HK1095592B

HK1095592B - Process for the preparation of n-amino substituted heterocyclic compounds

Info

Publication number: HK1095592B
Application number: HK07102562.7A
Authority: HK
Inventors: Franz Weiberth; George E. Lee; Reda G. Hanna; Silke Dubberke; Roland Utz; Jurgen Mueller-Lehar
Original assignee: Aventis Pharmaceuticals Inc.
Priority date: 2003-10-03
Filing date: 2004-10-01
Publication date: 2010-04-23

Description

Process for preparing N-amino substituted heterocyclic compounds

Background

Technical Field

The invention relates to a method for the serial N-amination of nitrogen-containing heterocyclic compounds. More particularly, the present invention relates to an improved process for the preparation of N-aminoindoles by N-amination of indoles. The present invention also relates to an improved process for the preparation of N- (N-propyl) -N- (3-fluoro-4-pyridinyl) -1H-3-methyl-indol-1-amine and products derived therefrom.

Description of the Prior Art

A variety of N-amino substituted azaheterocyclic compounds have been used as intermediates in the preparation of a variety of organic compounds, which are used primarily for pharmaceutical applications, among others. A particularly important class of nitrogen heterocycles are the N-aminoindoles. It has been reported in the literature that N-amination of indoles and other nitrogen heterocyclic substances such as carbazoles and pyrroles can often be carried out by adding hydroxylamine-O-sulfonic acid (HOSA) to the indole in portions in a solvent such as Dimethylformamide (DMF) in the presence of excess potassium hydroxide, see for example Somei, m.; natsume, m.tetrahedron Letters 1974, 461. Similar N-amination processes, such as indoles, are described in U.S. Pat. No.5,459,274, which is incorporated herein by reference in its entirety.

However, the above-described methods have some limitations and are disadvantageous for the preparation of some N-aminoindoles, especially with respect to large scale and commercial synthesis of N-aminoindoles. For example, adding hygroscopic HOSA as a solid portion by portion causes problems and is not practical. In addition, the reaction must be carried out under heterogeneous conditions, resulting in unacceptably low product yields. In practice, the product yield is generally at a low level of about 40% and can generally vary depending on the surface area and mass of potassium hydroxide used and the efficiency of the agitation of the reaction medium. Therefore, the method is not suitable for scale-up operation. Most importantly, a large excess of base is typically used, and therefore there must be excessive waste disposal problems after neutralization and processing of the product, thereby making the process uneconomical for commercial operation.

It is also disclosed in the literature that N-amination of hexamethyleneimine can be carried out using HOSA in the presence of an aqueous solvent and an inorganic base, see for example EP patent application No.0249452, the entire content of which is incorporated herein by reference. The inorganic bases disclosed therein include alkali metal hydroxides and alkaline earth metal hydroxides. In particular, it is disclosed in the process that N-amination can be carried out by simultaneously feeding an aqueous solution of HOSA and an aqueous solution of sodium hydroxide into an aqueous solution of hexamethyleneimine. However, this process similarly suffers from all the disadvantages described above, and in addition it is particularly applicable to hexylidene imine, a stronger base than many other nitrogen heterocyclic compounds such as indoles, carbazoles, pyrroles and the like. Nevertheless, the reported product yields are very low. Thus, there is a need for an improved process for the N-amination of nitrogen-containing heterocyclic compounds.

As noted above, the N-amino nitrogen heterocycles so formed are useful as intermediates for the formation of N-alkylamino nitrogen compounds, such as N-alkylaminoindoles. In general, the N-alkylation of amino groups can be carried out using an alkylating agent, such as a haloalkane, in the presence of a base. However, such alkylation reactions often result in significant amounts of by-products resulting from competitive alkylation of the heterocyclic ring and are therefore undesirable, see, for example, U.S. patent No.5,459,274. In addition, such alkylation processes also generate excessive by-products such as basic halides, which must be disposed of, making them unsuitable for industrial scale-up operations.

It is therefore an object of the present invention to provide a novel homogeneous process for the N-amination of a variety of nitrogen heterocycles.

It is another object of the present invention to provide a process for the N-amination of nitrogen heterocyclic compounds involving organic bases, whereby N-amino heterocyclic compounds are prepared in high yield and in high purity.

It is a further object of the present invention to provide a novel N-alkylation process which does not result in any by-products, thereby providing N-alkylaminoheterocycle compounds of high purity.

Other objects and further scope of applicability of the present invention will become apparent from the detailed description given hereinafter.

Summary of The Invention

It has now been found that N-amination of a wide variety of nitrogen heterocycles can be carried out in a homogeneous medium using an organic base and an organic solvent, for example an aprotic solvent. Thus, according to one aspect of the present invention, there is provided a process for the preparation of a compound of formula II:

the method of this aspect of the invention comprises the steps of:

(a) in step (a), preparing a hydroxylamine-O-sulfonic acid (HOSA) solution in a suitable organic solvent;

(b) in step (b), preparing a solution of a suitable base in a suitable organic solvent;

(c) in step (c), preparing a solution of a compound of formula I in a suitable organic solvent;

(d) finally in step (d) the solution prepared in step (a) and the solution prepared in step (b) are added simultaneously and proportionally to the solution prepared in step (c) contained in a suitable reaction vessel at a suitable reaction temperature to provide the compound of formula (II) in high purity and yield,

wherein

R is hydrogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, benzyloxy or of the formula C_nH_xF_yOr OC_nH_xF_yWherein n is an integer of 1 to 4, x is an integer of 0 to 8, y is an integer of 1 to 9, and the sum of x and y is 2n + 1;

R₁and R₂Are identical or different and are selected independently of one another from hydrogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, benzyloxy or of the formula C_nH_xF_yOr OC_nH_xF_yWherein n is an integer of 1 to 4, x is an integer of 0 to 8, y is an integer of 1 to 9, and the sum of x and y is 2n + 1; or

R₁And R₂Together with the carbon atom to which they are attached form C₅-C₈A ring; and

m is 1 or 2.

In another aspect of the invention, there is also provided another process for preparing a compound of formula II as described herein. The method of this aspect of the invention comprises the following steps. In step (a), a solution of hydroxylamine-O-sulfonic acid and a compound of formula I as described herein is prepared in a suitable organic solvent. In step (b), a solution of a suitable base is prepared in a suitable organic solvent. In step (c), the solution prepared in step (a) is contacted with the solution prepared in step (b) simultaneously and proportionally at a suitable reaction temperature to provide the compound of formula (II) in high purity and high yield. R, R therein₁、R₂And m is as defined above.

In another aspect of the invention, there is also provided a process for preparing a compound of formula IV:

in this aspect of the invention, the method involves the following. A solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent are added simultaneously and proportionally to a solution of a compound of formula I as described herein in a suitable organic solvent at a suitable reaction temperature, wherein the compound of formula (I) as described herein is contained in a suitable reaction vessel. This reaction may provide a compound of formula (II) as described herein.

The resulting N-aminoindole compound (II) is then reacted with a compound of formula (III) in the same reaction vessel to provide a compound of formula (IV).

R, R therein₁、R₂And m is as defined above, and R₃And R₄Are identical or different and are independently of one another selected from hydrogen or C₁-C₄An alkyl group.

Finally, in another aspect of the invention, there is also provided a process for preparing a compound of formula VI:

in this aspect of the invention, the method comprises the steps of:

in step (a), a compound of formula (IV) as described herein is first prepared substantially in accordance with the procedures of the above embodiments. That is, a solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent are added simultaneously and proportionally to a solution of the compound of formula I in a suitable organic solvent at a suitable reaction temperature, wherein the compound of formula (I) as described herein is contained in a suitable reaction vessel. This reaction provides a compound of formula (II) as described herein. The resulting N-aminoindole compound (II) is then reacted with a compound of formula (III) in the same reaction vessel to provide a compound of formula (IV).

In step (b) of the process of the invention, the compound of formula (IV) is reacted with a suitable reducing agent to provide a compound of formula (V):

finally, in step (c) of the process of the invention, the compound of formula (V) is then reacted with the compound of formula (VII) in the presence of hydrochloric acid

To provide the compound of formula (VI) as its hydrochloride salt. R, R therein₁、R₂、R₃、R₄And m is as described above. R₅Is hydrogen, nitro, amino, halogen, C_1-4Alkyl radical, C_1-4Alkanoylamino, phenyl-C_1-4Alkanoylamino, phenylcarbonylamino, alkylamino or phenyl-C_1-4An alkylamino group; x is halogen; n is 1 or 2, and p is 0 or 1.

In another aspect of the invention, there is also provided a compound of formula (IV), wherein the substituents are as described herein, with the proviso that when R and R are₃When is hydrogen, R₄Is not hydrogen or methyl.

Detailed Description

The terms used herein have the following meanings:

the expression "C" as used herein_1-4Alkyl "includes methyl and ethyl and straight or branched propyl and butyl. Specific alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as "C" may be understood accordingly_1-4Alkoxy group "," phenyl-C_1-4Alkylamino "," amino-C_1-4Alkyl group "," C_1-4Alkylamino "," mono-or di-C_1-4Alkylamino radical C_1-4Alkyl group "" diphenyl-C group_1-4Alkyl group "," phenyl-C_1-4Alkyl group "," phenylcarbonyl-C_1-4Alkyl "and" phenoxy-C_1-4Alkyl groups ".

The expression "C" as used herein_1-6Alkanoyl "will have the same general formula as" C_1-6Acyl "has the same meaning and may also be structurally represented as" R-CO- ", wherein R is C as defined herein_1-5An alkyl group. In addition, "C_1-5The alkylcarbonyl group "will react withC_1-6Acyl groups have the same meaning. In particular, "C_1-6Acyl "will mean formyl, acetyl or acetyl, propionyl, n-butyryl and the like. Derived expressions such as "C" may be understood accordingly_1-4Acyloxy group and C_1-4Acyloxyalkyl group "," C_1-6Alkanoylamino "," phenyl-C_1-6An alkanoylamino group ".

The expression "C" as used herein_1-6Perfluoroalkyl "means that all of the hydrogen atoms in the alkyl group have been replaced with fluorine atoms. Illustrative examples include trifluoromethyl and pentafluoroethyl, and also straight-chain or branched heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and tridecafluorohexyl. The derived expression "C" may be understood accordingly_1-6A perfluoroalkoxy group ".

The expression "heteroaryl" as used herein includes all known heteroatom-containing aryl groups. Representative 5-membered heteroaryl groups include furyl, thienyl or thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, and the like. Representative 6-membered heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like. Representative examples of bicyclic heteroaryls include benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, and the like.

The expression "heterocycle" as used herein includes all known heteroatom-containing cyclic groups. Representative 5-membered heterocyclic groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, 2-thiazolinyl, tetrahydrothiazolyl, tetrahydrooxazolyl, and the like. Representative 6 membered heterocyclic groups include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like. Many other heterocyclic groups include, but are not limited to, aziridinyl, azepanyl, diazepanyl, diazabicyclo [2.2.1] hept-2-yl, and triazacycloheptyl (triazocanyl), and the like.

"halogen" or "halo" refers to chlorine, fluorine, bromine, and iodine.

As used herein, "patient" refers to warm-blooded animals such as rats, mice, dogs, cats, guinea pigs, and primates such as humans.

The term "pharmaceutically acceptable salt" as used herein means that a salt of a compound of the present invention is useful for medical applications. However, other salts may also be used in the preparation of the compounds according to the invention or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which may be formed, for example, by mixing a solution of a compound according to the invention with a solution of a pharmaceutically acceptable acid, for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, 2-hydroxyethanesulphonic acid, p-toluenesulphonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. Metal salts such as sodium monohydrogen orthophosphate (sodium monohydrogen orthophosphate) and potassium hydrogen sulfate may also be formed. The salts so formed may also be present as mono-or di-acid salts, and may be present in hydrated form or may be substantially anhydrous. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic ligands such as quaternary ammonium salts.

The expression "stereoisomers" is a general term for all isomers of a single molecule, which isomers differ only in the orientation of their atoms in space. Generally, it includes the mirror image isomers (enantiomers) that are typically formed due to at least one asymmetric center. In the case of compounds according to the invention having two or more asymmetric centers, they may additionally exist as diastereomers, as well as certain individual molecules as geometric isomers (cis/trans). Similarly, certain compounds of the present invention may exist as a mixture of two or more structurally distinct, rapidly equilibrating forms (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

The term "substituted" is to be taken in a broad sense to include all permissible substituents of organic compounds. In several particular embodiments disclosed herein, the term "substituted" refers to substitution with one or more substituents independently selected from the group consisting of: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_1-6Perfluoroalkyl, phenyl, hydroxy, -CO₂H. Esters, amides, C₁-C₆Alkoxy radical, C₁-C₆Thioalkyl, C₁-C₆Perfluoroalkoxy, -NH₂Cl, Br, I, F, -NH-lower alkyl and-N (lower alkyl)₂. However, any other suitable substituent known to those skilled in the art may also be used in these embodiments.

Thus, according to one aspect of the present invention, there is provided a method of preparing a plurality of N-amino substituted heterocyclic compounds. Thus in one broad aspect of the invention, any azacyclic compound of formula (IA) may be used to prepare the corresponding N-amino-heterocyclic compound, as shown in scheme 1.

Scheme 1

Representative examples of monocyclic azaheterocyclic compounds of formula (IA) useful in the methods of the present invention include, but are not limited to, substituted or unsubstituted pyrroles, pyrazoles, imidazoles, 1, 2, 3-triazoles, 1, 2, 4-triazoles, and the like. Representative examples of bicyclic nitrogen heterocycles of formula (IA) useful in the methods of the invention include, but are not limited to, substituted or unsubstituted indole, 4, 5, 6 or 7-aza-indole, purine, indazole, 4, 5, 6 or 7-aza-indazole, benzimidazole, 4, 7-diazaindole, and various other isomeric diazaindoles, and the like. Representative examples of tricyclic azacyclic compounds of formula (IA) useful in the methods of the present invention include, but are not limited to, substituted or unsubstituted carbazoles or a variety of well-known heteroatom-substituted carbazoles. As defined hereinabove, any possible substituent may be used in the context of the above-mentioned substituted heterocyclic compounds, provided that such substituent does not interfere with the process of the present invention.

Accordingly, in one particular embodiment of the invention there is provided a process for the preparation of a compound of formula II:

the method of this aspect of the invention comprises the steps of:

wherein

m is 1 or 2.

It should be noted that the compound of formula (II) may be prepared using the procedures as described hereinbefore, not necessarily in different reaction vessels but may be carried out using essentially these procedures in the same reaction vessel. Also, the order of addition of the reactants can be changed, if necessary, by changing the order of these steps.

In one aspect of the process of the present invention, any suitable organic solvent known to those skilled in the art may be used for steps (a) and (b) of the process of the present invention. Specific types of organic solvents that may be used broadly include polar aprotic solvents as well as a variety of non-polar aprotic solvents or mixtures thereof. An aprotic organic solvent as used herein means that the solvent is neither a proton donor nor a proton acceptor. In general, aprotic solvents are more suitable for steps (a) and (b) of the process of the invention.

Representative examples of aprotic solvents suitable for the process of the invention include, but are not limited to, N-methylpyrrolidinone (NMP), N-Dimethylformamide (DMF), dimethylacetamide (DMAc), Dimethylsulfoxide (DMSO), Hexamethylphosphoramide (HMPA), and the like. Mixtures of these solvents in any proportion may also be used. Examples of non-polar organic solvents include, but are not limited to, Tetrahydrofuran (THF), n-hexane, n-heptane, petroleum ether, and the like. Various halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, and the like can also be used. Other combinations of any polar and non-polar solvents may also be used, such as NMP/hexane, NMP/heptane, and the like.

As mentioned, the process of the present invention uses a base in step (b) of the process of the present invention. In general, any base which can produce the desired effect can be used in this step of the process of the invention. It is generally advantageous to use an organic base in this step, especially one that is soluble in the solvent used. Thus, the reaction can be carried out in a homogeneous manner. In addition, bases having a pKa value at least about the same as that of indole are more suitable for this step of the process of the present invention.

Suitable organic bases for this step include alkali metal alkoxides. Examples of suitable alkali metal alkoxides include, but are not limited to, lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide, and cesium tert-butoxide, and the like. Mixtures of these organic bases may also be used. It has been found that potassium tert-butoxide is a particularly suitable alkali metal alkoxide in the practice of the process of the present invention.

In step (c) of the process of the present invention, the solvent used is also an aprotic solvent. Any of the aprotic solvents listed above may be used in this step of the process of the invention. The same solvents as used in steps (a) and (b) may also be used in this step. For example, such aprotic solvents include, but are not limited to, NMP, DMF, DMAc, and the like, and/or mixtures thereof.

Any reaction temperature that produces the desired result can be employed in the process of the present invention. In general, suitable reaction temperatures may range from sub-ambient temperature (subambient temperature) to ambient temperature. For example, reaction temperatures of about-5 ℃ to about 40 ℃ are suitable for practicing the process of the present invention. Even more suitably, reaction temperatures of from about 0 ℃ to about 25 ℃ may be used in the process of the present invention. One skilled in the art will generally understand and appreciate that higher temperatures generally increase the rate of reaction. Therefore, in some cases super ambient temperature (i.e. above room temperature) up to the reflux temperature of the solvent may be used.

Generally, the process of the invention is carried out with an excess of base. For example, the base may be present in an amount of from about 1mol to about 10mol relative to the compound of formula I. However, to practice the process of the present invention, the base may be present in an amount of from about 3mol to about 6mol relative to the compound of formula I.

Similarly, HOSA is present in excess when compared to the compound of formula (I). It is often advantageous in the process of the invention to use more than one molar excess of HOSA. More advantageously, it has been found that only about a 2 molar excess of HOSA is sufficient to produce the best results by practicing the present invention.

Contacting the reaction solutions prepared in steps (a) and (b) with the reactant solution from step (c) may be carried out by any method known in the art. For example, but not limited thereto, said contacting in step (d) may be carried out in a continuous reactor wherein the reactants are continuously fed, or by static mixing, such as static mixing with limited residence time or static mixing combined with a loop system, or by a microreactor. For this purpose, various well-known static mixers, continuous reactors and microreactors can be used. The continuous reaction can be carried out in a continuous manner or batchwise by methods known in the art.

The contacting in step (d) may also be carried out in a batch reactor. Any known reactor that produces the desired results may be used. For example, the reaction solutions from steps (a) and (b) are fed in a batch operation to a reactor, e.g. a stirred tank reactor, containing the reaction solution from step (c). Various modifications known to those skilled in the art can be used to influence the addition of these reaction solutions in this mode of operation.

As noted above, a variety of azacyclic compounds may be used in the process of the invention. For example, without any limitation, where R and R are used in the process of the invention₁Is hydrogen and R₂A compound of formula (I) which is methyl. Wherein R is₁And R₂Compounds of formula (I) which together with the carbon atom to which they are attached form a benzene ring are also preferred. Specific examples of these compounds are described above. For example, substituted or unsubstituted carbazoles may be used.

In another aspect of the invention, there is also provided another process for preparing a compound of formula II as described herein. The method of this aspect of the invention includes the following steps. In step (a), a solution of hydroxylamine-O-sulfonic acid and a compound of formula I as described herein is prepared in a suitable organic solvent. In step (b), a solution of a suitable base is prepared in a suitable organic solvent. In step (c), the solution prepared in step (a) is contacted with the solution prepared in step (b) simultaneously and proportionally at a suitable reaction temperature to provide the compound of formula (II) in high purity and high yield. R, R therein₁、R₂And m is as defined above.

Furthermore, any reactor known in the art may be used to carry out the process of the invention as described above. For example, but not limited thereto, a stirred tank reactor, a continuous reactor, a microreactor or a static mixer may be used. The process of the invention described above is particularly suitable for carrying out the amination reaction in a continuous stirred tank reactor.

In this embodiment of the invention, any solvent suitable for carrying out the reaction may be used. More suitably, all solvents as described above may also be used in this embodiment. Generally, aprotic solvents as described herein, such as NMP, DMF or DMAc, are more suitable solvents.

In this embodiment, the bases used are those that produce the desired results. Any known base may be used. More suitably, however, a base such as the organic bases described above may be used in this embodiment of the invention. In general, it is more suitable to use an organic base which is soluble in the solvent used as reaction solvent as described hereinbefore. Specific examples of organic bases suitable for this embodiment include alkali metal alkoxides such as potassium tert-butoxide.

It is also understood by those skilled in the art that any reaction temperature that produces the desired results can be used in this embodiment of the invention. To reiterate, as noted above, sub-ambient to ambient temperatures are generally suitable for carrying out the process of the invention. However, super ambient temperatures may also be used in some cases.

Furthermore, it is often advantageous to carry out the process of the invention using an excess of base and HOSA when compared to the compound of formula (I). More advantageously, as noted above, even in this embodiment, only about a 2 molar excess of HOSA is sufficient to produce the best results. Similarly, as described above, an excess of base of about 1mol to about 10mol may be used, but the base may be present in an amount of about 3mol to about 6mol relative to the compound of formula I.

in this aspect of the invention, the method includes the following. A solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent are added simultaneously and proportionally to a solution of a compound of formula I as described herein in a suitable organic solvent at a suitable reaction temperature, wherein the compound of formula (I) as described herein is contained in a suitable reaction vessel as described above. This reaction provides a compound of formula (II) as described herein.

The resulting N-amino-indole compound (II) is then reacted with a compound of formula (III) in the same reaction vessel to provide a compound of formula (IV).

In this embodiment of the invention, the amination of the compound of formula (I) to the compound of formula (II) is carried out using a procedure substantially similar to that described above in the other two embodiments of the invention. Thus, all of the solvents, bases and reaction vessels described above may be used in this embodiment. Similarly, the same reaction conditions as described above may be used. In general, aprotic solvents such as NMP, DMF or DMAc and organic bases such as potassium tert-butoxide and HOSA in the temperature range of about-5 ℃ to about 40 ℃ can be employed. Temperatures of about 0 ℃ to about 25 ℃ are particularly preferred.

Furthermore, as mentioned above, it is generally advantageous to carry out the process of the invention using an excess of base and HOSA when compared to the compound of formula (I). More advantageously, as noted above, even in this embodiment, only about a 2 molar excess of HOSA is sufficient to produce the best results. Similarly, as described above, an excess of base of about 1mol to about 10mol may be used, but the base may be present in an amount of about 3mol to about 6mol relative to the compound of formula I.

Advantageously, it has now been found that the reaction of the compound of formula (II) with the compound of formula (III) can be carried out in the same reaction vessel by adding the compound of formula (III). In general, the compound of formula (III) may be added separately after the formation of the compound of formula (II). However, some organic or inorganic acids may be advantageously added. Suitable organic acids include acetic acid, propionic acid, n-butyric acid, and the like. It has also been found advantageous to use water with organic acids. Suitable inorganic acids include hydrochloric acid, nitric acid, sulfuric acid, and the like. The acid is generally added in an amount such that the reaction medium is maintained at a pH of about 4.

The addition reaction can generally be carried out at ambient temperature, but subambient to superambient temperatures can also be employed, depending on the type of compound of formula (II) and (III) used. Generally, temperatures of from about 0 ℃ to about 100 ℃ may be employed. Temperatures of about 5 ℃ to about 30 ℃ are preferred. More particularly an ambient temperature of about 20 c is preferred.

A variety of compounds of formula (III) may be used in the process of the invention. Examples of such compounds include, but are not limited to, a variety of well-known aldehydes and ketones. Specific examples of aldehydes include, but are not limited to, formaldehyde, acetaldehyde, propionaldehyde, n-butyraldehyde, isobutyraldehyde, benzaldehyde, phenylacetaldehyde, and the like. Suitable ketones for use in the process include, but are not limited to, acetone, methyl ethyl ketone, diethyl ketone, acetophenone, benzophenone, and the like. Generally, aldehydes are more suitable reactants in the process of the invention, propionaldehyde being the most suitable compound of formula (III).

In another aspect of the invention, an embodiment of the invention includes a product made according to the method of the invention. In particular R, R of the product prepared according to the process of the invention₁And R₄Is hydrogen, R₂Is methyl, and R₃Is ethyl. More particularly, the product prepared according to the process of the present invention is 3-methyl-N- (propylidene) -1H-indol-1-amine.

in this aspect of the invention, the method comprises the steps of:

in step (a) of this process embodiment of the invention, a compound of formula (IV) as described herein is first prepared substantially in accordance with the steps of the above embodiments. That is, a solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent are added simultaneously and proportionally to a solution of the compound of formula I in a suitable organic solvent at a suitable reaction temperature, wherein the compound of formula (I) as described herein is contained in a suitable reaction vessel. This reaction provides a compound of formula (II) as described herein.

finally, in step (c) of the process of the invention, the compound of formula (V) is then reacted with the compound of formula (VII) in a suitable organic solvent in the presence of a suitable base,

to provide a compound of formula (VI). Optionally treating the compound of formula (VI) with a mineral acid such as hydrochloric acid to provide a salt (e.g., hydrochloride salt) of the compound of formula (VI). R, R therein₁、R₂、R₃、R₄And m is as described above. R₅Is hydrogen, nitro, amino, halogen, C_1-4Alkyl radical, C_1-4Alkanoylamino, phenyl-C_1-4Alkanoylamino, phenylcarbonylamino, alkylamino or phenyl-C_1-4An alkylamino group; x is halogen; n is 1 or 2 and p is 0 or 1.

It will also be understood that the steps described above are for illustration purposes only. The order in which these steps are performed may be varied and/or one or more of these steps may be performed simultaneously and/or concurrently. Thus, variations of these steps also form part of the invention. More advantageously, all these steps can be carried out in the same reaction vessel, either in a single batch operation or in a continuous reactor.

Thus according to this aspect of the invention, in step (a) of this embodiment, the amination of the compound of formula (I) to form the compound of formula (II) is carried out in substantially the same manner as described above by using a solvent (preferably an aprotic solvent), a base (preferably an organic base) and HOSA at about sub-to ambient reaction temperature.

The compound of formula (II) thus formed is then converted to the compound of formula (IV), typically in the same reaction vessel, by reacting the compound of formula (II) with the compound of formula (III) as described above. The reaction conditions and suitable compounds of formula (III) are the same as those described above.

The compound of formula (IV) is then reduced to the compound of formula (V) as described. The reduction reaction may be carried out using any method known in the art. In general, the reduction may be carried out using any of the well-known C ═ N reducing agents (such as those typically used to reduce schiff bases, hydrazones, or imines). Examples of suitable reducing agents include, but are not limited to, lithium aluminum hydride, sodium borohydride and glacial acetic acid, sodium acetoxyborohydride, sodium diacetyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium ethoxide, hydrogen, and catalysts, and the like.

Other reducing agents such as dibutyltin dichloride (Bu) in HMPA may also be used₂SnClH). A variety of boron reagents may also be used. Specific examples include: diborane, boron-sulfide complexes, e.g.Boron-dimethyl sulfide or boron-1, 4-thioxane complexes; boron etherates such as boron-THF complexes; boron-amine complexes such as boron-ammonia, boron-tert-butylamine, boron-N-ethyl-diisopropylamine, boron-N-ethyl morpholine, boron-N-methyl morpholine, boron-piperidine, boron-pyridine, boron-triethylamine and boron-trimethylamine; boron-phosphine complexes such as boron-tributylphosphine or boron-triphenylphosphine; mixtures of borohydrides such as sodium borohydride and tetraalkylammonium borohydride; reagents for in situ generation of boranes, e.g. sodium and iodine borohydride and BF₃-a combination of diethylether, sodium borohydride and chlorotrimethylsilane, tetraalkylammonium borohydride and alkyl bromides such as n-butyl bromide; and so on. It has now been found that sodium borohydride in the presence of glacial acetic acid is generally a more suitable reducing agent in this step of the process of the invention.

The reduction is likewise carried out in the presence of a suitable organic solvent. In general, aprotic polar solvents such as those described herein are more suitable for performing this reduction step. Specific examples of such organic solvents include, but are not limited to, NMP, DMF, DMAc, THF, heptane, hexane, toluene, petroleum ether, and the like.

It has now surprisingly been found that a mixture of a polar aprotic solvent and a non-polar solvent provides several advantages in particular in carrying out this reduction step. Specific examples of such solvent mixtures include, but are not limited to, NMP/heptane, NMP/hexane, NMP/petroleum ether, DMF/hexane, DMF/n-heptane, and the like. In particular, it has now been found that a mixture of NMP and n-heptane can provide certain advantages in the process of the present invention, as it can significantly reduce foaming of the reagent.

The reduction of the compound of formula (IV) to the compound of formula (V) may generally be carried out at any temperature that produces the desired result. Thus, sub-to super-ambient temperatures may be employed depending on the type of compound and reagent used. Generally, temperatures of from about 0 ℃ to about 60 ℃ are suitable. Temperatures of about 5 ℃ to 40 ℃ are generally employed. Preferably at a temperature of about 30 deg.c.

The compound of formula (V) may be further isolated as a suitable salt, for example the hydrochloride salt, by reaction with a suitable acid, for example hydrochloric acid. In general, the salt of the compound of formula (V) is a crystalline solid, and thus provides a method of purifying the compound of formula (V), if necessary, prior to conversion of the compound of formula (V) to the compound of formula (VI) in a subsequent reaction with the compound of formula (VII).

The reaction of a compound of formula (V) with a plurality of pyridine derivatives of formula (VII), preferably with a compound of formula (VII) wherein X is Cl and p is 0, may be carried out to form a compound of formula (VI). Examples of such compounds of formula (VII) include, but are not limited to, 4-chloropyridine, 4-chloro-3-fluoropyridine, 4-chloro-2-fluoro-pyridine, and 4-chloro-3, 5-difluoropyridine.

The reaction is carried out in an aprotic polar solvent such as, but not limited to, NMP, DMF, DMAc, THF, heptane, hexane, toluene, petroleum ether, etc., as used in the previous method steps, or in a mixture of polar aprotic and nonpolar solvents such as, but not limited to, NMP/heptane, NMP/hexane, NMP/petroleum ether, DMF/hexane, DMF/n-heptane, etc. A variety of other solvents may also be used in this step of the process of the present invention. Examples of solvents suitable for this step include: ether solvents such as bis (2-methoxyethyl) ether, diethyl ether, dimethoxy ether, dioxane or THF; a polar aprotic solvent as described herein, comprising DMF, DMAc, HMPA or DMSO; or protic solvents such as methanol, ethanol, isopropanol, and the like. In addition, as noted, any combination of mixtures of these solvents may also be used. Generally, the reaction is carried out using the same solvent, such as NMP or a mixture of NMP and heptane.

Suitable organic bases for this step include alkali metal alkoxides. Examples of suitable alkali metal alkoxides include, but are not limited to, lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide, cesium tert-butoxide, and the like; alkali metal hydrides such as sodium hydride or potassium hydride and the like. Mixtures of organic bases may also be used. It has been found that potassium tert-butoxide is a particularly suitable alkali metal alkoxide in this step of carrying out the process of the present invention.

The reaction of the compound of formula (V) with the pyridine derivative (VIII) to form the compound of formula (VI) may generally be carried out at any temperature that produces the desired result. Thus, sub-to super-ambient temperatures may be employed depending on the type of compound and reagent used. Generally, temperatures of about 70 ℃ to about 150 ℃ are suitable.

The compound of formula (VI) may be further reacted with a suitable mineral acid to give a suitable salt of the compound of formula (VI). An example of such an inorganic acid is hydrochloric acid, to give the hydrochloride salt of the compound of formula (VI). In general, the salts of the compounds of formula (VI) are crystalline solids, and thus provide a method of purifying the compounds of formula (VI) if desired, before using them for, e.g., pharmaceutical purposes.

The reaction may be carried out in the same reaction vessel or in a different vessel after isolation of the compound of formula (V) as described above. Any reactor known in the art may be used to carry out the process of the invention described above. In addition, stirred tank reactors, continuous reactors, microreactors or static mixers may be used. The process of the invention described above is particularly suitable for carrying out the coupling reaction in a static mixer with a loop system or in a continuous stirred tank reactor. Advantageously, the reaction is operated in a batch mode.

In another aspect of the invention, an embodiment of the invention includes a product made according to the method of the invention. In particular, the product prepared is N- (N-propyl) N- (3-fluoro-4-pyridyl) -1H-3-methylindole-1-amine hydrochloride.

In a further aspect of the invention there is also provided a compound of formula (IV) wherein the substituents are as described herein, with the proviso that when R and R are₃When is hydrogen, R₄Is not hydrogen or methyl.

As mentioned, several within the scope of formula (IV)Compounds are known and are therefore excluded from the present invention. For example, Somei et al Tet.Lett.No.41, 3605-page 3608 (1974) describe a compound in which m is 0, R₁、R₂、R₃＝H，R₂Methyl, R₄A compound of formula (IV) which is methyl, the entire content of which is incorporated herein by reference.

In another aspect of this embodiment of the invention, a suitable compound of formula (IV) is that wherein R, R₁And R₃Is hydrogen and R₂A compound that is methyl. Specific compounds within the scope of the invention include, but are not limited to, the following:

3-methyl-N- (propylidene) -1H-indol-1-amine;

n- (propylidene) -1H-indol-1-amine;

5-benzyloxy-N- (propylidene) -1H-indol-1-amine;

5-methoxy-N- (propylidene) -1H-indol-1-amine;

and N- (propylidene) -1H-carbazol-1-amine.

The invention is further illustrated by the following examples, which are provided for illustrative purposes and in no way limit the scope of the invention.

Examples (in general)

The following abbreviations are used in the following examples:

HOSA hydroxylamine-O-sulfonic acid

HPLC high performance liquid chromatography

KOtBu potassium tert-butoxide

NMP N-methylpyrrolidone

NMR nuclear magnetic resonance spectroscopy

Universal analytical techniques for characterization: various analytical techniques are used to characterize the compounds prepared in accordance with the practice of the present invention, including the following: recording was performed using a Varian XL300 or Gemini300 spectrophotometer operating at 300, 75 and 282MHz respectively¹H、¹³C and¹⁹f NMR spectrum.¹H NMR spectroscopic data is expressed as δ in parts per million (ppm) relative to Tetramethylsilane (TMS) as an internal standard, and the following abbreviations are used to summarize the data: s is singlet and d is doublet; t is a triplet; q is quartet; m is multiplet; dd ═ doublet of doublets; br ═ broad peak. A3.9X 150mm Waters Symmetry C is typically used on a Perkin-Elmer Integral 4000 liquid chromatograph₁₈HPLC data were collected on a column, 5. mu.l, acetonitrile/0.1N ammonium formate in an equal mobile phase (isocratic mobile phase), flow rate 1.0 mL/min and UV detection. Mass spectra were obtained on a Finnigan TSQ700 spectrometer. Elemental analysis was performed by Robertson Microlit, Inc. Other abbreviations used herein include the following: LC ═ liquid chromatography; MS ═ mass spectrum; EI/MS — electron jet impact/mass spectrometer; RT ═ residence time; m⁺A molecular ion.

Example 1

1H-indol-1-amines

A solution of 33.8kg (32.8 kg corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) and 15.8kg (15.6 kg corrected for 99% purity) of indole in 120.2kg of N-methylpyrrolidone (NMP) was prepared and cooled to 0-5 ℃. Another solution was prepared from 67.0kg (63.7 kg corrected for 95% purity) of potassium tert-butoxide and 122.6kg of NMP. The amination vessel was charged with an initial charge of 47.0kg of NMP and 2.2kg of potassium tert-butoxide/NMP solution. This HOSA/indole/NMP solution and the remaining potassium tert-butoxide/NMP solution were then metered simultaneously and proportionally into the amination vessel over 185 minutes using a metering pump system consisting of a double-headed plunger pump together with a Coriolis mass flow meter while maintaining a reaction temperature of 20 to 30 ℃ to give a solution containing 15.9kg (90.2% yield) of 1H-indol-1-amine as measured by external standard HPLC analysis.

Example 2

5-benzyloxy-1H-indol-1-amine

A solution of 5.3kg (5.2 kg corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 19.1kg of N-methylpyrrolidone (NMP) was prepared and cooled to 0-5 ℃. Another solution was prepared from 10.6kg (corrected to 10.0kg for 95% purity) of potassium tert-butoxide and 19.3kg of NMP. The amination vessel was charged with an initial charge of 5.0kg (4.7 kg corrected for 94% purity) of 5-benzyloxyindole, 15.5kg of NMP and 0.4kg of potassium tert-butoxide/NMP solution. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution were then metered simultaneously and proportionally into the amination vessel over 166 minutes while maintaining a reaction temperature of 14 to 29 ℃ to give a solution containing 4.3kg (86.0% yield) of 5-benzyloxy-1H-indol-1-amine as measured by external standard HPLC analysis. After adding 105L of water and cooling to 0-5 ℃, the mixture was filtered. The filtered solid is separated with 63L of n-butyl acetate and 8.5L of water and then filtered. The organic phase was concentrated under reduced pressure to give a solid containing 3.9kg (77.4% yield) of 5-benzyloxy-1H-indol-1-amine as measured by external standard HPLC analysis.

Example 3

5-methoxy-1H-indol-1-amines

A solution of 10.0g (9.7 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 33.7g N-methylpyrrolidone (NMP) was prepared and cooled to 0-5 ℃. Another solution was prepared from 20.1g (19.1 g corrected for 95% purity) of potassium tert-butoxide and 34.4g of NMP. The amination vessel was charged with an initial charge of 5.9g of 5-methoxyindole, 17.8g of NMP and 0.7g of potassium tert-butoxide/NMP solution. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution were then metered simultaneously and proportionally into the amination vessel over 86 minutes while maintaining a reaction temperature of 15 to 22 ℃ to give a solution containing 5.6g (87% yield) of 5-methoxy-1H-indol-1-amine as measured by internal standard HPLC analysis.

Example 4

1H-carbazol-1-amines

A solution of 10.0g (9.7 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 35.9g N-methylpyrrolidone (NMP) was prepared and cooled to 0-5 ℃. A second solution was prepared from 20.3g (19.3 g corrected for 95% purity) of potassium tert-butoxide and 35.3g of NMP. The amination vessel is charged with an initial charge of 7.0g (6.7 g corrected for 99% purity) of carbazole, 21.7g of NMP and 1.3g of potassium tert-butoxide/NMP solution. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution were then metered simultaneously and proportionally into the amination vessel over 86 minutes while maintaining a reaction temperature of 22-30 ℃ to give a solution containing 85% yield of 1H-carbazole-1-amine as measured by HPLC.

Example 5

1H-3-methyl-indol-1-amines

A36.1% (wt/wt) KOtBu/NMP solution (sufficient for 2 amination batches) was prepared by charging 35.6kg of potassium tert-butoxide and 63.1kg of N-methylpyrrolidinone (NMP) under nitrogen into a 30 gallon Hastelloy reactor and then stirring for 30 minutes at 20-25 ℃. A19.0% (wt/wt) solution of hydroxylamine-O-sulfonic acid (HOSA) in NMP (sufficient for 2 amination batches) was prepared by charging 75.4kg of NMP and a total of 17.7kg of HOSA (in triplicate over 45 minutes) into a 30 gallon Hastelloy reactor under nitrogen, stirring at 30-35 deg.C for 40 minutes (until dissolution occurred), and then cooling to 10 deg.C. The amination vessel was prepared by charging a 30 gallon glass lined reactor with 4.5kg (34.3mol) of 3-methylindole, 10.0L of NMP, and 0.4kg (0.1 eq.) of potassium tert-butoxide under nitrogen. A proportional metering pump system consisting of a double-headed plunger pump and a pair of mass flow meters was used to simultaneously pump the HOSA solution at 0.47kg/min and the KOtBu solution at 0.49kg/min to the amination reactor (through a subsurface injection tube in the amination vessel). The temperature of the slightly exothermic amination process was controlled at 25-35 ℃ by adjusting the jacket cooling. The feed was stopped after 90 minutes, at which point a total of 43.9kg of KOtBu solution (4.1 equivalents) and 42.0kg of HOSA solution (2.1 equivalents) had been fed in and a conversion to N-amino-3-methyl-indole of 97% was achieved (analysis by HPLC). The operation is performed in two parts. Half of the batch was transferred to a quench vessel (30 gallon reactor) containing 60L of cold water and 12L of toluene. Stirring for 10 minutes at 20-25 ℃ and then separating the phases. The aqueous phase was extracted with 3X12-L portions of toluene. The other half of the batch was treated similarly. The organic phases from each part of the treatment were combined and concentrated (60 ℃, < 50 mbar, 50L rotary evaporator) to give 5.2kg of N-amino-3-methylindole as a pasty solid corresponding to 4.5kg of product corrected for solvent (3.4 wt% toluene and 6.9 wt% NMP) as measured by NMR, 89.7% yield, 95.9% purity by HPLC.

Similarly, additional amination was performed using the remaining portions of the HOSA and KOtBu solutions following the same procedure described above to give 4.6kg (corrected) N-amino-3-methylindole in 91.1% yield.

Example 6

1H-indol-1-amines

Step 1-preparation of HOSA/indole solution: 120.2kg (116.3L) of NMP were charged to a 50 gallon glass lined steel reactor under a nitrogen sweep and slight venting while maintaining the reactor temperature at 19-23 ℃. 33.8kg (corrected to 32.8kg for 97% purity) of HOSA was fed in three portions (about 15.8kg, 9.0kg and 9.0kg) through the manholes with stirring (about 130rpm) at intervals of about 15 to 30 minutes. The heat release is expected at the first 10-15 ℃ temperature rise. Cooling water is circulated through the jacket or heated with a mild jacket to maintain a tank temperature of 20-35 deg.C (preferably 30-35 deg.C to aid dissolution). It is expected to dissolve after 1 to 2 hours of stirring. The contents of the reactor were cooled to a temperature of about 20 ℃ (10-25 ℃) and 15.8kg (corrected to 15.6kg for 99% purity) of indole was fed through the manhole. After dissolution (minutes), the contents of the reactor are cooled to a temperature of about 0-5 ℃ (-5 to 15 ℃), the stirring is reduced to about 50rpm and then the temperature is maintained at about 0-5 ℃ (-5 to 15 ℃)The remainder of the process.

Step 2-preparation of Potassium tert-butoxide solution: 122.6kg (118.7L) of NMP were charged to a 50 gallon glass lined steel reactor equipped with an air condenser tube under a nitrogen sweep and slight venting while maintaining the reactor temperature at about 17-19 deg.C (15-22 deg.C). 67.0kg (63.7 kg corrected for 95% purity) of potassium tert-butoxide (KOtBu) was fed through the manhole with stirring at about 150rpm (100-200 rpm). A slight exotherm to 20-25 ℃ was observed. Cooling is performed to maintain the temperature below 25 c, if necessary. After dissolution is achieved (within 15-60 minutes), the remainder of the process is carried out with stirring at about 50rpm and a temperature of about 17-25 ℃.

Step 3 amination: 47.0kg (45.5L) NMP was charged to a 150 gallon glass lined steel reactor under a nitrogen sweep and slight venting and cooled to 10-22 ℃ with stirring at about 180 rpm. About 0.05 equivalents of the KOtBu solution from step 2 (6.7mol, total 2.2kg solution) was charged as an initial amount. The two solutions prepared above in steps 1 and 2 were then pumped simultaneously through sparge tubes (3/8 inches, outside diameter 304, SS tube) inserted in nozzles on opposite sides (about 180 degrees apart) of the top of the reactor at the following rates: the HOSA/indole solution from step 1 at a rate of 0.8L/min of 0.9kg/min for a total time of 187.4 minutes; the KOtBu solution from step 2 was 1.0kg/min at a rate of 1.0L/min for a total time of 187.4 minutes while maintaining good stirring (> 180rpm) and cooling with chilled water to maintain the reaction temperature at about 15-30 c, preferably 24-30 c. The progress of the reaction was monitored by taking a sample of the reaction mixture at 0.5 equivalent HOSA feed intervals (35 seconds per 43 minutes during the simultaneous reagent feeds) for HPLC analysis as further detailed below. The simultaneous proportionate feeding was continued until all reagents (133.5mol scale) had been fed and the amination was judged to be complete as confirmed by HPLC analysis. The reactors from steps 1 and 2 were each washed with 5L of NMP and the wash liquid was pumped into the 150 gallon reactor during this step. The batch from this step is then used as is in the preparation of N-propylidene-1H-indol-1-amineAnd (4) carrying out the next step.

The reaction mixture was monitored by HPLC analysis using the following conditions:

column: phenomenex, IB-SIL 5 Phenyl, 150x4.6mm, 5 micron

Mobile phase: 65: 35 of 0.1N ammonium formate/acetonitrile

Flow rate: 1.5mL/min

Detecting: 275nm UV

Sample preparation: approximately 15. mu.L of the reaction mixture was diluted with 2mL of a 50: 50 mobile phase mixture

Injection amount: 10 μ L

Example 7

N-propylidene-1H-indol-1-amines

About 21.6kg of acetic acid was added to a 1H-indol-1-amine solution prepared in a 150 gallon steel reactor according to the procedure described in example 6 at a rate of about 1kg/min under nitrogen purge, slight venting, agitation at about 150rpm at 10-25 deg.C (preferably 10-18 deg.C) and with slow jacket cooling until the pH was 3.9-4.0 (0.1 mL of reaction mixture in 5mL of water). If necessary, gradually increasing amounts of more HOAc are charged to maintain the pH level. The pump was washed with about 2L NMP. 10.8L of water (a slight increase in temperature of about 3 to 6 ℃ is expected) are fed in essentially one portion (about 1 minute addition time). 14.4kg (corrected to 13.9kg for 97% purity) of propionaldehyde was fed at about 0.8kg/min (0.5-1.0 kg/min) while maintaining 10-24 ℃, preferably 10-20 ℃. A mild exotherm is expected. Depending on the addition and cooling rates, the temperature is expected to rise by about 5 ℃. The pump was washed with about 3L NMP. Stirring at 10-24 ℃, preferably 17-20 ℃ until the end of the reaction is judged by HPLC analysis of the conditions detailed further below (> 99% conversion in 2-3 hours). The progress of the reaction was monitored by taking a sample of the reaction mixture for HPLC analysis. When the end of the reaction is judged, it is ready for direct vacuum distillation from the reactor into a suitable receiver. Volatile initial distillates (about 45-50L) comprising tert-butanol and water are expected to be initially present at 50-70 ℃ and about 30-40 mm pressure. When the distillation rate is slowed down, the temperature of the tank is gradually increased to 95-100 ℃, the pressure is reduced to 5-25 mm and NMP starts to be collected. A total of about 320kg of distillate was collected (to give 9.5 parts w/w relative to the weight of the can of the initial indole feed) and then the vacuum was released with nitrogen and cooled to 10-25 ℃. If necessary or for convenience, the distillation can be interrupted at any time by releasing the vacuum with nitrogen, cooling to < 30 ℃, storing under nitrogen and then restarting as needed. The reaction was carried out by charging 133L of heptane through the reactor feed nozzle (to achieve a process volume of up to about 450L), followed by cooling with cooling water to maintain the exothermic temperature below 30 ℃ and charging 234L of water. Stir > 10 minutes and then allow the phases to separate. The bottom aqueous phase was extracted with 54L heptane. The organic extracts were combined and washed with aqueous potassium bicarbonate solution (prepared from 0.6kg of potassium bicarbonate dissolved in 58L (58-95L) of water), followed by 58L of water. The organic phase was concentrated to give crude N-propylidene-1H-indol-1-amine as an oil. Purifying by short path distillation, a first pass at about 120 ℃ evaporator and a pressure of about 200 to 800 mbar to remove volatiles, and then a second pass at 110 ℃ evaporator and a pressure of 0.2 to 0.4 mbar to collect the purified product.

column: phenomenex, IB-SIL 5 Phenyl, 150x4.6mm, 5 micron

Mobile phase: 65: 35 of 0.1N ammonium formate/acetonitrile

Flow rate: 1.5mL/min

Detecting: 275nm UV

Sample preparation: 2 drops of the reaction mixture were added per 1mL of acetonitrile and an injection volume of 10. mu.L

Example 8

N- (propylidene) -1H-indol-1-amines

A solution of 86.6g (771mmol) of potassium tert-butoxide in 160mL of N-methylpyrrolidone (NMP) is prepared. A solution of 36.4g (322mmol) of hydroxylamine-O-sulfonic acid (HOSA) in 175mL of NMP was also prepared. After a clear solution was obtained the HOSA solution was cooled to 10 ℃.

A solution of 11.9g (102mmol) of indole in 20mL of NMP is additionally prepared and an initial amount of 0.08 to 0.12 equivalents of KOtBu solution is added to the indole solution. The HOSA and KOtBu solutions were then added simultaneously and proportionally to the reaction mixture over 60 minutes at 20 ℃ by means of a double syringe pump. After the end of this addition, 9mL (500mmol) of water, 12mL (300mmol) of glacial acetic acid and 15mL (173mmol) of propionaldehyde were added to the resulting dark brown suspension. The mixture was stirred at 20 ℃ until the reaction was complete. The reaction mixture was then worked up by adding 500mL of water and 200mL of n-heptane. Allowing the phases to separate. The aqueous phase was extracted once more with 300mL of n-heptane and twice more with 200mL of toluene. The combined organic phases were washed twice with 100mL of water. The resulting brown heptane solution was evaporated to dryness. This gave 14g of N- (propylidene) -1H-indol-1-amine (80%) as a brown liquid.

Boiling point 130 ~ 135 ℃ (1.3 ~ 1.4 mbar)

¹H-NMR(DMSO-d₆，300MHz，TMS)[δ，ppm]：1.2(t，3H，CH₃)、2.5(m，2H，CH₂) 6.6(d, 1H, aromatic), 7.1(t, 1H, aromatic), 7.2(t, 1H, aromatic), 7.6(dd, 2H, aromatic), 8.0(d, 1H, aromatic), 8.2(t, 1H, NCH)

MS(EI+，70eV)：172[M⁺]，116[M⁺-NC₃H₆]

Example 9

N-propyl-1H-indol-1-amines

A solution of 12.3g (69.7mmol) N- (propylidene) -1H-indol-1-amine in 45mL NMP is prepared and 1.6g (41.8mol) of sodium borohydride is added. A solution of 2.5g (41.8mmol) of glacial acetic acid in 15mL of NMP was then prepared. The acetic acid solution was added to the above reaction mixture at 30 ℃ over about 30 minutes. Hydrogen evolution will occur immediately. The reaction mixture was stirred at 35 ℃ until the end of the reaction. At the end of the reaction, the reaction mixture was worked up by slowly adding 50mL of water at 35 ℃. Care was taken during the addition of water to minimize foaming that would occur and to allow for foaming by allowing sufficient headspace. The free headspace was kept up to three times the volume of the liquid contents of the reactor to control foaming. The reaction mixture was extracted with 50mL of n-heptane, the phases were allowed to separate and the aqueous phase was extracted again with 25mL of n-heptane. The combined organic phases were evaporated to dryness. This gave 10.9g of N-propyl-1H-indol-1-amine (90%) as a brown liquid.

Boiling point 115 to 125 deg.C (1.1 mbar)

¹H-NMR(DMSO-d₆，300MHz，TMS)[δ，ppm]：0.9(t，3H，CH₃)、1.35(m，2H，CH₂)、3.0(m，2H，NCH₂) 6.35(d, 1H, aromatic), 6.5(t, 1H, NH), 7.0(t, 1H, aromatic), 7.15(t, 1H, aromatic), 7.4(m, 1H, aromatic), 7.5(dd, 2H, aromatic)

MS(EI+，70eV)：174[M⁺+H]，131[M⁺+H-NHC₃H₇]

Example 10

(3-Fluoropyridin-4-yl) - (indol-1-yl) -propylamine hydrochloride

A solution of 18.0g of potassium tert-butoxide in 53mL of NMP was prepared and the suspension was stirred at 20 ℃ until a clear solution was obtained. The solution was cooled to-20 ℃. To the cooled solution was added a mixture of 9.3g (53.4mmol) of N-propyl-1H-indol-1-amine, 7.4g (53.4mmol) of 4-chloro-3-fluoropyridine and 53mLNMP while maintaining the internal reaction temperature at about-15 ℃. The reaction mixture was stirred at-20 ℃ for about 30 minutes after the end of the addition. The reaction mixture was then added to 100mL of water and 13mL of HCl (37%). Then 50mL of n-heptane (2 x) was added and the phases were allowed to separate. 10mL NaOH (32%) was added to the aqueous phase and the aqueous phase was extracted twice with 50mL n-butyl acetate and the combined n-butyl acetate phases were washed with 50mL water. 4.5mL of HCl (37%) was added to the resulting n-butyl acetate phase. The mixture was distilled using a Dean-Stark trap to remove water completely. The solid precipitated during distillation. The suspension was cooled to 5 ℃ and filtered. Drying at 60-70 ℃ leaves 10.8g of (3-fluoropyridin-4-yl) - (indol-1-yl) -propylamine hydrochloride (75%) as a pale yellow solid.

¹H-NMR(DMSO d₆，300MHz，TMS)[δ，ppm]：0.9(t，3H，CH₃)、1.65(m，2H，CH₂)、4.0(dm，2H，NCH₂) 6.35(t, 1H, aromatic), 6.7(d, 1H, aromatic), 7.2(m, 2H, aromatic), 7.4(d, 1H, aromatic), 7.65(d, 1H, aromatic), 7.7(d, 1H, aromatic), 8.25(d, 1H, aromatic), 8.9(d, 1H, aromatic)

MS(CI+)：270[M⁺+ H, free base]

Example 11

3-methyl-N- (propylidene) -1H-indol-1-amine

A solution of 44.7kg (398mol) of potassium tert-butoxide in 80kg of N-methylpyrrolidone (NMP) was prepared. A solution of 21.5kg (190mol) of hydroxylamine-O-sulfonic acid (HOSA) in 98kg of NMP was additionally prepared and, after a clear liquid had been obtained, the HOSA solution was cooled to 10 ℃.

A solution of 10kg (76.2mol) of 3-methylindole in 50kg of NMP is prepared and an initial amount of 0.08 to 0.12 equivalents of KOtBu solution is added to the 3-methylindole solution. The HOSA and KOtBu solutions were added simultaneously and proportionally to the reaction mixture over 120 minutes at 20 ℃ via mass flow meters. After the end of the addition, 6.9L (381mol) of water, 13.7kg (228.6mol) of acetic acid (100%) and 7.5kg (129.2mol) of propionaldehyde were added to the dark brown suspension obtained. The mixture was stirred at 20 ℃ for about 1 hour until the reaction was complete. The reaction mixture was then worked up by adding 248L of water and 42kg of n-heptane. The undesired salt precipitates from the reaction mixture. The resulting suspension was filtered and the phases were allowed to separate. The aqueous phase was extracted 3 more times with 42kg of n-heptane. The combined organic phases were washed twice with 63L of water. The resulting brown heptane solution was evaporated to dryness. This yielded 11.6-12.5 kg of 3-methyl-N- (propylidene) -1H-indol-1-amine as a brown liquid (yield 81-90%).

Boiling point 121 ~ 123 deg.C (1 mbar)

¹H-NMR(300MHz，DMSO-d₆，TMS)[δ，ppm]：1.15(t，3H，CH₃)、2.3(s，3H，CH₃)、2.45(m，2H，CH₂) 7.05(t, 1H, aromatic), 7.2(t, 1H, aromatic), 7.5(2d, 2H, aromatic), 7.8(s, 1H, aromatic), 8.05(t, 1H, NCH)

MS(CI+)：187[M⁺+H]，130[M⁺-NC₃H₆]

Example 12

3-methyl-N-propyl-1H-indol-1-amines

A solution of 3.0kg (74.4mol) sodium borohydride and 26.8kg (124mol, 86% purity) 3-methyl-N- (propylidene) -1H-indol-1-amine in 108kg NMP was prepared in a 800L vessel. A solution of 4.5kg (74.4mol) of glacial acetic acid in 27kg of NMP was prepared. The acetic acid solution was added to the sodium borohydride solution at 30 ℃ over about 30 minutes. Hydrogen gas was immediately evolved. The reaction mixture was stirred at 30 ℃ until the end of the reaction (about 1 hour). 6.3kg of ethanol were added to the reaction mixture and foaming occurred immediately. The reaction mixture was then worked up by carefully adding an additional 80L of water. Care is taken to control foaming during the addition of water, and it is especially recommended to add water slowly at the beginning to avoid uncontrolled foaming. Care was taken to ensure that no or only minimal foaming occurred when the first 1-2L of water was added. The reaction mixture was allowed to stand overnight. The aqueous phase was extracted three times with 45kg of n-heptane and the combined organic phases were washed with 66L of water. The combined organic phases were evaporated to dryness. This gave 22.4kg of 3-methyl-N-propyl-1H-indol-1-amine as a brown liquid (yield 90%, 94% purity).

¹H-NMR(300MHz，DMSO d₆，TMS)[δ，ppm]：0.9(t，3H，CH₃)、1.4(m，2H，CH₂)、2.2(s，3H，CH₃)、2.95(m，2H，NCH₂) 6.3(t, 1H, NH), 7.0(t, 1H, aromatic), 7.1(t, 1H, aromatic), 7.15(s, 1H, aromatic), 7.4(d, 1H, aromatic), 7.45(d, 1H, aromatic)

MS(CI+)：189[M⁺+H]，130[M⁺-NC₃H₇]

Example 13

3-methyl-N-propyl-1H-indol-1-amines

A solution of sodium borohydride (4.54kg, 120mol) in 38kg of NMP was prepared. To this solution was added a solution of 3-methyl-N- (propylidene) -1H-indol-1-amine (38.6kg, 190mol) in 78kg of N-heptane. A solution of 6.8kg (120mol) of glacial acetic acid in 32kg of n-heptane is prepared. The acetic acid solution was added to the sodium borohydride solution using a pump at 30 ℃ over about 30 minutes. Hydrogen evolution occurred immediately. The pump was rinsed with 3kg of n-heptane and the washings were added to the reaction mixture. The reaction mixture was stirred at 30 ℃ until the end of the reaction (about 1 hour). The reaction mixture was then worked up by adding 76L of water. No or only minimal foaming was observed during the addition of water. The mixture was stirred overnight and the phases were allowed to separate. 2.82kg HCl (30%) and 4.75kg water were added to the n-heptane phase, the pH was checked and more HCl was added if the pH was above 1. The mixture was heated to an internal temperature of 75 ℃ for about 2 hours. The mixture was cooled to 25 ℃ to control hydrogen evolution. If no more residual hydrogen evolution occurred, the pH level was adjusted to 7, a further 30kg of water were added, the phases were allowed to separate and the n-heptane phase was washed twice with 37kg of water. The n-heptane phase was evaporated to dryness. This gave 37.5kg of 3-methyl-N-propyl-1H-indol-1-amine (98%) as a brown liquid.

Example 14

(3-Fluoropyridin-4-yl) - (3-methylindol-1-yl) -propylamine hydrochloride

A solution of 58.8kg of potassium tert-butoxide in 135.8kg of NMP is prepared and the suspension is stirred at 20 ℃ until a clear solution is obtained, which is designated solution A.

A solution of 36.1kg (175.6mol) 3-methyl-N-propyl-1H-indol-1-amine and 24.3kg (184.4mol) 4-chloro-3-fluoropyridine in 68.5kg of NMP was prepared and designated solution B.

The two solutions A and B prepared as above were simultaneously charged (about 24kg/h solution A and about 17.2kg/h solution B) into a reactor previously charged with 15kg of NMP and 2kg of solution A while maintaining the internal temperature at-20 ℃. The liquid volume in the reaction vessel was kept constant at the same level during the entire addition of solutions a and B by passing the mixed solution into another vessel. The reaction solution thus collected in the other vessel was quenched with 19kg of water. After the addition of the total amount of solutions A and B, the reactor was washed with 20kg of NMP. For further processing, 275kg of water were added and the aqueous alkaline phase was extracted 4 times with 57kg of n-heptane. The combined n-heptane phases were extracted twice with 175kg of water and 13.2kg of HCl (30%), so that the phases separated and 30.9kg of naoh solution (33%) were added to the aqueous phase. The aqueous phase was extracted twice with 155kg of n-butyl acetate and the combined n-butyl acetate phases were washed with 176kg of water. Samples of n-butyl acetate extract were removed for analysis of free base. Based on this analysis, the n-butyl acetate phase was diluted to contain about 10% free base (w/w). The water was stripped off under vacuum and 18.5kg of HCl (30%) were added to the resulting n-butyl acetate phase. The mixture was distilled using a Dean-Stark trap to remove water completely. The solid precipitated during distillation. The suspension was cooled to 5 ℃ and filtered. The filter cake was washed twice with 76kg of n-butyl acetate. Drying at 60-70 ℃ leaves 43.8kg of (3-fluoropyridin-4-yl) - (3-methylindol-1-yl) -propylamine hydrochloride as a pale yellow solid (77.3%).

Melting point 219 deg.C (DSC, heating rate 5 deg.C/min, HCl loss and decomposition)

¹H-NMR(300MHz，DMSO-d₆，TMS)[δ，ppm]：0.9(t，3H，CH₃)、1.7(m，2H，CH₂)、2.5(m，3H，CH₃)、4.0(dm，2H，CH₂) 6.3(m, 1H, aromatic), 7.2(m, 2H, aromatic), 7.3(m, 1H, aromatic), 7.4(d, 1H, aromatic), 7.7(dd, 1H, aromatic), 8.2(d, 1H, aromatic), 8.9(d, 1H, aromatic)

MS(EI+，70eV)：283[M⁺Free base]，240[M⁺-C₃H₇]130[ 3-methylindole fragment]96[ fluoropyridine fragment]

Example 15

4-chloro-3-fluoropyridines

A30 gallon Hastelloy reactor was charged under nitrogen with 2.5kg (25.8mol) of 3-fluoropyridine, 3.4kg (29.6mol, 1.2 eq.) of Tetramethylethylenediamine (TMEDA), and 20L of methyl tert-butyl ether (MTBE). The solution was cooled to-50 ℃. A total of 15.5L (12.6L, 29.6mol, 1.15 equivalents) of a 1.9M solution of Lithium Diisopropylamide (LDA) (heptane/THF/ethylbenzene) was added over 24 minutes while maintaining a temperature of-40 to-48 ℃. The brownish suspension was stirred for 50 minutes at-44 to-48 ℃. A solution of 7kg (29.6mol, 1.15 eq.) of hexachloroethane in 20L of MTBE was added over 48 minutes while maintaining a temperature of-40 to-46 ℃. After stirring at-40 ℃ for 20 minutes the reaction was heated to 0 ℃ and then quenched into a reactor containing 54L of cold water. After stirring for 20 minutes at 20-25 ℃, the mixture was filtered through celite to break the tiny emulsion. The layers are separated. The aqueous layer was extracted with 5L MTBE. The organic layers were combined and then extracted with several portions (1x21L, 3x13L) of 2N HCl. The acidic aqueous phases were combined, partitioned with 16L MTBE and then basified to pH 6.19 by addition of 6.5kg of 50% NaOH while maintaining a temperature of 15-20 ℃. The layers are separated. The aqueous phase was extracted with 10L of MTBE. The combined organic phases were dried over 3.0kg sodium sulfate, then filtered and concentrated (56 ℃, 575 mbar for most of the concentration period, 400 mbar for the final concentration) to give 3.7kg of 4-chloro-3-fluoropyridine as a brown liquid, 2.4kg corrected by NMR for 31.2% of solvent, 95.5% purity by HPLC, 70.2% yield.

Example 16

(3-Fluoropyridin-4-yl) - (3-methylindol-1-yl) -propylamine hydrochloride

A solution of 510g (4.5mol) of potassium tert-butoxide in 1190g of NMP is prepared and the suspension is stirred at 20 ℃ until a clear solution is obtained (solution A).

A solution of 154.1g (769mmol, 94% purity) 3-methyl-N-propyl-1H-indol-1-amine, 112.7g (846mmol, 99% purity) 4-chloro-3-fluoropyridine and 622g NMP was prepared (solution B).

950g of solution A were charged into a loop system which was connected to a Continuous Stirred Tank Reactor (CSTR) and a static mixer with a ring pump. The loop system was cooled to-15 ℃. Solution A was initially charged to the CSTR and solution B was charged from the static mixer and both solutions were added for 53 minutes under temperature control (-15 ℃). The volume in the CSTR was kept constant at about 360mL during the addition. The reaction mixture was quenched with 247g of water. After the end of the feed the loop system was vented and the system was washed with 951g of water. An additional 1224g of water was added to the washings and the quenched reaction solution. The aqueous phase was extracted 4 times with 380g of n-heptane. The resulting n-heptane phase was extracted twice with a solution of 771g water and 45.4g HCl (37%). To the resulting aqueous phase was added 131g NaOH (33%) and extracted twice with 680g n-butyl acetate. The resulting n-butyl acetate phase was washed once with 775g of water. 79.6g of HCl (37%) were added and the resulting mixture was distilled under vacuum using a Dean-Stark trap until no more water was removed. The reaction mixture was cooled to 5 ℃ when the product started to crystallize and the product was filtered. Drying under vacuum in a tray dryer. This gave 164.4g of 3-fluoropyridin-4-yl- (3-methylindol-1-yl) -propylamine hydrochloride (71% yield).

Example 17

N- (propylidene) -1H-indol-1-amines

A solution of 26.8kg (239mol) of potassium tert-butoxide (KOtBu) in 50kg of N-methylpyrrolidone (NMP) was prepared. A solution of 13.8kg (120mol) of hydroxylamine-O-sulfonic acid (HOSA) in 71kg of NMP was additionally prepared and after obtaining a clear liquid the HOSA solution was cooled to 10 ℃.

A solution of 6.4kg (54.6mol) indole in 25kg NMP was prepared. The HOSA and KOtBu solutions prepared as above were added to the solution simultaneously and proportionally through a mass flow meter over 180 minutes and the reaction mixture was maintained at 15 ℃. After the end of the addition, 4.3L (239mol) of water, 9.7kg (161.5mol) of acetic acid (100%) and 5.3kg (91.3mol) of propionaldehyde were added to the dark brown suspension obtained. The mixture was stirred at 20 ℃ for about 1 hour until the reaction was complete. The reaction mixture was then worked up by adding 180L of water and 21kg of n-heptane. The undesired salt precipitates from the reaction mixture. The resulting suspension was filtered and the phases were allowed to separate. The aqueous phase is extracted again 4 times with 21kg of n-heptane. The combined organic phases were washed twice with 45L of water. The resulting brown heptane solution was evaporated to a 15-25% solution. This gives 6.3 to 7.0kg of N- (propylidene) -1H-indol-1-amine as a brown liquid (yield corrected for 19.7 to 24.1% analysis 67 to 74%).

¹H-NMR(400MHz，DMSO-d₆，TMS)[δ，ppm]：1.19(t，3H，CH₃)、2.48(m，2H，CH₂) 6.60(d, 1H, aromatic), 7.08(t, 1H, aromatic), 7.22(t, 1H, aromatic), 7.57(d, 1H, aromatic), 7.61(d, 1H, aromatic), 8.03(d, 1H, aromatic), 8.19(t, 1H, NCH)

MS(ES+)：173[M⁺+H]，117[M⁺-NC₃H₆]

Example 18

N-propyl-1H-indol-1-amines

A solution of 0.83kg (21.9mol) of sodium borohydride in 16.6kg of NMP was prepared. 31.9kg of N- (propylidene) -1H-indol-1-amine are added as a 19.7% solution in n-heptane (36.5mol) and a further 7.7kg of n-heptane. A solution of 1.32kg (21.9mol) of glacial acetic acid in 2.8kg of n-heptane was prepared. The acetic acid solution was added to the sodium borohydride solution using a pump at 30 ℃ over about 30 minutes. Hydrogen evolution will occur immediately. The pump was washed with 2kg of n-heptane. The reaction mixture was stirred at 30 ℃ until the end of the reaction (about 1 hour). The reaction mixture was worked up by adding 20L of water. No or only minimal foaming was observed during the addition of water. The mixture was stirred overnight and the phases were allowed to separate. 0.9kg HCl (30%) and 3.4kg water were added to the n-heptane phase to check if the pH was below 1. If necessary, an additional amount of HCl is added to adjust the pH to about 1. The mixture was heated to an internal temperature of 75 ℃ for about 2 hours. The mixture was cooled to 25 ℃ to control the evolution of residual hydrogen. If no more residual hydrogen evolution occurred, additional 20.3kg of water were added and the pH was adjusted to a level > 7 with NaOH (33%). The phases were allowed to separate and the n-heptane phase was washed with 20.3kg of water. The n-heptane phase was evaporated to dryness. This gave 5.84kg of N-propyl-1H-indol-1-amine (82.6%) as a brown liquid.

¹H-NMR(400MHz，DMSO-d₆，TMS)[δ，ppm]：0.91(t，3H，CH₃)、1.35(m，2H，CH₂)、3.00(m，2H，CH₂) 6.33(d, 1H, aromatic), 6.43(t, 1H, NH), 7.12(t, 1H, aromatic), 6.98(t, 1H, aromatic), 7.35(d, H, aromatic), 7.46(d, 1H, aromatic), 7.50(d, 1H, aromatic)

MS(ES+)：175[M⁺+H]

Example 19

Indol-1-yl-propyl-pyridin-4-yl-amine hydrochloride

A solution of 12.4kg (110.7mol) of potassium tert-butoxide in 23.6kg of NMP is prepared and the suspension is stirred at 20 ℃ until a clear solution is obtained (solution A).

A second solution (solution B) of 5.84kg (27.7mol, analytical result 82.6%) N-propyl-1H-indol-1-amine and 4.36kg (29.1mol) 4-chloropyridine hydrochloride in 15kg NMP was prepared.

Solution a was added to solution B while maintaining the temperature at 20 ℃. Stir for 1 hour and check the completion of the reaction. The reaction mixture was quenched in 135kg of water. The pH of the solution was adjusted to about 2 with HCl (30%) and extracted twice with 20kg of n-heptane. The organic layer is removed. The pH of the aqueous layer was adjusted to 12 with NaOH (33%) and extracted twice with 16kg of n-butyl acetate. The aqueous layer was removed. The organic layer was washed with 23kg of water. 10.8kg of methanolic HCl (29.9mol, 10.1% assay) was added to the organic layer at 20 ℃. After crystallization the mixture was cooled to 5 ℃, the product was filtered and washed with n-butyl acetate. Drying in a tray dryer under vacuum at 80 ℃. This will yield 5.8kg of indol-1-yl-propyl-pyridin-4-yl-amine hydrogen chloride as a white to beige solid (73% yield).

¹H-NMR(400MHz，DMSO-d₆，TMS)[δ，ppm]：0.94(t，3H，CH₃)、1.62(m，2H，CH₂)、4.05(dm，2H，CH₂) 6.74(d, 1H, aromatic), 7.19(m, 1H, aromatic), 7.28(m, 1H, aromatic), 7.30(d, 1H, aromatic), 5.8-7.6 (s v br, 2H, aromatic), 7.63(d, 1H, aromatic), 7.70(d, 1H, aromatic), 8.43(d br, 2H, aromatic), 15.2(s br, 1H, NH)⁺)

MS(ES+)：252[M⁺+ H, free base]

The following example illustrates the N-aminated product obtained by following the procedure described in EP 0249452.

Comparative example 1

1H-indol-1-amines

A solution of 3.3g (3.2 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 7.7g of water was prepared and cooled to 0-5 ℃. An amination vessel was charged with 10.0g indole and 50.0g water. The HOSA/water solution and 7.3mL of 30% NaOH solution were then metered simultaneously into the amination vessel over 120 minutes while maintaining a reaction temperature of 20-25 ℃. HPLC analysis indicated no formation of 1H-indol-1-amine.

While the invention has been illustrated by certain of the foregoing examples, it is not intended to be limited thereby; rather, the invention encompasses the generic scope as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

Claims

1. A process for the preparation of a compound of formula II,

which comprises the following steps:

(a) preparing a hydroxylamine-O-sulfonic acid solution in a suitable organic solvent;

(b) preparing a solution of a suitable base in a suitable organic solvent;

(c) preparing a solution of a compound of formula I in a suitable organic solvent;

(d) contacting said solution from said step (a) and said solution from said step (b) simultaneously and proportionally with said solution from step (c) in a suitable reaction vessel at a suitable reaction temperature to provide said compound of formula (II);

wherein

m is 1 or 2.

2. The process according to claim 1, wherein the solvent in steps (a) and (b) is an aprotic solvent.

3. The process according to claim 2, wherein the aprotic solvent is N-methylpyrrolidone.

4. The process according to claim 2, wherein the solvent is N, N-dimethylformamide.

5. The process according to claim 2, wherein the solvent is N, N-dimethylacetamide.

6. The process according to claim 1, wherein the base in step (b) is an organic base.

7. A process according to claim 6, wherein the base has a pKa value at least the same as that of the indole.

8. The process according to claim 6, wherein the organic base is an alkali metal alkoxide.

9. The process according to claim 8, wherein the alkali metal alkoxide is selected from: lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide and cesium tert-butoxide.

10. The process according to claim 8, wherein the alkali metal alkoxide is potassium tert-butoxide.

11. The process according to claim 1, wherein the solvent in step (c) is an aprotic solvent.

12. The process according to claim 11, wherein the aprotic solvent is N-methylpyrrolidone.

13. The process according to claim 11, wherein the aprotic solvent is N, N-dimethylformamide.

14. The process according to claim 11, wherein the aprotic solvent is N, N-dimethylacetamide.

15. The process according to claim 1, wherein the reaction temperature is from-5 ℃ to 40 ℃.

16. The process according to claim 1, wherein the reaction temperature is from 0 ℃ to 25 ℃.

17. The process according to claim 1, wherein the base is present in an amount of from 1mol to 10mol with respect to the compound of formula I.

18. The process according to claim 1, wherein the base is present in an amount of from 3mol to 6mol with respect to the compound of formula I.

19. The process according to claim 1, wherein said contacting in said step (d) is performed by static mixing.

20. The process according to claim 1, wherein said contacting in said step (d) is carried out by a continuous reactor.

21. The process according to claim 1, wherein said contacting in said step (d) is carried out in a batch reactor.

22. The method according to claim 1, wherein R and R₁Is hydrogen and R₂Is methyl.

23. The method according to claim 1, wherein R₁And R₂Together with the carbon atoms to which they are attached form a benzene ring.

24. A process for the preparation of a compound of formula IV,

the method comprises the following steps:

adding simultaneously and proportionally a solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent at a suitable reaction temperature to a solution of a compound of formula I in a suitable organic solvent to provide a compound of formula (II), wherein said compound of formula (I) is contained in a suitable reaction vessel,

and reacting the compound of formula (II) with a compound of formula (III) in the reaction vessel to provide a compound of formula (IV),

wherein

R₁and R₂Are identical or different and are selected independently of one another from hydrogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, benzyloxy or of the formula C_nH_xF_yOr OC_nH_xF_yWherein n is an integer of 1 to 4, x is an integer of 0 to 8,y is an integer of 1-9, and the sum of x and y is 2n + 1;

R₃and R₄Are identical or different and are independently of one another selected from hydrogen or C₁-C₄An alkyl group; and m is 1 or 2.

25. The method according to claim 24, wherein the solvent is an aprotic solvent.

26. The method according to claim 25, wherein the aprotic solvent is N-methylpyrrolidinone.

27. The method according to claim 25, wherein the aprotic solvent is N, N-dimethylformamide.

28. The process according to claim 25, wherein the aprotic solvent is N, N-dimethylacetamide.

29. The process according to claim 24, wherein the base is an organic base.

30. The process according to claim 29, wherein the organic base is an alkali metal alkoxide.

31. The process according to claim 30, wherein the alkali metal alkoxide is selected from: lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide and cesium tert-butoxide.

32. The process according to claim 30, wherein the alkali metal alkoxide is potassium tert-butoxide.

33. The process according to claim 24, wherein the reaction temperature is from-5 ℃ to 40 ℃.

34. The process according to claim 24, wherein the reaction temperature is from 0 ℃ to 25 ℃.

35. The process according to claim 24, wherein the base is present in an amount of from 1mol to 10mol with respect to the compound of formula I.

36. The process according to claim 24, wherein the base is present in an amount of from 3mol to 6mol with respect to the compound of formula I.

37. The method of claim 24, wherein R, R₁And R₄Is hydrogen, R₂Is methyl, and R₃Is ethyl.

38. A process for the preparation of a compound of formula VI or a suitable salt thereof,

which comprises the following steps:

(a) adding simultaneously and proportionally a solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent at a suitable reaction temperature to a solution of a compound of formula I in a suitable organic solvent to provide a compound of formula (II), wherein said compound of formula (I) is contained in a suitable reaction vessel,

and reacting the compound of formula (II) with a compound of formula (III) in the reaction vessel to provide a compound of formula (IV);

(b) reacting the compound of formula (IV) with a suitable reducing agent to provide a compound of formula (V);

(c) reacting said compound of formula (V) with a compound of formula (VII) in a suitable organic solvent in the presence of a suitable base

Reacting to provide a compound of formula (VI), optionally reacting it with a suitable mineral acid to provide a salt of the compound of formula (VI);

wherein

R₃And R₄Are identical or different and are independently of one another selected from hydrogen or C₁-C₄An alkyl group; and m is 1 or 2;

R₅is hydrogen, nitro, amino, halogen, C_1-4Alkyl radical, C_1-4Alkanoylamino, phenyl-C_1-4Alkanoyl radicalAlkylamino, phenylcarbonylamino, alkylamino or phenyl-C_1-4An alkylamino group;

x is halogen;

m and n are 1 or 2, and p is 0 or 1.

39. The method according to claim 38, wherein said reducing agent in said step (b) is sodium borohydride.

40. The process according to claim 38, wherein said reacting in said step (b) is carried out in a suitable organic solvent.

41. The method according to claim 40, wherein the solvent is an aprotic polar solvent.

42. The process according to claim 40, wherein the solvent is N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, heptane, hexane, toluene, petroleum ether or a mixture thereof.

43. The process according to claim 40, wherein the solvent is N-methylpyrrolidone or a mixture of N-methylpyrrolidone and N-heptane.

44. The process according to claim 38, wherein the reaction temperature in step (a) is from-70 ℃ to 150 ℃.

45. The process according to claim 38, wherein the reaction temperature in step (a) is from-20 ℃ to 15 ℃.

46. The process according to claim 38, wherein said base in step (c) is potassium tert-butoxide.

47. The process according to claim 38, wherein said step (c) is carried out by a static mixer.

48. The process according to claim 38, wherein said step (c) is carried out in a continuous stirred tank reactor.

49. The process according to claim 38, wherein said step (c) is carried out in a batch reactor.

50. The method according to claim 38, wherein said step (c) is carried out in a microreactor.

51. The process according to claim 38 wherein said step (c) is carried out in a continuous stirred tank reactor in combination with a static mixer in a loop system.