HK1090036A

HK1090036A - Imidazopyridine intermediates

Info

Publication number: HK1090036A
Application number: HK06110462.2A
Authority: HK
Inventors: Peter Jan Zimmermann; M. Vittoria Chiesa; Andreas Palmer; Christof Brehm; Wilm Buhr
Original assignee: Altana Pharma Ag
Priority date: 2003-05-06
Filing date: 2004-05-04
Publication date: 2006-12-15

Description

Imidazopyridine intermediates

Technical Field

The present invention relates to a novel compound which is useful as an intermediate of value in the preparation of active compounds in the pharmaceutical industry.

Prior Art

International patent applications WO 01/72758, WO 01/72754, WO 01/72755, WO 01/72757, WO 02/34749, WO 03/018310, WO 03/014120 and WO 03/014123 disclose tricyclic imidazopyridine derivatives with specific substitution patterns that are effective in the treatment of gastrointestinal disorders, and processes for their preparation. In the Drugs Fut2001, 26(6), 590, a process for the preparation of tetrahydrobenzopyrans by cyclization using the orthoesters is disclosed.

Description of the invention

The present invention relates to a novel process for the preparation of the above tricyclic imidazopyridine derivatives and to intermediates of value in this process.

The present invention therefore relates in a first aspect to the compounds of formula (1) below and to their salts

R1 is hydrogen, 1-4C alkyl, 3-7C cycloalkyl, 3-7C-cycloalkyl-1-4C alkyl, 1-4C alkoxy-1-4C alkyl, 1-4C alkoxycarbonyl, 2-4C alkenyl, 2-4C alkynyl, fluoro-1-4C alkyl or hydroxy-1-4C alkyl,

r2 is hydrogen, 1-4C alkyl, aryl, 3-7C cycloalkyl, 3-7C-cycloalkyl-1-4C alkyl, 1-4C alkoxycarbonyl, hydroxy-1-4C alkyl, halogen, 2-4C alkenyl, 2-4C alkynyl, fluoro-1-4C alkyl, cyanomethyl,

r3a is hydrogen, halogen, fluoro-1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, carboxy, 1-4C alkoxycarbonyl, hydroxy-1-4C alkyl, 1-4C alkoxy-1-4C alkyl, fluoro-1-4C alkoxy-1-4C alkyl or is the group-CO-NR 31R32,

r3b is hydrogen, halogen, fluoro-1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, carboxy, 1-4C alkoxycarbonyl, hydroxy-1-4C alkyl, 1-4C alkoxy-1-4C alkyl, fluoro-1-4C alkoxy-1-4C alkyl or is the group-CO-NR 31R32,

wherein R31 is hydrogen, 1-7C alkyl, hydroxy-1-4C alkyl or 1-4C alkoxy-1-4C alkyl, and

r32 is hydrogen, 1-7C alkyl, hydroxy-1-4C alkyl or 1-4C alkoxy-1-4C alkyl,

or therein

R31 and R32 together, also including the nitrogen atom to which these 2 groups are attached together, are pyrrolidinyl, piperidinyl, piperazinyl, N-1-4C alkylpiperazinyl or morpholinyl,

arom is a mono-or bicyclic aryl substituted with R4, R5, R6 and R7, Arom is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1, 2, 3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, quinolinyl and isoquinolinyl,

wherein

R4 is hydrogen, 1-4C alkyl, hydroxy-1-4C alkyl, 1-4C alkoxy, 2-4C alkenyloxy, 1-4C alkylcarbonyl, carboxy, 1-4C alkoxycarbonyl, carboxy-1-4C alkyl, 1-4C alkoxycarbonyl-1-4C alkyl, halogen, hydroxy, aryl-1-4C alkyl, aryloxy, aryl-1-4C alkoxy, trifluoromethyl, nitro, amino, mono-or di-1-4C alkylamino, 1-4C alkylcarbonylamino, 1-4C alkoxycarbonylamino, 1-4C alkoxy-1-4C alkoxycarbonylamino, or sulfonyl,

r5 is hydrogen, 1-4C alkyl, 1-4C alkoxy, 1-4C alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,

r6 is hydrogen, 1-4C alkyl or halogen, and

r7 is hydrogen, 1-4C alkyl or halogen,

wherein

Aryl is phenyl or substituted phenyl having one, two, or three identical or different substituents selected from the group consisting of 1-4C alkyl, 1-4C alkoxy, carboxy, 1-4C alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano.

1-4C alkyl means a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

3-7C cycloalkyl is intended to mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.

3-7C cycloalkyl-1-4C alkyl means one of the aforementioned 1-4C alkyl groups, substituted by one of the aforementioned 3-7C cycloalkyl groups. Examples which may be mentioned are cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.

1-4C alkoxy means a group which, in addition to the oxygen atom, also contains a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, and preferably ethoxy and methoxy.

1-4C alkoxy-1-4C alkyl means one of the aforementioned 1-4C alkyl groups, substituted by one of the aforementioned 1-4C alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl and the butoxyethyl radical.

1-4C alkoxycarbonyl means a carbonyl group to which the aforementioned 1-4C alkoxy group is attached. Examples which may be mentioned are methoxycarbonyl (CH)₃O-C (O) -) and ethoxycarbonyl (CH)₃CH₂O-C(O)-)。

2-4C alkenyl means a straight or branched chain alkenyl group having 2 to 4 carbon atoms. Examples which may be mentioned are 2-butenyl, 3-butenyl, 1-propenyl and 2-propenyl (allyl).

2-4C alkynyl means straight or branched chain alkynyl having 2 to 4 carbon atoms. Examples which may be mentioned are 2-butynyl, 3-butynyl and preferably 2-propynyl (propargyl).

fluoro-1-4C alkyl means one of the aforementioned 1-4C alkyl groups, substituted with 1 or more fluorine atoms. An example which may be mentioned is trifluoromethyl.

hydroxy-1-4C alkyl means 1-4C alkyl as mentioned before, substituted by one hydroxy group. Examples which may be mentioned are hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl.

Halogen as defined herein is bromine, chlorine and fluorine.

1-4C alkoxy-1-4C alkoxy means one of the aforementioned 1-4C alkoxy groups, substituted by another 1-4C alkoxy group. Examples which may be mentioned are 2-methoxyethoxy (CH)₃-O-CH₂-CH₂-O-) and 2-ethoxyethoxy (CH)₃-CH₂-O-CH₂-CH₂-O-)。

1-4C alkoxy-1-4C alkyl means one of the aforementioned 1-4C alkoxy-1-4C alkyl groups, substituted by the aforementioned one 1-4C alkoxy group. Examples which may be mentioned are 2-methoxyethoxymethyl (CH)₃-O-CH₂-CH₂-O-CH₂-)。

fluoro-1-4C alkoxy-1-4C alkyl means one of the aforementioned 1-4C alkyl groups, substituted by fluoro-1-4C alkoxy. fluoro-1-4C alkoxy in this case means that one, all or most of the aforementioned 1-4C alkoxy groups are substituted by fluorine atoms. Examples which may be mentioned of 1-4C-alkoxy which is substituted wholly or largely by fluorine atoms are 1, 1, 1, 3, 3, 3-hexafluoro-2-propoxy, 2-trifluoromethyl-2-propoxy, 1, 1, 1-trifluoro-2-propoxy, perfluoro-tert-butoxy, 2, 2, 3, 3, 4, 4, 4-heptafluoro-1-butoxy, 4, 4, 4-trifluoro-1-butoxy, 2, 2, 3, 3, 3-pentafluoropropoxy, perfluoroethoxy, 1, 2, 2-trifluoroethoxy, especially 1, 1, 2, 2-tetrafluoroethoxy, 2, 2, 2-trifluoroethoxy, trifluoromethoxy and preferably difluoromethoxy.

1-7C alkyl means a straight or branched chain alkyl group having 1 to 7 carbon atoms. Examples which may be mentioned are heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3, 3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2, 2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

2-4C alkenyloxy means a group which, in addition to containing an oxygen atom, contains a 2-4C alkenyl group. Examples which may be mentioned are allyloxy.

1-4C alkylcarbonyl means a radical which, in addition to the carbonyl group, contains a 1-4C alkyl radical as mentioned above. Examples which may be mentioned are acetyl.

carboxy-1-4C alkyl means, for example, carboxymethyl (-CH)₂COOH) or carboxyethyl (-CH)₂CH₂COOH)。

1-4C alkoxycarbonyl-1-4C-alkyl means a 1-4C-alkyl group as mentioned which is substituted by a 1-4C alkoxycarbonyl group as mentioned. Examples which may be mentioned are ethoxycarbonylmethyl (CH)₃-CH₂-OC(O)CH₂-)。

aryl-1-4C alkyl means an aryl-substituted 1-4C alkyl group. Examples which may be mentioned are benzyl.

aryl-1-4C alkoxy means an aryl-substituted 1-4C alkoxy group. Examples which may be mentioned are benzyloxy.

Mono-or di-1-4C alkylamino containing, in addition to the nitrogen atom, 1 or 2 of the aforementioned 1-4C alkyl groups. Di-1-4C alkylamino is preferred, and in particular dimethyl-, diethyl-or diisopropylamino is preferred in the present invention.

1-4C alkylcarbonylamino represents an amino group to which a 1-4C alkylcarbonyl group is attached. As examples there may be mentioned propionylamino (C)₃H₇C (O) NH-) and acetylamino (acetylamino) (CH)₃C(O)NH-)。

1-4C alkoxycarbonyl amino represents an amino group which is substituted by one of the aforementioned 1-4C alkoxycarbonyl groups. Examples which may be mentioned are ethoxycarbonylamino and methoxycarbonylamino.

1-4C alkoxy-1-4CAlkoxycarbonyl represents a carbonyl group to which one of the aforementioned 1-4C alkoxy-1-4C alkoxy groups is attached. Examples which may be mentioned are 2- (methoxy) ethoxycarbonyl (CH)₃-O-CH₂-CH₂-O-CO-) and 2- (ethoxy) ethoxycarbonyl (CH)₃CH₂-O-CH₂CH₂-O-CO-)

1-4C alkoxy-1-4C alkoxycarbonylamino represents an amino group which is substituted by one of the aforementioned 1-4C alkoxy-1-4C alkoxycarbonyl groups. Examples which may be mentioned are 2- (methoxy) ethoxycarbonylamino and 2- (ethoxy) ethoxycarbonylamino.

As aryl there may be mentioned, for example, the following groups: 4-acetoxyphenyl group, 4-acetylaminophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-benzyloxyphenyl group, 4-benzyloxyphenyl group, 3-benzyloxy-4-methoxyphenyl group, 4-benzyloxy-3-methoxyphenyl group, 3, 5-bis (trifluoromethyl) phenyl group, 4-butoxyphenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-chloro-6-fluorophenyl group, 3-chloro-4-fluorophenyl group, 2-chloro-5-nitrophenyl group, 4-chloro-3-nitrophenyl group, 3- (4-chlorophenoxy) phenyl group, 2, 4-dichlorophenyl group, 3, 4-difluorophenyl group, 2, 4-dihydroxyphenyl group, 2, 6-dimethoxyphenyl group, 3, 4-dimethoxy-5-hydroxyphenyl group, 2, 5-dimethylphenyl group, 3-ethoxy-4-hydroxyphenyl group, 2-fluorophenyl group, 4-hydroxyphenyl group, 2-hydroxy-5-nitrophenyl group, 3-methoxy-2-nitrophenyl group, 3-nitrophenyl group, 2, 3, 5-trichlorophenyl group, 2, 4, 6-trihydroxyphenyl group, 2, 3, 4-trimethoxyphenyl group, 2-hydroxy-1-naphthyl group, 2-methoxy-1-naphthyl group, 4-methoxy-1-naphthyl group, 1-methyl-2-pyrrolyl group, 2-pyrrolyl, 3-methyl-2-pyrrolyl, 3, 4-dimethyl-2-pyrrolyl, 4- (2-methoxycarbonylethyl) -3-methyl-2-pyrrolyl, 5-ethoxycarbonyl-2, 4-dimethyl-3-pyrrolyl, 3, 4-dibromo-5-methyl-2-pyrrolyl, 2, 5-dimethyl-1-phenyl-3-pyrrolyl, 5-ethyl-4-methyl-2-pyrrolyl, 3, 5-dimethyl-2-pyrrolyl, 2, 5-dimethyl-1- (4-trifluoromethylphenyl) -3-pyrrolyl, 1- (2, 6-dichloro-4-trifluoromethylphenyl) -2-pyrrolyl, 1- (2-nitrobenzyl) -2-pyrrolyl, 1- (2-fluorophenyl) -2-pyrrolyl, 1- (4-trifluoromethoxyphenyl) -2-pyrrolyl, 1- (2-nitrobenzyl) -2-pyrrolyl, 1- (4-ethoxycarbonyl) -2, 5-dimethyl-3-pyrrolyl, 5-chloro-1, 3-dimethyl-4-pyrazolyl, 5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl, 1- (4-chlorobenzyl) -5-pyrazolyl, 1, 3-dimethyl-5- (4-chlorophenoxy) -4-pyrazolyl, 1-methyl-3-trifluoromethyl-5- (3-trifluoromethylphenoxy) -4-pyrazolyl, 4-methoxycarbonyl-1- (2, 6-dichlorophenyl) -5-pyrazolyl, 5-allyloxy-1-methyl-3-trifluoromethyl-4-pyrazolyl, 5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl, 3, 5-dimethyl-1-phenyl-4-imidazolyl, 4-bromo-1-methyl-5-imidazolyl, 2-butylimidazolyl, 1-phenyl-1, 2, 3-triazol-4-yl, 3-indolyl, 4-indolyl, 7-indolyl, 5-methoxy-3-indolyl, 5-benzyloxy-3-indolyl, 1-benzyl-3-indolyl, 2- (4-chlorophenyl) -3-indolyl, 7-benzyloxy-3-indolyl, 6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3-indolyl, 4, 5, 6, 7-tetrafluoro-3-indolyl, 1- (3, 5-difluorobenzyl) -3-indolyl, 1-methyl-2- (4-trifluorophenoxy) -3-indolyl, 1-methyl-2-benzylimidazolyl, 5-nitro-2-furyl, 5-hydroxymethyl-2-furyl, 3-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 4-ethoxycarbonyl-5-methyl-2-furyl, 5- (2-trifluoromethoxyphenyl) -2-furyl, 5- (4-methoxy-2-nitrophenyl) -2-furyl, 4-bromo-2-furyl, 5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo-2-furyl, 2-benzofuranyl, 2-thienyl, 3-methyl-2-thienyl, 4-bromo-2-thienyl, 5-nitro-2-thienyl, 5-methyl-2-thienyl, 5- (4-methoxyphenyl) -2-thienyl, 4-methyl-2-thienyl, 3-phenoxy-2-thienyl, 5-carboxy-2-thienyl, 2, 5-dichloro-3-thienyl, 3-methoxy-2-thienyl, 2-benzothienyl, 3-methyl-2-benzothienyl, 2-bromo-5-chloro-3-benzothienyl, 2-thiazolyl, 2-amino-4-chloro-5-thiazolyl, 2, 4-dichloro-5-thiazolyl, 2-diethylamino-5-thiazolyl, 3-methyl-4-nitro-5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methyl-2-pyridyl, 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl, 2, 6-dichloro-4-pyridyl, 3-chloro-5-trifluoromethyl-2-pyridyl, 4, 6-dimethyl-2-pyridyl, 4- (4-chlorophenyl) -3-pyridyl, 2-chloro-5-methoxycarbonyl-6-methyl-4-phenyl-3-pyridyl, 2-chloro-3-pyridyl, 6- (3-trifluoromethylphenoxy) -3-pyridyl, 2- (4-chlorophenoxy) -3-pyridyl, 2, 4-dimethoxy-5-pyrimidyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-chloro-3-quinolyl, 2-chloro-6-methoxy-3-quinolyl, 8-hydroxy-2-quinolyl and 4-isoquinolyl.

Possible salts (depending on the substitution pattern) of the compounds of formula 1 are in particular all acid addition salts. Specifically, pharmacologically acceptable salts of inorganic acids and organic acids generally used in pharmaceutical preparations may be mentioned. Those suitable salts are water-soluble and water-insoluble acid addition salts with, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid, or 3-hydroxy-2-naphthoic acid, where the acids are used in the preparation of the salts (depending on whether a mono-or polybasic acid is used and depending on the salt desired) in equimolar or unequal molar ratios.

It is known to the person skilled in the art that the compounds of the invention and their salts, for example if isolated in crystalline form, may contain varying amounts of solvent. The invention thus also includes all solvates and in particular all hydrates of the compounds of formula 1, and all solvates and in particular all hydrates of the salts of the compounds of formula 1.

The compounds of formula 1 have two chiral centers in the parent structure. The invention thus relates to all possible stereoisomers, including the pure enantiomers, which are present in any desired mixing ratio with one another and which are preferred subjects of the invention.

An embodiment of the invention (embodiment 1) is a compound of formula 1 wherein R1 is 1-4C alkyl, and

r2, R3a, R3b and Arom have the meanings given above.

Another embodiment (embodiment 2) of the invention is a compound of formula 1 wherein R2 is 1-4C alkyl, and

r1, R3a, R3b and Arom have the meanings given above.

Another embodiment (embodiment 3) of the invention is a compound of formula 1 wherein R3a is hydrogen, and

r1, R2, R3b and Arom have the meanings given above.

Another embodiment (embodiment 4) of the invention is a compound of formula 1 wherein R3b is hydrogen, and

r1, R2, R3a and Arom have the meanings given above.

Another embodiment (embodiment 5) of the invention is a compound of formula 1 wherein Arom is phenyl, and

r1, R2, R3a and R3b have the meanings indicated above.

Compounds to be emphasized are those of the formula 1 and salts thereof, in which

R1 is hydrogen, 1-4C alkyl, 3-7C cycloalkyl, 1-4C alkoxy-1-4C alkyl, 2-4C alkynyl or fluoro-1-4C alkyl,

r2 is hydrogen, 1-4C alkyl, aryl, hydroxy-1-4C alkyl, halogen, 2-4C alkenyl, 2-4C alkynyl, fluoro-1-4C alkyl,

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, halogen, 1-4C alkyl or a group-CO-NR 31R32,

r32 is hydrogen, 1-7C alkyl, hydroxy-1-4C alkyl or 1-4C alkoxy-1-4C alkyl,

or wherein R31 and R32 together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl or morpholinyl,

arom is a monocyclic aromatic group substituted with R4, R5, R6 and R7, selected from phenyl, furyl and thienyl,

wherein R4 is hydrogen, 1-4C alkyl, hydroxy-1-4C alkyl, 1-4C alkoxy, 1-4C alkylcarbonyl, carboxy, 1-4C alkoxycarbonyl, halogen, hydroxy, trifluoromethyl, 1-4C alkylcarbonylamino, 1-4C alkoxycarbonylamino, 1-4C alkoxy-1-4C alkoxycarbonylamino or sulfonyl,

r6 is hydrogen, and

r7 is hydrogen.

Compounds to be particularly emphasized are those of the formula 1 and salts thereof, in which

R1 is 1-4C alkyl or 1-4C alkoxy-1-4C alkyl,

r2 is hydrogen, 1-4C alkyl, phenyl, hydroxy-1-4C alkyl or halogen,

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, and R3 is hydrogen,

arom is phenyl, furyl or thienyl.

Among the compounds of the present invention, including the compounds of embodiments 1 to 5 and the compounds to be emphasized and particularly emphasized, formula 1^*Optically pure compounds are preferred

Formula 1^*Preferred compounds of (b) are those in which

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, halogen, 1-4C alkyl or a group-CO-NR 31R32,

r32 is hydrogen, 1-7C alkyl, hydroxy-1-4C alkyl or 1-4C alkoxy-1-4C alkyl,

or wherein R31 and R32, including the nitrogen atom to which they are attached, together are pyrrolidinyl, piperidinyl, or morpholinyl,

arom is phenyl, furyl or thienyl.

Compounds of particular emphasis which bear the substituents illustrated are those of formula 1^*Compounds and salts thereof:

wherein R1 is hydrogen, methyl, cyclopropyl, methoxymethyl or trifluoromethyl,

r2 is hydrogen, methyl, phenyl, hydroxymethyl, fluoro, chloro, bromo, ethynyl, trifluoromethyl,

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, fluorine, methyl or a group-CO-N (CH)₃)₂，

Arom is phenyl.

Particularly preferred, exemplified formula 1^*The compounds are those in which

R1 is a methyl group, and R1 is a methyl group,

r2 is hydrogen, methyl, fluorine, chlorine, bromine, hydroxymethyl or trifluoromethyl,

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, and R3 is hydrogen,

arom is phenyl.

Particularly preferred are the compounds given as end products in the examples and their salts.

The invention also relates to the use of compounds of formula 1 (wherein R1, R2, R3a, R3b and Arom have the meanings indicated above) for the preparation of compounds of formula 2 and salts thereof,

wherein R1, R2, R3a, R3b and Arom have the meanings given above, and R8 is hydrogen, 1-4C alkyl or aryl, as defined above.

The preparation of the compound of formula 2 is carried out, for example, as shown in reaction scheme 1, i.e., a compound of formula 1 (wherein R1, R2, R3a, R3b and Arom have the previously described definitions) and a compound of formula R8-C (OR9)₃Wherein R8 is hydrogen, 1-4C alkyl or aryl, as previously described, and R9 is 1-4C alkyl,

reaction scheme 1

According to the invention, it is emphasized that formula 1^*In the preparation of the compound of formula 2^*The use of the compounds and their salts,

wherein R1, R2, R3a, R3b and Arom have the meanings given above, and R8 has the meaning given above for hydrogen, 1-4C alkyl or aryl, as given above.

The conversion of the compound of formula 1 into the cyclisation product of formula 2 according to reaction scheme 1 is carried out in a manner known to experts, for example analogously to the process disclosed in Drugs Fut2001, 26(6), page 590.

The compound of formula 1 of the present invention (wherein R1, R2, R3a, R3b and Arom have the aforementioned definitions) can be prepared from a compound of formula 3 wherein R1, R2, R3a, R3b and Arom have the aforementioned definitions,

for example for Compound 1^*And 3^*The above preparation can be accomplished by reacting with a mineral acid by the method shown in the following reaction formula 2:

reaction formula 2:

for the reaction shown in equation 2, preferred inorganic acids are phosphoric acid, hydrochloric acid or sulfuric acid.

The starting compounds of formula 3 are known (see WO 01/72755 or WO 02/34749) or they may be prepared by analogous methods to those of known compounds, for example, for formula 3^*A compound, which can be prepared by the method shown in the following reaction scheme 3),

reaction formula 3

The group X in equation 3 is a suitable leaving group, for example a halogen atom, preferably chlorine, or a 1-4C alkoxy group, preferably methoxy.

The following examples serve to illustrate the invention in more detail, without restricting it, and, as such, further compounds whose preparation is not explicitly described can be prepared analogously or by methods familiar to the person skilled in the art using customary process techniques, the abbreviations min for minutes, h for hours and m.p. for melting points.

Examples

Compounds of formula 1

1.2-methyl-7- [ (2R, 3S) -2, 3-dihydroxy-3-phenylpropan-1-one-1-yl ] imidazo [1, 2-a ] -pyridin-8-ol

156 g (0.442 mol) of 2-methyl-7- [ (2R, 3S) -2, 3-O, O-isopropylidene-2, 3-dioxo-3-phenylpropan-1-on-1-yl ] imidazo [1, 2-a ] pyridin-8-ol are dissolved in 3 l of 6 mol hydrochloric acid over a period of 30 minutes. After stirring at room temperature for 1 hour, the reaction mixture was cooled with an ice bath and neutralized to ph6.5 to 7 with 6 molar sodium hydroxide solution. The precipitate was filtered, washed with water and the maximum portion redissolved in 0.5 molar hydrochloric acid. The remaining residue is separated by filtration and the filtrate is neutralized again to a pH of 6.5 to 7 with 6 molar sodium hydroxide solution. The resulting precipitate was filtered off and dried in vacuo to yield 84.6 g (0.271 mol, 61% yield) of the analytically pure title compound as a beige solid.

Melting point: 110-

2, 3-dimethyl-7- [ (2R, 3S) -2, 3-dihydroxy-3-phenylpropan-1-one-1-yl ] imidazo [1, 2-a ] -pyridin-8-ol

10 g (0.027 mol) of 2, 3-dimethyl-7- [ (2R, 3S) -2, 3-O, O-isopropylidene-2, 3-dioxo-3-phenylpropan-1-on-1-yl ] imidazo [1, 2-a ] pyridin-8-ol are dissolved in 50 ml of 6 mol hydrochloric acid. After stirring at room temperature for 30 minutes, the reaction mixture was cooled with an ice bath and neutralized to ph6.5 with 6 molar sodium hydroxide solution. The resulting residue was filtered off, washed with water and dried under vacuum at 55 ℃. The crude product was purified by chromatography on silica gel (eluent dichloromethane/methanol: 5/1) to give 5.77 g (0.018 mol, 65% yield) of the title compound as ochre crystals.

¹H-NMR(CDCl₃)：(ppm)＝2.25(3H，s)，2.38(3H，s)，5.32(1H，d)，5.55(1H，d)，7.13(1H，d)，7.18-7.25(3H，m)，7.51(2H，dd)，7.70(1H，d)。

The invention relates to the use of a compound of formula 1 for preparing a compound of formula 2

(8R, 9R) -8-acetoxy-2-methyl-9-phenyl-7H-8, 9-dihydropyrano [2, 3-c ] imidazo [1, 2-a ] pyridin-7-one

150 ml (1.166 mol) of trimethyl orthoacetate, 7.5 g (0.030 mol) of pyridinium-p-toluenesulfonate and 13.5 ml (0.358 mol) of formic acid were added at room temperature to a solution of 93.4 g (0.299 mol) of 2-methyl-7- [ (2R, 3S) -2, 3-dihydroxy-3-phenylpropan-1-one-1-yl ] imidazo [1, 2-a ] pyridin-8-ol in 2.3 l of dichloromethane. After stirring at room temperature for 2 hours, the reaction mixture was poured into 1.5 l of a 0.25 molar solution of sodium bicarbonate. After stirring at room temperature for 15 minutes, the organic phase is separated off and the aqueous phase is extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and the solvent was removed in vacuo. The resulting solid was recrystallized from diisopropyl ether and dried under vacuum to give 91.3 g (0.271 mol, yield 90.8%) of the title compound as pale yellow crystals.

Melting point: 220 ℃ and 222 ℃ (diisopropyl ether).

(8R, 9R) -8-acetoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydropyrano [2, 3-c ] imidazo [1, 2-a ] pyridin-7-one

3.18 ml (0.025 mol) of trimethyl orthoacetate, 0.16 g (0.0006 mol) of pyridinium p-toluenesulfonate and 0.28 ml (0.007 mol) of formic acid are added at room temperature to a solution of 2 g (0.006 mol) of 2, 3-dimethyl-7- [ (2R, 3S) -2, 3-dihydroxy-3-phenylpropan-1-one-1-yl ] imidazo [1, 2-a ] pyridin-8-ol in 40 ml of dichloromethane. After stirring at room temperature for 16 h, the reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by thin layer filtration over silica gel (solvent dichloromethane/methanol: 100/1). After removal of the solvent, 1.8 g (0.005 mol, yield 84%) of the title compound were obtained as colorless crystals.

Melting point: 205 deg.C and 206 deg.C (diethyl ether/acetone)

(8R, 9R) -2, 3-dimethyl-8-isobutyryloxy-9-phenyl-7H-8, 9-dihydropyrano [2, 3-c ] imidazo [1, 2-a ] pyridin-7-one

1.81 ml (0.012 mol) of trimethyl orthoisobutyrate, 0.08 g (0.0003 mol) of pyridinium p-toluenesulfonate and 0.14 ml (0.004 mol) of formic acid were added at room temperature to a solution of 1 g (0.003 mol) of 2, 3-dimethyl-7- [ (2R, 3S) -2, 3-dihydroxy-3-phenylprop-1-on-1-yl ] imidazo [1, 2-a ] pyridin-8-ol in 10 ml of dichloromethane. After stirring at room temperature for 16 h, the reaction mixture was poured into saturated sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane, the combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (solvent dichloromethane/methanol: 100/3) to yield 0.98 g (0.003 mol, yield 85%) of the title compound as colorless crystals.

Melting point: 207 ℃ and 208 ℃ (acetone)

Industrial applicability

The compounds of formula 1 and their salts are valuable intermediates for the preparation of some active compounds (such as those disclosed in the following international patent applications): WO 88/54188, WO 01/72758, WO 01/72754, WO 01/72755, WO 01/72767, WO 02/34749, WO 03/016310, WO 03/014120 and WO 03/14123.

Claims

1. Compounds of formula 1 and salts thereof

r32 is hydrogen, 1-7C alkyl, hydroxy-1-4C alkyl or 1-4C alkoxy-1-4C alkyl,

or therein

wherein

r6 is hydrogen, 1-4C alkyl or halogen, and

r7 is hydrogen, 1-4C alkyl or halogen,

wherein

2. A compound of formula 1 according to claim 1 and salts thereof, wherein

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, halogen, 1-4C alkyl or a group-CO-NR 31R32,

r32 is hydrogen, 1-7C alkyl, hydroxy-1-4C alkyl or 1-4C alkoxy-1-4C alkyl,

or wherein R31 and R32 together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl, piperazinyl, N-1-4C alkylpiperazinyl or morpholinyl,

r6 is hydrogen, and

r7 is hydrogen.

3. A compound of formula 1 according to claim 1 and salts thereof, wherein

R1 is 1-4C alkyl or 1-4C alkoxy-1-4C alkyl,

r2 is hydrogen, 1-4C alkyl, phenyl, hydroxy-1-4C alkyl, halogen,

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, and R3 is hydrogen,

arom is phenyl, furyl or thienyl.

4. A compound according to claim 1 and salts thereof, characterized by having the general formula 1^*，

Wherein R1 is hydrogen, 1-4C alkyl, 3-7C cycloalkyl, 1-4C alkoxy-1-4C alkyl, 2-4C alkynyl or fluoro-1-4C alkyl,

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, halogen, 1-4C alkyl or a group-CO-NR 31R32,

r32 is hydrogen, 1-7C alkyl, hydroxy-1-4C alkyl or 1-4C alkoxy-1-4C alkyl,

arom is phenyl, furyl or thienyl.

5. A compound according to claim 1 and salts thereof, characterized by having formula 1 given in claim 4^*Wherein

R1 is hydrogen, methyl, cyclopropyl, methoxymethyl or trifluoromethyl,

r2 is hydrogen, methyl, phenyl, hydroxymethyl, chloro, bromo, ethynyl, trifluoromethyl,

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, fluorine, methyl or a group-CO-N (CH)₃)₂，

Arom is phenyl.

6. A compound according to claim 1 and salts thereof, characterized by having formula 1 given in claim 4^*Wherein

R1 is a methyl group, and R1 is a methyl group,

r3a is hydrogen, and R3 is hydrogen,

r3b is hydrogen, and R3 is hydrogen,

arom is phenyl.

7. Use of a compound of formula 1 as claimed in claim 1, wherein R1, R2, R3a, R3b and Arom have the meanings indicated in claim 1, for the preparation of a compound of formula 2 or a salt thereof,

wherein R1, R2, R3a, R3b and Arom have the meanings indicated in claim 1, and R8 is hydrogen, 1-4C alkyl or aryl, wherein aryl has the meanings indicated in claim 1.

8. The compound of formula 1 as claimed in claim 4^*In the preparation of the compound of formula 2^*Use of a compound of formula 1 or a salt thereof^*Wherein R1, R2, R3a, R3b and Arom have the meanings indicated in claim 4,

wherein R1, R2, R3a, R3b and Arom have the meanings indicated in claim 4, and R8 is hydrogen, 1-4C alkyl or aryl, wherein aryl has the meanings indicated in claim 1.

9. A process for the preparation of a compound of formula 1 as claimed in claim 1, wherein R1, R2, R3a, R3b and Arom have the meanings indicated in claim 1, which comprises deprotecting a compound of formula 3 with a mineral acid and then working up,

wherein R1, R2, R3a, R3b and Arom have the definitions indicated in claim 1.

10. The compound of claim 4 represented by the formula 1^*A process for the preparation of compounds wherein R1, R2, R3a, R3b and Arom have the meanings indicated in claim 4, which comprises reacting a compound of formula 3^*The compound is deprotected by inorganic acid and then finished,

wherein R1, R2, R3a, R3b and Arom have the meanings indicated in claim 4.