Title of Invention

SYNTHESIS OF AMINES AND INTERMEDIATES FOR THE SYNTHESIS THEREOF

Abstract

The present invention relates to a first embodiment to a method for the manufacture of esters of the formula 1, or especially of amides of the formula II wherein the symbols have the meanings given in the specification, as well as other intermediates and compounds useful in the synthesis of tryptamines and other substances mentioned in the title. The synthesis methods and intermediates are useful in the synthesis of pharmaceuticals.

Full Text

The present invention provides a novel process (= method) for the manufacture of derivatives, espedally precursors,of tryoiamine, horsfiline or ooerulesdne, novel partial reactions and novel intermedfates. The derivatives or precursors of trypiamtne, horsfiline and coerulescine are useful e.g. in the pharmaoeufical area. Background of the invention Derivatives of tryptamine 1 have been synthesized from substituted anllines. Some pertinent anilines are prepared from 4-nitro benzyl chloride (precursors for anti migraine pharmaceuticals such as Sumatriptan 2 see: DE 3,320,621, US 4,816,470, Almotdptan 3 see: Res. Discl. 1898, 412, 1088, Rizatriptan 4 see; EP 0497512A2) or Zoimitriptamn 5 from 4-nitro phenyl alanine see: WO 91/18887. A varlety of strategies have been disclosed for the conversion of the anillines 2, 3,4, or 5 Thus, the use of α-keto-δ-valerolactone as the carbonyl component for the Fischer- or substituted alkoxy, formyl or other alkanoyl, unsubslituted or substitited alkenyl or unsubstituted or substituted alkynyl; wherein n, R1 and R2 have the meanings given under formula 1 and NB is a tertiary nitrogen base where the nitrogen is not part of a ring. A compound of the formula Xb, e.g. as obtained in the above reactions can aurpridingly be R' is unsubstituted or substituted alkyl; bromo or lodo; espedally preferred is n =1 with R1 Mk\g In p-position to the oxindole nitrogen. may be further reacted as described below. These are compounds wherein Surpriaingly, here it is possible to retain the "dangling" amide functionality. diezabicyclo[2,2,2]ociane (DABCO) and subsequent dehydrogenation or oxidation with an unsubstituted or substituted alkyl, especially tower alkyl or preferably hydrogen, cyano. unsubstituted or substituted alkyl, especially lower alkyl or preferably hydrogen, cyano between 10 and 50bar, preferably at elevated temperatures, e.g. from 40 to 150°C, for 7) a compound of the formula XiII substituted alkynyl. Of special technical intereat is a compound of the formula XiV wherein alkyl, such as benzyl. reaction preferably takes place in acetic add in the presence of an acidle catalyst, between about -100 and 0 °C. It is preferably carried out under exclusion of moisture and oxygen, e.g. under Inert atmosphere, and In an appropriate solvent such as ether (e.g. Intermediates (compounds) that are part of the present invention are described in the subsequent examples, thus forming very preferred embodiments of the invention. Examples: The following examples serve to illustrate the invention without limiting the scope thereof. Wherever amblent temperature or room temperature is mentioned, this denotes a When most of the isatine has dissolved, ethyl acetate (100 mL) is added to prevent blocking comblined organic layers are washed with water (800 mL) and brine (700 mL.), and and IB-extracted into ethyl acetate (500 mL). The organic layer is washed with brine (2 x To a solution of 3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde (Example 13) (0.216 g. Under inert atmosphere, a flask is charged with manganese dioxide (8.7 g, 0.1 mol) and 2- 177.13(0-2). (80%), 316.47(20%) (MH+). WE CLAIM: 1. A compound of the formula I as claimed in claim 1, or a salt thereof, wherein n is 1-4, and each R1 unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, sulfonyl alkyl, N-mono- or N,N-disubstltuted or unsubstituted aminosulfonyl alkyl, hydroxy, meroapto, nitro, halogen, cyano, carboxamido, N-mono- or N,N-disubstituted carboxamido, carboxhydrazido, unsubstituted or substituted alkoxycarbonyl, unsubstituted or subsituted alkoxy, formyl or other alkanoyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, alkanoyloxy, N-mono- or N,N-disubstituted or unsubstituted amino, unsubstituted or substituted hydrazino, or is a residue of a boronic acid or an ester thereof; provided that when n is 1 and R\ is loweralkyl, R\ is located in the position para to the isatine nitrogen (5-position), and with the exception of a compound of the formula I wherein R1 is 5-or 7-chloro or 5-or 7-hydroxy or alkoxy or alkanoyloxy, and with further exception of the compound 3-hydroxy-3-bulytoxycarbonymethyl-7-ethyl-6-hydroxy-indofldin-2-one. 2. The compound of the formula III, wherein n, RI and R2 have the meanings given for compounds of the formula I or II in claim 1 or 3, except for a compound of formula I wherein n is zero or 1 and RI is lower alkyl. wherein Ac is acetyl and R2, R3 and R4 have the meanings indicated for compounds of the formula II with the proviso that in the compound of the formula II and of the formula VII, R2 Is other than hydrogen; by the reaction with formaldehyde or a precursor thereof in the presence of acetic acid. wherein R2, R3 and R4 are as defined under formula VII. 5. The method as claimed in claim 4 further comprising reacting the alcohol of the formula VIII shown in claim 2 with an oxidising agent to give the corresponding compound of the formula IX wherein R2, R3 and R4 have the meanings given under formula VII, 6. The method as claimed in any one of claims 1, where an amide compound of the formula II wherein R2 has one of the meanings given in claims 1 or 3 other than hydrogen Is fiirther reacted with a dehydrating agent to give a compound of the formula Xa, wherein n arid Ri are as defined under formula land R3 and R4 are, independently of each other, unsubstituted or substituted alkyl, or together form an unsubstituted or substituted alkylene bridge. 7. The method as claimed in claim 6 , further comprising reducing the compound of the formula Xa In the presence of a reductant to a compound of the formula Xb, 8. The method as claimed in claims 1 where a compound of the formula Xb as defined In claim 7 is obtained by hydrogenation of the benzytio 3-hydroxy group In a compound of the formula 11 comprising converting a compoimd of the formula Xb as claimed in claim 7 to a spiro indole of the formula XI by reaction with formaldehyde or a precursor thereof, wherein n, RI and R2 are as claimed in claim 7. 10. The compound of the formulae VII or VIII as claimed in claim 4 or of the formula IX as claimed in claim 5 or of the formula Xa as claimed in claim 6 or of the formula Xb as claimed irm claim 7 or of the formula XI as claimed in claim 9. by introduction of a moiety P2 which Is unsubstituted or substituted alkyl, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted aryi, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, silyl substituted by three moieties independently selected from unsubstituted or substituted alkyl and substituted or unsubstituted aryl, or acyl; wherein unsubstituted or substituted alkyl is introduced by reaction with a strong base, e,g, NaH, with a corresponding unsubstituted or substituted alkyl derivative of the formula XV, Alk-L (XV) wherein Alk is unsubstituted or substituted alkyl, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted aryl, carbamoyl, N-mono or N,N-disubstituted carbamoyl, and L is a leaving group, to give the corresponding compound of the formula XII or XIV wherein R2 Is unsubstituted or substituted alkyl; or acyl is introduced by reaction with the corresponding acylhalogenides or mixed or symmetric acid anhydrides with one or two of the corresponding acyl moieties; or the silyl derivatives are introduced using the corresponding silylhalogenides, respectively. 13. A process for the introduction into a compound of the formula II where n is zero and the other substituents are as claimed in claim 1 or 3, of a moiety Pi resulting from electrophillo substitution reaction with a halogen Rj, by reaction with a halosuccinimide, or nitro by reaction with nitric acid, leading to a compound of the formula XVI, wherein Hal is nitro or halogen, and R2, R3 and R4 have the meanings given for a compound ofthe formula II. wherein n is 1 or 2, Rl is unsubstltuted or substituted aryl or unsubstituted or substituted heterocyclyl and R2, RB and P4 have the meanings given under formula II in claim 1 or 3, comprising reacting a compound of the formula II for the synthesis of compound II, or of the formula XII for the synthesis of compound XII\ or of the formula XIV for the synthesis of compound XIV', wherein in each case n is 1 or 2 and Rl is halogen, under the conditions of the Suzuki coupling or analogous conditions with a compound of the formula (A), wherein Ar is unsubutituted or substituted aryl or heterocyclyl and Y is OH, into the corresponding compounds ofthe formulae 111 XII1 or XIV1 respectively. 15. A process for the reaction of a compound of the formula II of the formula XII as defined In any one of claims or a compound of the formula XIV as claimed in any one of claims with the proviso that in each of the compounds of the formulae II, XII and XIV, n is 1 and Rl is halogen, to a compound of the formulae 112 from compound II2, to a compound of the formula XII from compound XII or to a compound of the formula XIV from compound XIV, respectively, 16. The process for the reaction of compounds of the formula II a, of the formula XII or of compounds of the formula XV, with the proviso that in each of the compounds of the formulae II, XII and XIV n is 1 and Rl Is halogen, to compounds of the formulae II3(from compound II), Xll3(from compoundXII) or XIV3(from compoundXIV) respectively. wherein Z* is as just defined under conditions of or analogous to the Heck reaction to yield the corresponding compounds of the formulae II3, XII8 or XIV3, respectively. 17. The process for the reaction of compounds of the formula II as claimed in claim 22, of the formula XII, or of compounds of the formula XIV, with the proviso that in each of the compounds of the formulae II, XII and XIV n is 1 and Rl is halogen, to compounds of the formulae II4 (from compound II), XII4 (from compound XII) or XlV4 (from compound XIV) respectively, wherein R2, R3 and R4 are as claimedabove for a compound of the formula II, by reaction with a cyanide salt In the presence of a palladium catalyst. 18. A process for the reaction of compounds of the formula II of the formula XII as claimed in any one of claims or of compounds of the formula XIV as defined in any one of claims with the proviso that in each of the compounds of the formulae II, XII and XIV n is 1 and Rl is halogen to compounds of the formulae 115 (from compound II), XI15 (from compound XII) or XrV^ (from compound XIV) respectively, wherein R5 jS unsubstituted or substituted alkyl, or unsubstiluted or substituted aryl, and R2, R3 and R4 are as defined for the compounds of the formula II, by reaction with CO in the presence of the corresponding alcohol R5-OH. wherein R2, R3, R4 and R5, are as claimed in claim Ifor formula II, provided that one of R3 or R4 is not methyl and R3 and R4 together are not phthalyl, or a salt thereof by conversion of a compound of the formula XX6 into the corresponding compound of the formula XXI1 by reaction with a Wittig or Wittig Homer reagent in the presence of a suitable base. 23. A compound of any of the formule XIIIa, XVI, II1, XII1, XIV1,II2 XII2, XIV2

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5032-CHENP-2007 AMENDED PAGES OF SPECIFICATION 15-10-2012.pdf

5032-CHENP-2007 AMENDED CLAIMS 15-10-2012.pdf

5032-CHENP-2007 OTHER PATENT DOCUMENT 15-10-2012.pdf

5032-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 15-10-2012.pdf

5032-CHENP-2007 FORM-1 15-10-2012.pdf

5032-CHENP-2007 FORM-3 15-10-2012.pdf

5032-CHENP-2007 POWER OF ATTORNEY 15-10-2012.pdf

5032-CHENP-2007 CORRESPONDENCE OTHERS 04-04-2012.pdf

5032-chenp-2007-abstract.pdf

5032-chenp-2007-claims.pdf

5032-chenp-2007-correspondnece-others.pdf

5032-chenp-2007-description(complete).pdf

5032-chenp-2007-form 1.pdf

5032-chenp-2007-form 26.pdf

5032-chenp-2007-form 3.pdf

5032-chenp-2007-form 5.pdf

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