WO1998043973A1 - Intermediate products and method for the production of pyrimidine derivatives - Google Patents

Abstract

The invention relates to a new method for the production of a compound having formula (I) or one of its salts. In this formula, the radicals have the meanings given in the description. This method relates to a new intermediary compound having formula (II), in which the radicals have the meanings given in the description. Said intermediary compound can also come as a salt, or in protected form. The invention also concerns new crystalline forms of formula (I) and their production. Compounds of formula (I) arepharmacologically effective, for example, against proliferative diseases.

Description

Intermediates and process for the preparation of pyrimidine derivatives

The invention relates to a new process for the preparation of pharmaceutically usable pyrrolopyrimidines and salts thereof and new intermediates and salts thereof, provided that a salt-forming group is present; as well as new crystal modifications of the compounds mentioned.

Background of the Invention

European patent application EP 0 682027 (published on November 15, 1995) and international application WO 97/02266 (published on January 23, 1997) describe pyrrolopyrimidine compounds which have specific inhibitory effects, primarily as inhibitors of protein kinases, in particular as protein Tyrosine kinase inhibitors and / or as inhibitors of protein serine / threonine kinases, and so valuable pharmacologically usable properties, for example for the treatment of tumor diseases and / or psoriasis, but also for the treatment of other diseases on which protein -Tyrosine kinases, which are involved in signal transmission by trophic factors. The two patent applications mentioned are incorporated here by reference. Insofar as these two patent applications are mentioned, the corresponding priority documents are always included, which are accessible to the public through inspection of the files.

Summary of the invention

Compared to the production processes for the pyrrolopyrimidines disclosed in the two patent applications EP 0 682027 and WO 97/02266, the production process according to the invention has a number of unexpected advantages: The production process is based on new intermediate products and is advantageously suitable for large-scale implementation directly an end product of very high purity and with a high yield and in particular in the preferred embodiments has more. unexpected advantages, for example controlled development of carbon dioxide instead of its abrupt release, which thus hinders the large-scale synthesis of release, Possibility of dispensing with protective groups and / or one-pot reactions in the production of certain precursors.

The process is therefore excellently suited for the production of pyrrolopyrimidines on an industrial scale and thus for the production of the resulting active ingredients.

In addition, the invention relates to surprisingly and unexpectedly found new crystal forms of pyrrolopyrimidines and processes for their preparation. These crystal formers have advantageous storage properties and are well suited for pharmaceutical formulations.

Full description of the invention

The invention relates primarily to a process for the preparation of a compound of the formula I,

or a salt thereof, wherein n is 0 to 5; q represents 0 or 1;

Ri and R ₂ independently for

(a) lower alkyl,

(b) unsubstituted or by halogen, trifluoromethyl, lower alkyl, lower alkoxy, carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy Lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, NN-di-lower alkylcarbamoyl, cyano or nitro substituted phenyl,

(c) hydrogen, (d) unsubstituted or Ha - or lower alkyl-substituted pyridyl,

(e) N-benzylpyridinium-2-yl,

(f) naphthyl,

(g) cyano, (h) carboxy,

(i) lower alkoxycarbonyl, (j) carbamoyl, (k) N-lower alkylcarbamoyl, (I) N, N-di-lower alkylcarbamoyl, (m) N-benzylcarbamoyl, (n) formyl, (o) lower alkanoyl, (p) lower alkenyl, (q ) Lower alkenyloxy; or (r) lower alkyl, softened by

Halogen, amino, lower alkylamino, piperazino, di-lower alkylamino; Phenylamino which is unsubstituted or in the phenyl radical by halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- lower alkyl-carbamoyl, N, N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N- Diniederalkylamino or trifluoromethyl is substituted; Hydroxy, lower alkoxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, mercapto or a radical of the formula AS (O) _m -, in which A is lower alkyl and m is 0, 1 or 2 , is substituted; stand or

Ri and R ₂ together represent an alkylene chain with 2 to 5 carbon atoms, which is unsubstituted or substituted by lower alkyl; or

R 1 and R ₂ together denote C -C ₁₀ alkadienylene which is unsubstituted or by amino, lower alkanoylamino, lower alkylamino, di-lower alkylamino, nitro, halogen, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl or cyano is substituted; or Ri and R ₂ together mean aza-1,4-alkadienylene with up to and including 9 carbon atoms;

R _{3 represents} halogen, lower alkyl, trifluoromethyl, lower alkoxy, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-diniederalkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino or diniederalkylamino; and

R _{4 represents} hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl carbamoyl or N, N-di-lower alkyl carbamoyl; or a salt of it.

A compound of the formula I, or a salt thereof, is prepared by the process according to the invention, in which an imino compound of the formula II,

in which the radicals have the meanings given for a compound of the formula I, and in which functional groups which are not intended to participate in the reaction are, if necessary, in protected form, or a salt thereof, rearranged and present in a suitable solvent or solvent mixture at elevated temperature Splits off protective groups,

and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt, converting an available salt into the free compound of formula I or another salt thereof and / or at an as Compound of the formula I obtainable isomer mixture carries out a separation into isomers. (Reaction A) Compounds of the formula II, or salts thereof, are new and are therefore also an object of the present invention, as are the processes for their preparation mentioned below.

Preferred is a process for the preparation of a compound of the formula I, or a salt thereof, in which the compound of the formula II used for the preparation of a compound of the formula I or its salt, in which functional groups which are not involved in the reaction to give a compound of the Formula I should participate, may be in protected form, or a salt thereof, is obtained by using a cyanopyrrole compound of formula III,

wherein R 1 and R _{2 have} the meanings given for compounds of the formula I, with an imino compound of the formula IV,

wherein F, R ₄ , n and q have the meanings given for compounds of the formula I and R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A

wherein R ₃ , R ₄ , n and q have the meanings given for compounds of the formula I, are reacted, functional groups in a cyanopyrrole compound of the formula III, an imino compound of the formula IV or in both which are not intended to participate in the reaction , if necessary, are in protected form, and the compound of the formula III, the compound of the formula IV or both can also be in the form of a salt, and, if desired, splits off protective groups which are no longer required, converts an available free compound of the formula II into a salt or converts an available salt of a compound of the formula II into the free compound of the formula II or another salt and / or with an available isomer mixture of a compound of the Formula II carries out a separation into isomers. (Reaction B)

Preference is given to a process for the preparation of a compound of the formula I, or a salt thereof, in which the process for the preparation of a compound of the formula II or its salt, in which functional groups which are not intended to participate in the reaction to give a compound of the formula I, can be in protected form, imino compound of formula IV used, or a salt thereof, in which functional groups which should not take part in the reaction can be in protected form are obtained by using an amino compound of formula V,

wherein R ₃ , FU, n and q have the meanings given for a compound of the formula I, in the presence of a suitable acid with an orthoformate of the formula VI,

(RsVCH (VI)

wherein R ₅ 'is lower alkoxy or substituted lower alkoxy, wherein free functional groups in an amino compound of the formula VI, an orthoformate of the formula VI or both, which are not to take part in the reaction, are in protected form if necessary, and wherein the compound of the formula V, the compound of the formula VI or both can also be in the form of a salt if a salt-forming group is present,

and, if desired, splits off protective groups which are no longer required, converts an available free compound of the formula IV into a salt or converts an available salt of a compound of the formula IV into the free compound of the formula IV or another salt and / or with an available isomer mixture of a compound of the Formula IV carries out a separation into isomers. (Reaction C) In a highly preferred embodiment of the process according to the invention, a compound of the formula II, or a salt thereof, in which functional groups which should not participate in the reaction to a compound of the formula I can be present in protected form, is obtained by directly Amino compound of the formula V, in which R ₃ , R .., n and q have the meanings given for a compound of the formula I, with an orthoformate of the formula VI, in which R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A, as shown above, in which R _3l F, n and q have the meanings given for compounds of the formula I, and with a cyanopyrrole compound of the formula III in which R, and R _{2 have} the meanings given for compounds of the formula I (one-pot Reaction without isolation of intermediates, for example of the formula IV), functional groups in a cyanopyrrole compound of the formula III, an amino compound of the formula V, in an orthoformic acid ester of the formula VI or in two or all three of these compounds which are not intended to participate in the reaction, if necessary in protected form, and the compound of the formula III, the compound of the formula V, the compound of Formula VI or two or all three of these compounds can also be in the form of a salt,

and, if desired, splits off protective groups which are no longer required, converts an available free compound of the formula II into a salt or converts an available salt of a compound of the formula II into the free compound of the formula II or another salt and / or with an available isomer mixture of a compound of the Formula II carries out a separation into isomers. (Reaction B / C)

This one-pot reaction is also an object of the present invention by itself.

The reaction of a cyanopyrrole compound of the formula III, in which R 1 and R _{2 have} the meanings given for compounds of the formula I, with an imino compound of the formula IV, in which R ₃ , F, n and q have the meanings given for compounds of the formula I and R _{5 is} a radical of the formula IV-A, in which R ₃ , R4, n and q have the meanings given for compounds of the formula I, to a compound of the formula II, or a salt thereof, is preferred. (Reaction B *) Also an imino compound of the formula IV, in which R ₃ , FU, n and q have the meanings given for compounds of the formula I and R _{5 is} a radical of the formula IV-A, in which Rs, Ri, n and q are those for compounds of the formula I meanings, in particular the meanings given for compounds of the formula I designated as preferred, are a preferred subject of the present invention.

Cyanopyrrole compounds of the formula III are known or can be prepared by processes known per se. For example, they can be produced by or analogously to a process described in European patent application EP 0 682 027 (published on November 15, 1995) or international application WO 97/02266 (published on January 23, 1997).

A preferred process for the preparation of a compound of the formula III, or a salt thereof, in which functional groups can be present in free or protected form, and in which R ₂ and Ri have one of the meanings given for compounds of the formula I, is based on an amino acid of the formula VII

from in which R _{T has} one of the meanings given for compounds of the formula I which are reacted with a reactive acid derivative of the formula VIII

in which R _{2 has} the meanings given for a compound of the formula I and L is halogen, azido, an activated aryloxy radical or an acyloxy radical of the formula R ₂ -C (= O) -O-, in which R _{2 is} a compound of the formula I can have meanings mentioned, in the presence of a tertiary nitrogen base or an alkaline earth metal or alkali metal salt of an acid of the formula R ₂ -C (= O) -OH, in which R _{2 has} the meanings mentioned for compounds of the formula I, to give a compound of the formula X

is implemented, wherein R _T and R _{2 have} the meanings given for a compound of formula I; where in an amino acid of the formula VII functional groups which are not intended to take part in the reaction are, if necessary, in protected form;

and, if desired, splits off protective groups which are no longer required, converts an available free compound of the formula X with a salt-forming group into a salt or converts an available salt of a compound of the formula X into the free compound of the formula X or another salt and / or with an available one Isomer mixture of a compound of formula X separates into isomers. (Reaction D)

A particularly preferred process for the preparation of a compound of the formula III, or a salt thereof, in which functional groups can be present in free or protected form, and in which R _{2 is} lower alkyl (so that even if the process is continued via a compound of the formula II to be obtained end product of formula I, or a salt thereof, R _{2 is} lower alkyl) and Ri has one of the meanings given for compounds of formula I, is based on an amino acid of formula VII

from, in which i has one of the meanings given for compounds of the formula I, which with an acid anhydride of the formula VIII *

wherein R ₂ 'is lower alkyl in the presence of a carboxylic acid of formula IX,

wherein R ₂ 'is lower alkyl, and a tertiary nitrogen base to a compound of formula X.

is implemented in which R _{1 has} the meanings given for a compound of the formula I and R ₂ 'is lower alkyl; where in an amino acid of the formula VII functional groups which are not intended to take part in the reaction are, if necessary, in protected form;

and, if desired, splits off protective groups which are no longer required, converts an available free compound of the formula X * with a salt-forming group into a salt or converts an available salt of a compound of the formula X * into the free compound of the formula X * or another salt and / or in the case of an available isomer mixture of a compound of the formula X *, it is separated into isomers. (Reaction D *)

This reaction (reaction D *) is also the subject of the present invention. The hitherto unknown, unexpectedly possible addition of a carboxylic acid of the formula IX surprisingly enables the reaction in a very particularly preferred embodiment by continuous or stepwise metering

(i) a reagent of formula VII, which is used alone or as a mixture with the tertiary nitrogen base (preferred), further with the carboxylic acid of formula IX * or with both, as component A

to the acid anhydride of formula VIII *. which is present alone or preferably as a mixture with the tertiary nitrogen base, with the carboxylic acid of the formula IX * or preferably both, as component B, or further

(ii) conversely, by metering in a corresponding component B to a component A

to achieve a controllable release of the carbon dioxide formed during the reaction. This is a great advantage in particular for large-scale syntheses, since according to the Dakin-West reaction known to date, the release of the carbon dioxide could not be controlled without the lower alkanoic acid, and the reaction was therefore unsuitable for large-scale use. It is only the addition of acid that enables the sensible use of synthesis on an industrial scale.

The preparation of a compound of the formula III, or a salt thereof, in which functional groups can be present in free or protected form, and in which the radicals have the meanings given for a compound of the formula I (in which R ₂ preferably denotes lower alkyl, especially methyl) , can then be achieved by reacting a compound of the formula X, as defined above, in which the radicals have the meanings given for a compound of the formula I (preferably a compound of the formula X *, in which R ₂ 'is lower alkyl and the other radicals have the meanings given for a compound of the formula I, which is then referred to in formula III as R ₂ ) with malononitrile in the presence of a base,

if desired, protective groups present in an available compound of the formula IM are split off, an available free compound of the formula IM is converted into its salt, an available salt of a compound of the formula III is converted into the free compound or another salt and / or in the case of an available mixture of isomers a compound of formula III separates into isomers. (Reaction E)

The invention also relates to new crystal forms of compounds of the formula I. Particularly preferred are new crystal forms of the free base of the compound of the formula I, in which Ri. and R ₂ each represents methyl; q represents 0 (zero); n represents 1 (one); and R _{3 represents} chlorine in the meta position of the pheny ring relative to the binding nitrogen on the pyrrolopyrimidine ring. Particularly preferred is the crystal form designated as Form I of the compound of the formula I with the name 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, which is characterized by a melting point range of and with 244 ° C up to and with 250 ° C; and / or is preferably characterized by the following main lines in the X-ray diagram obtained using copper Kα1 radiation with a diffractometer:

2Θ intensity

6.2 medium

8.1 very strong

9.7 very strong

12.0 medium

14.7 very strong

15.0 medium

15.4 medium

17.5 weak

17.8 weak

19.0 very weak

19.7 strong

21.9 weak

22.8 medium

23.8 very weak

25.4 very weak

26.1 medium

26.8 strong

26.9 strong

29.7 weak

32.0 weak

Also preferred is a crystal form, referred to as Form II, of the compound of formula I with the name 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, which is represented by the following main lines The X-ray diagram obtained using copper Kα1 radiation with a Guinier camera is characterized: 2Θ intensity

8.1 weak

11.3 medium

13.0 medium

13.8 medium

14.0 very weak

15.3 weak

16.3 strong

20.9 weak

24.2 weak

24.9 weak

25.6 very strong

26.1 strong

27.0 very weak

27.5 strong

27.8 weak

Also preferred is a crystal form, referred to as Form III, of the compound of formula I with the name 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, which is represented by the following main lines The X-ray diagram obtained using copper Kα1 radiation with a diffractometer is characterized:

2Θ intensity

8.8 very strong

13.4 medium

14.5 medium

15.2 medium

15.7 medium

16.0 weak

17.0 medium

17.9 strong

19.6 weak

20.1 weak 20.4 weak

21.0 weak

23.2 medium

24.9 medium

25.5 medium

25.9 very strong

26.6 very strong

27.2 very weak

28.8 medium

29.5 very weak

31.9 very weak

32.5 very weak

Form I is the preferred of these three crystal forms due to its thermodynamic stability.

The crystal modifications are obtained by converting a salt of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine into the free base by contact with water; the longer the treatment, the less Form II and IM is obtained, while the longer Form I forms.

The general terms used above and below in the context of the present disclosure have in particular the meanings mentioned below:

The prefix "lower" denotes a radical up to and with a maximum of 7, in particular up to and with a maximum of 4, especially with 1 or 2 carbon atoms.

"Furthermore" usually stands for residues or conditions that are not as preferred as those previously mentioned.

If asymmetric carbon atoms are present, compounds of the formula I, as well as precursors, can be in the form of mixtures of enantiomers, for example racemates, or (in the case of 2 or more centers of asymmetry) in the form of mixtures of diastereomers, or wise in the form of an enriched, especially pure enantiomer or diastereomer.

n is preferably 0 or 1.

Lower alkyl is unbranched or has one or more branches. Preferred is n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or especially ethyl or especially methyl.

Halogen is preferably fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine and primarily bromine or especially chlorine.

Lower alkoxy is especially methoxy or ethoxy.

Lower alkoxycarbonyl is, for example, methoxycarbonyl.

Niederalkanoylamino is especially acetylamino.

Lower alkylamino is, for example, methylamino.

N, N-di-lower alkylamino is, for example, dimethylamino.

Lower alkanoyloxy is, for example, acetoxy.

N-Lower alkyl-carbamoyl is preferably N-methyl-carbamoyl, furthermore N- (n-butyl) -carbamoyl or N- (3-methyl-but-1-yl) -carbamoyl.

N, N-Diniederalkyl-carbamoyl is, for example, N, N-dimethyl-carbamoyl.

Substituted phenyl R _T or R ₂ may carry one or more, preferably not more than 3, substituents which are the same or different; Substituted phenyl preferably carries only one substituent which is bonded in the ortho, meta or preferably para position. Phenyl-substituted phenyl R _T or R ₂ is, for example, 4-biphenylyl.

Pyridyl is, for example, 2-pyridyl.

Lower alkanoyl is preferably acetyl.

Lower alkenyl is, for example, vinyl, prop-1-enyl or prop-2-enyl (allyl).

Lower alkenyloxy is, for example, vinyloxy, prop-1-enyloxy or prop-2-enyloxy (allyloxy).

Substituted lower alkyl R 1 or R ₂ can carry one or more, preferably not more than three, substituents, which can be identical or different. Substituted lower alkyl R 1 or R ₂ preferably has only one substituent.

By unsubstituted or in the phenyl radical by halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N, N-diniederalkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-diniederalkylamino Trifluoromethyl-substituted phenylamno-substituted lower alkyl R 1 or R ₂ is in particular appropriately substituted methyl, for example anilino-methyl or 4-methoxyanilino-methyl.

Alkylene with 2 to 5 carbon atoms formed from R 1 and R ₂ is an ethylene, propylene or preferably a pentiene or in particular butylene chain which is substituted or preferably unsubstituted by lower alkyl, in particular methyl or ethyl.

C ₄ -C ₁ -alkadienylene formed from R 1 and R ₂ together is a divalent buta-1, 3-diene radical in which the carbon atoms with the numbers 1 and 2 have a free valence and which can be substituted by lower alkyl, where however, the bivalent radical may not have more than 10 carbon atoms in total, preferably buta-1,3-dien-1, 4-ylene. Aza-1,4-alkadienylene with up to and including 9 carbon atoms is C ₄ -C ₁₀ -1,4-alkadienylene, as defined above, in which at least one carbon atom of the butadiene chain, in particular a terminal carbon atom of the butadiene chain, is replaced by nitrogen, for example 1-aza-1,4-alkadienylene, in particular 1-aza-buta-1,3-diene-1,4-ylene. Aza-1,4-alkadienylene preferably contains 1 to three carbon atoms, especially one. 1-aza-1,4-alkadienylene with only one nitrogen atom is preferably bonded via this nitrogen atom to carbon atom 6 of the 7H-pyrrolo [2,3-d] pyrimidine ring system.

Salts are primarily the pharmaceutically usable salts of compounds of the formula I or intermediates of the formula II, the formula III, the formula IV, the formula V, the formula VI, the formula VII or the formula X (and also other starting compounds or intermediates ) if there is a salt-forming group.

For the isolation or purification of compounds of formula I or the intermediates mentioned, pharmaceutically unsuitable salts, such as e.g. Picrates or perchlorates can be used. Only the pharmaceutically usable salts or the free compounds of the formula I (optionally in the form of pharmaceutical preparations) are used therapeutically, which are therefore preferred.

Such salts are formed, for example, from the end products of the formula I or the intermediates of the last-mentioned formulas with a basic nitrogen atom as acid addition salts, preferably with organic or inorganic acids, in particular the pharmaceutically usable salts. Suitable inorganic acids are, for example, hydrohalic acids, such as hydrochloric acid; Sulfuric acid; Nitric acid; Carbonic acid; or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfonamic acids, for example acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, pivalic acid, decanoic acid, dodecanoic acid, stearic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, glucose monocarboxylic acid, fumaric acid, fumaric acid , Adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, acetone dicarboxylic acid, amino acids such as glutamic acid, aspartic acid, N-methylglycine, acetyiaminoacetic acid, N-acetylasparaginic acid, n-acetytraceticinic acid, N-acetytracosinic acid, N-acetytracosinetic acid 2- or 3-glycerophosphoric acid, glucose-6-phosphoric acid, glucose-1-phosphoric acid, fructose-1, 6-bisphosphoric acid, maleic acid, hydroxymaleine- acid, methyl maleic acid, malonic acid, oxalic acid, sorbic acid, cyclohexane carboxylic acid, adamantane carboxylic acid, embonic acid, benzoic acid, 2,5-dihydroxy-benzoic acid, salicylic acid, anisic acid, 1 - or 3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoe - Acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, glucuronic acid, galacturonic acid, methane or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1, 2-disulfonic acid, benzenesulfonic acid Naphthalenesulfonic acid, 1, 5-naphthalenedisurfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, camphor-10-sulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexyisulfamic acid, N-methyl-, N-ethyl- or N- Propylsulfamic acid, or other organic protonic acids, such as ascorbic acid or saccharin.

In the presence of negatively charged residues such as carboxy, salts can also be formed with bases, e.g. Metal or ammonium salts such as alkali metal or alkaline earth metal salts, e.g. Sodium, potassium, magnesium or calcium salts or ammonium salts with ammonia or suitable organic amines such as tertiary monoamines, e.g. Triethylamine or tri- (2-hydroxyethyl) amine, or heterocyclic bases, e.g. N-ethyl-piperidine or N, N'-dimethyl-piperazine.

If a basic and an acidic group are present in the same molecule, a compound of the formula I or one of the intermediates mentioned can also form internal salts.

Lower alkoxy R ₅ or R ₅ 'is preferably ethoxy.

Substituted lower alkoxy R ₅ or R ₅ 'is preferably methyl or ethyl substituted by aryl, such as phenyl, by lower alkoxy, such as methoxy, or further by any other substituent.

The invention preferably relates to the preparation of a compound of the formula I in which

n represents 0 or 1; q represents 0 or 1; R _T denotes lower alkyl, in particular methyl, hydroxyphenyl, in particular 4-hydroxyphenyl, lower alkanoylaminophenyl, in particular 4-acetylaminophenyl, or N-lower alkylcarbamoyl, in particular N-methylcarbamoyl; especially methyl;

R _{2 is} lower alkyl, especially methyl, or hydrogen; especially methyl;

R _{3 is} halogen, in particular halogen bonded in the meta position to the phenyl ring, especially chlorine, or hydrogen; and

R _{4 is} lower alkyl, especially methyl; or a salt of it.

The preparation of a compound of the formula I in which

n represents 1; q represents 0;

Ri is lower alkyl, especially methyl;

R _{2 is} lower alkyl, especially methyl;

R ₃ in the meta position on the phenyl ring is halogen, especially chlorine; and

R _{4 is} lower alkyl, especially methyl; or a salt thereof.

In the process of the present invention, preference is given to using starting materials which lead to these compounds of the formula I which are described as particularly valuable and which therefore carry the corresponding substituents.

A preferred intermediate of formula II according to the invention is a compound of formula II, wherein n represents 0 or 1; q represents 0 or 1;

R _T denotes lower alkyl, in particular methyl, hydroxyphenyl, in particular 4-hydroxyphenyl, lower alkanoylaminophenyl, in particular 4-acetylaminophenyl, or N-lower alkylcarbamoyl, in particular N-methylcarbamoyl; especially methyl;

R _{2 is} lower alkyl, especially methyl, or hydrogen; especially methyl;

R _{3 is} halogen, in particular halogen bonded in the meta position to the phenyl ring, especially chlorine, or hydrogen; and

R _{4 is} lower alkyl, especially methyl; or a salt of it.

A compound of the formula II, in which

n represents 1; q represents 0;

i is lower alkyl, especially methyl;

R _{2 is} lower alkyl, especially methyl;

R ₃ in the meta position on the phenyl ring is halogen, especially chlorine; and

R _{4 is} lower alkyl, especially methyl; or a salt of it.

Preferred reaction conditions General conditions:

In the following more detailed description of the conditions for the preparation process of compounds of the formula I, the radicals R 1, R ₂ , R ₃ , R ₄ and the symbols n and q each have the meanings given for a compound of the formula I, unless stated otherwise; preferred are the meanings mentioned above or below as preferred. In a compound of formula IV, R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of formula IV-A as defined above, preferably methoxy or a radical of formula IV-A, wherein n, y, R ₃ and R _{4 are} those for compounds of the formula I have meanings, preferably the meanings mentioned above and below as preferred. R ₅ 'in a compound of formula VI is lower alkoxy or substituted lower alkoxy, especially methoxy. R ₂ 'in a compound of the formulas VIII, IX or X is lower alkyl, in particular methyl, and corresponds to the corresponding radical R ₂ in a compound of the formula I.

Starting materials and intermediates can be used in pure form, for example after working up, in partially purified form or, for example, directly as a crude product.

As a result of the close relationship between compounds of the formula I and the compounds mentioned above and below as starting compounds and intermediates with at least one salt-forming group, in particular the corresponding compounds of the formulas M, IM, IV, V, VI, VII, VIII, VIII * and X, in free form and in the form of their salts, above and below, the free compounds or their salts are also to be understood as meaningful and expediently the corresponding salts or free compounds if the compounds contain salt-forming groups.

The compounds, including their salts, can also be obtained in the form of hydrates, or their crystals can e.g. include a solvent used for crystallization (solvates).

All of the reactions mentioned above and below can take place in the presence or absence of protective gas, such as nitrogen or argon.

Functional groups that should not participate in a reaction are present in protected form in the starting and intermediate products. If one or more further functional groups, for example carboxy, hydroxy, amino or mercapto, are or must be in protected form because they should not be involved in the reaction, they are those which are customarily used in the synthesis of peptide compounds, but can also be used by cephalosporins and penicillins as well as nucleic acid derivatives and sugars. These protective groups can already be present in the precursors and are intended to protect the functional groups in question against undesired side reactions such as acylations, etherifications, esterifications, oxidations, solvolysis and the like. In certain cases, the protective groups can also bring about a selective, for example stereoselective, course of reactions. It is characteristic of protective groups that they can be easily split off, ie without undesired side reactions, for example solvolytically, photolytically or also enzymatically, for. B. also under physiological conditions; or also reductively, functional groups then having to be reintroduced for further reactions after one of the reductions and / or hydrogenations mentioned above. The person skilled in the art knows or can easily find out which protective groups are suitable in the reactions mentioned above and below.

It is characteristic of protective groups that they are easy, i. H. can be split off without undesired side reactions, for example solvolytically, reductively, photolytically or also enzymatically, e.g. B. also under physiological conditions analogous conditions, and that they are not present in the end products.

The protection of functional groups by such protective groups, the protective groups themselves, and their cleavage reactions are described, for example, in standard works such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in Th. W. Greene, "Protective Groups in Organic Synthesis ", Wiley, New York

1981, in "The Peptides"; Volume 3 (E. Gross and J. Meienhofer, ed.), Academic Press, London and New York 1981, in "Methods of Organic Chemistry", Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974 , in H.-D. Jakubke and H. Jescheit, "Amino Acids, Peptides, Proteins", Verlag Chemie, Weinheim, Deerfield Beach and Basel

1982, and in Jochen Lehmann, "Chemistry of carbohydrates: Monosac charide and derivatives", Georg Thieme Verlag, Stuttgart 1974. A carboxy group is e.g. B. protected as an ester group that is selectively cleavable under mild conditions. A carboxy group protected in esterified form is primarily esterified by a lower alkyl group which is preferably branched in the 1-position of the lower alkyl group or substituted in the 1 - or 2-position of the lower alkyl group by suitable substituents.

A protected carboxy group which is esterified by a lower alkyl group is, for example, methoxycarbonyl or ethoxycarbonyl.

A protected amino group is protected by an amino protecting group, e.g. B. in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group or as an azido group.

In an acylamino group, acyl is preferably lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl.

The protecting groups, which are not part of the desired end product of the formula I or of intermediate compounds, are split off in a manner known per se, e.g. B. by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by means of reduction, in particular hydrogenolysis or by means of other reducing agents, and photolysis, if appropriate stepwise or simultaneously, it being also possible to use enzymatic methods. The splitting off of the protective groups is described, for example, in the standard works mentioned earlier in the section on "Protective Groups".

In the additional process measures which are carried out if desired, functional groups of the starting compounds which are not intended to participate in the reaction can be unprotected or in a protected form, for example by one or more of the protective groups mentioned above. The protective groups are then split off in whole or in part by one of the methods mentioned above.

For the conversions into other compounds of the formula I, starting compounds and intermediates, for example, the conversion processes mentioned in the two patent applications EP 0 682 027 and WO 97/02266 are suitable for the compounds, starting compounds and intermediates disclosed therein. Salts of compounds of the formula I or starting compounds or intermediates with a salt-forming group can be prepared in a manner known per se. For example, their acid addition salts can be obtained by treatment with an acid or a suitable anion exchange reagent. In particular, the acids mentioned in the definition of salts are used as acids. Salts of a compound of formula I, a starting compound or an intermediate with an acidic group, e.g. a carboxy group, can be treated, for example, by treatment with a metal compound, e.g. an alkali metal salt of a suitable organic carboxylic acid such as an alkali metal salt of 2-ethyl-hexanoic acid, an alkali - or alkaline earth metal salt of an inorganic acid, such as a hydroxide, carbonate or hydrogen carbonate, for example sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate or with ammonia or a suitable organic amine, preferably the stoichiometric amount or an excess of salt-forming agent can be used.

Salts can be converted into the free compounds in a conventional manner, for example by treatment with a suitable basic agent, for example with alkali metal carbonates, bicarbonates or hydroxides, for example potassium carbonate or sodium hydroxide. The free compounds of formula I can also be obtained from a salt of a compound of formula I as an alternative to conversion with a metal salt, ammonia or an organic amine by contact with water without treatment with a basic agent. The conversion of a salt of a compound of the formula I to a free compound of the formula I then preferably takes place at a temperature between -5 ° C. and the reflux temperature of the reaction mixture. A salt of a compound of the formula I (solid, as a suspension or as a solution in a suitable solvent or solvent mixture) is admixed with water or a water-containing solvent in such a way that the free compounds of the formula I can form in various crystal modifications. Suitable solvents for this process are: water, aqueous acids, such as aqueous inorganic acids, for example hydrochloric acid, aqueous buffers, for example phosphate buffers, ketones, such as acetone, methyl isopropyl ketone or methyl isobutyl ketone, nitriles, such as acetonitrile, alcohols, for example C1-C10 Alkanols, such as methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, amyl alcohol or octanol, diols, such as ethylene glycol, unsubstituted or substituted by lower alkyl, hydroxy or oxo-cyclic hydrocarbons, such as cyclohexane, methylcylohexane, Cyclohexanoi and cyclohexanone, Ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, diethylene glycol, diethylene glycol methyl ether, diethylene glycol ethyl ether, diethylene glycol n-butyl ether, dioxane, tetrahydrofuran, carboxamides, such as N, N-dimethylformamide or N, N -Dimethylacetamide, carboxylic acids, such as acetic acid and formic acid, carboxylic acid esters, such as ethyl acetate, isopropyl acetate or butyl acetate, hydroxy-lower alkylamines, such as ethanolamine, lower alkylsulfinyl-lower alkanes, such as dimethyl sulfoxide, aliphatic hydrocarbons, such as hexane or aromatic hydrocarbons, such as hexane or heptane Toluene or xylene, or mixtures of two or more of these solvents.

Crystal modifications of the free base of a compound of the formula I can be achieved, for example, by adding a salt of a compound of the formula I, in particular 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine, converted to the free base by contact with water. In order, for example, to obtain the free base as a form I crystal modification, a salt of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, in particular the methanesulfonate salt, is preferably added a temperature between room temperature and the reflux temperature of the reaction mixture. For example, to obtain Form II or III, a salt of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, especially the methanesulfonate salt, preferably at a temperature between 20 and 30 ° C, in particular at about 25 ° C, preferably suspended in a water-containing solvent for about 20 or less than 20 hours, are converted into the corresponding free base as crystal modification II and IM. The appropriate solvents can be found in the previous section.

Mixtures of stereoisomers, e.g. B. mixtures of diastereomers can be separated into the corresponding isomers in a manner known per se by suitable separation processes. Diastereomer mixtures can thus be separated into the individual diastereomers by fractional crystallization, chromatography, solvent distribution and the like. This separation can take place both at the stage of one of the starting products and in the compounds of the formula I itself. Enantiomers in mixtures of enantiomers can be separated by formation of diastereomeric salts, for example by salt formation with an enantiomerically pure chiral acid, or by chromatographic means, for example by chromatography, for example HPLC, using chromatographic support materials with chiral ligands. To reaction A)

The rearrangement of a compound of formula II into a compound of formula I is preferably carried out at elevated temperature, in particular at temperatures between 40 ° C. and the reflux temperature of the reaction mixture, in a suitable solvent or solvent mixture, in particular in water, an aqueous alkali, for example an aqueous one Alkali metal or ammonium hydroxide solution, such as aqueous sodium hydroxide, potassium hydroxide or ammonia, an aqueous acid, such as an aqueous inorganic acid, for example hydrochloric acid, a ketone, such as acetone, methyl isopropyl ketone or methyl isobutyl ketone, a nitrile, such as acetonitrile, an alcohol, for example ad-C ₁₀ -alkanol, such as methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, amyl alcohol or octanol, a diol, such as ethylene glycol, an unsubstituted or by lower alkyl, hydroxy or oxo substituted cyclic hydrocarbon, such as cyclohexane, methylcyclohexane, Cy clohexanol and cyclohexanone, an ether such as diisopropyl ether, tert-butyl methyl ether, diethylene glycol, diethylene glycol methyl ether, diethylene glycol ethyl ether, diethylene glycol n-butyl ether, dioxane, tetrahydrofuran, a carboxylic acid amide such as N, N - Dimethyrformamide or N, N-dimethylacetamide, a carboxylic acid, such as acetic acid or formic acid, a carboxylic acid ester, such as ethyl acetate, isopropyl acetate or butyl acetate, a hydroxy-lower alkylamine, such as ethanolamine, a lower alkylsulfinyl-lower alkane, such as dimethylsulfoxide, an aliphatic aliphatic such as hexane or heptane, or an aromatic hydrocarbon, such as toluene or xylene, or a mixture of two or more, preferably up to three, of these solvents, preferably in a lower alkanol, in particular ethanol, a lower alkanediol, in particular ethylene glycol, water or a mixture of two or more of these solvents. The reaction is therefore a variant of the Dimroth rearrangement.

Reaction B:

The reaction of a cyanopyrrole compound of the formula III with an imino compound of the formula IV takes place at a preferred temperature between 0 and 200 ° C, in particular between 20 and 60 ° C, for example between room temperature and approximately 40 ° C; with the addition of an acid, in particular to adjust a pH between 3 and 10, especially between 5 and 8, the acid preferably being a carboxylic acid, for example a lower alkanoic acid, such as formic or acetic acid, or a pyridinecarboxylic acid, such as nico- tic acid, a suifonic acid, for example a lower alkanesulfonic acid, such as methane or ethanesulfonic acid, or an arylsulfonic acid, such as toluene-4-sulfonic acid, or further one of the other acids mentioned in the definition of salts; or a salt of such an acid with a nitrogen base, in particular a tertiary or quaternary nitrogen base, such as a base of an unsubstituted or, for example, mono- or bicyclic heterocycle which is substituted by di-lower alkylamino and has at least one ring nitrogen atom, for example pyridine, preferably a pyridine or a tetra-lower alkylammonium salt of the acid in question , especially the tetraethylammonium or tetrabutylammonium salt; pyridinium (toluene-4-sulfonate), tetraethylammonium or tetrabutylammonium (toluene-4-sulfonate) is preferably used as the acid; mixtures of two or more of the acids mentioned or their salts with a nitrogen base may also be present; in a suitable solvent or solvent mixture, in particular an alcohol, such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, amyl alcohol or octanol, a diol, such as ethylene glycol, a nitrile, such as acetonitrile, an ether , such as dioxane or tetrahydrofuran, or an ester, for example a lower alkanoic acid lower alkyl ester, such as ethyl acetate or isopropyl ester; an alcohol, in particular methanol or ethanol, is preferred.

Reaction C:

The reaction of an amino compound of the formula V with an orthoformic acid ester of the formula VI is preferably carried out at elevated temperature, in particular a temperature between 50 ° C. and the boiling point of the corresponding reaction mixture, in particular an existing solvent being distilled off while continuously or gradually increasing the temperature in the range given ; in the presence of a suitable acid, in particular a carboxylic acid, for example a lower alkanoic acid, such as formic or acetic acid, or a pyridinecarboxylic acid, such as nicotinic acid, a suifonic acid, for example a lower alkanesulfonic acid, such as methane or ethanesulfonic acid, or an arylsulfonic acid, such as toluene-4-sulfonic acid , or one of the other acids mentioned in the definition of salts; or a salt of such an acid with a nitrogen base, in particular a tertiary or quaternary nitrogen base, such as an unsubstituted or, for example, mono- or bicyclic heterocycle substituted by lower alkyl or di-lower alkylamino having 3 to 14, preferably 4 to 10, ring nitrogen atoms and at least one ring nitrogen atom, preferably 1 up to 3 nitrogen atoms, for example pyridine, preferably a pyridine or a tetraniederalkylammonium salt of the acid in question, in particular the tetraethylammonium or tetrabutylammonium salt; preferred acid is a lower alkanoic acid, in particular acetic acid, or pyridinium (toluene-4-suifonate), tetraethylammonium or tetrabutylammonium (toluene-4-sulfonate); a lower alkanoic acid, in particular acetic acid, is particularly preferred; in suitable solvents or solvent mixtures, in particular an alcohol, preferably a lower alkanol or lower alkanol substituted on the lower alkyl, in particular an alcohol of the formula R ₅ '-H, in which R ₅ ' has the meanings given for compounds of the formula VI, in particular lower alkoxy.

If the reaction serves to prepare a substituted formimidate of the formula IV, in which R _{5 is} lower alkoxy or substituted lower alkoxy and the other radicals have the meanings given for formula IV, one of the salts mentioned in a nitrogen base, in particular pyridinium, is preferably used for the reaction -4- sulfonate. The imino compound of the formula V is used, based on the molar amount of the orthoformate of the formula VI, preferably in a deficit, in particular in the molar ratio of imino compound: orthoformate = 1: 1, 5 to 2.

Serves the reaction of the preparation of a substituted formamidine of formula IV, wherein R _{5 is} a radical of formula IV-A, in which the radicals have the meanings given for formula IV-A, and in which the remaining radicals have the same meanings for a compound of formula IV Have meanings, the imino compound of the formula V is preferably used, based on the molar length of the orthoformic acid ester of the formula VI, in excess, in particular in a 1.5 to five-fold excess, in particular in a molar ratio of imino compound: orthoformic acid ester = 1.5 to 2.5: 1.

Reaction B / C:

The preferred one-pot reaction involving the reaction of an amino compound of the formula V, as defined above, with an orthoformate of the formula VI, as defined above, and with a cyanopyrrole compound of the formula IM, as defined above, to give a corresponding compound of the formula II is carried out in particular at a temperature between 0 and 100 ° C, especially between 20 and 60 ° C, in particular at about 40 ° C, in the presence of a suitable acid, in particular a carboxylic acid, for example a lower alkanoic acid, such as formic or acetic acid, or a pyridinecarboxylic acid, such as nicotinic acid, a suifonic acid, for example a lower alkanesulfonic acid, such as methane or ethanesulfonic acid, or an arylsulfonic acid fonic acid, such as toluene-4-sulfonic acid, or one of the other acids mentioned in the definition of salts; or a salt of such an acid with a nitrogen base, in particular a tertiary or quaternary nitrogen base, such as a base of an unsubstituted or, for example, mono- or bicyclic heterocycle which is substituted by di-lower alkylamino and has at least one ring nitrogen atom, for example pyridine, preferably a pyridine or a tetra-lower alkylammonium salt of the acid in question , especially the tetraethylammonium or tetrabutylammonium salt; preferred acid is a lower alkanoic acid, in particular acetic acid, or pyridinium (toluene-4-sulfonate), tetraethylammonium or tetrabutylammonium (toluene-4-sulfonate); a lower alkanoic acid, in particular acetic acid, is particularly preferred; in a suitable solvent or solvent mixture, in particular an alcohol, such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, amyl alcohol or octanol, a diol, such as ethylene glycol, a nitrile, such as acetonitrile, an ether , such as dioxane or tetrahydrofuran, or an ester, for example a lower alkanoic acid lower alkyl ester, such as ethyl acetate or isopropyl ester; an alcohol, in particular methanol or ethanol, is preferred.

Reaction B *

The particularly preferred one-pot reaction, also forming an object of the present invention, of a cyanopyrrole compound of the formula IM, in which R 1 and R _{2 have} the meanings given for compounds of the formula I, with an imino compound of the formula IV, in which R ₃ , P _H , n and q have the meanings given for compounds of the formula I and R ₅ denotes a radical of the formula IV-A, in which R ₃ , R-ι, n and q have the meanings given for compounds of the formula I, to give a compound of the formula II is preferably carried out at a preferred temperature between 0 and 200 ° C, in particular between 20 and 60 ° C, for example between room temperature and approximately 40 ° C; with the addition of an acid, in particular to adjust a pH between 3 and 10, especially between 5 and 8, the acid preferably a carboxylic acid, for example a lower alkanoic acid, such as formic or acetic acid, or a pyridinecarboxylic acid, such as nicotinic acid, a suifonic acid , for example a lower alkanesulfonic acid, such as methane or ethanesulfonic acid, or an arylsulfonic acid, such as toluene-4-sulfonic acid, or one of the other acids mentioned in the definition of salts; or a salt of such an acid with a nitrogen base, in particular a tertiary or quaternary nitrogen base, such as a base of an unsubstituted or, for example, substituted by di-lower alkylamino ten mono- or bicyclic heterocycle with at least one ring nitrogen atom, for example pyridine, preferably a pyridine or a tetran-lower alkylammonium salt of the acid in question, in particular the tetraethylammonium or tetrabutylammonium salt; a lower alkane carboxylic acid, in particular acetic acid, is preferably used as the acid; mixtures of two or more of the acids mentioned or their salts with a nitrogen base may also be present; in a suitable solvent or solvent mixture, in particular an alcohol, such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, amyl alcohol or octanol, a diol, such as ethylene glycol, a nitrile, such as acetonitrile, an ether , such as dioxane or tetrahydrofuran, or an ester, for example a lower alkanoic acid lower alkyl ester, such as ethyl acetate or isopropyl ester; an alcohol, in particular methanol or ethanol, is preferred.

Reaction D:

In a reactive acid derivative of formula VIII, halogen is preferably fluorine or chlorine; activated aryloxy preferably means a conventional radical for activated esters, for example nitrophenyl, such as 4-nitrophenyl or 2,4-dinitrophenyl. Particular preference is given to using a compound of the formula VIII in which L is an acyloxy radical of the formula R ₂ -C (= O) -O-, that is to say an anhydride, preferably a symmetrical anhydride.

The process for the preparation of a compound of formula MI, or a salt thereof, in which functional groups may be in free or protected form, starting from an amino acid of formula VII which is reacted with a reactive acid derivative of formula VIII; where in an amino acid of the formula VII functional groups which are not intended to take part in the reaction are, if necessary, in protected form; preferably takes place at temperatures between 0 ° C. and the reflux temperature of the respective reaction mixture, in particular at temperatures, in particular between 30 ° C. and reflux temperature, preferably between 30 and 140 ° C. or reflux temperature; in the presence or preferably the absence of a suitable solvent or solvent mixture, such as water; wherein the tertiary nitrogen base used is preferably an unsubstituted or mono- or bicyclic heterocycle having 3 to 14, in particular 4 to 10 ring nitrogen atoms and at least one ring nitrogen atom, for example substituted by lower alkyl or di-lower alkylamino, preferably a corresponding monocycle with at least one ring nitrogen atom, preferably 1 to 3 nitrogen atoms , for example pyridine, picoline, such as 2-, 3- or 4-picoline, di-lower alkylaminopyridine, such as 2,6-lutidine, 4- (N, N-dimethylamino) pyridine; or a tri-lower alkylamine such as triethylamine; or a mixture of these nitrogen bases; or the alkaline earth metal or alkali metal salt used of an acid of the formula R ₂ -C (= O) -OH, preferably a sodium or potassium salt, in particular a sodium or potassium lower alkyl carbonate (gives compounds of the formula X in which R _{2 is} lower alkyl, and is suitable for the preparation of corresponding compounds of the formula I in which R _{2 is} lower alkyl), for example sodium or potassium acetate (R ₂ = methyl).

The amino acid of the formula VIII * can be in the D, L or (preferably) D, L form.

Response D *:

The particularly preferred process for the preparation of a compound of the formula IM, or a salt thereof, in which functional groups can be present in free or protected form, and in which R _{2 is} lower alkyl (so that even if the process is continued via a compound of the formula II to be obtained end product of formula I, or a salt thereof, R _{2 is} lower alkyl) and Ri has one of the meanings given for compounds of formula I, and which starts from an amino acid of formula VII, wherein Ri is one of the compounds of formula I. has the meanings mentioned, which is reacted with an acid anhydride of the formula VIII *, in which R ₂ 'is lower alkyl, in the presence of a carboxylic acid of the formula IX, in which R ₂ ' is lower alkyl, and a tertiary nitrogen base to give a compound of the formula X *, wherein Ri has the meanings given for a compound of formula I and R ₂ 'is lower alkyl; where in an amino acid of the formula VII functional groups which are not intended to take part in the reaction are, if necessary, in protected form; is particularly characterized by the presence of the acid of the formula IX and is preferably carried out at temperatures between 0 ° C. and the reflux temperature of the respective reaction mixture, in particular at temperatures, in particular between 80 ° C. and reflux temperature, preferably between 80 and 140 ° C. in the presence or preferably the absence of a suitable solvent or solvent mixture; wherein the tertiary nitrogen base used is preferably an unsubstituted or mono- or bicyclic heterocycle having 3 to 14, in particular 4 to 10 ring nitrogen atoms and at least one ring nitrogen atom, for example substituted by lower alkyl or di-lower alkylamino, preferably a corresponding monocycle with at least one ring nitrogen atom, preferably 1 to 3 nitrogen atoms , for example pyridine, picoline, such as 2-, 3- or 4-picoline, di-lower alkylaminopyridine, such as 2,6-lutidine, 4- (N, N-dimethylamino) pyridine; or a tri-lower alkylamine such as triethylamine; or a mixture of these nitrogen bases, for example of triethylamine and 4- / NN-dimethylamino) pyridine.

The amino acid of the formula VIII * can be in the D, L or (preferably) D, L form.

In the very particularly preferred embodiment variant, the reaction can be carried out according to variant (i) or (ii). With continuous or stepwise metering in, the metering is metered in evenly or in portions over a longer period (which depends in particular on the total amount of the reaction mixture), for example over one or more hours, e.g. with a size of the batch after adding all components of about 0.5 liters over an hour. Mixtures of the reagents can be present as solutions or suspensions.

In the preferred variant (i), preference is given to the acid anhydride of the formula VIII * in a mixture with a carboxylic acid of the formula IX * and the tertiary nitrogen base, which (in the order mentioned) in a molar ratio (2-4) :( 0.3-1 ): 1 are present as a mixture, and then the mixture of a compound of the formula VII and a tertiary base in a molar ratio (0.2-0.5): 1 is added, the amount of the tertiary base in the mixture added to that in the mixture added is 1: 1, 5.

Reaction E:

The reaction of a compound of formula X, in particular X *, in which the radicals have the meanings given under formula X or X *, with malononitrile in the presence of a base is preferably carried out at a temperature between above the melting temperature of the reaction mixture and 100 ° C., in particular between about 0 and 30 ° C, in a suitable solvent or solvent mixture, for example water, a ketone, such as acetone, methyl isopropyl ketone or methyl isobutyl ketone, a nitrile, such as acetonitrile, an alcohol, for example a CrCno-alkanol, such as methanol, Ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, amyl alcohol or octanol, a diol such as ethylene glycol, an unsubstituted or substituted by lower alkyl, hydroxy or oxycyclic hydrocarbon such as cyclohexane, methylcylohexane, cyclohexanol and Cyclohexanone, an ether such as diisopropyl ether, diethylene glycol, diethylene glycol methyl ether, diethylene glycol ether, di ethylene glycol n-butyl ether, dioxane, tetrahydrofuran, egg a carboxylic acid amide, such as N, N-dimethylformamide or N, N-dimethylacetamide, a carboxylic acid, such as acetic acid, a carboxylic acid ester, such as ethyl acetate, isopropyl acetate or butyl acetate, a hydroxy-lower alkylamine, such as ethanolamine, a lower alkylsulfinyl-lower alkane, such as dimethyl sulfoxide an aliphatic hydrocarbon, such as hexane or heptane, or an aromatic hydrocarbon, such as toluene or xylene, or a mixture of two or more, preferably up to three, of these solvents, preferably in a lower alkanol, in particular ethanol, a lower alkane diol, in particular ethylene glycol, water or a mixture of two or more of these solvents, especially in water.

In the preferred process variants mentioned below, if appropriate and expedient, general reaction conditions are preferably replaced by the conditions mentioned above for the corresponding specific reaction conditions.

Preferred is a process for the preparation of a compound of formula I, in which the radicals have the meanings mentioned, in particular as preferred, in which a cyanopyrrole compound of formula III,

in which RT and R _{2 have} the meanings given for compounds of the formula I, with an imino compound of the formula IV,

wherein Ft ₃ , *, n and q have the meanings given for compounds of the formula I and R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A

wherein Rs, FU, n and q have the meanings given for compounds of the formula I, is reacted (reaction B), an imino compound of the formula II

receives, in which the radicals have the meanings given for a compound of the formula I,

and then rearranging a compound of the formula II obtained into a compound of the formula I in a suitable solvent or solvent mixture at elevated temperature (reaction A),

where in the starting and intermediate compounds, which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to take part in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;

and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt, converting an available salt into the free compound of formula I or another salt thereof and / or at an as Compound of the formula I obtainable isomer mixture carries out a separation into isomers. A process for the preparation of a compound of the formula I in which the radicals have the meanings mentioned, in particular as preferred, is more preferred, in which an amino compound of the formula V

wherein Ffe, R _A , n and q have the meanings given for a compound of the formula I, in the presence of a suitable acid, with an orthoformate of the formula VI,

(RsVCH (VI)

where R ₅ 'denotes lower alkoxy or substituted lower alkoxy, (reaction C),

then a cyanopyrrole compound of the formula IM,

wherein R _T and R _{2 have} the meanings given for compounds of the formula I, with an imino compound of the formula IV obtainable by the previous reaction,

wherein R, R ₄ , n and q have the meanings given for compounds of the formula I and R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A

in which Fb, F, n and q have the meanings given for compounds of the formula I, is reacted (reaction B), an imino compound of the formula II

receives, in which the radicals have the meanings given for a compound of the formula I,

and then rearranging a compound of the formula II obtained into a compound of the formula I in a suitable solvent or solvent mixture at elevated temperature (reaction A),

where in the starting and intermediate compounds, which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to take part in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;

and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt, converting an available salt into the free compound of formula I or another salt thereof and / or at an as Compound of the formula I obtainable isomer mixture carries out a separation into isomers.

Even more preferred is the above-mentioned process for the preparation of a compound of formula I, in which the radicals have the meanings mentioned, in particular as preferred, by directly an amino compound of the formula V, in which R ₃ , Fu, n and q have the meanings given for a compound of the formula I, with an orthoformate of the formula VI, in which R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A, such as shown above, in which R ₃ , *, n and q have the meanings given for compounds of the formula I, and with a cyanopyrrole compound of the formula III, in which R 1 and R _{2 have} the meanings given for compounds of the formula I, in a one-pot reaction ( Reaction B / C), an imino compound of the formula II being obtained without isolation of intermediate compounds

receives, in which the radicals have the meanings given for a compound of the formula I,

and then rearranging a compound of formula II obtained into a compound of formula I in a suitable solvent or solvent mixture at elevated temperature,

where in the starting and intermediate compounds, which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to participate in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;

and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt, converting an available salt into the free compound of formula I or another salt thereof and / or at an as Compound of the formula I obtainable isomer mixture carries out a separation into isomers. A process for the preparation of a compound of the formula I is very preferred, in which the radicals have the meanings given for a compound of the formula I, in particular the meanings mentioned as preferred, in which an amino acid of the formula VII,

wherein Ri has one of the meanings given for compounds of the formula I, with a reactive acid derivative of the formula VIII,

in which R _{2 has} the meanings given for a compound of the formula I and L is halogen, azido, an activated aryloxy radical or an acyloxy radical of the formula R ₂ -C (= O) -O-, in which R _{2 is} a compound of the formula I can have meanings mentioned, in the presence of a tertiary nitrogen base or an alkaline earth metal or alkali metal salt of an acid of the formula R ₂ -C (= O) -OH, in which R _{2 has} the meanings mentioned for compounds of the formula I, to give a compound of the formula X

reacted (reaction D), wherein R _T and R _{2 have} the meanings given for a compound of the formula I;

and then converted into a compound of the formula III by reaction with malononitrile in the presence of a base,

wherein R 1 and R _{2 have} the meanings given for compounds of the formula I (reaction E),

then a obtained cyanopyrrole compound of the formula III with an imino compound of the formula IV obtainable by the reaction mentioned below,

wherein R ₃ , R, n and q have the meanings given for compounds of the formula I and R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A

in which R ₃ , R ₄ , n and q have the meanings given for compounds of the formula I, is reacted (reaction B), an imino compound of the formula II

receives, in which the radicals have the meanings given for a compound of the formula I,

and then rearranging a compound of the formula II obtained into a compound of the formula I in a suitable solvent or solvent mixture at elevated temperature (reaction A), wherein an imino compound of formula IV is prepared by using an amino compound of formula V,

wherein R ₃ , R ₄ , n and q have the meanings given for a compound of the formula I, in the presence of a suitable acid with an orthoformate of the formula VI,

(RβVCH (VI)

wherein R ₅ 'is lower alkoxy or substituted lower alkoxy, (reaction C);

(wherein preferably the reaction of a cyanopyrrole compound of the formula III, as defined above, directly with an amino compound of the formula V, in which R ₃ , R4, n and q have the meanings given for a compound of the formula I and with an orthoformic acid ester of the formula VI, wherein R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A, as shown above, wherein R ₃ , Rv, n and q have the meanings given for compounds of the formula I, whereby an imino compound is isolated without isolation of intermediate compounds Formula II as defined above is obtained (Reaction B / C));

where in the starting and intermediate compounds, which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to take part in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers; and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt, converting an available salt into the free compound of formula I or another salt thereof and / or at an as Compound of the formula I obtainable isomer mixture carries out a separation into isomers.

The new processes, process conditions and intermediates mentioned in the examples are very preferred.

Examples:

The following examples serve to illustrate the invention, without their

To limit scope.

Temperatures are measured in degrees Celsius. Unless otherwise stated, reactions take place at room temperature. The ratios of solvents used in solvent mixtures are given in volume fractions (v / v).

Abbreviations: abs. absolutely

Alanine D, L-Alanine related to

CDCI ₃ deuterochloroform

DMSO dimethyl sulfoxide

DSC differential scanning calorimetry

Ethanol 97% 97% ethanol h hour (s) min minute (s)

¹ H-NMR Magnetic proton nuclear magnetic resonance

RT room temperature

Boiling point

Mp melting point

Decay under decomposition

¹ H-NMR spectra: These are recorded on a Varian Gemini 200 (200 MHz). The chemical shifts are given in ppm and based on the solvent peak. Multi- pliz ^'rtäten: s = singlet, d = doublet, t = triplet, q = quartet.

DSC melting points are determined with a PERKIN-ELMER DSC7 using a DSC thermogram. DSC is the technique of dynamic differential calorimetry. With this technique it is possible to measure the melting temperature by heating the sample only until a thermal event, i.e. an endothermic or exothermic sensation. The DSC melting points specified in this text are measured on a PERKIN-ELMER DSC7, with approximately 1.5 to 2.5 mg of the respective sample being weighed into an aluminum crucible under an ambient air atmosphere and measured at a heating rate of 10 K / min (start at 30 ° C.) become.

Crystal modifications can be distinguished by their X-ray diagrams. X-ray diagrams, recorded with a diffractometer or a Guinier camera in transmission geometry and using Cu-Kα1 radiation, are preferably used to characterize solids of organic substances. In particular, X-ray diffraction diagrams are successfully used to determine the crystal modification of a substance. To characterize the crystal modifications Form I, Form II and Form IM described below, the measurements in the angular range (2Θ) of 2 ° and 35 ° are carried out with substance samples which were kept at room temperature.

Example 1. Variant 1: 3-acetylamino-2-butanone

80 ml (1.0 mol) of pyridine, 285 ml (3.0 mol) of acetic anhydride and 29 ml (0.5 mol) of acetic acid are placed in a flask inertized with nitrogen and heated to a temperature of 120-125 ° C. A suspension of 44.5 g (0.5 mol) of alanine in 120 ml (1.5 mol) of pyridine is metered into this mixture over the course of 1 h, with a uniform evolution of CO 2 occurring. When the addition is complete, the reaction mixture is kept at 120-125 ° C. for 1 h and then cooled. The solvent mixture is distilled off under vacuum, leaving the crude 3-acetylamino-2-butanone as a distillation residue in the form of a brown, slightly oily liquid (crude yield approx. 80%). It can be used in the next stage without further cleaning. Pure 3-acetylamino-2-butanone in the form of a clear, colorless oil is obtained by high vacuum distillation of the crude product. Bp 101-102 ° C at 1 mbar; ¹ H NMR (CDCI3): 6.42 (s, 1 H), 4.59 (m, 1 H), 2.21 (s, 3H), 2.00 (s, 3H), 1.37 ( d, 3H).

The same connection can also be obtained as follows:

Variant 2: A mixture of 250 ml (2.64 mol) of acetic anhydride, 420 ml (3.0 mol) of triethylamine, 35 ml (0.6 mol) of acetic acid and 1.47 g (12 mmol) of 4-dimethylaminopyridine is added at 45-50 ° within 6 hours C 108 g (1.2 mol) alanine metered in, which is accompanied by a continuous gas evolution. When the addition is complete, stirring is continued at 45 ° C. for 12 h. The solvent mixture is then distilled off in vacuo and crude 3-acetylamino-2-butanone is obtained in the form of a reddish-brown oil. It can be used in the next stage without further cleaning.

Example 2: 2-Amino-3-cyano-4,5-dimethylpyrrole

The crude 3-acetylamino-2-butanone from Example 1 is dissolved in 250 ml of water and 33 g (0.5 mol) of malononitrile are added at RT. The brown solution is cooled to 0 ° C. and, with vigorous stirring, 157 ml (3.0 mol) of a 50% strength aqueous sodium hydroxide solution are added for 20-30 min, which is accompanied by heating. The resulting suspension is stirred for 15 min at 0 ° C and then poured onto 600 ml of ice water. After stirring at 0 ° C. for 1 h, the mixture is filtered off and washed with water. After drying the suction filter, 49 g (0.36 mol, 73% or alanine) of 2-amino-3-cyano-4,5-dimethylpyrrole are obtained in the form of a light beige powder. Mp 160 ° C; ^" Η NMR (DMSO): 9.83 (s, 1H), 5.36 (s, 2H), 1.92 (s, 3H), 1.83 (s, 3H).

Example 3/1: N- (3-chlorophenyl) formimidic acid ethyl ester

74 ml (0.7 mol) of 3-chloroaniline, 180 ml (1.1 mol) of triethyl orthoformate and 420 mg (2 mmol) of pyridinium (toluene-4-sulfonate) are placed in a flask inertized with nitrogen and heated to 80 ° C. . The temperature of the oil bath is gradually increased to 135 ° C. in the course of 2 hours, the ethanol formed being continuously distilled off. The temperature is kept at 135 ° C. for a further 2 h. It is then cooled and the excess triethyl orthoformate distilled off in vacuo. The crude ethyl N- (3-chloro. Pheny!) Formimate remains as a distillation residue and can be used in this form in the next stage. Vacuum distillation gives pure ethyl N- (3-chlorophenyl) formimide. Bp 80 ° C at 2 mbar; ¹ H NMR (CDCI3): 7.70 (s, 1 H), 7.28-6.84 (m, 4H), 4.32 (q, 2H), 1.38 (t, 3H). Example 3/2: N, N'-bis (3-chlorophenyl) formamidine

A solution of 41 ml (0.4 mol) 3-chloroaniline, 32 ml (0.2 mol) orthoformic acid triethyl ester and 100 ml abs. 0.25 ml (4 mmol) of acetic acid is added to ethanol and the mixture is heated to 50 ° C. over 2 h. The mixture is cooled to 0 ° C. and the product is filtered off. After washing with cold abs. Ethanol and drying give 46.4 g (0.17 mol, 89%) of N, N'-bis (3-chlorophenyl) formamidine in the form of white crystals. Mp 108 ° C; ¹ H NMR (CDCI3): 8.45 (s, 1H), 8.15 (s, 1H), 7.30-6.86 (m, 8H).

Example 4. Variant 1: 3-f3-chlorophenyl) -5,6-dimethyl-4H-pyrrolor2.3-dlpyrimidin-4-imine To a suspension of 42 g (0.31 mol) of 2-amino-3-cyano-4, 5-dimethylpyrrole in 460 ml abs. Ethanol is added to 71.5 g (0.4 mol) of the crude ethyl N- (3-chlorophenyl) formimidate from Example 3/1. The pH is adjusted to 8.0 by adding a 10% solution of pyridinium (toluene-4-sulfonate) in ethanol. The suspension is stirred at RT for 24 h, after which 60 ml of water are added. After cooling in an ice bath, the mixture is filtered off and washed with ethanol / water (4: 1). After drying the filter cake, 69 g (0.25 mol, 82%) of crystalline 3- (3-chlorophenyl) -5,6-dimethyl-4H-pyrrolo [2,3-d] pyrimidin-4-imine are obtained in the form of a pale yellow powder. Mp> 150 ° C (dec.); ¹ H NMR (DMSO): 10.97 (s, 1H), 10.26 (s, 1 H), 8.56 (s, 1 H), 7.39-7.14 (m, 4H), 2.08 (s, 3H), 1.96 (s, 3H).

The same connection can also be obtained as follows:

Variant 2: A suspension of 3.0 g (22.19 mmol) of 2-amino-3-cyano-4,5-dimethylpyrrole in 50 ml of ethanol is mixed with 6.5 g (24.51 mmol) of N, N'- Bis- (3-chlorophenyl) formamidine (Example 3/2) and 0.10 ml (1.6 mmol) acetic acid were added and the mixture was stirred at RT for 5 h. 5 ml of water are then added, the mixture is cooled to 0 ° C. and filtered off. The filtrate is washed with ethanol / water (4: 1). After drying, 5.07 g (18.6 mmol, 84%) of 3- (3-chlorophenyl) -5,6-dimethyl-4H-pyrolo [2,3-d] pyrimidin-4-imine in the Form of a pale yellowish powder.

The same compound is preferably obtained in a one-pot reaction as follows:

Variant 3: A suspension of 25 g (0.2 mol) of 2-amino-3-cyano-4,5-dimethylpyrrole in 75 ml abs. Ethanol, 47 ml (0.3 mol) of triethyl orthoformate and 23 ml (0.2 mol) of 3-chloroaniline are mixed with 0.81 ml (12.86 mmol) of anhydrous acetic acid and heated to 40.degree. After 4 hours of stirring at 40 ° C., the mixture is cooled in an ice bath and then filtered off. 37.9 g (0.14 mol, 75%) of finely crystalline 3- (3-chlorophenyl) -5,6-dimethyl-4H-pyrrolo [2,3-d] pyrimidin-4-imine are obtained as a yellow powder .

Example 5. Variant 1: 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo ^r 2,3-d] pyrimidine 300 g (1.1 mol) 3- (3-chlorophenyl) -5,6-dimethyl -4H-pyrrolo [2,3-d] pyrimidin-4-imine are suspended in 750 ml of water, 750 ml of ethanol and 1500 ml of ethylene glycol and heated to reflux (95 ° C.) within about 2 hours. The suspension is boiled at 95 ° C. for 3 hours and then cooled to 25 ° C. within 90 minutes. The mixture is stirred for 1 h, the product is filtered off and washed with water. After drying the filter cake, 277 g (1, 02 mol, 92%) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine are obtained as colorless crystals. ¹ H NMR (DMSO): 11, 53 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.95 (d, 1H), 7.71 (t, 1 H), 7.33 (t, 1H), 7.03 (q, 1H), 2.41 (s, 3H), 2.28 (s, 3H).

The crystal modification of the 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine obtained in the following, called Form I, melts at a heating rate in the DSC of 10 ° C./min Interval of 240 ° C and 255 ° C with a melting point range from and with 244 ° C to and with 250 ° C. The crystal modifications referred to below as Form II and Form IM are less stable and are converted into the crystal modification Form I when heated. Tables 1, 2 and 3 show the X-ray diffraction diagrams of the crystal modifications Form I, Form II and Form IM.

Table 1: X-ray diffraction diagram (reflection lines and intensities of the most important lines) of the crystal modification Form I of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolor2.3-dlpyrimidine (recorded with a X-ray diffractometer).

2Θ intensity

6.2 medium

8.1 very strong

9.7 very strong

12.0 medium

14.7 very strong

15.0 medium

15.4 medium

17.5 weak

17.8 weak 19.0 very weak

19.7 strong

21.9 weak

22.8 medium

23.8 very weak

25.4 very weak

26.1 medium

26.8 strong

26.9 strong

29.7 weak

32.0 weak

The 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine obtained can be recrystallized according to the following procedure:

58 g (0.21 mol) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine are suspended together with 2.9 g of activated carbon in a mixture of 900 ml of tetrahydrofuran and 100 ml of water and heated to reflux. The suspension is filtered, boiled briefly and then crystallized by cooling to 20 ° C. within 3 h. 200 ml of water are added within 1 h, the mixture is cooled to 2 ° C. within 1 h and the product is filtered off. After washing with cold abs. Ethanol is dried in a high vacuum. 44.7 g (0.16 mol, 77.1%) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine are obtained in the form of white crystals. (Mp and NMR data as above). The crystal modification of the product is characterized by the X-ray diffraction pattern of Form I.

The same connection can also be obtained as follows:

Variant 2: 20 g (0.054 mol) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine methanesulfonate (Example 6) are suspended in 400 ml of water and for 10 h stirred at 25 ° C. The product is filtered and washed with water. After drying under high vacuum, 12.6 g (0.046 mol, 85%) of 4- (3-chlorophenylamino) - 5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine are obtained in the form of white crystals. (NMR data as above). The crystal modification of the product is characterized by the X-ray diffraction pattern of Form I. The same compound can be obtained in two further crystal modifications as follows:

Variant 3: 75 mg (0.0002 mol) of 4- (3-chlorophenyiamino) -5,6-dimethyl-7H-pyrrolo [2,3-djpyrimidine methanesulfonate (Example 6) are suspended in 20 ml of water and for 20 h stirred at 25 ° C. The product is filtered and dried in room air. 4- (3-Chlorophenylamino) -5,6-dimethyl-7H-pyrroio [2,3-d] pyrimidine methanesulfonate is obtained in the form of white crystals (NMR data as above). It is found that the product obtained in this way is present in a further crystal form in addition to the crystal forms Form I and Form IM. Form II is characterized by the X-ray diffraction pattern shown in Table 2 below.

Table 2: X-ray diffraction diagram (reflection lines and intensities of the most important lines, recorded with a Guinier camera) of the crystal modification Form II of 4- (3-chlorophenylamino) -5.6-dimethyl-7H-pyrrolof2.3-dlpyrimidine.

2Θ intensity

8.1 weak

11.3 medium

13.0 medium

13.8 medium

14.0 very weak

15.3 weak

16.3 strong

20.9 weak

24.2 weak

24.9 weak

25.6 very strong

26.1 strong

27.0 very weak

27.5 strong

27.8 weak

Variant 4: 20 g (0.054 mol) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-djpyrimidine methanesulfonate (Example 6) are suspended in 400 ml of water and while Stirred at 25 ° C for 2 h. The product is filtered and washed with water. After drying under high vacuum, 12.6 g (0.046 mol, 85%) of 4- (3-chlorophenylamino) - 5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine are obtained in the form of white crystals. (NMR data as above). It was found that the product obtained in this way is in a crystal modification which is different from Form I and Form, namely Form III. .. Form III is characterized by the following X-ray diffraction pattern (Table 3):

Table 3: X-ray diffraction diagram (reflection lines and intensities of the most important lines) of the crystal modification Form IM of 4- (3-chlorophenylamino) -5.6-dimethyl-7H-pyrrolo [2.3-dlpyrimidine.

2Θ intensity

8.8 very strong

13.4 medium

14.5 medium

15.2 medium

15.7 medium

16.0 weak

17.0 medium

17.9 strong

19.6 weak

20.1 weak

20.4 weak

21.0 weak

23.2 medium

24.9 medium

25.5 medium

25.9 very strong

26.6 very strong

27.2 very weak

28.8 medium

29.5 very weak

31.9 very weak

32.5 very weak The X-ray diffraction diagrams confirm that the crystal modifications of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, designated Form I, Form II and Form III, are completely different polymorphic forms.

Example 6: 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2.3-d] pyrimidine methanesulfonate 50 g (0.18 mol) 4- (3-chlorophenylamino) -5,6-dimethyl- 7H-pyrrolo [2,3-d] pyrimidine are suspended in 650 ml of 97% ethanol, and 18.6 g (0.19 mol) of methanesulfonic acid are added at RT. The yellow suspension is heated to reflux, a clear light yellow solution being formed. The solution is filtered, boiled briefly again and then cooled to 0 ° C. within 2 h. The suspension formed is stirred for 2 h at 0 ° C., filtered off and washed with cold abs. Washed ethanol. After drying the product, 61.9 g (0.17 mol, 92%) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine methanesulfonate are obtained in the form of colorless crystals. The product melts at a DSC heating rate of 10 ° C / min in an interval of 207 ° C and 225 ° C with a melting point range from and with 215 ° C to and with 222 ° C. ¹ H NMR (DMSO): 12.53 (s, 1H), 9.55 (s, 1H), 8.28 (s, 1H), 7.70 (s, 1H), 7.54-7 , 50 (m, 2H), 7.43-7.38 (m, 1H), 2.38 (s, 3H), 2.34 (s, 3H), 2.32 (S, 3H).

If necessary, the 4- (3-chlorophenylamino) -5.6-dimethvl-7H-pvrrolof2,3-dlpyrimidine methanesulfonate can be recrystallized according to the following procedure: 16 g (0.04 mol) of crude 4- (3-chloro-henylamino) -5,6 -dimethyl-7H-pyrrolo [2,3-d] pyrimidine methane sulfonate are suspended in 580 ml acetone / water 95: 5 and heated to reflux. The solution formed is filtered, boiled briefly and then crystallized by cooling to 2 ° C. within 3 h. It is filtered off, washed with cold acetone and dried in a high vacuum. 11.7 g (0.03 mol, 73.3%) of 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine methanesulfonate are obtained as white crystals (NMR data as above). Alternatively, a recrystallization from ethanol 97% can also be carried out.

Example 7: N- (2-chlorophenyl) formimidic acid ethyl ester

28 g (0.22 mol) of 2-chloro-aniline, 55 ml (0.33 mol) of triethyl orthoformate and 180 mg (0.7 mmol) of pyridinium (toluene-4-sulfonate) are placed in a flask inertized with nitrogen and heated to 80 ° C. The temperature of the heating medium is gradually increased to 140 ° C. in the course of 2 hours, the ethanol formed being continuously distilled off. The temperature is maintained for a further 1 h. It is then cooled and the excess triethyl orthoformate is distilled off in vacuo. The crude N- (2-chlorophenyl) form ethyl imidate remains as a distillation residue and can be used in the next stage without purification. ¹ H-NMR (CDCI3): 7.65 (s, 1 H), 7.41-7.37 (m, 1 H), 7.27- 7.15 (m, 1 H), 7.09- 7.00 (m, 1H), 6.91-6.86 (m, 1H), 4.40 (q, 2H), 1.42 (t, 3H).

Example 8: 3- (2-Chlorophenvh-5.6-dimethyl-4H-pyrrolof2.3-dlpyrimidin-4-imine 19.2 g (0.14 mol) of 2-amino-3-cyano-4,5-dimethylpyrrole from Example 2 is suspended in 120 ml of absolute ethanol and heated to 50 ° C. 31 g (0.17 mol) of N- (2-chlorophenyl) formimidic acid ethyl ester from Example 7 are added and the solution is allowed to slowly cool to RT. The suspension is stirred for a further 20 h at room temperature, after which 74 ml of ethanol / water (1: 1) are added, and after stirring for 1 h at 25 ° C., the mixture is filtered off and washed with ethanol / water (4: 1) after drying the filter cake 25 g (91 mmol, 65%) of crystalline 3- (2-chlorophenyl) -5,6-dimethyl-4H-pyrrolo [2,3-d] pyrimidin-4-imine are obtained as yellow crystals, mp 186-188 ° C; ¹ H-NMR (DMSO): 11.00 (s, 1 H), 9.49 (s, 1 H), 8.37 (s, 1 H), 8.15 (s, 1 H) , 7.53-7.49 (m, 1H), 7.40-7.32 (m, 1H), 7.15-7.07 (m, 1H), 2.06 (s, 3H) , 1.96 (s, 3H).

Example 9: 4- (2-chlorophenylamino) -5,6-dimethyl-7H-pyrrolof2.3-cηpyrimidine 15 g (55 mmol) 3- (2-chlorophenyl) -5,6-dimethyl-4H-pyrrolo [2,3- d] pyrimidin-4-imine are suspended in 135 ml of ethylene glycol and 15 ml of water and heated to 100 ° C. within 1 h. The suspension is stirred at 100 ° C. for 40 min and then cooled to RT within 3 h. It is cooled in an ice bath, filtered off and washed with water. After drying the filter cake, 14 g (51 mmol, 94%) of 4- (2-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine are obtained as fine light beige needles. Mp 248-249 ° C; ¹ H NMR (DMSO): 11, 56 (s, 1 H), 8.54 (q, 1 H), 8.20 (s, 1 H), 7.87 (s, 1 H), 7, 54 (q, 1H), 7.43-7.35 (m, 1H), 7.15-7.07 (m, 1H), 2.46 (s, 3H), 2.30 (s , 3H).

Example 10: 4- (2-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2.3-d] pyrimidine methanesulfonate 6 g (22 mmol) 4- (2-chlorophenylamino) -5,6-dimethyl-7H- pyrrolo [2,3-d] pyrimidine are suspended in 67 ml of 97% ethanol, and 2.33 g (24 mmol) of methanesulfonic acid are added at RT. The solution is heated to reflux, filtered hot and, after boiling again briefly, slowly cooled to 0 ° C. within 2 h. The suspension formed is stirred for 1 h at 0 ° C., filtered off and washed with cold abs. Washed ethanol. After drying the product, 7.1 g (19 mmol, 88%) of 4- (2-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine methanesulfonate are obtained as colorless crystals. M.p. 208-211 ° C; ¹ H NMR (DMSO): 12.63 (s, 1H), 9.69 (s, 1H), 8.26 (s, 1H), 7.79-7.70 (m, 2H), 7 , 59-7.51 (m, 2H), 2.40 (s, 3H), 2.35 (s, 6H). If necessary, the title compound can be recrystallized from ethanol 97% or acetone / water. Example 11: N- (4-chlorophenformimidic acid ethyl ester

200 g (1, 6 mol) of 4-chloroaniline, 359 g (2.4 mol) of orthoformate triethyl ester and 930 mg (3.7 mmol) of pyridinium (toluene-4-sulfonate) are placed in a flask inertized with nitrogen and brought to 80 ° C heated, the temperature is raised to 115 ° C within 2 h, during which the ethanol formed is distilled off. The temperature is kept at 115 ° C. for a further 15 min, the reaction mixture is cooled to RT and the excess triethyl orthoformate is distilled off in vacuo. The distillation residue is cooled to 5 ° C. for 8 h, the suspension formed is filtered, and 227 g (1, 2 mol, 73%) of ethyl N- (4-chlorophenyl) formimate are obtained as a yellow oil. It can be implemented without cleaning. ¹ H NMR (CDCI ₃ ): 7.68 (s, 1H), 7.28-7.24 (m, 2H), 6.91-6.86 (m, 2H), 4.31 (q , 2H), 1.38 (t, 3H).

Example 12: 3- (4-Chlorophenvπ-5.6-dimethyl-4H-pyrrolof2.3-dlpyrimidin-4-imine 113.5 g (0.8 mol) of 2-amino-3-cyano-4,5-dimethylpyrrole from Example 2 are suspended in 730 ml of absolute ethanol and heated to 50 ° C. 184 g (1.0 mol) of the crude ethyl N- (4-chlorophenyl) formimidate from Example 11 are added to the suspension Heated to 55 ° C. and cooled to RT within 4 h and then stirred for 16 h at 25 ° C. The pH is adjusted to 8.0 by adding a 10% solution of pyridinium (toluene-4-sulfonate) in ethanol The mixture is stirred at RT for a further 24 h, 420 ml of ethanol / water (1: 1) are added and the mixture is cooled to -10 ° C. The mixture is then stirred for 1 h at -10 ° C. and the product is filtered off / Water (4: 1), dried and obtained as yellow crystals (216 g, 94%) (0.8 mol), mp. 185-193 ° C. (dec.); ¹ H-NMR (DMSO): 10 , 95 (s, 1H), 10.20 (s, 1H), 7.41 (s, 1H), 7.50-7.25 (m, 4H), 2.07 (s, 3H), 1.95 (s, 3H).

Example 13: 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolor2.3-dlpyrimidine 15 g (55 mmol) 3- (4-chlorophenyl) -5,6-dimethyl-4H-pyrrolo [2,3- d] pyrimidin-4-imine are suspended in 135 ml of ethylene glycol and 15 ml of water and heated to 110 ° C. within 30 minutes. The suspension is stirred at 110 ° C. for 17 h, cooled to 5 ° C. and then filtered off. The product is washed with water and dried. This gives 12 g (44 mmol, 80%) of 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine as yellowish needles. Mp 249-252 ° C; ¹ H NMR (DMSO): 11.49 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.78 (q, 2H), 7.36 (q, 2H) , 2.41 (s, 3H), 2.28 (s, 3H). The 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine obtained can be recrystallized according to the following procedure: 104 g of 4- (4-chloropheny! Amino) -5,6- dimethyl-7H-pyrrolo [2,3-d] pyrimidine are suspended together with 5.2 g of activated carbon in a mixture of 4300 ml of tetrahydrofuran and 2500 ml of water and heated to reflux. The suspension is filtered, boiled briefly and then crystallized by cooling to 2 ° C. within 3 h. After filtration of the product, cold abs. Washed ethanol and dried in a high vacuum. 78.8 g (75.8%) of 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine are obtained in the form of white crystals. (Mp and NMR data as above).

Example 14: 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolof2.3-dlpyrimidine methanesulfonate 6 g (22 mmol) 4- (4-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2, 3-d] pyrimidine are suspended in 130 ml of ethanol 97% and mixed with 2.33 g (24 mmol) of methanesulfonic acid. The mixture is heated to reflux, the solution is filtered, briefly heated to reflux and cooled to RT within 2 h. After cooling in an ice bath, the mixture is filtered off with abs. Washed and dried ethanol. 6.6 g (18 mmol, 82%) of the title compound are obtained as bright crystals. Mp 259-262 ° C: 1 H NMR (DMSO): 12.59 (s, 1H), 9.66 (s, 1H), 8.25 (s, 1H), 7.59 (s, 4H) ), 2.39 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H). If necessary, the product can be recrystallized from 97% ethanol or acetone / water.

Claims

Claims:

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

or a salt thereof, wherein n is 0 to 5; q represents 0 or 1;

Ri and R ₂ independently for

(a) lower alkyl,

(b) unsubstituted or by halogen, trifluoromethyl, lower alkyl, lower alkoxy, carbamoyl-methoxy, carboxy-methoxy, benzyloxycarbonyl-methoxy, lower alkoxycarbonyl-methoxy, phenyl, amino, lower alkanoylamino, lower alkylamino, N, N-di-lower alkylamino, hydroxy, lower alkanoyloxy, carboxy Lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, cyano or nitro substituted phenyl,

(c) hydrogen,

(d) unsubstituted or halo or lower alkyl-substituted pyridyl,

(e) N-benzylpyridinium-2-yl,

(f) naphthyl,

(g) cyano, (h) carboxy,

(i) lower alkoxycarbonyl, (j) carbamoyl, (k) N-lower alkylcarbamoyl, (I) N, N-di-lower alkylcarbamoyl, (m) N-benzylcarbamoyl, (n) formyl, (o) lower alkanoyl, (p) lower alkenyl, (q) lower alkenyloxy; or (r) lower alkyl, which by

Halogen, amino, lower alkylamino, piperazino, di-lower alkylamino; Phenylamino which is unsubstituted or in the phenyl radical by halogen, lower alkyl, hydroxy, lower alkanoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N- lower alkyl-carbamoyl, N, N-di-lower alkyl-carbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N- Diniederalkyiamino or trifluoromethyl is substituted; Hydroxy, lower alkoxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, mercapto or a radical of the formula AS (O) _m -, in which A is lower alkyl and m is 0, 1 or 2 , is substituted; stand or

Ri and R ₂ together represent an alkylene chain with 2 to 5 carbon atoms, which is unsubstituted or substituted by lower alkyl; or

R 1 and R ₂ together mean C ₄ -C ₁₀ alkadienylene which is unsubstituted or by amino, lower alkanoylamino, lower alkylamino, di-lower alkylamino, nitro, halogen, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkyl- carbamoyl or cyano is substituted; or

Ri and R ₂ together mean aza-1,4-alkadienyls with up to and including 9 carbon atoms;

R _{3 represents} halogen, lower alkyl, trifluoromethyl, lower alkoxy, hydroxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-diniederalkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino or diniederalkylamino; and

RA represents hydrogen, lower alkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl or N, N-di-lower alkyl! -Carbamoyl; or a salt thereof, characterized in that an imino compound of the formula II,

in which the radicals have the meanings given for a compound of the formula I, and in which functional groups which are not intended to participate in the reaction are, if necessary, in protected form, or a salt thereof, rearranged and present in a suitable solvent or solvent mixture at elevated temperature Splits off protective groups,

and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt, converting an available salt into the free compound of formula I or another salt thereof and / or at an as Compound of the formula I obtainable isomer mixture carries out a separation into isomers.

2. The method according to claim I for the preparation of a compound of formula I, wherein n is 0 or 1; q represents 0 or 1;

R _{T is} lower alkyl, in particular methyl, hydroxyphenyl, in particular 4-hydroxyphenyl, lower alkanoylaminophβnyl, in particular 4-acetylaminophenyl, or N-lower alkylcarbamoyl, in particular N-methylcarbamoyl; especially methyl;

R _{2 is} lower alkyl, especially methyl, or hydrogen; especially methyl;

R _{3 is} halogen, in particular halogen bonded in the meta position to the phenyl ring, especially chlorine, or hydrogen; and

R _{4 is} lower alkyl, especially methyl; or a salt thereof, characterized in that an appropriately substituted starting compound of the formula I is used.

3. The method according to claim I for the preparation of a compound of formula I, wherein n is 1; q represents 0;

R _{T is} lower alkyl, especially methyl;

R _{2 is} lower alkyl, especially methyl;

R ₃ in the meta position on the phenyl ring is halogen, especially chlorine; and

R _{4 is} lower alkyl, especially methyl;

or a salt thereof, characterized in that an appropriately substituted starting compound of the formula II is used.

4. The method according to claim 1, 2 or 3 for the preparation of a compound of the formula I, in which the radicals have the meanings given, in which a cyanopyrrole compound of the formula IM,

wherein R and R _{2 have} the meanings given for compounds of the formula I, with an imino compound of the formula IV,

wherein Ffe, R *, n and q have the meanings given for compounds of the formula I and R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A

wherein R ₃ , FU, n and q have the meanings given for compounds of the formula I, is implemented, wherein an imino compound of the formula II

receives, in which the radicals have the meanings given for a compound of the formula I,

and then rearranging a compound of formula II obtained into a compound of formula I in a suitable solvent or solvent mixture at elevated temperature,

where in the starting and intermediate compounds, which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to take part in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;

and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt, converting an available salt into the free compound of formula I or another salt thereof and / or at an as Compound of the formula I obtainable isomer mixture carries out a separation into isomers.

5. The method according to any one of claims 1 to 3 for producing a compound of

Formula I, in which the radicals have the meanings mentioned, in particular as preferred, in which an amino compound of the formula V,

wherein R ₃ , R ₄ , n and q have the meanings given for a compound of the formula I, in the presence of a suitable acid with an orthoformate of the formula VI,

(RsVCH (VI)

where R ₅ 'denotes lower alkoxy or substituted lower alkoxy,

then a cyanopyrrole compound of the formula IM,

wherein R _T and R _{2 have} the meanings given for compounds of the formula I, with an imino compound of the formula IV obtainable by the previous reaction,

wherein R3, R ₄ , n and q have the meanings given for compounds of the formula I and R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A

in which R ₃ , R ₄ , n and q have the meanings given for compounds of the formula I, is reacted, an imino compound of the formula II

receives, in which the radicals have the meanings given for a compound of the formula I,

and then rearranging a compound of formula II obtained into a compound of formula I in a suitable solvent or solvent mixture at elevated temperature,

where in the starting and intermediate compounds, which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to take part in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;

and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt, converting an available salt into the free compound of formula I or another salt thereof and / or at an as Compound of the formula I obtainable isomer mixture carries out a separation into isomers.

6. The method according to claim 5 for the preparation of a compound of formula I, in which the radicals have the meanings mentioned,

in which an amino compound of the formula V, in which R ₃ , R4, n and q have the meanings given for a compound of the formula I, directly with an orthoformate of the formula VI, in which R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV -A, in which R ₃ , FU, n and q have the meanings given for compounds of the formula I, and with a cyanopyrrole compound of the formula III, in which RT and R _{2 have} the meanings given for compounds of the formula I, in a one-pot reaction, an imino compound of the formula II being obtained without isolation of intermediate compounds

receives, in which the radicals have the meanings given for a compound of the formula I,

and then rearranging a compound of formula II obtained into a compound of formula I in a suitable solvent or solvent mixture at elevated temperature,

where in the starting and intermediate compounds, which can also be present as salts, provided that at least one salt-forming group is present, functional groups which are not intended to take part in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;

and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt converting the available salt into the free compound of the formula I or another salt thereof and / or for a compound of the formula I obtainable as an isomer mixture, it is separated into isomers.

7. The method according to any one of claims 1 to 3 for the preparation of a compound of formula I, wherein the radicals have the meanings given for a compound of formula I, in which an amino acid of formula VII,

wherein Ri has one of the meanings given for compounds of the formula I, with a reactive acid derivative of the formula VIII,

in which R _{2 has} the meanings given for a compound of the formula I and L is halogen, azido, an activated aryloxy radical or an acyloxy radical of the formula R ₂ -C (= O) -O-, in which R _{2 is} a compound of the formula I can have meanings mentioned, in the presence of a tertiary nitrogen base or an alkaline earth metal or alkali metal salt of an acid of the formula R ₂ -C (= O) -OH, in which R _{2 has} the meanings mentioned for compounds of the formula I, to give a compound of the formula X

implements in which R _Λ and R _{2 have} the meanings given for a compound of formula I;

and then converted into a compound of the formula III by reaction with malononitrile in the presence of a base,

wherein R 1 and R _{2 have} the meanings given for compounds of the formula I,

then a obtained cyanopyrrole compound of the formula III with an imino compound of the formula IV obtainable by the reaction mentioned below,

wherein R ₃ , R ₄ , n and q have the meanings given for compounds of the formula I and R _{5 is} lower alkoxy, substituted lower alkoxy or a radical of the formula IV-A

wherein Rs, FU, n and q have the meanings given for compounds of the formula I, is implemented, wherein an imino compound of the formula II

receives, in which the radicals have the meanings given for a compound of the formula I,

and then rearranging a compound of formula II obtained into a compound of formula I in a suitable solvent or solvent mixture at elevated temperature, wherein an imino compound of formula IV is prepared by using an amino compound of formula V,

wherein R ₃ , R ₄ , n and q have the meanings given for a compound of the formula I, in the presence of a suitable acid with an orthoformate of the formula VI,

(RsVCH (VI)

wherein R ₅ 'represents lower alkoxy or substituted lower alkoxy;

where in the starting and intermediate compounds, which may also be in the form of salts, provided that at least one salt-forming group is present, functional groups which are not intended to take part in the reaction are, if necessary, in protected form and protective groups which are no longer required are eliminated at a suitable reaction stage, and, if desired, intermediates obtainable as a free compound are also converted into the corresponding salts, intermediates obtainable as salts can be converted into the free compound or another salt, and / or, in the case of a mixture of isomers of an intermediate which is obtainable, carries out a separation into isomers;

and, if desired, converting an available compound of formula I into another compound of formula I, converting an available compound of formula I into a salt, converting an available salt into the free compound of formula I or another salt thereof and / or at an as Compound of the formula I obtainable isomer mixture carries out a separation into isomers.

8. A compound of formula II

wherein n represents 0 or 1; q represents 0 or 1;

R 1 is lower alkyl, in particular methyl, hydroxyphenyl, in particular 4-hydroxyphenyl, lower alkanoylaminophenyl, in particular 4-acetylaminophenyl, or N-lower alkylcarbamoyl, in particular N-methylcarbamoyl; especially methyl;

R _{2 is} lower alkyl, especially methyl, or hydrogen; especially methyl;

R _{3 is} halogen, in particular halogen bonded in the meta position to the phenyl ring, especially chlorine, or hydrogen; and

R _{4 is} lower alkyl, especially methyl; or a salt of it.

9. A compound of formula II according to claim 8, wherein n is 1; q represents 0;

Ri is lower alkyl, especially methyl;

R _{2 is} lower alkyl, especially methyl;

R ₃ in the meta position on the phenyl ring is halogen, especially chlorine; and

R _{4 is} lower alkyl, especially methyl; or a salt of it.

10. A process for the preparation of a compound of formula II

or their salt, wherein n is 0 or 1; q represents 0 or 1;

R 1 is lower alkyl, in particular methyl, hydroxyphenyl, in particular 4-hydroxyphenyl, lower alkanoylaminophenyl, in particular 4-acetylaminophenyl, or N-lower alkylcarbamoyl, in particular N-methylcarbamoyl; especially methyl;

R _{2 is} lower alkyl, especially methyl, or hydrogen; especially methyl;

R _{3 is} halogen, in particular halogen bonded in the meta position to the phenyl ring, especially chlorine, or hydrogen; and

FU means lower alkyl, especially methyl; or from a salt thereof;

in which functional groups can be in protected form, characterized in that an amino compound of the formula V,

wherein R ₃ , R-ι, n and q have the meanings given for a compound of the formula II, in the presence of a suitable acid with an orthoformate of the formula VI,

(RsVCH (VI) wherein R ₅ 'is lower alkoxy or substituted lower alkoxy, directly with a cyanopyrrole compound of the formula IM

wherein R 1 and R _{2 have} the meanings given for compounds of the formula II,

where the free functional groups in the starting compounds which are not to take part in the reaction are, if necessary, in protected form, and the starting compounds are a compound of the formula V, the formula VI or the formula III, or two or all of these compounds, can also be in the form of a salt if there is a salt-forming group,

and, if desired, splits off protective groups which are no longer required, converts an available free compound of the formula II into a salt or converts an available salt of a compound of the formula I into the free compound of the formula II or another salt and / or with an available isomer mixture of a compound of the Formula II carries out a separation into isomers.

11. An imino compound of the formula IV,

wherein F ^, F, n and q have the meanings given for compounds of the formula I n is 0 or 1; q represents 0 or 1;

R _{3 is} halogen, in particular halogen bonded in the meta position to the phenyl ring, especially chlorine, or hydrogen; and R _{4 is} lower alkyl, especially methyl;

and R _{5 is} a radical of the formula IV-A

wherein R ₃ , R ₄ , n and q have the meanings given above, or a salt thereof.

12. A compound of formula IV according to claim 11, wherein n is 1; q represents 0;

R ₃ in the meta position on the phenyl ring is halogen, especially chlorine; and

F is lower alkyl, especially methyl; or a salt of it.

13. A crystal form of the compound designated 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, designated as Form I, which is characterized by a melting point range of and with 244 ° C up to and with 250 ° C.

14. A crystal form of the compound designated 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, referred to as Form I, which is characterized by the following main lines in use X-ray diagram of copper Kα1 radiation obtained with a diffractometer:

26 intensity

6.2 medium

8.1 very strong

9.7 very strong

12.0 medium

14.7 very strong

15.0 medium

15.4 medium

17.5 weak

17.8 weak

19.0 very weak

19.7 strong

21.9 weak

22.8 medium

23.8 very weak

25.4 very weak

26.1 medium

26.8 strong

26.9 strong

29.7 weak

32.0 weak

15. A crystal form of the compound called Form II, called 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, which is indicated by the following main lines in the use of copper Kα1 radiation with an X-ray diagram obtained using a Guinier camera is characterized:

2Θ intensity

8.1 weak

11.3 medium

13.0 medium

13.8 medium

14.0 very weak

15.3 weak

16.3 strong

20.9 weak

24.2 weak

24.9 weak

25.6 very strong

26.1 strong

27.0 very weak

27.5 strong

27.8 weak

16. A crystal form, referred to as Form IM, of the compound of the formula I with the name 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine, which is indicated by the following main lines in below Use of copper Kα1 radiation with a diffractometer obtained X-ray diagram is characterized:

2Θ intensity

8.8 very strong

13.4 medium

14.5 medium

15.2 medium

15.7 medium

16.0 weak

17.0 medium

17.9 strong

19.6 weak

20.1 weak

20.4 weak

21.0 weak

23.2 medium

24.9 medium

25.5 medium

25.9 very strong

26.6 very strong

27.2 very weak

28.8 medium

29.5 very weak

31.9 very weak

32.5 very weak