brings it by adding Nat? iumbi @ £ rbönat with ®ln®n pH value of 4, extracted after removing the glacial acetic acid ± m vacuum at a temperature equal to or below 40 ° G i @ n residue with chloroform, dried over anhydrous silicon sulfate, filtered and concentrated the piittrate enters in vacuo at a temperature equal to or below 40 ° C. The Buckstani » fi - / r _! -p * 'oil-benzene-boyl ~ (5-methoxy'e> 2-methylindolylJ7 * Ot> i ^ -epoxypropionic acid "is used directly for example 6"

If you do the above steps, but instead of d @@ Xnials

^ 22 i-

9Ό99Α3 / 1754

8AD ORIGINAL

12 135 «Η

and p-chlorobensoyl chloride 5-dimethy lamino * «2 ~ iae thy lindol-3-aldehyde, 5-amino-2-methylindole-3-aldehyde or S-ethoxy-S-thylindol-3-aldehyde and 3-pyridinoyl- ohlorid bsw · Thiasol-4-carbon ~ • If acid chloride is used, the corresponding N-acylated one is used Obtain indole.

Examples

. 1 - (p ~ Ohlorbeng oyl) -5-ae th oxy-2 "me thy lind ol-" 3 ~ ace taldehyd

The RÜotfltand from Example 5 b) (0.1 mol} is stirred with a 0 · miβoh of 200 ml of water and 500 ml of Beneol _f , while the temperature is maintained at 65 to 70 ° C, sodium carbonate while stirring with such At a rate such that the pH of the aqueous layer does not exceed 8.0, after 30 minutes of stirring at 25 to 50 ° C. the mixture cools to room temperature, extracted with water and saturated salt solution. The aldehyde is obtained and recrystallized as described in Example 4, pp. 118-120 ° 0, HMR spectrum identical to that of the samples taken before.

Example 7

fi _i p epoxypropionatture

To 450 ml of methanol is added 0.1 mol of benzyl / i- ^ Tp-chlorbeneoyl- (5-methoxy-2-methylindolyljj- Qi , ft -epoxypropionate eu, cools the mixture to 15 ° C after dissolving, sets 2.0 g 10 ^ i Palladium-on-activated coble is added, the mixture is hydrogenated at 2.8 kg / cm 2 and room temperature for 3 hours until 0.1 mol of hydrogen has been absorbed, the catalyst is separated off by filtration, washed with two 50 ml portions of methanol, concentrated After combining the filtrate and the washing solutions, the mixture in the Va-

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ORIGINAL

12 135

kuum at a temperature equal to or below 40 ° C su an oil, the oily residue is taken up in 200 ml of ethyl acetate and placed on a column with Silioagal. The eluate, which contains the Ottyä epoxy acid, is concentrated in vacuo at a temperature equal to or below 40 ° C. _f 4 - "poxypropionic acid, eu. This acid is converted as described in Example 6, eu 1- (p-Chlorb'ens®yl)"! Maet! i oxy-Z-methylindole-I-acetaldehyde.

The above reductive debenzylation is achieved even if other Konaentrationen of used Falladium-on · activated carbon for 10 $ "are and if other Bydrierunge as Raney Hlokel instead of Salladium-Xatalysatoirs be. j '

Example 8 . 1 "p" chlorobenzene oyl-? ~ Lthynyl "5-metho"y-'2"methyl indole

Dry acetylene is added to 0.1 part of ethylmagneslum bromide in ether for 0.5 hours, the flow of acetylene is slowed down to pale white, while the mixture is heated for 2 1/2 hours under reflux conditions, and after cooling to room temperature it is added the solution is added dropwise with stirring eu 0.1 mol of 1-p-chlorobenzoyl-5 ~ bydroxy-5 "methoxy" 2 ~ methylindole in ether, the mixture is kept under reflux conditions for 1.5 hours, cools to room temperature and sets 120 ml 17% ammonium chloride, see below. The layers are separated, washed with water and neutrality and then washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated. The residue, 1-p-chloroboboyl-3 ~ äthinyl-5- methoxy-2-methylindW, used in Example 9.

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ORIGINAL

12 135 if

Example 9

1- (p-Chl orb eng oyl · KS-methoxy ^ -methylindole-S'-acetaldehyde.

90 ml of 1m sodium borohydride in diglyme are added dropwise with stirring at 0 to 5 ° 0 0.12 mol of boron trifluoride ätfcerat to. Instead of preparing the material in situ, diborane complexes can be used * After aging for 2 hours at 0 ° C add the contents dropwise to a stirred solution of 0.1 mol of i-p-chlorobenzoyl-S-ethiiiyl-S-methoxy - ^ - methylindole in Add 35 ml diglyme at 0 to 10 ° C and allow the mixture to stand warm to room temperature to complete the hydroboration.

After 1 hour at room temperature, the mixture is cooled in a Bia salt bath to 0 ° C again, adds 75 ml of 15% hydrogen peroxide, maintains the pS value through controlled addition of 3N sodium hydroxide upright between 7 and 8, dilute the mixture with 1 ice water, bring to heuiralite with glacial acetic acid and extract with benzene. The benzene phase is extracted successively with water and saturated salt solution. After this Dry over anhydrous magnesium sulfate and filter * the piltrate is concentrated to dryness. The crude product 1- (p-chlorobenzoyl) -5-methoxy-2-methylinole "3-acetaldehyde is recrystallized from methanol-n-bexane, melting point 118-120 ° 0, with an HMB spectrum those'ji of the earlier samples identical.

Example 10

1 - ( p-chlorobenzoyl) 3-ethoxyftthynyl 5-methoxy-2-methyl cylinder oil

Add dropwise to 0.1 part of ethyl magnesium bromide in ether 0.1 mol xthoxyacetylene in ether is added to the mixture over the course of? ü minutes the mixture under nitrogen for 2.5 hours at reflux «

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8AÖ ORlGiAfA:

conditions, then cools to room temperature and adds 0.1 mol of 1 "p-chlorobinsioyl" 3-hydroxy-5-ethoxy-2-ethylindGl in ither m " ! fee iemiaofe becomes 11/2 Hours under reflux conditions, the content is cooled to C5 ° C and 120 ml of 17% ammonium enloride are used. eye adds. Hau separates the layers "is washed with water bi © mzr neutrality and then bit saturated brine, UNAE · filtration and Binengen used by the drying over anhydrous Magnesluaeulf-at the Rücketand, 1-p 5-methoxy-2-iaetbylindoi, in Example. 11

Example 11

2u ö, | 35 g of 4 years of KU, which has been poisoned with quinoline (BeIv. Acta,, 20, 1911 ^ 9477) are added to the mixture at Baumtempt? Atur and 2, 8 kg / cm ² hydrogenated until there are about 0.1 mol of hydrogen. The catalyst is removed by filtering, the filtrate is introduced and the methanol is removed. in 200 ml Beneol, rinsed, add 0.5 g p-7oluol8ulfcm®äur © zn, he then warmed because · Oemisch for 4 hours at 50 to 60 ° O ₉ extracts the NaOH! ^ the mixture cool to room temperature, washed successively with water and saturated Hatrlumchlori & ^ LISeungs drys the Senεöl phase over anhydrous magnesium sulfate _s filtered and concentrated the Pil entered to dryness. Sas product,

from methanol-ß-Ηβχβη umkriatallisiert, 7p. 118-120 ° C

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Claims (16)

Claims 1./Process for the production of Xndol-3 ~ acetaldehydes of all proper formula where R _{1 is} aroyl or heteroaroyl, either substituted or unsubstituted, R _{2 is} hydrogen or low molecular weight alkyl and R. Alkoxy is alkyl, amino, monoalkylamino or dialkylamino, characterized in that an indole of the general formula with carbon monoxide in the presence of an acid, copper (II) -ohlCK rid and aluminum chloride treated or in some other way the said indole tilt an amide of formic acid in Presence of a phosphorus oxyhalide treated to produce a first aldehyde of the general formula « H - 27 -909843 / 175 / · 191712? 12 155 if see below and treat this first aldehyde bit of a compound of formula ICH ₂ COCB ₆ , in which X is halogen and Rg is hydrogen, alkyl or aralkyl, in the presence of an alkali alkoxide, via an epoxy compound of the general formula Then form this epoxy compound with an Aeyll®.ruiage w Asking which contains an Ayl group S ₁ , acylated to form a 2r ₁ -aylated derivative of the named Spoxy compound and then hydrolyze this acylated Bpoxy compound Eiert, among other things the indole - ^ - acetaldehyde see below. 2. The method according to claim 1, characterized in that di® Hydrolysis of the aoylated epoxy compound is a basic factor Hydrolysis is when Rg is hydrogen and an acid hydrolysis »when Rg Alley is 1 or aralkyl, or that in another way, when Rg is aralkyl, the aoylated« Bp <o * y ~ Ver & in ~ manure is catalytically hydrogenated, including the Üpoxy-indole eu eria & l « ten «where Rg is hydrogen. 3. The method according to claim 1 or 2, characterized in that that the acylation is carried out at any stage of the process ©. 4. Method according to any of the claims arising from the goal, characterized in that Rg is alkyl or aralkyl, and dl® Hydrolysis with p-toluenesulfonegure is achieved. - 28 8G9843 / 135 Λ3 5. The method according to any one of the preceding claims, characterized in that R _{6 is} hydrogen and the hydrolysis is achieved with sodium carbonate. 6. The method according to any one of the preceding claims »characterized in that X is chlorine. 7. The method according to any one of the preceding claims, characterized in that sodium hydroxide is used as the alkali hydroxide. 8. The method according to any one of the preceding claims, characterized in that there is ale amide of formic acid Dimethylformamide is used. <L 9. The method according to any one of the preceding claims »characterized« in that iaan all phosphorus oxyhalide Phosphorus oxychloride used. 10. Process for the preparation of indole-5-acetaldehydes of the general formula t R ₁ : wherein R _{1 is} aroyl or heteroaroyl, either substituted or unsubstituted, R _{2 is} hydrogen or low molecular weight alkyl and R _{5 is} alkoxy, alkyl, amino, monoalkylamino or bialkylamino, characterized in that a compound of the general formula 909843 / 17SA 3 ί ^^ 1 wherein R, hydrogen or , but preferably E ^ let, with an Acetylen ^ magnesium halogeiild or an alkoxyli th derivative thereof treated to an ethynyl compound the general formula su form »where R» is hydrogen or alkoxy, and one « When IU is hydrogen, this ithinyl «compound is treated with diborane to form a borohydride of the general formula 2U obtained and then this borohydride is oxidized to obtain the aol "<oefcaldehyde and, if Rj is alkoxy, the ethynyl mixture is hydrogenated in the presence of a chiraolin-poisoned palladium catalyst to bond the general 909843/1754 BATH ORIGINAL 135 l when the ethylene compound comes into contact with acid, the ΙηβοΙ-9-aoetaldehyde is obtained when R ^ equals A ₁ and who X ^ has hydrogen, some rare $ «iaz" t "n A ^ "Ntiudt" ndtß compounds la Ir-C "ndtin" B3t "älua of the process old in acylitrungeal agent. "If an AcqrX-Gritppc R ₁ " is necessary, "oyllert 11. Yerfahrail nacli A & oprudh 10, characterized in that one used as Aoetylen-YerbinduQg Aoetylen ^ ttagneeiumbroaid. 12, method according to claim 10, characterized in that daea aftn Xthoxyacetylene Haagneeiuabromid used as the acetylene bond. 13 * Method naoli d «n claims 11 vaa &% 2 ₉ thereby identified tttiXt daee« an dae.Borhydrid old lfa «serc% effperoxide is oxidized into a basic medium. 14. <Process naoh the AnaprUohtn 10 and 12 "deduroh gekennselohnet you _t that Rthylenioche connection" it p-Toluoleulfonsäure brought into contact · Method according to any one of the preceding claims, characterized in that R _{2 is} methyl. 16. The method according to any one of the preceding claims, characterized in that R «is kethoxy. -51 909843/1 155 IX 17. The method according to any one of the preceding claims, characterized in that R _{5 is} dimethylamine). 18, method according to any one of the preceding claims, characterized in that it is dinoyl or 4-pyridinoyl. characterized by the fact that R ₁ p-Oblorbensoyl, 3- - 32 - 909843/1754 ORIGfMAL INSPECTED