WO2011024039A1 - Synthesis of novel 5-(2-(phenylsulfonyl)ethyl)-1h-indole derivatives - Google Patents

Abstract

An objective of the present invention is to develop commercially viable methods for the synthesis of 5-[2-phenylsulfony)ethyl]-1H-indole of Formule (II), where R¹ and R² are same or different and each independently represent a hydrogen, fluorine, or di(lower alkyl)amino, acyl, or alkoxy carbonyl or chlorine atom, or a lower alkyl, lower alkoxy, nitro, cyano, aminolower alkylamine group Formula (II). Another objective of the present invention is to convert the product Formula (II) to Formula (I) in high yields, where R¹ and R² are same or different and each independently represent a hydrogen, fluorine, or di(lower alkyl)amino, acyl, or alkoxy carbonyl or chlorine atom, or a lower alkyl, lower alkoxy, nitro, cyano, aminolower alkylamine group Formula (I). One of the first processes attempted was by reacting the indole derivative of Formula (III) with aryl vinyl sulphones of Formula (V) as shown in Scheme-III. Another process attempted was by reacting the aniline derivative of Formula (VI) with aryl sulphones of Formula (VII) as shown in Scheme-III. Scheme IV.

Description

Title: ¹ ! SψrtΗESlS OF NOVEL 5-(2-(PHENYLSULFONYL) ETHYL)-1H-INDOLE

DERϊVjpT bi

BACKriROUN Q = THE iNVENTlON:

The syfitfi .sis >f -[(2-phenyJsulfony)ethenyl]-lH-indole of formula II, is described in US6201131.

There areitwe examples describing the synthesis of the compound of formula Il

Exam es Tibes the process by the reaction of 5-bτomoiπdole (III) with the methyl sulfonyl derivative of f»enyfsuffonyj)ethanσl (IV). The process is given in scheme-! o /

^. -⁰V J)

Br' *^

IV m

Scheme-I

In this pH>ce< ;, 1 ie product is obtained in 23% yield.

r

Exempli jl3 f as described the synthesis by the reaction of 5-iodoindole (Ilia) with trifluoacetyl derivative of (2-bh.lW«s ilfi ιnyl)ethanol (IV) as represented in scheme Il

,CF₃ «s ^^ J

\

o Il

IY ma IV

5cheme-ll

Usfngt^ls pr >cι ss, the product is obtained in about 5296 yield.

By bόttjlthe ne hods, yields of the required product are moderate to good.

5-[(2-pfti.nyl ul onyJethenyll-lH-iπdole (If) is an important building block in developing indole derivatives < f tt ierapcutic importance.

Hence there is in urgent requirement to achieve excellent yields of these types of indole derivatives SUMNJAάV O! Jl E INVENTION:

An obji»ctive < Ftl ie present Invention is to develop commercially viable methods for the synthesis of 5- [(2-phέπyisulf m) )ethyl]-lH-lndole of formula II,

where R¹ and R² arc the same QΓ different and each independently

represent a hydrogen, fluorine, or diflowcr αikyOamino, scyl, or

alkony caibβnyl or chlorine βom, or a lonπr nlkyl, lower aJkςBCV.

niito, cyaπσ, amiπolower alkylemmc group

Formula Il

Another!I biij j,efetife of the present invention is to convert the product formula Il to formula I in high yields.

where Tl¹ and R² ore tho same βr different and rarh independently

represent a hydrogen, fluorine, or di(lower altyl)ajnhio, aeyl, or

aϋcoxy carbonyl αr chlorine atom, or a loner alkyl, lower βJkoxy,

nitro. ι-ynnn, aminotσwer aHcylaminc group

Formula I

One of the ffrstl processes attempted was by reacting the indole derivative of formula III with aryl vinyl

I ' J l

sulphυries oqfojmula V as shown in Scheme-Ill .

Scheme-Ill

Another! brnφsfj attempted was by reacting the aniline derivative of formula Vl with aryl sulphones of formulaml aa sHown in Scheme-Ill.

Scheme-IV

III with aryl vinyl

Scheme-Ill a

The aryl v^nyl slulfbne is represented by formula V, given below

where R¹ and R² arc the same or different and each independently represent a hydrogen, fluorine, or diflower alkyl)amtflo, acyi, or alkoxy caibonyl or chlorine atom, or a lower atkyl, lower alkoxy, nitro. ryaππ, αminolσwer alkylamine group

Foπrnda-V

R⁵ is Acetyl, propyl, trlfluoacetyt,

fcbuftw rartooπyl, benzyloxy carbonyl or fluoroa/y, oxycartaonyl

Vl

is reacte'ijf wlψi sjn 2-aryl sulfonyloxy ethyl hatide of formula VII,

VII

whereiri IR¹ ajid R² are as described earlier, X is chlorine or bromine

Scheme-V

An orgbnit o in vganic base is used, wherein inorganic base is selected from the group consisting sod liiuuππil cirbo , potassium carbonate or cesium carbonate and the organic base is selected from the gro uupp toπs iiisstti ig of triethylamine, diisopropytethylamine, N-methγlmorpholine, pyridine, α-picoline, β- picolinb όi v-p co Iπe.

A phas Ie t irans er catalyst is used, when an inorganic base is used. The PTC is selected from the group consis nitπft! of zγhriethylammoπium chloride, tetrabutγlarπrπoπium bromide, tetrobυtylammonium hydrogeri lsulp ia1 e, 15 Crown 5 or 10 Crown 6.

The reaciron I eferably carried out at a temperature of 30 to 150⁰C, more preferably at 40-130⁰C and most preterab y 160-120⁰C.

On compitetlo per TLC monitoring, the reaction mixture is worked up to give the product of formula x I!

The product c Ffc rmula X Is converted to the product of formula Xl as per scheme VII

Fonniilfr-Xl

Scheme-VII

The proαuct

is hydrolyzed to the product formula I as represented in scheme-VIII

Scheme-VIH

EXAMPlifeS in the follow ng examples, the preferred embodiments of the present invention are described only by way of (llυst Ig the process of the invention. However, these do not limit the scope of the present fπvetiUc/n fn < rvy way.

Examplefl

Example-ll

Examples-Ill

N-(4-(2-tøher rts{jlfoπyl)ethyl)pheπy!)acetamide, VIII

20gm ofA-(2 _hl sroethylsυlfonyl) benzene in 125ml of dichloromethαne was cooled to S⁰C. 13gm of N- phenylacetan id ! was added to the reaction mixture and 55gm of anhydrous AlG₃ was slowly added maintaining i he temperature of the reaction mixture at S⁰C- After completion of the reaction, the reaction¹ imix ur > was quenched into 500ml of ice water containing hydrochloric acid. Separated dichlorσmetr an s was concentrated to give 7figm of N-(4-(2-(phenylsulfonγl)ethyl)phenyl)acetamide as waxy solid.

Examμl^lV

N-(2,2-dfeth( xy !thyl)-N-(4-(2-(phenylsυlfonyl)ethyl)phenyl)acetamide, X

10gm of|N-(' -(phenylsulfonyl)ethyl)phe«yl)acetamide was dissolved in 100ml of dimethyfformamide, 0.5gm of t« tπ butylammoniumbromide and 4gm of potassium carbonate added. 7.5gm of 2- bromoάletd Ji iyde diethyl βcctαl was added and temperature was raised to 65^ήC After the reaction was cortiplet 3d the reaction mixture was filtered and filtrate added into 300ml of water. Product was extract*-! ir < lchtorom^pthane and concentrated to get llgm of N-(2,2-diethoxyethyl)-N-(4-(2- (pheny&ulfo tyl ethyf)pheπyl)acetamide.

obtained, N-aι^βt^l-S-{2-(ph*>nylsιilfoπvl)ethvl)-lH-iπdole 6.0gm, showed a melting point

Example^VI

5-(2-(Phenyis lf<jnyl)ethyl)-lH-tndo!e, I

5gm of sN-ac sty -5-(2-(phenylsulfonγl)ethyl)-lH-ϊndole was dissolved in 40ml αf ethanol and 1.5gm of potassium ca be nate added. The reaction was stirred at room temperature till the reaction complete, The reaction mi cture filtered and Nitrate concentrated under reduced pressure to give 4gm of 5-(7- (phenγlsiilfor !thyl)-lH-indole

Claims

novel 5-(2-(phenyl5ulfoπy()ethyl)-lH-ϊndole derivative of formula-l

to

of

ύ) rβict^'Aig product of formufa-VlH with product of formuta-!X to get product of formυla-X same or amino,

6. ^s cl m id in claim Ib, wherein, catalytic hydrogeπation is carried out preferably in the pfresi of 10% pH/r..

7- As c !d in claim 2a, wherein, Fried el -Crafts reaction is carried In solvent selected from HhethΛ e chloride or dichloromethane, preferably dϊchloromethane

8. As cl m ;d in claim 2b, wherein, the reaction of product of formula VI(I with the product of form IX is carried out selected from aeetonitrile, N,N-dimethytformamϊrifi, N,N-dimethyl dceta e or N-methyl pyrrolidin-2-one in the presence of a base selected from sodium carbo e, potassium carbonate, cesium carbonate, triethyl amine, diisσpropyl ethylamine or N- meth rr orpholine, preferably in N,N-dimethγl formamide and potassium carbonate

9. As cl m id in claim 2c, wherein, the cyclizatlσn of the product of formula X to the product of form Xl Is carried out a reagent chosen from sulphuric acid, trifluoro acetatic acid or πγdi rch jric acid at 40^βC to 100^βC, preferably in sulphuric acid at 60-7(TC

10. As cl; m d in claim 2d, wherein, the conversion of the product of formula-X to formula-l is

έarrli ut a selected from methanol, ethanol, lsoproanol or n-butaπol in the presence of a base cted from sodium carbonate, potassium carbonate or cesium carbonate aτ 60-120"c, prefe y in ethanol containing potassium carbonate at 6O-80°C