DE1695475A1 - Process for the preparation of 3-indolyl acids - Google Patents

Description

MERCK Λ CO., INC
126 East Lincoln Avenue, Rahway, Ν "J · 07065" V.St.A.

Process for the preparation of 3-indolylaic acids

The invention relates to a new method of manufacture certain 1-benzoyl-2-methyl-3-indolyleacetic acid derivatives and in particular a process for the preparation of 1-p-oblobenzoyl-2-methyl-5-R-3-indolyleeeaeaic acids the formula

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- -γ - CH ₂ OOOH JI OH,

wherein R is methoxy or dimethylamine. These connections are described in U.S. Patent No. 3,161,654. the The invention also relates to the creation of new intermediate

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products for use in this process

Oemäee of the USA patent pens are i-p-Ohlorbensoyl-2-methyl-3-indolyleauren made by means of a Uaseteung grater, where «on a 2-methyl-3-indoiyleeelgellure nut Entapreous anhydride is dehydrated because the anhydride is tert-butyl alcohol with the recovery of the ente-preheating beter then treats the tert-butyl ester at the 1-position p-Ohlorbensoylohlorld aoylated and the 1-aoylate obtained by means of a pyrolysis process for free Bssigssure-Serl- ▼ at It is an object of the invention to provide a new process for the preparation of these compounds. Sin Another aim of the invention is the creation of new intermediaries. products for use in these «procedures. Other goals and two-way information result from the following description

According to the invention, it was found that 1-p-Ohlorbensoyl-2-methyl-3-indolyl acetic acid of forael I by the decarboxylation of 2,3-lieige acid derivatives of forael (ID

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OB ₂ OOGB OB ₂ OOQB

C-O

II

can produce. Decarboxylation can be achieved by simply dissolving the compound of the formula ZI in an inert solvent and diluting the solution until the evolution of carbon dioxide ceases. The development of carbon dioxide begins> when the solution is ^{heated to a temperature above 50 0} O. Its faster development is achieved at higher temperatures. The solution can be obtained by faster decarboxylation to the reflux temperature of the solvent. Solvents which can be used for the purpose of this set-up are "aromatic hydrocarbons" such as benzene, "toluene and xylene," halogenated aromatic solvents "such as chlorinated benzene," elheohlieeslleh mono-chloro- and di-chloro-benzene sol, "halogenated aliphatic hydrocarbons such as chloroform or methylene dichloride and high-endes Xther «like" glyme * and "diglyae".

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After decarboxylation, the product mentioned can be Iorael X Isolate by evaporating the solvent Iv vacuum and umkrietallieieren de · Rücketande in a Löeungeaittelf such as tert-butanol or tetrahydrofuran.

The origins of the proceedings of the present Invention are novel compounds which can be obtained in several different ways, such as ee i * below foraeleoheaa stated latt

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646

.CB ₂ OOOOBj

VI

LiJ
2,6-Xittldln

Compound of formula II

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According to this, one can obtain a 1 ~ p ~ chlorobensoyl-3-indolyles8iga acid (Connection of Ponael III) at the 2-position carbomethoxymetbyHeren by treatment with 1 equivalent of methyl diaso ~ acetate in a solvent such as tetrahydrofuran under Ultraviolet radiation. The irradiation is continued " until the evolution of nitrogen ceases, Bae reaction mixture should, if necessary, by external cooling at ambient temperatures quenching of the reaction mixture » The methyl-i-p-chlorobensoyl-2-methoiyoarbonylmethyl-indole-3-acetate falls into egg water the formula IY from «

. The combination of formula IV can be used as the starting material for formula II can be converted by splitting off ester groups with a reagent such as lithium iodide and 2,6-lutidine a nitrogen atmosphere at reflux temperatures.

There is another way to combine the formula II Manufacture from the i-p-chlorobenzoyl-5-R-indole of the formula V by treating the latter with 2 equivalents of methyl slide acetate. Irradiate the Renkt ionegemiecb.ee with ultraviolet light leads to the formation of the compound of formula VI. The latter is converted to the starting material of formula II by peeling off groups of ethers with a reagent such as lithium iodide in 2,6-lutidine.

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As yet another alternative, one can use the Auegangevertoindüngen the formula II obtained according to the following reaction scheme t

VII

0 "C-CH ₂ OuOR X-CHCH ₂ COOR ⁰

VIII

CH ₂ COOH CH ₂ COOH ^ "

CH ₂ COOR 'OH ₂ COOR'

IZ

.CH ₂ COOR 'CH ₂ OOOR *

II

In the preceding forms, R corresponds to that given above Definition, X is bromine or, less preferred, chlorine or iodine and R 'is low molecular weight alkyl (e.g. methyl or tort.-butyl) or alkyl, especially monocyclic aryl (lower molar alkyl), like B may1, or dibydropyranyl-2- · Die Implementation between compounds VII and VIII can be

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by heating a mixture of the compounds · which contain an excess of the aniline «derivative» to reflux temperature. It can be implemented with or without solvents. Suitable solvents are Benaol! Toluene, high-boiling ether "alcohols and various other inert I ¹ IUeslgkeiten in which the reactants are löslioh. The indole derivative of the formula IX obtained can be isolated from the reaction mixture by extracting with a solvent such as chloroform and then purifying by customary methods. Compound IX can be converted to compound X by acylation with a 1-p-chlorobensoyl halide, such as iodide, bromide or, in particular, chloride. The acylation is achieved by mixing the compound IX with at least 1 equivalent of the acylating agent in the presence of sodium hydride and dimethylformamide. The cleavage of the ester groups from the compound X gives the desired starting material of the formula II. The cleavage of the ester groups can be achieved in various ways. When R ^{f is} methyl it is best achieved by treatment with lithium iodide and 2,6-lutldine. If R 'is bensyl or dihydropyranyl-2-, the splitting off of ester groups can be achieved by hydrogenolysis in the presence of a palladium catalyst β. If S * is tert-butyl, the ester groups are split off by pyrolysis until a theoretical amount of isobutylene has been developed.

j 1 R C] R 4 7 R

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The following examples explain the invention further Beis piel 1

Production of methyl 1- <p <-ohlorben8oyX-2-kethoxyoa? Bonyl * methyl ~ 5- "methoxyindole" - ^ - acetate

2u 0.01 Hol 1 »p-chlorobenzoyl ~ 5-methoxyindole in 100 al! Tetrahydrofuran adds a solution of 0 ₉ 021 Hol Mstfayl diaeoacetate in 25 al tetrahydrofuran sw, irradiated» as soon as the addition is complete (15 minutes) Reaktionsgeeisoh ait Ultraviolettlieht until the Stlekstoffentwloklung aitfhurt, keeping the temperature during the irradiation by äuaeere cooling at 20 to 25 ⁰ C, gieast once the Bestrahlungo period is over, the Reaktlonsgeaisoh tin 1 liter Biswasser, filtered, the precipitated product & b and cleans it by recrystallizing it from tert «-» butane! ·

They implementation can also be performed duroh Srhitien or using catalysts such as copper powder, copper-8a 1 Ben or Di- ^ t-chlordl-'lT-allyldipalladiua instead of the Irradiation old ultraviolet light «Bs is also preferred, a small excess »over the above 2 equiv." Use lente of Kethyldlaeoacetat · in a corresponding manner can the implementation at jsd? r temperature swisohen the freezing and boiling points of the solvent are carried out »if

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temperatures such as those used in the example are also preferred will. Other solvents may also contain Tetrahydrofuran are inhaled · among these are Xther and Diozan.

If one follows the above procedure with the exception that one uses i-p-Ghlorbensoyl-S-dimethylaminoindole instead of the If the indoles used there are used, methy 1-1-p-chi orbeneoyl-a-ethoxycarbonylmethyl-S-dinetbylaminoindole ^ acetate is obtained.

Example g

! Production of 1-p-chlorobensoyl-2 »methozyoarbonylmethyl« Sl · » methoarrindole-S-acetic acid

To 0.01 mol of ip-chloroboboyl-S-methoxy-J-indolyleeigetture in 100 ml of tetrahydrofuran is added «a solution of 0.011 mol of methyl diasoacetate in 13 ml of tetrahydrofuran irradiated» as soon as the addition is complete (in about 10 minutes) The reaction is mixed with ultraviolet rays until the nitrogen development ceases, the temperature being maintained during the irradiation by means of external cooling at 20 to 25 ⁰ O. As soon as the irradiation period is over, the reaction liquid is poured into 1 liter of organic water and the precipitated water is filtered Product and purified by recrystallization from tert-butanol.

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The same product is obtained if the methyl ester is used instead of the output material used in Example 2 will·

In a similar way, aan receives the corresponding 5-3 iaetbylaminoindole by using i-p-chlorobensoyl-S-dimethylamino ~ 3-indolyl acetic acid in the aforementioned procedures.

As in Example 1, scan the Diaso reagent in other ways be set as duroh irradiation (duroh application of catalysts or heat). Similarly, as in Example 1 described "the temperatures and solutions average to be changed.

Example 3

Production of ip-Chlortjensoyl ^ -carboxynethyl-S-methoxy- 3-indolylacetic acid

Wan holds a mixture of 0.01 mol of ip-Ohlorbensoyl-2-methoxycarbonylmethyl - ^ - methozy-S-indolylacetic acid, 8.5 g of anhydrous lithium iodide and 200 ml of freshly distilled 2,6-lutidine under nitrogen for 8 hours with stirring at reflux conditions , setst after cooling to tree temperature, 100 ml of chloroform and 100 ml of cold 2N Salssäure su _t separated after shaking, the layers, the aqueous phase extracted

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noohnale with chloroform, the combined organic washes Extracts with cold, diluted hydrochloric acid (2 parts of 100 ml) and with Vaaaer (2 portions of 100 ml) and dry then over magnesium sulfate. Removal of the solvent "under reduced pressure gives i-p-chlorobensoyl-2-carboxymethyl" 5-methoxy-3-indolyleaeige acid

The corresponding 5-dimethylamino derivative is obtained duroh A set of i-p-OblorbenBoyl - ^ - methoxycarbonylaetbyl-S-dimethylamlno *> 3-indolyle8slgic acid in the process of Examples 3. The product is also precipitated from the HCl washing solutions Binatellen dea pH value to 5 bla 6 duroh addition of a base.

Example 4

Preparation of 1-p-chlorobensoyl-2-carboxymethyl-5-methoxy- 3-indolyleaalgic acid

A mixture of 0.01 mol of methyl-iP-chlorbeneoyl-a-methoxyoarbonylmethyl-S-bethoxyindole-I-aoetat, 17 g of anhydrous lithium iodide and 400 ml of freshly distilled 2,6-lutidine is kept under nitrogen for 8 hours with drilling at reflux conditions adds NAOB cooling to tree temperature, 100 ml of chloroform and 100 ml of 2N Salsaäure au _v separated after shaking, the layers, the aqueous phase re-extracted with chloroform, washed the combined organiaohen Ex-

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Treat well with cold, diluted hydrochloric acid (2 parts of 100 ml) and with water (2 portions of 100 ml) and then dried over magnesium sulfate. Removal of the solution amittola under reduced pressure results in 1 ~ p-chlorobensoyl ~ 2-arboxy ~ methyl-5-methoxy-3-indolylv) S8igetture,

The corresponding 5-dimethylamine derivative is obtained by Bineets of methyl-i-p-chlorobenzoyl-2-ethoxyoarbonylmethyl-5-dimethylaminolndol ~ 3 ~ aoetate in the procedure of Example 4 The product is obtained from the HOl WaaohlÖaungen by Sin set the pH values to 5 to 6 by adding a base.

Example 5

1-p-ChlorbanBoyl-2-Bethoxy »; arbonylinethyl-5-ethoxyindole-.3- acetic acid

One erhitst a well stirred mixture of 26.64 g (0.20 mol) of p-Anisidln and 26.71 g (0.1 mol) dimethyl "3-keto-4-bromadipat under nitrogen to 100 ⁰ O, it holds 3 Hours at this temperature, then cools the mixture, separates the crude product by extraction in chloroform, washes the extract once with dilute hydrochloric acid and then with water, kneaded over anhydrous magnesium sulfate and removed the solvent, In the crude methyl-S- to obtain roethoxyoarbonylmethyl-S-niethoxTindol 3-acetate.

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B. liner Aufaohltaaung you 5 g 50 jflger latriuahydrld-Sauleion In 50 «1 Diaethylfonaaaid adds» at 5 to 1O ⁰ O «in · solution clay 27 g of the product au · fail A di ···· Examples in 300 al dry · · Siaethjrlforaaaid au »stirs there · Oealaoh for 1 hour, us di · Formation d ·· Vatriuaaalae« au τ · γτο11-etestand, Mtat di «e« r reading drop by drop «in · solution τοη 24 gp-Ohlorbsnsoylohlorid during a side failure το 1 Sttm ~ dau »treats the mulling beforehand ait 10 al leaven-« tture and then dilutes the heat chemistry further in 1 liter of water. The mine is extracted to a great extent ait Ohlorofor ». The Ohloroform-lxtrakt · _t are combined ait Vaeeer gewäsohen, dried and concentrated "include methyl-ip-ohlorbenaoyl-2-Bethoxyoarbonylaethyl-5 ~ aetboxyindol-3-aoetat give au.

Production τοη ip-Ohlorbenaoyl-2-BethoxyoarbonylBethyl- 5 ** i dl 3ito

A stirred Kliohung the · products clay part B these · examples (0.01 NoI) ₉ 8.5 g waeeer-free lithium iodide and 200 al frieoh distilled · 2,6-lutidine under nitrogen for β hours on reflux conditions, added after cooling Bauateaperatur 100 al Ohlorofom and 100 al cold · in Salseiure su ₉ separates naoh Sohütteln the · 8ohlohten _v extracts the wiesiger · phase · newerlloh old Ohlorofor », which means the · v« purified organic extracts well old cold diluted saline

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BATH

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acid (2 parts τοη 100 ml) and old water (2 parts of 100 ml) and dry over magnesium sulfate. Remove the Solvent under reduced pressure gives 1-p-chlorobenzoyl-2-carboxymethyl-5-methoxy-3-indolylacetic acid.

If the procedure of Example 5 is followed with the exception that _{Η-dimethylphenylenedlamine is used instead of p-anlside in part AS 9} , 1-p-chlorobensoyl-2-ethoxy-carbonylmethyl-5-diraethylamino-3-indolyleade is obtained. The product is isolated from the HCl washing solutions by adjusting the pH to 5 to 6 by adding a base.

Example 6

Production of ip-OhlorbenBoyl ^ -aethyl-S-ethoxy-J-indolyl acetic acid

A solution of 0.01% 1-p-chlorobenzene * oy1-2-carboxymethyl-5-methoxy-3-indolyacetic acid is obtained in 100 ml dichlorobenzene under reflux conditions until the evolution of carbon dioxide ceases, whereupon heating la yakuum continues until the solvent has evaporated. The residue is recrystallized from tert-butanol and gives the result Product 1-p-chloroboboyl-c-methyl - ^ - methoxy - ^ - indolyl acetic acid.

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There is another way of reacting to the doctrine of oxylation Use the previous examples a solution, such as chloroform or ethylenediochloride and keeping the reaction equilibrium at low flow conditions, before the carbon dioxide development stops.

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Claims (5)

10 646 Patentana, prttohe 1. Process for the preparation of 1-p-chlorobenzoyl-.2-methyl-5-.B ~ 3-indolylee eggs of the formula where B is methoxy or dimethylamino, known thereby, that you can connect the formula OB ₂ OOOB 0 * 0
♦ Dissolves in an inert solvent and the obtained 109816/2227 646 solution until the carbon dioxide development stops and in this way the desired product wins 2. The method according to claim 1 »characterized in that one o-dichlorobensol used as solvent 3 · Method according to claim 1, characterized in that one connect a compound in which B is hethoxy 4 · Linking the formula , 0OCH OH ₂ OOCB where E is Hethojqr or Dimethylamine. 5. Connection naoh Atwpruoh 4 _t characterized by the fact that H Mothoxy 1st - 18 - 109816/2227