[go: up one dir, main page]

WO2004041781A1 - Preparation of 3-aminoalkyl-substituted indole derivatives from phenylhydrazines and aminoketones - Google Patents

Preparation of 3-aminoalkyl-substituted indole derivatives from phenylhydrazines and aminoketones Download PDF

Info

Publication number
WO2004041781A1
WO2004041781A1 PCT/IN2002/000226 IN0200226W WO2004041781A1 WO 2004041781 A1 WO2004041781 A1 WO 2004041781A1 IN 0200226 W IN0200226 W IN 0200226W WO 2004041781 A1 WO2004041781 A1 WO 2004041781A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxo
acid
phenyl
process according
hydrazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2002/000226
Other languages
French (fr)
Other versions
WO2004041781A8 (en
Inventor
Venkata Satya Nirogi Ramakrishna
Rama Sastri Kambhampati
Vikas Shreekrishna Shirsath
Venkateswarlu Jasti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suven Life Sciences Ltd
Original Assignee
Suven Life Sciences Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suven Life Sciences Ltd filed Critical Suven Life Sciences Ltd
Priority to AU2002356428A priority Critical patent/AU2002356428A1/en
Publication of WO2004041781A1 publication Critical patent/WO2004041781A1/en
Publication of WO2004041781A8 publication Critical patent/WO2004041781A8/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • the present invention relates to a process for the preparation of indole derivatives, particularly those, which are useful as pharmaceutical intermediates. Background of the invention
  • US patent 6,133,453 describes a method to prepare 3-hydroxyalkyl indoles using hydrazines and dihydrofuran.
  • US patent 5,179,211 describes a method wherein indole derivatives are prepared in aqueous medium in short reaction time and good yields.
  • the process of this invention has much more broad scope for preparing substituted 3- aminoalkyl indole intermediates than it was possible earlier with Fischer indole synthesis.
  • the present process is a one-pot process, wherein the desired substituted 3-aminoalkyl indole intermediate is prepared by reacting the appropriately substituted ketone amines of varying diversity with aryl hydrazines.
  • the process uses substituted ketone amines thus there is no additional derivatization or deprotection step. 4.
  • the above feature is especially useful when 3-aminoalkyl indoles are intermediates in a multi-step synthesis.
  • reaction time is shorter as compared to other methods witiiout incurring any additional operational changes or costly equipment.
  • the amounts of impurities formed are relatively less irrespective of nature and dilution of the reaction medium.
  • the present invention relates to the process for the preparation of compounds of general formula (I),
  • R represents hydrogen, Ci-Cio alkyl, C 2 -C ⁇ o alkenyl, C 2 -C ⁇ 0 alkynyl, phenyl-(-R 5 )b, CH 2 -phenyl-(-
  • a is 1 to 4
  • b is 1 to 5
  • q is 2 or 3;
  • ] represents C C ⁇ 0 ⁇ kyl, C 2 -C ⁇ 0 alkenyl, C 2 -C ⁇ 0 alkynyl, phenyl-(-R 5 ) b , -(CH 2 )- ⁇ henyl(-R5) a ,
  • R 2 represents C C 6 alkyl, phenyl-(-R 5 ) b , -(CH 2 )-phenyl(-R 5 )b, -(CH 2 ) m Het; wherein Het is a 5- or
  • 6- membered saturated or unsaturated ring containing from one to three heteroatoms selected from the groxip containing nitrogen, oxygen and sulfur; and also includes mono or bicyclic group, which may be further attached to above defined heterocycles;
  • R 3 represents hydrogen, Ci-Cio alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C ⁇ 0 alkynyl, C(0)R 9 , C(0)ORs; optionally, R 2 and R 3 together may fonn a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; R 4 represents lvydrogen, C-.-C 10 alkyl, and is attached to any one or more than one carbon atoms present in tire side chain;
  • Re represents hydrogen, C r C 10 alkyl, - €(0)0 ⁇ , phenyl-(-R 5 ) b , -(CH 2 )- ⁇ henyl-(-R 5 ) b , -(CH 2 ) m Het, and is attached to any one or more than one carbon atoms present in the side chain;
  • R 7 represents hydrogen, C 1 -C 1
  • R 8 represents hydrogen, C1-C10 alkyl, C 2 -C ⁇ o alkenyl, C-2-C 1 0 alkynyl, phenyl-(-Rs)b, -(CH 2 )b- phenyl-(-R 5 ) b , -(CH 2 )b- Het;
  • R 9 represents hydrogen, hydroxy, ORs, NRsR 7 ;
  • rmg form a cyclic structure containing 5 to 8 carbon atoms, which may contain 1 to 3 double bonds, optionally it may contain one to three hetero atoms selected from the group containing oxygen, sulfur and nitrogen; n is 1 to 4 and relates only to carbon atoms; said process comprising of one-pot reaction in the presence of acidic catalyst and a suitable solvent, and if desired, removing in any known manner , water fonned in the reaction.
  • the compounds of formulae (I) may have one or more asyinmetric carbon.
  • the process of invention also includes preparation of such chiral compounds of formula (I) using the corresponding chiral oxo amines wherein the reaction proceeds with complete retention of configuration at the asymmetric carbon atom.
  • the compounds of formula (I) may also posses geometric isomerism, wherein also the process of this invention can be used to prepare such compounds.
  • Suitable phenyl hydrazines for the process according to this invention are : phenyl hydrazine, 4-methyl ⁇ henyl hydrazine, 4-ethylphenyl hydrazine, 4-propylphenyl hydrazine, 4- dodecj phenyl hydrazine, 4-methoxyphenyl hydrazine, 2,5-dimethylphenyl hydrazme, 3,4- dimethylphenyl hydrazine, 4-ethoxyphenyl hydrazine, 4-benzyloxyphenyl hydrazine, 4- chlorophenyl hydrazine, 4-bromophenyl hydrazine, 4-fluorophenyl hydrazine, 4-iodophenyl hydrazine, 5-chloro-2-methylphenyl hydrazine, 4-(l-(l,3-oxazolidine-2-one-4- yl)methylene)phenyl hydra
  • Suitable ketones for tlie process according to the invention are: N,N-dimethyl-4-oxo- pentanamine, N,N-diethyl-4-oxo-pentanamine, N-methyl,N'-etl ⁇ yl-4-oxo-pentanamine, N,N,2- trimetl ⁇ yl-4-oxo-pentana ⁇ nine, N,N,3-trimethyl-4-oxo-pentanamine, N,N,2-trietlryl-4-oxo- pentanamine, N,N,3-triethyl-4-oxo-pentanamine, N,N-dimetl ⁇ yl-5-oxo-hexanamine, N.N-diethyl- 5-oxo-hexanamine, N-metl ⁇ yl,N'-etl ⁇ yl-5-oxo-hexanamine, N,N,2-trhnetl ⁇ yl-5-oxo-hex
  • N,N-diethyl benzoylpropanamine N,N-dimethyl (4- bromobenzoyl)propanamine, N,N-dimethyl benzoylbutanamine, N.N-dietiryl benzoylpentanamine, N,N-dimethyl (4-bromobenzoyl)butanamine and N,N-dimetl ⁇ yl (4-metl ⁇ ylbenzoyl)pentanamine.
  • the present mvention relates to a process for the preparation of compounds of general formula (I),
  • R represents hydrogen, C ⁇ -C* 0 alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C ⁇ 0 alkynyl, phenyl-(-R 5 ) b , CH 2 -phenyl-(- R 5 ) a , S0 2 -phenyl(-R 5 ) a , C(0)R 9 , C(0)ORs, (CH 2 ) q NR 7 Rs, C(0)NR 7 Rs, (CH 2 ) m Het,
  • a is 1 to 4
  • b is 1 to 5
  • q is 2 or 3;
  • Ri represents Ci- o alkyl, C 2 -C ⁇ o alkenyl, C 2 -C ⁇ 0 alkynyl, phenyl-(-R 5 ) b , -(CH 2 )-phenyl(-R 5 ) a>
  • R 2 represents C C 6 alkyl, phenyl-(-R 5 )b, -(CH 2 )-phenyl(-R 5 ) b , -(CH 2 ) m Het; wherein Het is a 5- or
  • 6- membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group containing nitrogen, oxygen and sulfur; and also includes mono or bicyclic group, which may be further attached to above defined heterocycles;
  • R 3 represents hydrogen, C ⁇ -C ⁇ 0 alkyl, C 2 -C 0 alkenyl, C 2 -C ⁇ o alkynyl, C(0)R 9 , C(0)OR6; optionally, R 2 and R 3 together may form a part of cychc structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; R t represents hydrogen, -Cio alkyl, and is attached to any one or more than one carbon atoms present in the side chain;
  • R 5 represents either same or different substitutents such as hydrogen, halogen, hj'droxyl, -X-R « (X
  • R 7 represents hydrogen, Ci-Cio alkyl
  • R 8 represents hydrogen, C C ⁇ o alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C ⁇ 0 alkynyl, phenyl-(-R 5 ) b , -(CH 2 ) b - phenyl-(-R s ) b , -(CH 2 ) b - Het;
  • R 9 represents hydrogen, hydroxyl, ORs, NR5R7;
  • CO(0)Rg phenyl, 0-CH 2 -0-; Rio and Rn together with the two adjacent carbon atoms of phenyl ring form a cyclic structure containing 5 to 8 carbon atoms, which may contain 1 to 3 double bonds, optionally it may contain one to three hetero atoms selected from the group containing oxj'gen, sulfur and nitrogen; n is 1 to 4 and relates only to carbon atoms; and the said process wherein comprises of an one-pot reaction in the presence of acidic catalyst and a suitable solvent, optionally having a suitable mechanism to remove water fonned in the reaction.
  • Suitable salts of phenyl hydrazine represented by the general formula (IP) includes the hydrochloride salt, the hydrobromide salt, the salts of H 2 S0 , HN0 3 , H 3 P0 and the like, prepared by reacting phenyl hydrazme of formula (II) with the corresponding mineral acids.
  • Halogen when mentioned is fluorine, chlorine, bromine or iodine.
  • Suitable acid catalysts include mineral acids as well as organic acids, characterized in that glacial acetic acid, perchloric acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, orthophosphoric acid, polyphosphoric acid and the hke.
  • Optionally Lewis acids such as almninum chloride, titanium tetrachloride, zinc chloride etc. can be used as a catalyst in some cases.
  • Preferable acid catalysts used include trifluoroacetic acid, sulfuric acid, orthophosphoric acid or glacial acetic acid in suitable concentrations and optionally the acid catalyst used may be dissolved in an aqueous solvent.
  • Suitable mechanism for removing water from a reaction mixture includes those described in the literature and known to a skilled artisan. Dehydrating agents such as sulfuric acid, molecular sieves, or removing water by azeotropic distillation are examples of techniques described in the prior art.
  • the process comprises of reacting the phenyl hydrazme compound of formula (II) or its salt (IP) with the ketone amine compound of formula (III) in presence of suitable solvent and an acid catalyst.
  • the reaction may be carried out at temperature ranging between 60 °C to the reflux temperature of the solvent/s used, for about half-hour to 4 hours.
  • water formed in the reaction may be removed using the techniques known in the art.
  • the reaction may be conducted in . an inert atmosphere.
  • Phenyl hydrazine of formula (II) or its salt (IP) and ketone amine of formula (III) can be present in 1: 1 molar ratios to 1: 5 molar ratio of each other.
  • the compound of formula (II) or its corresponding salt (IP) optionally may be first dissolved in a solvent, and then added to the reaction mixture and the vice-versa.
  • Suitable solvents for the phenyl hydrazine of formula (II) or its salt (IP) include ethers, alcohols, nitroalkanes, acetonitrile, dimethylsulfoxide, dimethyl formamide, and hexametiiylphosphoramide. While suitable solvents for the ketone amine of formula (III) includes inert solvents, such as, hydrocarbons, chlorinated hydrocarbons or acyclic ethers and the mixtures thereof.
  • Suitable substitutcnts for either hydrazine derivative or the ketone amine compound are those, which are compatible with the reaction, i.e., do not significantly reduce the yield of reaction and do not cause a significant amount of side reactions.
  • Suitable acid catalysts include organic as well as mineral acids characterized in that glacial acetic acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, perchloric acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like.
  • the preferred acid catalyst is dissolved in protic or polar solvents such as alcohols or ethers, for example, methanol, ethanol, propanol; ethers such as tetrahydrofuran, diisopropyl ether; and even water upto 50 % may be present in some cases.
  • the acid employed can be present in the mole ratio of 1 to 10 mole equivalents per mole of ketone amine.
  • the particular molar proportions employed will depend upon the concentration of the acid employed as illustrated in the examples.
  • Preferable acid catalysts used in the process of this invention include trifluoroacetic acid, sulfuric acid or glacial acetic acid in suitable concentrations and optionally dissolved in a solvent may be used to carry out the process of this mvention.
  • the concentration of acid catalyst employed in the reaction can vary from about 10 % to 100 % or from 10 % to 75 % with the range 15 to 75 % representing the preferred range of concentration. Wliere higher concentrations are employed, it is preferred to employ inert organic solvents such as toluene, xylene, or cl-lorobenzene.
  • the initial step of hydrazone formation requires a little amount of acidic catalyst and results into formation of 1 mole equivalent of water.
  • the latter may be removed, if desired, using various tecl-niques known in the art such as using either a dehydrating condition, molecular sieves or by distillation.
  • the reagents are typically mixed slowly, e.g., drop- wise.
  • the optimal reaction time and temperature depends on factors such as the solvent and concentration, which the skilled artisan will be able to adjust so as to maximize the yield of the product.
  • the reaction is maintained at temperatures ranging from room temperature to reflux temperature of the solvent employed until completion of the reaction. It is known fact that the mode of addition of one reactant in another can accelerate the rate of reaction or at least minimize the formation of xmdesired components thus improving the economy of the process.
  • the aqueous portion is isolated, neutralized, the substituted indole derivative is obtained in organic phase; if required, the indole can be purified further in a manner well known to those skilled in the art.
  • reaction may be monitored by conventional techniques such as gas chromatograpliy, thin layer chromatograpliy etc or any other convenient technique known in the field of art. After it is confirmed that the reaction is complete the reaction mixture is allowed to cool slowly to room temperature.
  • the product may be isolated by addition of reaction solvent to an aqueous splvent, which may contain pH-modifying agents.
  • Water is such preferred solvent, and the reaction mixture is latter neutralized with a suitable base such as sodium carbonate, liquid ammonia and the tike.
  • Latter solvents are evaporated under reduced pressure then extracted with low boiling organic solvent such as ethyl acetate, diethyl ether or methylene dichloride and the like.
  • the residue, if needed, may be further purified by using column cl romatography over a silica gel column using a solvent system containing ether, hexane, pentane, ethyl acetate, alcohols etc. or mixtures thereof. Again evaporating the solvent/s in an inert atmosphere under vacuum to obtain pure product, the structure of which is confirmed by characterizing with IR spectra, Mass spectra, NMR spectra, and melting point.
  • EXAMPLE 1 Preparation of N,N-dimetliyl-2-(2-metliylindol-3-yl)etliylamine hi a reaction flask provided with Dean-Stark apparatus, 10.8 g of phenyl hydrazine, 15.48 g of N,N-din ⁇ etlryl-4-oxo pentanamine, and 150 inL of toluene was charged under an inert atmosphere. Latter 55.6 g of ortlio phosphoric acid is added. The reaction mixture was then refluxed for 4 hrs by continuous stirring while monitoring the reaction and the temperature continuously.
  • reaction mixture was cooled and diluted with 200 inL water and pH was adjusted to about 10 - 11 using aqueous ammonia solution at low temperatures.
  • the product was extracted with ethyl acetate 2 x 75 niL; organic layer washed with brine 1 30 inL and dried over anhydrous magnesium sulfate and the solvent was evaporated to dryness under reduced pressure.
  • the product was extracted with ethyl acetate 2 x 25 mL; organic layer washed with brine 1 x 30 mL and dried over anhydrous magnesium sulfate and the solvent is evaporated to dryness under reduced pressure. The residue was triturated with n-hexane and the separated solids were dried. The compound obtained weighs 4.1 g (77.65 %), melting range: 112 - 114 °C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a process for the preparation of indole derivatives, particularly those, which are useful as pharmaceutical intermediates. The process involves formation of hydrazone derivative between a phenyl hydrazine and a ketone amine, followed by cyclisation to give desired 2,3-substituted indole derivative in the presence of acid catalyst.

Description

PREPARATION OF 3-AMINOALKYL-SUBSTITUTED INDOLE DERIVATIVES FROM PHENYLHYDRAZINES AND AMINOKETONES
Field of invention
The present invention relates to a process for the preparation of indole derivatives, particularly those, which are useful as pharmaceutical intermediates. Background of the invention
Recent advances in medical science opens numerous opportunities in developing either a new therapy or it brings forth-new insights in the existing ones. The elaborate classification of serotonergic receptors; structural elucidation of the different types and sub-tj^es of these receptors; their physiological role in humans, has lead to increased research interest in various disorders relating to central nervous system. Many substances in useful in these disorders preferably have indole nucleus. Also some indole derivatives are found to be useful in the treatment of various other disorders such as endocrine indications, cancer, immune system disorders, opthalmological diseases, and also therapeutic areas such as anti-inflammatory and dermatology.
Various 2,3-disubstituted indoles particularly those having 3-alkylamino substitutent in the side-chain are reported in literature. Examples include, US 5,817,689; US 5,756,507; US 5,571,833; US 5,436,264; US 5,276,051; US 5,179,211; US 5,030,640; US 4,839,377; US 4,672,067; US 4,544,663; US 4,803,218; US 3,669,960; US 3,472,870; EP 1,306,230 and PCT applications, WO 99/11619, WO 97/21703, WO 95/30655, WO 95/14004, WO 95/01334, WO 93/21178, WO 92/13856 and WO 90/05721.
As reported in the prior art the general methods to prepare 3-alkylamino substituted indoles using Fischer indole synthesis, involves at-least two steps, namely; initial formation of indole ring, which is followed by derivatization of conventional precursor for amines such as amide, cyano, acid chlorides, hydroxyl, chloro etc obtaining the desired 3-alkylamino substitution. In a typical conventional Fischer indole synthesis a substituted aryl hydrazine is condensed with a ketone or an aldehyde or its activated analogues such as ketals or acetals respectively.
US patent 6,133,453 describes a method to prepare 3-hydroxyalkyl indoles using hydrazines and dihydrofuran. US patent 5,179,211 describes a method wherein indole derivatives are prepared in aqueous medium in short reaction time and good yields.
Various processes to prepare substituted 3-aminoalkyl indole derivatives are described in the prior art. Though many of these are modifications of classical Fischer indole synthesis, only a few of these methods can be applied to prepare 3-aminoalkyl indole derivatives in one step. For example, a process used to prepare 3-hydroxyalkyl indoles in single step can not be extended to others which have strongly basic groups such as amines or highly electrophihc groups such as acid chlorides, ketones, aldehydes and esters at 3 -position of indole ring. Yet another one-pot synthesis employs relatively high dilution of solvents, preferably water, to maximize the purity of final product.
Hence we attempted to have an improved nethod to prepare substituted 3-aminoalkyl indole derivatives in one-pot, wherein initial non-cyclizing step is immediately followed by cyclization to give indole ring having the desired 3-aminoalkyl substitution. Accordingly, the process of this invention has number of advantages over the known art and is described in detail in the following specification.
From our extensive study, we have concluded that proper choice of solvents and co- solvents significantly reduces number and amount of impurities. Further, the by-products formed in the reaction can be easily removed witiiout involving any additional operational cost and equipment, which is a considerable technical advantage from scale-up point of view.
The advantages of this invention as envisaged by us are as follows:
I. The process of this invention has much more broad scope for preparing substituted 3- aminoalkyl indole intermediates than it was possible earlier with Fischer indole synthesis. 2. The present process is a one-pot process, wherein the desired substituted 3-aminoalkyl indole intermediate is prepared by reacting the appropriately substituted ketone amines of varying diversity with aryl hydrazines. 3. The process uses substituted ketone amines thus there is no additional derivatization or deprotection step. 4. The above feature is especially useful when 3-aminoalkyl indoles are intermediates in a multi-step synthesis.
5. Further the reaction time is shorter as compared to other methods witiiout incurring any additional operational changes or costly equipment.
6. The process of this invention allows more flexibility in terms of reaction conditions such as solvent, reactants. catalyst etc.
7. The process does not require excessive cooling or heating.
8. The amounts of impurities formed are relatively less irrespective of nature and dilution of the reaction medium.
9. As a result the process has good yields and purity as well. 10. The recovery of organic solvent/s used, is upto 80 %.
I I . Various indole derivatives substituted in 2nd and 3rd position can be prepared in a single step. 12. Though reactions of Fischer Indole type, exclude generally strongly basic and highly electrophilic group. The method of this invention answers this deficiency in the prior art as the hydrazine is treated with N,N-disubstituted compounds without any loss in yields or purity of the product. The process disclosed in this invention may be advantageously applied to prepare various analogues of indoles. Summary Of The Invention
The present invention relates to the process for the preparation of compounds of general formula (I),
Figure imgf000004_0001
General formula (I) which comprises of reacting a phenyl lvydrazine of the formula (II) or its salt represented by the formula (IF), each of which has at-least one ortho-position imsubstituted,
Figure imgf000004_0002
with a ketone amine represented by the formula (III),
Figure imgf000004_0003
(HI) wherein,
R represents hydrogen, Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cι0 alkynyl, phenyl-(-R5)b, CH2-phenyl-(-
R5)a, Sθ2-phenyl(-R5)a3 C(0)R9, C(0)OR,, (CH2)qNR7R8, C(0)NR7R8, (CH2)mHet,
(CH2)mO(CH2)0CH3, (CH2)m(C3-Cιo)cycloalkyl, (C3-Cιo)cycloalkyl, wherein o is 0 or 1, m is 1 or
2, a is 1 to 4, b is 1 to 5, q is 2 or 3; ] represents C Cι0 εύkyl, C2-Cι0 alkenyl, C2-Cι0 alkynyl, phenyl-(-R5)b, -(CH2)-ρhenyl(-R5)a,
(CH2)mHet, (CH2)m(C3-C10)cycloalkyL (C3-C]0)cycloalkyl andtlie hke;
R2 represents C C6 alkyl, phenyl-(-R5)b, -(CH2)-phenyl(-R5)b, -(CH2)mHet; wherein Het is a 5- or
6- membered saturated or unsaturated ring containing from one to three heteroatoms selected from the groxip containing nitrogen, oxygen and sulfur; and also includes mono or bicyclic group, which may be further attached to above defined heterocycles;
R3 represents hydrogen, Ci-Cio alkyl, C2-Cι0 alkenyl, C2-Cι0 alkynyl, C(0)R9, C(0)ORs; optionally, R2 and R3 together may fonn a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; R4 represents lvydrogen, C-.-C10 alkyl, and is attached to any one or more than one carbon atoms present in tire side chain;
R5 represents either same or different substitutents such as hydrogen, halogen, hydroxy, -X-R8 (X = -0-, - H-, -S-), nitro, amino, -NR5R7, -NHC(0)Rι, -OC(0)Rb -OC(0)Ru -C(0)Rι, trifluorornethyl, trifluoromethoxy, -S02N(R)(R), -CN, -CO(0)Rs, CrC4 alkyl, phenyl, -0-CH2-0-; Re represents hydrogen, CrC10 alkyl, -€(0)0^, phenyl-(-R5)b, -(CH2)-ρhenyl-(-R5)b, -(CH2)mHet, and is attached to any one or more than one carbon atoms present in the side chain; R7 represents hydrogen, C1-C10 alkyl;
R8 represents hydrogen, C1-C10 alkyl, C2-Cιo alkenyl, C-2-C10 alkynyl, phenyl-(-Rs)b, -(CH2)b- phenyl-(-R5)b, -(CH2)b- Het; R9 represents hydrogen, hydroxy, ORs, NRsR7;
Rio and Rπ each independently represents hydrogen, halogen, C]-C alkyl, C C4 haloalkyl, aryl, ar(C C4)alkyl, hydroxy, -X-R8 (X = O, NH, S), nitro, amino, -NRsR7, NHC(0)Rh OC(0)Rι, 0C(0)Ru C(0)Rl5 tiifluoromethyl, trifluoromethoxy, S02N(R)(R), (CH2)nS02N(R)(R), -CN, - CO(0)Rs, phenyl, 0-CH2-0-; Rio and n togetlier witli the two adjacent carbon atoms of pheiryl . rmg form a cyclic structure containing 5 to 8 carbon atoms, which may contain 1 to 3 double bonds, optionally it may contain one to three hetero atoms selected from the group containing oxygen, sulfur and nitrogen; n is 1 to 4 and relates only to carbon atoms; said process comprising of one-pot reaction in the presence of acidic catalyst and a suitable solvent, and if desired, removing in any known manner , water fonned in the reaction.
The compounds of formulae (I) may have one or more asyinmetric carbon. The process of invention also includes preparation of such chiral compounds of formula (I) using the corresponding chiral oxo amines wherein the reaction proceeds with complete retention of configuration at the asymmetric carbon atom.
Similarly the compounds of formula (I) may also posses geometric isomerism, wherein also the process of this invention can be used to prepare such compounds.
Suitable phenyl hydrazines for the process according to this invention are : phenyl hydrazine, 4-methylρhenyl hydrazine, 4-ethylphenyl hydrazine, 4-propylphenyl hydrazine, 4- dodecj phenyl hydrazine, 4-methoxyphenyl hydrazine, 2,5-dimethylphenyl hydrazme, 3,4- dimethylphenyl hydrazine, 4-ethoxyphenyl hydrazine, 4-benzyloxyphenyl hydrazine, 4- chlorophenyl hydrazine, 4-bromophenyl hydrazine, 4-fluorophenyl hydrazine, 4-iodophenyl hydrazine, 5-chloro-2-methylphenyl hydrazine, 4-(l-(l,3-oxazolidine-2-one-4- yl)methylene)phenyl hydrazine and 2,4-dichlorophenyl hydrazine.
Suitable ketones for tlie process according to the invention are: N,N-dimethyl-4-oxo- pentanamine, N,N-diethyl-4-oxo-pentanamine, N-methyl,N'-etlιyl-4-oxo-pentanamine, N,N,2- trimetlιyl-4-oxo-pentanaιnine, N,N,3-trimethyl-4-oxo-pentanamine, N,N,2-trietlryl-4-oxo- pentanamine, N,N,3-triethyl-4-oxo-pentanamine, N,N-dimetlιyl-5-oxo-hexanamine, N.N-diethyl- 5-oxo-hexanamine, N-metlιyl,N'-etlιyl-5-oxo-hexanamine, N,N,2-trhnetlιyl-5-oxo-hexanamine, N,N,3-trimethyl-5-oxo-hexanamine, N,N,2-triethyl-5-oxo-hexanamine, N,N,3-triethyl-5-oxo- hexanamine, N,N-dimetlιyl-6-oxo-heptanamine, N,N-diethyl-6-oxo-heptanamine, N-methyl,N'- ethyl-6-oxo-heptanamine, N,N,2-tiimeth}rl-6-oxo-heptanamine, N,N,3 -tiimethyl-6-oxo- heptanamine, N,N,2-triethyl-6-oxo-heptanamine, N,N,3-trietlιyl-6-oxo-heptanamine, N,N- dimetliyl benzoylpropanamine, . N,N-diethyl benzoylpropanamine, N,N-dimethyl (4- bromobenzoyl)propanamine, N,N-dimethyl benzoylbutanamine, N.N-dietiryl benzoylpentanamine, N,N-dimethyl (4-bromobenzoyl)butanamine and N,N-dimetlιyl (4-metlιylbenzoyl)pentanamine. DETAILED DESCRIPTION OF THE INVENTION
The present mvention relates to a process for the preparation of compounds of general formula (I),
Figure imgf000006_0001
General formula (I) which comprises of reacting a phenyl hydrazine of the formula (II) or its salt represented by the formula (IF), each of which has at-least one ortho-position ^-substituted,
Figure imgf000006_0002
with a ketone a ine represented by the formula (III),
Figure imgf000007_0001
(in) wherein,
R represents hydrogen, Cι-C*0 alkyl, C2-Cι0 alkenyl, C2-Cι0 alkynyl, phenyl-(-R5)b, CH2-phenyl-(- R5)a, S02-phenyl(-R5)a, C(0)R9, C(0)ORs, (CH2)qNR7Rs, C(0)NR7Rs, (CH2)mHet,
(CH2)mO(CH2)0CH3, (CH2)m(C3-Cιo)cycloalkyl, (C3-Cι0)cycloalkyl, wherein o is 0 or 1, m is 1 or
2, a is 1 to 4, b is 1 to 5, q is 2 or 3;
Ri represents Ci- o alkyl, C2-Cιo alkenyl, C2-Cι0 alkynyl, phenyl-(-R5)b, -(CH2)-phenyl(-R5)a>
(CH2)mHet, (CH2)m(C3-Cιo)cycloalkyl, (C3-Cι0)cycloalkyl and tlie like; R2 represents C C6 alkyl, phenyl-(-R5)b, -(CH2)-phenyl(-R5)b, -(CH2)mHet; wherein Het is a 5- or
6- membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group containing nitrogen, oxygen and sulfur; and also includes mono or bicyclic group, which may be further attached to above defined heterocycles;
R3 represents hydrogen, Cι-Cι0 alkyl, C2-C 0 alkenyl, C2-Cιo alkynyl, C(0)R9, C(0)OR6; optionally, R2 and R3 together may form a part of cychc structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; Rt represents hydrogen, -Cio alkyl, and is attached to any one or more than one carbon atoms present in the side chain;
R5 represents either same or different substitutents such as hydrogen, halogen, hj'droxyl, -X-R« (X
= -0-, -NH-, -S-), nitro, amino, -NR<;R7, -NHC(0)Rι, -OC(0)Rι, -OC(0)Rι, -C(0)Rb trifluoromethyl, trifluoromethoxy, -S02N(R)(R), -CN, -CO(0)R6, C C4 alkyl, phenyl, -0-CH2-0-; Rs represents hydrogen, C Cι0 alkyl, -C(0)ORι, phenyl-(-R5)b, -(CH2)-phenyl-(-R5)b, -(CH2)mHet, and is attached to any one or more than one carbon atoms present in the side chain;
R7 represents hydrogen, Ci-Cio alkyl;
R8 represents hydrogen, C Cιo alkyl, C2-Cι0 alkenyl, C2-Cι0 alkynyl, phenyl-(-R5)b, -(CH2)b- phenyl-(-Rs)b, -(CH2)b- Het; R9 represents hydrogen, hydroxyl, ORs, NR5R7;
Rio and n each independently represents hydrogen, halogen, Cι-C4 alkyl, C C haloalkyl, aryl, ar(C C4)alkyl, hydroxyl, -X-R« (X = O, NH, S), nitro, amino, -NR«R7, NHC(0)Rι, OC(0)R
OC(0)Rι, C(0)Rι, trifluoromethyl, trifluorometlioxy, S02N(R)(R), (CH2)nS02N(R)(R), -CN, -
CO(0)Rg, phenyl, 0-CH2-0-; Rio and Rn together with the two adjacent carbon atoms of phenyl ring form a cyclic structure containing 5 to 8 carbon atoms, which may contain 1 to 3 double bonds, optionally it may contain one to three hetero atoms selected from the group containing oxj'gen, sulfur and nitrogen; n is 1 to 4 and relates only to carbon atoms; and the said process wherein comprises of an one-pot reaction in the presence of acidic catalyst and a suitable solvent, optionally having a suitable mechanism to remove water fonned in the reaction.
Examples of suitable salts of phenyl hydrazine represented by the general formula (IP) includes the hydrochloride salt, the hydrobromide salt, the salts of H2S0 , HN03, H3P0 and the like, prepared by reacting phenyl hydrazme of formula (II) with the corresponding mineral acids.
Halogen when mentioned is fluorine, chlorine, bromine or iodine.
Suitable acid catalysts include mineral acids as well as organic acids, characterized in that glacial acetic acid, perchloric acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, orthophosphoric acid, polyphosphoric acid and the hke. Optionally Lewis acids such as almninum chloride, titanium tetrachloride, zinc chloride etc. can be used as a catalyst in some cases.
Preferable acid catalysts used include trifluoroacetic acid, sulfuric acid, orthophosphoric acid or glacial acetic acid in suitable concentrations and optionally the acid catalyst used may be dissolved in an aqueous solvent. Suitable mechanism for removing water from a reaction mixture includes those described in the literature and known to a skilled artisan. Dehydrating agents such as sulfuric acid, molecular sieves, or removing water by azeotropic distillation are examples of techniques described in the prior art.
The process comprises of reacting the phenyl hydrazme compound of formula (II) or its salt (IP) with the ketone amine compound of formula (III) in presence of suitable solvent and an acid catalyst. The reaction may be carried out at temperature ranging between 60 °C to the reflux temperature of the solvent/s used, for about half-hour to 4 hours. Optionally, water formed in the reaction may be removed using the techniques known in the art. The reaction may be conducted in . an inert atmosphere. Phenyl hydrazine of formula (II) or its salt (IP) and ketone amine of formula (III) can be present in 1: 1 molar ratios to 1: 5 molar ratio of each other. The compound of formula (II) or its corresponding salt (IP), optionally may be first dissolved in a solvent, and then added to the reaction mixture and the vice-versa.
Suitable solvents for the phenyl hydrazine of formula (II) or its salt (IP) include ethers, alcohols, nitroalkanes, acetonitrile, dimethylsulfoxide, dimethyl formamide, and hexametiiylphosphoramide. While suitable solvents for the ketone amine of formula (III) includes inert solvents, such as, hydrocarbons, chlorinated hydrocarbons or acyclic ethers and the mixtures thereof.
Suitable substitutcnts for either hydrazine derivative or the ketone amine compound are those, which are compatible with the reaction, i.e., do not significantly reduce the yield of reaction and do not cause a significant amount of side reactions.
Suitable acid catalysts include organic as well as mineral acids characterized in that glacial acetic acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, perchloric acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like. The preferred acid catalyst is dissolved in protic or polar solvents such as alcohols or ethers, for example, methanol, ethanol, propanol; ethers such as tetrahydrofuran, diisopropyl ether; and even water upto 50 % may be present in some cases.
The acid employed can be present in the mole ratio of 1 to 10 mole equivalents per mole of ketone amine. The particular molar proportions employed will depend upon the concentration of the acid employed as illustrated in the examples. Preferable acid catalysts used in the process of this invention include trifluoroacetic acid, sulfuric acid or glacial acetic acid in suitable concentrations and optionally dissolved in a solvent may be used to carry out the process of this mvention.
The concentration of acid catalyst employed in the reaction can vary from about 10 % to 100 % or from 10 % to 75 % with the range 15 to 75 % representing the preferred range of concentration. Wliere higher concentrations are employed, it is preferred to employ inert organic solvents such as toluene, xylene, or cl-lorobenzene.
The initial step of hydrazone formation requires a little amount of acidic catalyst and results into formation of 1 mole equivalent of water. The latter may be removed, if desired, using various tecl-niques known in the art such as using either a dehydrating condition, molecular sieves or by distillation.
Because the reaction is exothermic, the reagents are typically mixed slowly, e.g., drop- wise. The optimal reaction time and temperature depends on factors such as the solvent and concentration, which the skilled artisan will be able to adjust so as to maximize the yield of the product. Generally, after mixing the reaction is maintained at temperatures ranging from room temperature to reflux temperature of the solvent employed until completion of the reaction. It is known fact that the mode of addition of one reactant in another can accelerate the rate of reaction or at least minimize the formation of xmdesired components thus improving the economy of the process. hi the process according to this mvention it is possible initially to introduce either the phenyl hydrazine or ketone amine initially, together with the acid compound, in the solvent, and bring the mixture to the reflux temperature and then to add the reactant which is not added till then. It is frequently advantageous to introduce uhenyl hydrazine initially. It is advantageous to introduce the ketone amine at elevated temperature but before the reaction mixture reaches its maximum temperature.
It is also possible to add the phenyl hydrazine and the ketone amine simultaneously to the solvent, which is at the reflux temperature and contains the acid compound; in this case also it can be advantageous to introduce small amount of phenyl hydrazine in the begimiing of the reaction and latter add the two components simultaneously. This method of simultaneous addition is particularly suitable for a continuos operation, hi all cases, the formation of the phenyl hydrazone and its cyclisation to give indole, with the elimination of NH3, take place in immediate succession.
After termination of the process according to the invention the aqueous portion is isolated, neutralized, the substituted indole derivative is obtained in organic phase; if required, the indole can be purified further in a manner well known to those skilled in the art.
The reaction may be monitored by conventional techniques such as gas chromatograpliy, thin layer chromatograpliy etc or any other convenient technique known in the field of art. After it is confirmed that the reaction is complete the reaction mixture is allowed to cool slowly to room temperature.
The product may be isolated by addition of reaction solvent to an aqueous splvent, which may contain pH-modifying agents. Water is such preferred solvent, and the reaction mixture is latter neutralized with a suitable base such as sodium carbonate, liquid ammonia and the tike. Latter solvents are evaporated under reduced pressure then extracted with low boiling organic solvent such as ethyl acetate, diethyl ether or methylene dichloride and the like. The residue, if needed, may be further purified by using column cl romatography over a silica gel column using a solvent system containing ether, hexane, pentane, ethyl acetate, alcohols etc. or mixtures thereof. Again evaporating the solvent/s in an inert atmosphere under vacuum to obtain pure product, the structure of which is confirmed by characterizing with IR spectra, Mass spectra, NMR spectra, and melting point.
The following is the list of compounds prepared by the process of this invention,
1. N,N-dimetiιyl-2-(2-methylindol-3 -yl)ethylamine
2. N,N-dimethyl-2-(2,5 -dimethylindol-3 -yl)ethylamiιιe
3. N,N-dimetlιyl-2-(5 -fluoro-2-methylindol-3 -yl)etl ylamine 4. N,N-dimethyl-2-(5-chloro-2-methylindol-3-yl)ethylanώιe
5. N,N-dimetliyl-2-(5-bromo-2-metliylindol-3-yl)ethylamme
6. N,N-dimethyl-2-(5-methoxy-2-metlιylindol-3-yl)etlιylamine 7. N,N-dimetl yl-2-(2-pheπylindol-3-yl)etlιylamine
8. N,N-dimetl y]-2-(5-nιetli3'l-2-phenylindol-3-yl)etlιylamine
9. N.N-dimeth3-*l-2-(5-fluoro-2-phen3'lindol-3-yl)ethylanιine
10. N,N-dimetlιy]-2-(5-chIoro-2-phenylindo]-3-yl)etl ylamine 11. N,N-dimethyl-2-(5-bromo-2-phenylindol-3-yl)etl ylamine
12. N,N-dimethyl-2-(5-methoxy-2-phenylindol-3-y])etlιylanιine
13. N,N-din etiiyl-2-{5-(l,3-oxazohdine-2-one-4-yl-metliyl)-2-metliy]indol-3-yl}etli3'lainine The present will now be described with reference to the following e illustrative examples which should not be construed as the limiting scope of this invention. EXAMPLES
EXAMPLE 1 : Preparation of N,N-dimetliyl-2-(2-metliylindol-3-yl)etliylamine hi a reaction flask provided with Dean-Stark apparatus, 10.8 g of phenyl hydrazine, 15.48 g of N,N-dinιetlryl-4-oxo pentanamine, and 150 inL of toluene was charged under an inert atmosphere. Latter 55.6 g of ortlio phosphoric acid is added. The reaction mixture was then refluxed for 4 hrs by continuous stirring while monitoring the reaction and the temperature continuously. After completion, the reaction mixture was cooled and diluted with 200 inL water and pH was adjusted to about 10 - 11 using aqueous ammonia solution at low temperatures. The product was extracted with ethyl acetate 2 x 75 niL; organic layer washed with brine 1 30 inL and dried over anhydrous magnesium sulfate and the solvent was evaporated to dryness under reduced pressure. The residue was triturated with n-hexane and the separated solids are collected by filtration and chromatographed over a column of silica gel by elution with the ethyl acetate : methanol (9:l) to gettlιe title compomιdl5.8 g, 75.15 %), melting range: 96-98 °C.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1. EXAMPLE 2 :
Preparation of N,N-dimethyl-2-(2,5 -dimethylindol-3 -yl)ethylamine
To a reaction flask containing 150 mL aqueous sulfuric acid (10 %), warmed to 50-60 °C, under an inert atmosphere, 3.05 g of p-methylpheiryl hydrazine was added. Latter the temperature was heated to 90 °C, 3.89 g of N,N-dimethyl-4-oxo-pentamine was added drop-wise within 15 minutes. The reaction mixture was then refluxed for 4-5 hrs by continuous stirring while monitoring the reaction and the temperature continuously. After completion, the reaction mixture was quenched in 40 mL water and raised to the pH of about 10 using aqueous ammonia solution at low temperatures. The product was extracted with ethyl acetate 2 x 25 mL; organic la3'er was dried over anhydrous magnesium sulfate and the solvent was evaporated to dryness under reduced pressure. The residue was chromatographed over a column of silica gel by elution with the ethyl acetate : methanol (9:1) to get the title compound (3.09 g, 57.65 %), melting range: 126-129 °C
(uncorrected). The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1. EXAMPLE 3 :
Preparation of N,N-dimethyl-2-(5-fluoro-2-ιιιetli3*'liιιdol-3-yl)etl 3**laιιιiιιe 4-Fluorophenyl ltydrazine was used and the procedure as given in example 2 is followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data was given in Table 1.
EXAMPLE 4 :
Preparation of N,N-dimethyl-2-(5-chloro-2-metlιylindol-3-yl)etlιylamine
4-Chlorophenyl hydrazine was used and the procedure as given in example 2 is followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data was given in Table 1.
EXAMPLE 5 :
Preparation of N,N,-dimetlιyl-2-(5-bromo-2-methyhndol-3-yl)etlιylamine
4-Bromophenyl hydrazine was used and the procedure as given in example 1 is followed to obtain ti e title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
EXAMPLE 6 : Preparation of N,N-dimetliyl-2-(5-methoxy-2-metliylindol-3 -yl)etlιylamine
To a reaction flask, 9 mL acetic acid, 14 g of p-methox3φhenylhydrazine hydrochloride and 10.32 g of N,N-dimethyl-4-oxo pentanamme hydrochloride were added, under an inert atmosphere and the reaction mixture was warmed slowly till temperature reached 40-50 °C. After consumption of the reactants, a mixture of 9 mL acetic acid and 4 mL sulfuric acid were added dropwise, keeping the temperature below 60 °C, while contmuously stirring the reaction mixture in about half an hour. Later, , the reaction mixture was refluxed for about 3 to 4 hours, and continuously monitoriiig reaction and temperature. After the reaction was complete, the mixture was poured to 90 mL ice-cold water and the pH was adjusted to about 10 using sodium carbonate. The product was extracted with 2 x 50 mL methylene dichloride. The organic solution was dried over sodium sulfate and the solvent is evaporated to dryness under reduced pressure. The residue was cliromatographed over a column of silica gel and eluted with ethyl acetate to get the title compomid (14.5 g, yield = 78.2 %, melting range : 89 °C to 90 °C (uncorrected), purity = 98.5 % by HPLC).
The product obtained is characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1. EXAMPLE 7 : Preparation of N,N-dimethyl-2-(2-plienylindol-3-yl)ethylamine
To a reaction flask provided with Dean-Stark apparatus, 2.16 g of phenyl hydrazine, 3.8 g of N,N-dimethyl-4-oxo-4-phenyl butanamine, 12 g of ortho phosphoric acid and 50 mL of toluene were charged under an inert atmosphere. The reaction mixture was then refluxed for 4 hrs by continuous stirring and removing water azeotropically, monitoring the reaction and tiie temperature continuously. After completion, the reaction mixture was cooled and diluted with 50 mL water. The toluene layer was separated and recycled. The pH of the bottom aqueous layer was adjusted to about 10 - 11 using saturated sodium carbonate solution. The product was extracted with ethyl acetate 2 x 25 mL; organic layer washed with brine 1 x 30 mL and dried over anhydrous magnesium sulfate and the solvent is evaporated to dryness under reduced pressure. The residue was triturated with n-hexane and the separated solids were dried. The compound obtained weighs 4.1 g (77.65 %), melting range: 112 - 114 °C.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1. EXAMPLE 8: Preparation of N,N-dimethyl-2-(5-methyl-2-pheii3-Undol-3-yl)etliylainine
4-Methylphenyl hydrazine was used and procedure given in example 7 is followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data was given in Table 1. EXAMPLE 9:
Preparation of N,N-dimethyl-2-(5-fluoro-2-phen5 indol-3-yl)ethylamine
To a reaction flask provided with a Dean Stark apparatus, 3.17 g orthophosphoric acid, 1.0
, g of p-Fluorophenyl hydrazine l/2sulphate and 1.0 g of N,N-dimethyl-4-oxo-4-phenylbutanamine and toluene (25 mL) were added, under an inert atmosphere and the reaction mixture was heated to reflux. Latter, the reaction mixture was refluxed for about 4 to 5 hours. After completion of reaction, the toluene layer was separated and the residue was triturated with 30 mL water and tiie pH of aqueous layer was adjusted to about 10 using sodium carbonate. The product was extracted with 2 x 20 mL methylene dichloride. The organic solution was dried over sodium sulfate and the solvent was evaporated to dryness under reduced pressure. The residue was chromatographed over a column of silica gel and eluted with the ethyl acetate to get the title compound (1.32 g, yield
= 82 %, melting range : 104 °C to 105 °C (uncorrected)). The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1. EXAMPLE 10:
Prepai-ation ofN,N-dimetliyl-2-(5-chloro-2-phenylindol-3-yl)etliylamine 4-Chlorophenyl hydrazine was used and procedure given in example 7 was followed to obtain the title compoxuid.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1. EXAMPLE 11: Preparation of N,N-dimeti.iyl-2-(5-bromo-2-phenylhidol-3-yl)etliylamine
4-Bromophenyl hydrazine was used and procedure given in example 7 is followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
EXAMPLE 12:
Preparation of N,N-dimetlιyl-2-(5 -methoxy-2-phenylindol-3 -yl)ethylamine
4-Metlιoxyphenyl hydrazine was used and procedure given in example 6 is followed to obtain the title compound. The product obtained was characterized by IR spectra, NMR spectra and Mass spectra.
The corresponding data is given in Table 1.
EXAMPLE 13: Preparation of N,N-dimethyl-2-{5-(l,3-oxazohdine-2-one-4-yl-methyl)-2- metlιylindol-3 -yl} etliylamine
The corresponding hydrazine derivative was used and procedure given in example 7 was followed to obtain the title compound.
The product obtained was characterized by IR spectra, NMR spectra and Mass spectra. The corresponding data is given in Table 1.
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001

Claims

WE CLAIM:
1. A process for the preparation of compounds represented by the general formula I,
Figure imgf000018_0001
General formula (I) which comprises of reacting a phenyl hydrazine of the formula (II) or its salt represented by the formula (IP), each of which has at-least one ortho-position unsubstituted,
Figure imgf000018_0002
with a ketone amine represented by the formula (III),
Figure imgf000018_0003
(HI) wherein,
R represents hydrogen, C Cιo alkyl, C2-Cιo alkenyl, C2-Cι0 alkynyl, phenyl-(-R5)b, CH2-ρhenyl-(- R5)a, S02-phenyl(-R5)a, C(0)R9, C(0)ORs, (CH2)qNR7Rs, C(0)NR7Rs, (CH2)mHet, (CH2)mO(CH2)0CH3, (CH2)m(C3-Cιo)cycloalkyl, (C3-Cιo)cycloalkyl, wherein o is 0 or 1, m is 1 or 2, a is 1 to 4, b is 1 to 5, q is 2 or 3;
Ri represents C Cιo alkyl, C2-Cι0 alkenyl, C2-Cι0 alkynyl, plιenyl-(-R5)b, -(CH2)-phenyl(-R5)a> (CH2)mHet, (CH2)m(C3-Cιo)cycloalkyl and (C3-Cι0)cycloalkyl;
R2 represents Cι-C6 alkyl, phenyl-(-R5)b, -(CH2)-phenyl(-R5)b, -(CH2)mHet; wherein Het is a 5- or 6- membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group containing nitrogen, oxygen and sulfur; and also includes mono or bicyclic group, which may be further attached to above defined heterocycles;
R3 represents hydrogen, Ci-Cio alkyl, C2-Cιo alkenyl, C2-Cι0 alkynyl, C(0)R9, C(0)OR<;; optionally, R2 and R3 together may form a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three lieteroatom selected from the group of ox3'gen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; R4 represents hydrogen, C1-C10 a l, and is attached to any one or more than one carbon atoms present in the side chain;
R5 represents either same or different substitutents such as Irydrogen, halogen, hydroxyl, -X-R8 (X = -0-, -NH-, -S-), nitro, amino, -NR^RT, -NHC(0)Rι, -OC(0)Rι, -OC(0)Rι, -C(0)R,, trifluoromethyl, trifluorometlioxy, -S02N(R)(R), -CN, -00(0)^, C C4 alkyl, phenyl, -0-CH2-0-; Rg represents hydrogen, Cι-C10 alkyl, -C(0)OR,, phenyl-(-R5)b, -(CH2)-phenyl-(-R5)b, -(CH2)mHet, and is attached to any one or more than one carbon atoms present in tiie side chain; R7 represents hydrogen, C1- 0 alkyl;
R8 represents hydrogen, C1- 0 alkyl, C2-C]0 alkenyl, C2-C]0 alkynyl, phenyl-(-R5)b, -(CH2)b- phenyl-(-R5)b, -(CH2)b- Het; R9 represents hydrogen, hydroxyl, ORg, NRδR7;
Rio and Rn each independently represents hydrogen, halogen, Cι-C4 alkyl, C C haloalkyl, aryl, ar(Cι-C4)alkyl, hydroxyl, -X-R-s (X = 0, NH, S), nitro, amino, -NR<;R7, NHC(0)R OC(0)Rb OC(0)Rj, C(0)Rι, trifluoromethyl, trifluoromethoxy, S02N(R)(R), (CH2)nS02N(R)(R), -CN, - CO(0)R<5, phenyl, 0-CH2-0-; io and Rn together with the two adjacent carbon atoms of phenyl rmg form a cyclic structure containing 5 to 8 carbon atoms, which may contain 1 to 3 double bonds, optionally it may contain one to three hetero atoms selected from the group containing oxygen, sulfur and nitrogen; n is 1 to 4 and relates only to carbon atoms; said process comprising of one-pot reaction in the presence of acidic catalyst and a suitable solvent, and if desired, removing in any known manner, water formed in the reaction.
2. The process according to claim 1, wherein in said compomid of formula (III), R2 and R3 each independently include, CpCβ alkyl, exemplified by methyl, ethyl, isopropyl, butyl, sec-butyl, tert-butyl and iso-butyl.
3. The process according to claim 1 or 2 , , wherein 4 is hydrogen, C1-C10 alkyl; wherein R5 is hydrogen, C1-C10 alkyl, C(0)ORι and phenyl.
4. The process according to claim 3, , wherein R is hydrogen, C1-C3 alkyl; wherein Re is preferably hydrogen and C1-C3 alkyl.
5. The process according to claim 4, wherein R4 and Re both together are hydrogen.
6. The process according to any preceding claim , wherein said compound of formula (IP)comprises a hydrochloride salt, hydrobromide salt, salts of H2S0 , HN03, or H3P0 .
7. The process according to any preceding claim, wherein the compomid of formula (II) or its salt (IP) and the compound of formula (III) are present in 1: 1 molar ratios to 1: 5 molar ratio of each other.
8. The process according to claim 1, wherein the said acid catalyst includes mineral acids as well as organic acids, characterized in that glacial acetic acid, perchloric acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, orthophosphoric acid, and polyphosphoric acid.
9. The process according to claim 8, wherein tiie preferred acid catalyst includes glacial acetic acid, trifluoroacetic acid, orthophosphoric acid, hydrochloric acid, and sulfuric acid.
10. The process according to claim 9, wherein the concentration of said acid is 1 to 100 %.
11. The process according to any preceding claim, wherein said acid is dissolved in solvent preferably ethers or alcohols or mixtures thereof, preferably in the presence of methanol, ethanol, propanol; ethers such as tetrahydrofuran, diisopropyl ether; and optionally water upto 50 %.
12. The process according to claim 1, wherein the preferred acid is in mole ratio of 1 to 10 mole equivalents per mole of ketone amine.
13. The process according to claim 12, wherein the preferred acid is in mole ratio of 1 to 6 mole equivalents per mole of ketone amine.
14. The process according to any preceding claim, wherein the reaction mixture contains organic solvents such as toluene, xylene, chloroform and the mixtures thereof.
15. The process according to any preceding claim , wherein the reaction of said compound of formula (II) and the said compound of formula (III) is conducted at a temperature of 60 °C to tiie reflux temperature of the solvent mixture used.
16. The process according to any preceding claim , wherein water formed in the reaction is removed by azeotropliic distillation, molecular sieves or dehydrating agents.
17. The process according to claim 1, wherein the compomid of formulae (I) is selected from: i. N,N-dimethyl-2-(2-metlιyhndol-3 -yl)etlιylamine ii. N,N-dimetiιyl-2-(2,5-dimeth3*lindol-3 -yl)ethylamine iii. N,N-dimetl yl-2-(5-fluoro-2-methyHndol-3-yl)etlιylamine iv. N,N-dimethyl-2-(5-chloro-2-methylindol-3-yl)ethylainine v. N,N-dimetl yl-2-(5-bromo-2-niethyhndol-3-yl)etliylamine vi. N,N-dimethyl-2-(5-metlιoxy-2-metlιylindol-3-yl)ethylamine vii. N,N-dimethyl-2-(2-phenyUndol-3-yl)ethylamine viii. N,N-dimethyl-2-(5-metlιyl-2-phenylindol-3-yl)etlιylamine ix. N,N-dimethyl-2-(5-fluoro-2-pheιιylindol-3-yl)ethylamine x. N,N-dimetliyl-2-(5-chloro-2-phenylindol-3-yl)etliylamine xi. N,N-dimetiιyl-2-(5-bromo-2-phenylindol-3-yl)etiιylamiιιe xii. N,N-dimethyl-2-(5-methoxy-2-phenylinr'"l-3-yl)ethylamine and xiii. N,N-dinιetlιyl-2-{5-(l,3-oxazolidiιιe-2-one-4-yl-ιιιetlιyl)-2-metlιyliιιdol-3-yl}etlιylaιιιiιιe.
18. The process according to claim 1, wherein R]0 is l rogen, halogen, -Cio alk5'l, Ci-Cio alkoxy or a heterocycle.
19. The process according to claim 18, wherein Rio is hydrogen, fluorine, chlorine, bromine or iodine; methyl, methoxy, trifluoromethyl, trifluoromethoxy, benzyloxy or l,3-oxazolidine-2-one- 4-yl-methyl.
20. The process according to claim 1, wherein the said compound of formula (III) is selected from , N,N-dimethyl-4-oxo-peιιtanan ine, N,N-dietlιyl-4-oxo-pentanamine, N-methyl,N'-ethyl-4- oxo-pentanamine, N,N,2-trimetliyl-4-oxo-pentanamine, N,N,3-ttimethyl-4-oxo-pentanaϊ--ine, N,N,2-triethyl-4-oxo-pentanamine, N,N,3-triethyl-4-oxo-pentanamine, N,N-dimethyl-5-oxo- hexanamine, N,N-dietliyl-5-oxo-hexanamine, N-metlιyl,N'-etlιyl-5-oxo-hexanaιnine, N,N,2- trimethyl-5-oxo-hexanamirie, N,N,3-trhnethyl-5-oxo-hexanamine, N,N,2-triethyl-5-oxo- hexanamine, N,N,3-trietliyl-5-oxo-hexanamme, N,N-dhnethyl-6-oxo-lιeptanamine, N,N-dietlιyl-6- oxo-heptanamine, N-methyl,N'-ethyl-6-oxo-heptanamine, N,N,2-triniethyl-6-oxo-heptanamine, N,N,3-trime1-hyl-6-oxo-heptanamine, N,N,2-triethyl-6-oxo-heptanamine, N,N,3-triethyl-6-oxo- heptanamine, N,N-dimetlιyl benzoylpropanamine, N,N-dietlιyl benzoylpropanamine, N,N- dimethyl (4-bromobenzoyl)propanamine, N,N-dimethyl benzoylbutanamine, N,N-diethyl benzoylpentanamine, N,N-dimethyl (4-bromobenzoyl)butanan ine and N,N-dimethyl (4- metliylbenzoyl)pentananune.
21. The process according to claim 1, wherein the said compound of formula (II) is selected from , phenyl hydrazine, 4-methylphenyl hydrazine, 4-ethylphenyl hydrazine, 4-propylphenyl hydrazine, 4-dodecylphenyl hydrazine, 4-methoxyphenyl hydrazine, 2,5-dimethylphenyl hydrazme, 3,4-dimetlιylphenyl hydrazine, 4-ethoxyphenyl hydraz ie, 4-benzyloxypheιryl hydrazme, 4-chlorophenyl hydrazine, 4-bromophenyl hydrazine, 4-fluorophenyl hydrazine, 4- iodophenyl hydrazine, 5-clιloro-2-methylplιenyl hydrazine, 4-(l-(l,3-oxazolidine-2-one-4- yl)methylene)phenyl hydrazine and 2,4-dichlorophenyl hydrazine.
PCT/IN2002/000226 2002-11-07 2002-11-28 Preparation of 3-aminoalkyl-substituted indole derivatives from phenylhydrazines and aminoketones Ceased WO2004041781A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002356428A AU2002356428A1 (en) 2002-11-07 2002-11-28 Preparation of 3-aminoalkyl-substituted indole derivatives from phenylhydrazines and aminoketones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN817/MAS/2002 2002-11-07
IN817CH2002 2002-11-07

Publications (2)

Publication Number Publication Date
WO2004041781A1 true WO2004041781A1 (en) 2004-05-21
WO2004041781A8 WO2004041781A8 (en) 2004-09-16

Family

ID=32310094

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2002/000226 Ceased WO2004041781A1 (en) 2002-11-07 2002-11-28 Preparation of 3-aminoalkyl-substituted indole derivatives from phenylhydrazines and aminoketones

Country Status (1)

Country Link
WO (1) WO2004041781A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098233B2 (en) * 2001-06-21 2006-08-29 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. 5-halo-tryptamine derivatives used as ligands on the 5-HT6 and/or 5-HT7 serotonin receptors
WO2009088402A3 (en) * 2007-10-01 2009-12-23 Princeton University Identification of bacterial autoinducer and use in treating bacterial pathogenicity
US7645881B2 (en) 2004-07-22 2010-01-12 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7868037B2 (en) 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8013006B2 (en) 2004-07-14 2011-09-06 Ptc Therapeutics, Inc. Methods for treating hepatitis C

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE548818C (en) * 1930-02-07 1932-04-20 I G Farbenindustrie Akt Ges Process for the preparation of substituted indoles
DE878802C (en) * 1943-07-13 1953-06-05 Hoechst Ag Process for the preparation of basic indoles
GB895430A (en) * 1958-04-07 1962-05-02 Sterling Drug Inc Tryptamine derivatives and acid addition salts thereof
US5942536A (en) * 1995-10-10 1999-08-24 Eli Lilly And Company N- 2-substituted-3-(2-aminoethyl)-1H-indol-5-YL!-Amides: new 5-HT1F agonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE548818C (en) * 1930-02-07 1932-04-20 I G Farbenindustrie Akt Ges Process for the preparation of substituted indoles
DE878802C (en) * 1943-07-13 1953-06-05 Hoechst Ag Process for the preparation of basic indoles
GB895430A (en) * 1958-04-07 1962-05-02 Sterling Drug Inc Tryptamine derivatives and acid addition salts thereof
US5942536A (en) * 1995-10-10 1999-08-24 Eli Lilly And Company N- 2-substituted-3-(2-aminoethyl)-1H-indol-5-YL!-Amides: new 5-HT1F agonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEM. IND. (LONDON), 1957, 1215 *
CHEMICAL ABSTRACTS, vol. 52, no. 1, 1958, Columbus, Ohio, US; abstract no. 2835e, M. SLETZINGER ET AL.: "New Synthesis of Woolley's Benzyl Antiserotonin Compounds" XP002236791 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098233B2 (en) * 2001-06-21 2006-08-29 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. 5-halo-tryptamine derivatives used as ligands on the 5-HT6 and/or 5-HT7 serotonin receptors
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7868037B2 (en) 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8013006B2 (en) 2004-07-14 2011-09-06 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7645881B2 (en) 2004-07-22 2010-01-12 Ptc Therapeutics, Inc. Methods for treating hepatitis C
WO2009088402A3 (en) * 2007-10-01 2009-12-23 Princeton University Identification of bacterial autoinducer and use in treating bacterial pathogenicity
US8535689B2 (en) 2007-10-01 2013-09-17 The Trustees Of Princeton University Identification of bacterial autoinducer and use in treating bacterial pathogenicity

Also Published As

Publication number Publication date
WO2004041781A8 (en) 2004-09-16

Similar Documents

Publication Publication Date Title
DE69201058T2 (en) PERHYDROISOINDOL DERIVATIVES AND THEIR PRODUCTION.
US7550479B2 (en) Modified Pictet-Spengler reaction and products prepared therefrom
LU84070A1 (en) PHENYLCYCLOBUTYL DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION
DK155327B (en) METHOD OF ANALOGUE FOR THE PREPARATION OF 5H-2,3-BENZODIAZEPINE DERIVATIVES OR A PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALT
KR20040027878A (en) Process for preparation of amidine derivatives
HU194166B (en) Process for preparing 3-acyl-2-oxindole derivatives
WO2004041781A1 (en) Preparation of 3-aminoalkyl-substituted indole derivatives from phenylhydrazines and aminoketones
JPH11511487A (en) Synthesis of indolylmaleimide
WO2006039639A1 (en) Crystalline forms and process for preparing spiro-hydantoin compounds
JP2707936B2 (en) β-oxo-β-benzenepropanethioamide derivative
CA2607506A1 (en) Novel lactam compound
US5958942A (en) Tricyclic nitrogen ring compounds, their production and use
DE60021286T2 (en) PROCESS FOR PREPARING PYRAZOLO [1,5-B] PYRIDAZINE DERIVATIVES
EP1097152B1 (en) Synthesis of compounds useful in the manufacture of ketorolac
JPH0450315B2 (en)
FR2689889A1 (en) New derivatives of perhydroisoindole, and their preparation.
US4822895A (en) 3-aminoazetidine, its salts and intermediates of synthesis
JPH04244083A (en) Tricyclic pyridone derivative
MC1017A1 (en) Process for the preparation of indole derivatives
DE69702955T2 (en) Bis-imide derivatives, process for their preparation and pharmaceutical preparation containing them
JP2681873B2 (en) Method for producing tizanidine
Wang et al. A convenient and clean procedure for the synthesis of pyran derivatives in aqueous media catalysed by TEBAC
US4851420A (en) 2,6-diamino-3-halobenzylpyridines and processes for their manufacture as well as their use in pharmaceuticals
Rozhkov et al. Transformations of 2-aryl-4, 6-dinitroindoles
CA1294274C (en) Method of treating muscle tension, muscle spasticity and anxiety with 3-aryloxy-azetidinecarboxamides

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i

Free format text: IN PCT GAZETTE 21/2004 UNDER (72, 75) REPLACE "RAMKRISHNA, VENKATA SATYA NIROGI" BY "RAMAKRISHNA, VENKATA SATYA NIROGI"

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP