DE1917128A1 - Process for the preparation of 1-acylindolyl-3-alkanals - Google Patents

Description

Process for the production of 1 - => acylindolyl-3 ~ alkanals

The invention relates to a new method for the production of Xndolyl aldehydes and, in particular, a process for recovery of <X ~ (3-indolyl) aldehydes, which are part of the order of the Indole rings carry an aroyl or heteroar'oyl radical.

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

CH ₂ CiHO

R ₁

where R _{1 is} substituted or unsubstituted aroyl or substituted or unsubstituted heteroaroyl, R _{2 is} hydrogen or low molecular weight alkyl such as methyl, ethyl, propyl, butyl or the like and R is alkoxy, alkyl, amino, monoalkylamino or bialkylaaino.

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Examples of the groups R ₁ which may be present in the indolyl component are aroyl radicals, such as benzoyl and naphthoyl, which are preferably substituted by at least one functional substituent. Preferred substituents include halogen, alkyl, alkoxy, haloalkyl, and the like. Most preferred is halogen-substituted aroyl and in particular p-chlorobenzoyl and p-broabenzoyl. The heteroaroyl groups can represent 5- or 6-membered heterocycles which, as indicated above, are substituted or unsubstituted. Typical of such groups are those in which the hetero constituent is pyridyl, puryl, pyrryl, thiol, iyriraidinyl, and the like. These groups can be substituted by functional groups such as halogen, alkyl, haloalkyl, such as trifluoromethyl, alkoxy and the like. However, unsubstituted hetero-Be components are preferred.

They erfindungagemäss prepared ferblnduBgen are preference. ", Those wherein H ₁ p-halogenobenzoyl and ata most preferably p-Ohlorbensoyl or 3- or 4-pyridinoyl, R ₂ is lower alkyl, to most preferably methyl, waa R" lower alkoxy or dialkyl! amino, most preferably methoxy or methylamino. In general, the compounds are al © 1,2,5-trisubstituted indole «3-acetaldehydes, for which the following explanations show:

1- (3-pyridinoylJ-a

3-acetaldehyde

(p-Chlorobenzoyl) -2 ~ ethyl-5-raethylamine-indole-3 "aeetaldehyä, (3'-pyridinoyl ) -2 ~ methyl-5-d im © tbylasaino-inöol-3» aeetaldeayd

= .. 2 = »
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BAD OR! G! MÄL

1- (4- £ yridinoyl ^ -methyl-S-dimethylaiaino-indole ^ acetaldehyde 1 "(3-pyridinoyl) -2» »ethyl-5-ftthoxy-indole-3-aoetaldehyde.

Sevorsugt among the aforementioned elnds

1- (p-chloro-nioyl) -2 ^ ethyl- * 5-dimethylaeino-indole-3-acetaldehyde, \ - (3-pyridinoyl) -2-ethyl ~ 5 "" ethoxy-indoX-3-aoetaldehyde, 1 - (3-Iyridinoyl) ~ 2-sethyl-5 ~ dinethylamino ~ indole ~ 3 «aoetaldebyd ·

tvm erflsdung «eetttt« Ben Terfahren belongs as one of his stages the oscidation or ozidatire splitting of a connection of the Jor-

CH ₂ CH-B

I ₁ π.

"2

^R 4

in which H ₂ and R, as defined earlier above, Rj is hydrogen or H ₁ , A is hydroxy, aaino or alkylaaino

and B is carboalkoxy, a 1-hydroxyalkyl such as hydroxyethyl _t 1-hydroxyttthyl, (-OH 1 C 1 -C 3) and the like, or hydrogen, A being hydroxy only when B ^{1 is} hydrogen. When R _{4 is} hydrogen, the oxidative cleavage of the compound II leads to the non-acylated form of the compounds I, which can then be aoylated by using an acylation agent which contains the corresponding R ₁ -containing ingredient. The following Pliess scheme represents the overall process of the formation, whereby the compounds II are prepared from a phenylhydrazine and a keto compound and then added

Connections I »are converted
^a ι

909843/1755

BAO

B ₀ * I + R ₉ C.

Ira above flow scheme denotes the acid @ feestaaät © il öes acid additioaa product of III and A and B eistspreelieia i @ r before definition given ^{for A and B 1} and also includes those groupings in which A and B men can be around one To form alkylidene radicals, such as ithylidene, propylidene and the like. As you can see, the process begins in step a) with the sation of an appropriately substituted III with an appropriately substituted ketone. IT to form compounds II. These are then in stage b)

or directly by way of a naohetehend described d 'tlone ~ Zwlschenprodukt converted to the compounds Ia' AbhKngiiE *: orld of the special groups, which for the © Ute!

- 4 ■ ·
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B gewtfMt isisko special toeä ©? Ai5 © $ äl @ Sfesi? © &} & ®e V * vt ahrens the soap soap » ^ ακ & βί & ε & ΰΙθΩ iss? ] 2 & ^ 2 & ^ s ^j a8is »¥ Gffbinätiiig XII

σ © 2, βΙΐΘ ^ @ a ÄaufB ^? JssBi? Ei? A% iS £ ^> Ms ssas boiling point

of Loes uagsaittela r © ieb, @ ii ₉ where © AöEte Sea-geyatP.reB preferred "Until graze best results at temperatures of 60 to 90 C achieved" Conveniently, VFIR = S telajs- a Losungsmit-: em as Re & ti ons carrier used. Such Tjösungaiüit ·· ÖE "; _s vie methanol» acetic acid, benzene _f l'oluol, xylene and Bioxan eiVid suitable, with methanol and acetic acid are bevorsugt "The ilmse ': ■" ung is übltchei'weiss at the specified temperature range in a few hours completely and the reaction mixture W) T ¹ I then cooled to temperatures below room temperature »for example from C" to 15 ° 0 * in order to bring about the precipitation. Quenching with bis is suitable for this purpose. vJßnn ilie compound ΪΪ an amino acid iat _s like aB = if A is Aiai.no mid B is carboicyl, it is preferred to adjust the pH of the ab ^ eschreoikten <? etai.ache on the isoelsktrisean point., inter alia the separation of so as much proöuks as possible- 2U- The product obtained is then filti-JLert, gevjünsch tör? .tall3 glazed and dried and used in the next year- i "" ice stage "In general, the product is used directly without any cleaning *

The Phetiylhydrasin-VerbinchJtag XlX is recommended as an acid

preferably ei'ier mineral acid used, such as the ffsaurenj: Fßosphora & ure ^ - sulfuric acid and öer-Ss. s Rycr α is chloride

Mevi v / li'd state "that dig T ^ bdnßungesi ■ ΙΙΪ äen Acy!" Remainder H ₁ ei ^ iialter: oöer niöat eath & ltesa can ^ sies is in the Fl

9098A3 / 1 755

BATHROOM 0Rigj _NAL

t w I S I! & (Q) £ 255

schema ctarefe, you are application i @ s! © st® © 1 »ö © Fgest @ llt _s i @ F as hydrogen or Best R ₁ isiSc Is is-fe an Eferkaa ,!

Invention, iass We Acyl - '^ rnägp® I ₁₁ isa liela @ s funist i © 3 process' © ingefilfespig is ilas Reakti © asschema © mtspreefeeaS wi © (S @ iPg @ g © b © a typical, for € ie use

ia Fora. i @ r free Bea ©

Ol-p-Chl orbens oyl ~ C p-äth oxy plies jt} - ~ hjä ras in.

^ Qt-p-BrombeBsoyl-Ci

p-methoxyphenylhydragin,
P-methylamino-phenyIhydrazine, ρ ~ dimethylamino- * pheny! Hydrazine Ot-C3-pyridinoyl) <- p

ot "(4

and the like »Preferred are the acylated forms nn & most preferred are:

ot-p-'Chlorbenaoyl- (p ^ methosyphenyl 5 -hydrazine _f '- Ot ^ p "chlorobenzoyl- {p -' diiaethylaiai, s! iopbGriyl) -hydrazine nnü

The 'simplest and preferred & m? & U.d cash of the formula IV are those wherein A $ hydroxy and B is hydrogen and. which is therefore a connection of the structure

H ₂ C-CH ₂ OH ₂ CH ₂ OH

bilöen «If Rg is methyl, the ferbinehmg is _3

- 6 ... 9098 ^ 3/1755

11 255 ".I

a Verbinttogs, al® is jjsmiei © rte & ltliefo is «Unter

ä @ v OBEM Terbtaatmgen shown are typical result Veriss "formula _H5 wel © fairy si si fe ©? © öor Bttafe a)?

aGitB ^ l-5-a © 'Sfee22 ^ g-imi © ist 1) -i, t

ittolyl) -ethanol.

lia © "^ sitere Ifläutes ^ iag ä®f Eetöm-fQjr-öimäiangen IY _s oils as

IV applicable siai _s wherein A is amino and B is carboxy, © xo 'norleucine ₈ vrerden as strtateturell

O NH ₂
CH ₃ C ■ GH ₂ CH ₂ CR - QO (B.

", including the H-alkyl-substituted derivatives and the allyl esters thereof ο

The enoate methyl group appears after the condensation with the phenylhydrazine in the compounds IX as all radicals R ₂ . Accordingly, a corresponding substitution in compound XV will introduce the eatepreohende radical in compounds IX at this point. When such materials are used, typical compounds are obtained from the direct condensation stage a:

2 -Me thy 1-5 ^ -me th oxy-try pt ophan,
2 ~ Metbyl-5 ~ £ thoxy 'tryptophan,
2 ~ Metbyl ~ 5-d imethylamino-trypt ophan,

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GhI orbena oyl $ ~ 2πίηβ thy l-5 2 «-ethyl-5-2 ° ιβθethyl-5

1 ~ -> Ζ2Έ1 Pall! SoaaeBs

QHa ™ 2- © 2J is

is. &

ediere MEgeellttigbG alipbatl © che E @ foa®

äergleiebea. For example, the use of such saturated products is very popular with typical products

1-p- (3chlorobenzyl-2-ethyl "5-niet;hoxy" 3- ^s -allyl'-iradol _B ^< ! -P'Ctalorbeneoyl-2 "ethyl-5-idethoxy-> 5- (2'- butenyl) 1-p-chlorobenzoyl-2-methyl-5-ffiethylrtmino-3-allyl-indoil

- 2-butenyl) indole.

-3- (2-butenyl) indole and the like.

- 8 - 909843 / $ 175 _B AD ORiGiNAL

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In another way, when A and B are either in compounds IV or II taken together to form an alkylidene radical, an additional step is desirably carried out, which is referred to herein as a _s , wherein the vinyl or vinyls -Groupung üet side chain is first oxidized to the saturated bihydroxy form and this oxidation product is then subjected to stage b) . Condensation on the compounds IV can be brought about. The preferred reaction is shown by the following series of formulas:

-CH ₂ CH-CHR ₅

OH ₉ CB-CHRc

^C » Ί 3-

OH OH

The stage means the oxidation of the unsaturated side chain using an oxidizing agent, which enables 5.8t to convert olefins into glycols, such as Csmiumtetroxid * The reaction is preferably carried out in the presence of an inert solvent, like an ether, eater, erooatiBChen coal wagon 3 cder the like performed. Typical for the ones used Solvents are iHme thy lather-, Mäth ^ lather, Bioica Tetrahydrofuran, butyl acetate, benzene cause the same c The reaction is expediently carried out at rough temperature, if c; u «h partial peratureti in the range from 0 ° to 50 ° C is suitable

are, depending on.

? ₃ e rs etsrnsigs tampers door of the Aus

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raw materials and the boiling point ού & τ freezing point in the specific solvent used «

As a result d®r implementation wirct ä & s and tean according to known PROCEDURE "g <as may sweetness soluble oxidation remove" Indera isan they lsi © ine uiuLvaäΛ & ^^ ν / 'u ™ (AüataasiMM.öÄB ₉ as 2 · Β · "aas . sulfide the © Aalten © SSsmg wirü dam s _o ®Ò Verdampfea böfeandeltj to AEAS ®lyk @ ls. "geiidanan; it atsfet for further ümaetsung in step b) it © eggs ohn © at your disposal"

Typical manufactured glycols simds

i-p-Chlcrl 1,2-diol,

(p
1,2-diol,

3- (2-methyl ~ 5 ~ methoxy-3 ~ indolyl) -propane-1,

p
1,2-diol,

p
2,3-diol

and the same.

The oxidation reaction of the compounds II (in which A ^{9 is} hydroxy and £ 'hydrogen) and the compounds Ia in step b) can generally be carried out by any known oxidation process for the conversion of alcohols to aldehydes, for example by using Oxidation agents such as Liehromat in an acid such as dilute sulfuric acid, manganese dioxide and an acid such as sulfuric acid and the like. For reasons of host affinity should be around oxidation system

~ TO -909843/1755

11 255 M.

The essential changes to ana & r% n groups in the molecule

aerklisbe Mesigeia fl © s illk @ iä @ ls ssiis ⁵ Sfiiire instead of the aldehyde

lia feeseafilefE aütnliefees © Eiisti © HB-i3fst @ H εησ- üamiaiilung der

S ³ Ia © 3äiaid ^ aä gas IsSIfQSU ₀ ^ QffsoggjtjQSse elm alkyl-F'feeo i \ iaii? C7iia äs © QgQauQ ^ i; qI ^ qt Sfefe = lsi seis gelet. € äg "^ © E ^ Qiauiiaag νψί. Bioyelohexyl-earbodiimlä δοία osaäQE ¹ © ö © j? Fe © iilffiid © ₀ like DÜBopropyl- carbo-

«Sqü SaE ⁵ IeUiiaiien in ibrer Reak _o aeQi5Qai1; Fii aueb ^^ he ^ enßat be

IsSsu> ü © a _s Ia ätolisläer Uoisj® i® ^ © e beverzugt ,, Eiiaethyleulf ---

amofe smler © sulfoxide ₉ how tetramethy- and ä © rgle5, efe, ea asigew @na @ t can be «

Bi 122 © combination with the Oarbcdiiaid and the SuIfoxid zn comparable ^ fSQöQSiö® acid Irann any strong organic acid such as ¹ _s HRI tin © ressigsäure or Each of dee phosphorus acids "as thophosphat phoap ε or strength acid, phosphoric acid," Os *, Be monophenyl phosphate and the like. Other mineral acids, such as hydrochloric acid or sulfuric acid, can be used separately. However, phosphoric acid is preferred.

Bte Oxidatione-Reattion using carbodiimides, eine3 sulfoxides and an acid vorzugavteiee ofler in an inert solvent, such as Mathylenchlorid Bensöl auegeführt _t though the use of such Lüe \ mg3aitte! S is not necessary. The reaction is exothermic and therefore precautions are taken to carry out the oxidation at deep temperatures,

- 11 "

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191712®

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r E2? i / itii ^ if'f to «as Aoißo-S ti ecst of fat as ßiarftli ias H © 1 OgSYi ₅ um © itB iiwte / ßiles? rciaisi zu bild en _t "which Ssrm de follows lsi site üi.e Ei'ütcI ^ bq üev Xmisv-Gruppe _f welch® si tea Bildttiig eier © i«% ültigeiri A7. (9 © h ^ d --- connection

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9.0 98Ü3 / 1755

SAD ORiGMAL

process, ■ afiieretiit & t _s like &<, B * »wesm Sas oxidizing agent the entry« of a certain ^ © rsetsuag © ^ fOTöert, »lisa Sue" oxidizing agent3 in Treidelt sn eetsen «So wira Hst ^ iisä preferably in an acidic medium ^ ss ^ saöet, ArSere means küMiea, wie erwüasolit _? ven <? e & ost wsrSsa «Bia Ssaperatur the ümeetsuag is tsiel & t <sh taeai Faehaaisn well-known Yerfah-

the öiittailm. $ nö der * sxidla% iven Speltuttg l ervüneeht «sin tiddukt of the dissolved aldehyde .. to the purification ^ u ei» leiöhtera. Bies can reach ssan with l! Ia;: i -.! / Üi3ulffit as Adönktbilctoer ¹ , whereby the naah fsl-g & wHs? Te ± & etzt äee free aldehyde tiureh treat Xn © i '^ am alkaline Mediuta, vite eia-sr Natriuiaoarbanat solution, VIvU ₁ is sufficient.

or specified, you are oh the terms need Xa) as He » fier step b) in the acylic species of the sicate acylated

As a rule, either the Aoyl-Srupps R ₁ or What-ff ssi ^ s - depending on the substitution of the starting point--

sinB XIX, If IL in the Yer-

bvuiaELrisa T, IC: C Wasssrstc-ff is "then the acylation ar li -" - a-sia 7> a? ilct entiasjg aesi ¥ e £ 'fato ⁴ 8n8vjeg , or si.® te &ii'ü wa ü® n TerbiiFitmgam Ia) run uia them in

X uas ^ waiaoelia «, you acylation yourself can

through the ^ föKöslsi of xadol into the 1-sodium salt

«Ssfen ⁷ Äiüetsuiag with s * s ^ pssseMeB Ae ^ lhälogeniö« Sies' iäßsiy falls »rwiiasöht» -i ^ h an -de® Faeaylhjdrasia before the

erratoa-eri.-, B ^ i Sei * AtiSiühanmg des erfindung3 · iet eu \> $ ° J ~ .. 'gzugfc ₉ with ei'iisr' Aa äen ferbin-

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IXI already existing @ nS © n © £ i 'Aejl-feMgjsiti · um begiaa © a _a um mm e dei »Stisfe b)
len «

is »in the swesteissiger way fe © rg © st © ll ^

with © in®®

© im © fei? Li © alk @ 22r = §nip

Condensate! Ogisetujte wirä ia elnor HatJPiiim-Koiideiieatioii medium »wi® © iaem
ti one temperature for eiofa iiiefet hübte temperatures preferred "un a UmeetEung within a reasonable time fluegt®mperatüren are particularly suitable * The Hjifölyg © is sufficient in" wecksnäesiger Weis © mnter Verwenöuiag Õîä ©! Sediums as a hydrohalic acid, fabric acid particularly - is precautionary. ■ Increased icett that Hydrolyse.schneller expires MHI DAFE <ss> äst work at or near Rüskflusstemperatur t®ne amino acid · is Untes * Use v n AE® & ¥ eiffahr © n, unu won with or otoe B @ tnig & n ^ sationestufe used -

i J 4 J / ι / S S

11 2!

1 Q 1 1

17128

Ef ^ Gi ? Θ1ί3εΊ1 ©

EiGfeihErpiVtiliiigGS Ki'G'SQiUi

MjiG ^ :? 2; "0" OiT-. .ϊί

909843/1755 BAD

11 255

example

Condensation of acylated hyörazine hydrochloride with 5 norleucine

ι r

CH ₂ -CH ₂ -C-CO ₂ ^

-NH ₂ c HCl + O »C-CH ₃

H,

Cl

A mixture of 0.1 mol of OC-p-chlorobenzoyl- (X-praethoxyphenylhydrazine hydrochloride) is heated and 0 »11 mol 5" -0xo ~ norleu> » one in 120 ml Egg.8esöig with stirring for 5 hours at 90 ° C under nitrogen, then removes most of the acetic acid in a vacuum, quenching the neck in 200 ml of ice water the pH value of the vaseous phase carefully with AmTEoniutEb.ydroxid until the amino acid fills the solution, that collects 1-p-chlorobenzoyl-2-methyl-5 ifietboxy-tryptophariyV / ash with water and dries. The indelamic acid is used in Example 2 without further purification.

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BATH ORIGINAL

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Repeating the above procedure using equivalent Amounts of appropriately substituted phenylhydrazines or ketones, the following tryptophans are obtained:

1 ~ p ~ chlorobenzoyl '> 2 ~ methyl ~ 5 ^r = dimethylamino ~ tryptophan, 1- (3-pyridinoyl) ~ 2-methyl "5-methoxy-tryptophan, 1 ~ {3 ~ pyridinoyl) ~ 2-methyl-5 ~ dimethylamino ~ -tryptophan and i- (4 ~ pyridinoyl) ~ 2-raethyl ~ 5 methoxy-tryptophan.

For β ρ ie 1

1 ^ p-OhI orbenzoyl ~ 2-> methy 1 ~ 5-methoyy-indole-3-aoetaldehyde

H
CH ₂ ^ C-CO ₂ H CH ₃ O-.j <^ ^Vns y ₅ ji _{-CH 2} -CHO

HHO

CB ₃ O

C-O

0.095 moles of N-bromoeoinimide are laoated with and without stirring Cooling with 0.1 mol of 1 «p-chlorobensoyl ~ 2 ~ ethyl ~ 5" EevhQxy "trypto ~ phan React in 550 cnr Wesaar under a nitrogen atmosphere » then cool the mixture, extract with Benaol, then shake the Et5ii ", oil extract with ^ 50 al saturated sodium bisulfite solution Unä collects krisialline Bieulfit ~ Addufct and washes ea with absolute ethanol ug4 At-bar. The free aldehyde is

* Ί

909 8 4 3717 5 p

BATH ORIGINAL

917128

hold by treating the adduct with a saturated solution of sodium carbonate to low haze "occurs then the aldehyde with benzene is extracted, the solvent evaporated in vacuo and the residue aua tsrt ₀ ~ t Btrfcanol crystallized by 1 -p-Chlorbenaoyl ° '2- Flethyl-5 ~ metho3r: y-iftdol ^ 3 '= »acetaldehyde, pp. 118-120 ° C s? u.

If one. The above process on equivalent amounts of the The tryptophans obtained in Example 1 are repeated. get the following indole aldehydes:

- acetaldehyde,

1 ~ (3 ~ ^r 0PY idinoyl) - ^ - methyl · 5 ~ metho: Ky-indol ~ 3 ~ acetaldehyde,
1 "(3" pyridinoyl) -2-methyl-5 "öiiaethylamiiio-indole-" 3 acetaldehyde and 1- (4

Corresponding results are achieved if one = te method using equivalent Hengan of H-Chlor » guccinimid repeated instead of N-Bremsueeinimid »

- 18th
909843/1755 »AD

11 255

Example 3

1-p «OhlorbenBoyl-2-methyl'-5-etho3cy" 3 ~ allyl-ind oil

H-SH ₂ .HQ ,! ' ♦ CM5-0H ·

C-O

01

A slurry τοη 0.10 mol of OL-p-chlorobenzoyl-p-aethoxyphenyl-hydraain hydrochloride in 100 al glacial acetic acid adds nan 0.11 mol of 5-Htxen-2-one iu, then heats the reaction mixture for 5 hours under Rübren at 85 ° 0, with it under one Nitrogenateoephare is kept, the indolysis Qenlaoh cools to room temperature and then poured into 500 ml of ice water. The precipitate obtained, 1-p-chlorobenzoyl "2-ethyl" S-ethoxy-J-allyl-indole, is collected by filtration, with Vaeeer washed, dried in vacuo and used in Example 4 without further purification.

The foregoing procedure is similarly effective Production of the next-sequence AlIyI-indoles from the appropriate sub- »

-19-909843 / 1755

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olO

β titled phenylhydrazine and ketone:

1 - (3-Pyrid inoy1) -2-methyl-5-methoxy-3-allyl-ind oil,

1- (3-pyridinoyl) -2-ethyl-5-dimethylamino-3-allyl-indole, and 1- (4-pyridinoyl) -2-ethyl-5-methoxy-3- * llyl-indoil.

example

1-p-ChloPbeneoyl-2 "methoxy" -3-indolyl) "propane-1" 2-dol

OB OB CB,

0.096 mol of Oemiumtetrorid in dry, purified dioxane (300 ml) is added to a dioxane solution of 0 _K 1 mol of dee in Example. 3 obtained allyl-indoles eu, the solution left for 43 hours at room temperature and then saturated with sulfur waaeeretoff. A black precipitate forms which is filtered off. Subsequently, the dioxane solution is evaporated to dryness under reduced pressure and the residue, 3 - = - {1-p-chlorobenzoy-2-methyl-5-'taethoxy-3-indolyl)' propane ~ 1,2- diol, without further purification In Example 5.

- 20 -909841 / 17SS

®ÄD ORIGINAL

11 255

The following glycols are produced in a corresponding manner from the correspondingly substituted unsaturated compound posed:

3 = (1 ~ p ~ chlorobenzoyl ~ 2Maethyl ~ 5 "dimethylamino ~ 3-indolyl) propane 1,2-di oil,

* ß ~ { 3-pyridinoyl) -2 ~ methyl-5-diaethylamino ~ 3-indolyl propane-1,2-di oil,

diol _r

5,6 '' dihydroxy = -hexan-2- »one, 516 ^ dihydroxy ~ heptane-2 "On, 5, e-dihydroxy-heptene-S-one.

The above keto glycols can be used as ketone starting materials in Example 3 can be used and the glycol condensation product obtained is used in Example 5 directly.

Example 5

i-p-Chlorobenzoyl ^ a-methyl-S'-methoxy-indole-g ^ acetaldehyde

CH,

C-O

OH ρ * = * CH * ^ CH λ CH

CH ₂ -CHO

909843/1755

A solution of 0.1 mol of 3 - * (1 ^{t of} P-chlorobenzoyl-2-methyl-5-metboxy-3-indolyl) propane "1,2-dlol. In 250 ca ^ glacial acetic acid with 0.1 mol Sodium bismutate, stir the mixture until a clear solution is obtained, then add 30 ml of 3.5a phosphoric acid (0.105 mol) to precipitate Wisautphoopbat, which is then separated off by filtration, the filtrate is concentrated in vacuo to 100 ml and treated with 500 ml Eiewaseer The precipitate obtained is collected, washed with Vasaer and crystallized from tert-butanol to give 1-p-chloro-2-methyl-2-methyl-5-ethoxy-indole-3-acetaldehyde, pp. 18-120 ° C to obtain.

If. Repeat the above procedure using equivalent amounts of lead tetraacetate, meta per iodine acid or sodium hypochlorite instead of sodium bismuthate get appropriate results.

The following indole aldehydes are obtained in a similar manner from the correspondingly substituted glycol obtained according to Example 4

1 -p-chlorobenzoyl-2-methyl-5-diraethy lamino-indole-3-acetaldehyde, 1- (3-pyridinoyl) -2-ethyl-5 "diBethylaaino-indole-3-acetaldehyde and 1- (3-pyridinoyl) -2 ~ methyl-5-methoxy-indole-3-acetaldehyde.

example

This example is intended to illustrate a general process for the preparation of the amino acids (compounds IV) which are used in the condensation reactions of Example t can be used.

- 22 -909843/1755

5 ~ 0xo nor leucine

COOC ₂ R ₅

CH-C-CHkCH ₉ + HC ~ NHC CH,> CH ^ C-CH ₀ -CH ₉ -C-HHCvCi

COOC ₂ H ₅ / COOC ₂ H ₅

CH-C-OE ₀ -CHp-O-OOOH 3 «2 2 j

O H

Add 0.10; Mol of diethyl acetamidomilonate cu a solution of 0.15 g of sodium in 20 ml of absolute ethanol is added, while the mixture is stirred at room temperature, dropwise over a period of 2 hours, 0.13 mol of methyl vinyl ketone, stirring continues for 6 Hours at reflux conditions and then the reaction mixture evaporated under reduced pressure. The residue is heated to reflux conditions with 35 ml of Sn hydrochloric acid. 35 tnl of concentrated hydrochloric acid are then added in part during the first hour of heating and heating is continued for a further 6 hours. The cooled hydrolysis oemisoh is then concentrated in vacuo and adjusted to a pH value of 6 with concentrated ammonium hyaroxide in order to set free 5 ~ 0xo-norleucine «

Xn corresponding manner, the other amino acids are prepared by selecting a suitably substituted in ketones, _m such as those wherein the terminal alkyl Sruppe ethyl, propyl or the like instead of methyl.

- 23 -909843/17 55

11 255

Example 7

fl «(1. • p-Chlorbengoyl-2-methyl-5-methoxy-3-indolyl) -ethanol

; nh ₂ .hoi

), Cfl

C-O

A 1 liter round bottom flask is charged with 98 * 0 g & -p ~ Chlörben * oyl- (p-methoxyphenyl) -bydrazine hydrochloride, 540 ml of absolute methanol and 32.1 g of 3-acetyl-1-propanols are rinsed the mixture is stirred and heated under nitrogen for 3 hours at reflux conditions, the resulting dark cools Solution, the solvent is removed under vacuum, 500 ml of chloroform and 500 ml of water are added to the brown residue obtained, the aqueous layer is then separated off and extracted again with twice 100 ml of chloroform, then combined the chloroform extracts, treated ia with activated charcoal, dried over Magnesium sulphate, tight * to a semi-solid mass and continues to dry. The semi-solid mass obtained is in boiling

- 24 -90984 3/1755

11 255

Ethyl acetate redissolved and filtered. The dark brown solution is then stirred for a few hours and cooled in a sieve bath, at which point crystals form. The crystals are filtered and give 75.3 g of crude yS _ "" ■ (1-p-chlorobenzoyl-2-methyl "5-methoxy-3-indolyl) ethanol in the form of yellow crystals. The crude ß ~ (1-p -Chlorbenzoy1-2-methyl "'5- ⁱ methoxy-3 * ⁼ ' indolyl) -ethanol is recrystallized from boiling ethyl acetate to give essentially pure i $ ~ (1-p-chlorobenzoyl ~ 2-methyl-5-methoxy 3- ihdolyl) ethanol result as yellow needles eu.

Repeating the above procedure using equivalent amounts of appropriately substituted phenylhydrazines or ketones results in the following alcohols:

~ ethanol ethanol,

P - ^ T- (3-iyridinoyl) ~ 2-methyl-5-methoxy ~ 3 β - / T- (3-pyridinoyl) -2 * aethyl-5-dimethylaiaino ^

β- (4 = pyriflinoyl) «- 2-methyl-5-methoxy« 3-indolyl7-ethanol

Example 8

^ -acetaldehyde

V 25 -.

909843/1755

11 255 **

Into a 1 liter three-necked round bottom flask provided with a Motorrtihrer, an immersion thermometer and a drying tube _f iet with 13 »g 5 Teeter phosphoric acid and a solution of 78.5. gy ^ - (1-p ~ chlorobensoyl ~ 2-methyl - 5 "meth = oxy-3 = indolyl) ~ ethanol (see Example 7) in 215 ml of dry bimethyl sulfoxide (DMSO), then adds 141.5 g of dicyclohexyl carbodiiaid (BCC), the orange-colored reaction mixture is stirred for 2 hours at room temperature, the mixture is then filtered and the cake is washed color-free with methylene chloride. The combined methylene chloride filtrates are shaken with passer and the aqueous layer is separated off and further extracted with methylene chloride washes the combined methylene chloride extracts with water until they are neutral, treated with activated charcoal, dried over magnesium sulfate, concentrated under reduced pressure and dried further, over 119.6 g of crude 1 ~ p-chlorobenzene ~ boyl ~ 2H-methyl-5-ethoxy -indole ~ 3 ~ acetaldehyde, pp. 115-120 ° C eu.

If the above process is carried out using, in individual cases, equivalent amounts of Diehromat in dilute sehwe folic acid, magneaium dioxide in sulfuric acid or acetic acid * anhydride with Dlaethylsulfoxld instead of Carbodliaid in di-. "Repeated ethyleulfoxid, corresponding results are he hold w.

The crude 1-p chlorobenzoyl-2- = ethyl-5-methoxy-indole-3-acetaldehyde is isolated and purified as a bisulfite adduct by treating an ethanol solution of the crude aldehyde (65 ml of ethanol and 112 g of aldehyde) with 400 ml of saturated, aqueous sodium bisulfite solution. The formation of the bisulfite adduct is visible. quickly and the light yellow product separates quickly «The product is filtered, washed with ethanol and dried under reduced pressure.

". - 26 -§09843 / 1755

11 255 * ▼

If the above process is repeated with equivalent amounts of the alcohols obtained in Example 7, the receive the following xndolaldehydes:

1-p-Ohlorbeneoyl ^ -methyl-S-dinethylamino-indoil ^ -acetaldehyde, 1- (3-pyridinoyl) ~ 2Hmethyl ~ 5 <Huethoxy ~ indole ~ 3-aeetaldehyde, 1- (3 ⁱ -pyridinoxl) -2-methyl "5-diiaethylamino-indole-3-acetaldehyde and 1- (4-pyridinoyl)" 2- "ethyl-5-methoxy-3-acetaldehyde.

Recovery of the pure aldehyde from the sulfite adduct

A flask is charged with 60 g of crude 1-p-chlorobenzoyl-2-methyl-methoxy-S-acetaldehyde-sulphite adauct, 500 ml of benzene and 500 ml of waeeer, the mixture is stirred and then 15 ml of concomitant hydrochloric acid is slowly added. When the addition is slow, the mixture is stirred and heated on a steam bath for about 1 hour and then cooled to room temperature. The reaction mixture is filtered and the filtrate is washed with 500 ml of water once again ₍ until it is neutral. Then the mixture is treated with charcoal, dried over magnesium sulfate and concentrated to give 10.5 g of chlorobenzoyl-2H-methyl-5 - ■ • taoiy-indole-3-acetaldehyde al · light yellow crystalline solid eu obtained ·

If the material obtained above can be converted from tert-butanol are installed to produce essentially pure T-p-Ghlorbensoyl- » 2 ~ methyl-5 «methoxy« indole-3-aoetaldehyde cu win, which at 121.5-123.0 ° C sohmilBt.

~? 7 -909843/1765

^ß A0 ORIGINAL

Claims (1)

255 April 2, 1969 Godfather tans ρ r ü ehe 1. Process eur Production of aldehydes of the general For ^ mel wherein R _{1 is} aroyl or heteroaroyl, either substituted or unsubstituted, R «is hydrogen or low molecular weight alkyl and R, alkoxy, alkyl, amino _{p is} monoalkylamino or dialkylamino, characterized in that an indole compound of the general formula ^R 4 where R ^ is hydrogen or R ₁ , A is hydroxyl, amino or alkylamino and B is hydrogen, carboxyl, carbalkoxy or 1Hy = drcixyalkyl, where A is only hydroxy when B ^ is hydrogen, treated with a HaXogem-Feaungsraittel when A * amino or alkylamino, and treated with an oxidizing agent if A is hydroxy and, if R ^ is hydrogen, then acylated the compound thus obtained with an acylating agent which contains the radical R ₁ as an acyl radical. - 28 - 9Q9843 / 175S SAD OFIIGlNAL 2. The method according to claim 1, characterized in that in the Xffdöl Compound A ^{1 is} amino, B ¹ is carboxyl and is ale Halogenierungeraittel N-Brcxnsueeinimid or H-GhIorsuecinimid used. 3. The method according to claim 1 unfi / cder 2, characterized in that compounds are _{reacted in which R 1 is} p-chloro-likeyl, p-chromobenzoyl, 3-pyri £ inayl or 4-pyridinoyl and R ₁ is equal to R 1. 4. The method according to one or more of claims 1 to .3 »characterized in that R _{2 is} methyl. 5. The method according to one or more of claims 1 to 4, characterized in that R, methoxy, methylamine) or dimethylamino 1st. 6. The method according to claim 1, characterized in that in the Indöl · 'compound A ^{1 is} hydroxy and B ^{1 is} hydrogen and the oxidizing agent is any one from the group of a carbodiimide and a sulfoxide in the presence of an acid, a Diehromata In an acid, Hagnesiuadloxid used in an acid or a mixture of acidic anhydride and dinethyl sulfoxide. 7. The method according to claim 1, characterized in that in the xndol compound A ^{1 is} hydroxy and B ^{1 is} hydroxysaethyl and any one of the group of lead tetraacetate, perchloric acid, meta-periodic acid, alkali hypochlorite or alkali bismuth is used as the oxidizing agent. 8. The method according to one or more of claims 1, 6 and 7, characterized in that R _{1 is} p-chlorobenzoyl, p-bromobene - 29 -9 098 4 3/1755 ^BAD 255 ^όΌ acyl, 3 * pyridincyl or 4 ~ eyridinoyl is un <3 B ^ is the same as R ₁ . 9. The method according to one or more of claims 1, 6, 7 and 8, characterized in that R _{2 is} methyl. 10. The method according to one or more of claims 1, 6, 7, 8 and 9 »marked; that R. is methoxy, methylamino or dimethylamino. ■ * ^ 11. Process for the preparation of aldehydes of general formula CH ₂ CHO ^B 1 wherein R _{1 is} aroyl or heteroaroyl, either substituted or uneubstituted, R _{2 is} hydrogen or low molecular weight alkyl and R «is alkoxy, alkyl, amino, monoalkylamino or dialkylamino, characterized in that a phenylhydrazine of the general formula or an acid addition room thereof, wherein R ^ is hydrogen or Rf is, with a cat ^ »connection of the general for CH ₂ CH ₂ CH 0 ^ 09843/1755 SAD ORIGINAL reacted, where A is amines, aminoalkyl or hydroxy, B is hydrogen, carboxyl, carbealkoxy or 1 "hydroxyalkyl, and B is only hydrogen when A is hydroxy, and A and B su ~ eanommenonmen an alkylidene reed can form to one condensed end compound of the general formula CH ₉ OH B ¹ A ¹ au form, in which A is Aaino, Aminoalkyl or Hydroxy and E is hydrogen, carboxyl, Carfcoalkoxy or 1-Hydroxyalkyl, with the addition of mass that, if A and B together represent alkylides, the named keto compound or that initially obtained with it Treated condensation product with a first oxidizing agent which is capable of converting olefins into glycols and then treating said end-carbon product with an oxidizing agent if A is hydroxy or with a halogenating agent if A is amino or alkylamino and then if R is hydrogen is, the compound thus obtained is acylated with an aoylating agent which contains the R ₁ radical as aoyl radical. 12. The method according to claim II _1, characterized in that A is hydroxy and B is hydrogen. 13 · Method according to claim H, characterized in that A Aa? No and B Carbonyl Jet. 0G9843 / 1755 255 ^ 14. The method according to claim 11, characterized in that A is hydroxy and B is hydroxymethyl. 15. The method according to claim 11, characterized in that the © A and B taken together alkylidene <| arstell®x & and was? as The first oxidizing agent called Gemimte tr oxide is used. 16. Yerfaferea according to claim 13? flsöwreti, des® as a halogenating agent! «- bromosucein laid or! J = OhI or- succiraissld used. '■ ■ 17. Process according to claim 16, characterized in that H _{1 is} p-chlorobenzoyl, p-broafcensoyl, 3-pyridino, yl oä & r 4-pyricsinoyl iate and R. equals R ^ « 18. The method according to claim 16 and / or 17, characterized in that the R_ Hethosy, ^ ethylamino or dimethylamine * is. 19. The method according to one or more of claims 16, 17 and <3 18, characterized in that R ₂ methyl iate « 20. The method according to claim 12, characterized in that ale oxidizing agents of one of the group of a carbodiimide and a sulfoxide in the presence of an acid, dichromate in an acid, manganese dioxide in an acid or a mixture of acetic acid anhyaride and dimethyl sulfoxide used. 21c method according to claim 14 «characterized in that man -as an oxidizing agent from the group of lead tetra- - 32 ~ acetate, perchloric acid * meta-per ^ odic acid, alkali hypochlorite or Alkaliwiemutat used. 22. The method according to claims 20 and 21, characterized in that R _{1 is} p-chlorobenzoyl, p-bromobenzoyl, 3-pyridinoyl or 4-pyridinoyl and R ₁ is equal to R 1. 23 «Method according to one or more of claims 20, 21 and 22, characterized in that R, Meta oxy, methylamine » or is dimethylamine. 24. The method according to one or more of claims 20, 21, and 23t, characterized in that R2 is methyl i & t » _{! K} , 909843/1755