Patent EA-000963-B1 (EA)
Title: 2-azabicyclo[2.2.1]heptane derivatives, preparation and application thereof
Inventor: LARGEAU DENIS
IPC: C07D209/02
Filed: 1996-05-28
Abstract: 1. A 1R or 1S 2-azabicyclo /2.2.1/heptane derivatives configurations of general formulas (1) or (1'):    or     wherein R represents a hydrogen atom or, respectively, radical of formula (II) or (II'):   or    wherein R1 represents an alkyl radical with 1-4 carbon atoms and Ar represents a phenyl or α or β-naphthyl, optionally substituted by one or more identical or different atoms or radicals, selected from halogen atoms and alkyl radicals containing 1-4 carbon atoms, alkoxy radicals containing 1-4 carbon atoms or a nitro group. 2. 2-azabicyclo /2.2.1/heptane derivatives according to claim 1, wherein R1 represents a methyl or ethyl radical and Ar represents a phenyl optionally substituted by one or more methyl or methoxy-radicals. 3. 2-azabicyclo /2.2.1/heptane derivatives according to claim 1, wherein R1 represents a methyl radical and Ar represents a phenyl radical. 4. A process for preparing compounds as claimed in any of claims 1,2, or 3, wherein R represents radical of general formula (II) or (II') characterised in that, realizes bis-hydroxylation of a compound of general formula (III) or (III'):   or    wherein R1  and Ar are determined in any of claims 1,2 or 3. 5. A process as claimed in claim 4 characterised in that bis-hydroxylation is realized with potassium permanganate or osmium tetroxide in presence of N-methylmorpholineoxide or triethylaminoxide or potassium ferricyanide (K3FeCN6). 6. A process as claimed in claims 4, 5 characterised in that the prepared compound additionally is treated with hydrogen at presence of catalyzer such as palladium on the carrier, in the environment of organic solvent which is aliphatic alcohol with 1-3 carbon atoms with production of the compound of formula 1 or 1', wherein R is hydrogen. 7. A process as claimed in claims 4, 5 characterised in that for preparing the compound of general formula (1), wherein R is radical of general formula (II), additionally provide diastereoselective crystallisation of mixture of compound of general formula (1) with compound of general formula (1') wherein symbols R are accordingly radical of general formula (II) or radical of general formula (II'), with optically active acid, such as L-dimethoxysuccinic acid, in the environment of organic solvent which is aliphatic alcohol with 1-3 carbon atoms. 8. A process for preparing a compound of general formula (VIII):    wherein R'1 and R"1 identical or different, represent a residue of organic aliphatic acid with 2-4 carbon atoms, such as acetyl or propionyl or an aromatic acid, such as benzoyl residue, or R'1 and R"1 taken together form a methylene radical, whose carbon atom is optionally substituted by one or several radicals, which are identical or different, selected from alkyl radicals containing 1-4 carbon atoms, which taken together can form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and G2 represents a protecting group for aminofunction, characterised in that: a) protect hydroxyl functions of the compound according to any of claims 1,2 or 3, with forming of compound of general formula (VI):   wherein R'1 and  R''1 are determined above, and R is determined in any of claims 1,2 or 3, in ordinary conditions of esterification or acetalisation; b) compound of general formula (VI) is converted into compound of general formula (VII):   wherein R1 and  R''1 are determined above, and G2 represents a protecting group for nitrogen atom, either by: 1)  hydrogenolyse of the compound of general formula (VI), wherein R is a radical of the general formula (II) and influence of reagent, which allows to introduce a protective group for nitrogen atom, moreover hydrogenolyse and protection of nitrogen atom can be provided simultaneously; or  2) influence of reagent, which allows introducing a protective group for nitrogen atom, on the compound of general formula (VI), wherein R is hydrogen atom; then c) oxidize the compound of general formula (VII) up to the compound of general formula (VIII). 9. A process as claimed in claim 8, characterised in that protection of hydroxyl functions of compound according to any of claims 1,2 or 3 is provided with aliphatic acid containing 2-4 carbon atoms or aldehyde or ketone possibly as acetal in presence of acid, in organic inert solvent at the temperature from 50 degree C to boiling point of with reaction mixture is refluxed. 10. A process as claimed in claim 8, characterised in that hydrogenolyse is provided with hydrogen in presence of catalyser such as Pd/C, and protection of nitrogen atom is effected in ordinary protection conditions depending on the nature of protecting group. 11. A process as claimed in claim 8, characterised in that when G2 is tert-butoxycarbonyl radical, simultaneous hydrogenolyse and protection is effected by simultaneous introduction into interaction hydrogen in presence of catalyser such as Pd/C and di-tert.-butyldicarbonate in aliphatic alcohol with 1-3 carbon atoms at the temperature from 0 to 50 degree C. 12. A process as claimed in claim 8, characterised in that the compound of general formula (VII) is oxidized with ruthenium oxide (RuO4), if necessary provided in situ in presence of oxidant. 13. A process for preparation of compound of general formula (VIII):   wherein R'1 and R"1  and G2 are determined in claim 8, characterised in that product of general formula (VI) is oxidized:   wherein R1 and R"1 are determined in claim 8, and R is hydrogen atom, in conditions, described in claim 12 and than nitrogen atom of received lactam is protected in conditions, described in claim 11. 14. Compounds of general formula (VIII):   wherein R'1 and R"1,  are identical or different, represent residue of organic aliphatic acid containing 2-4 carbon atoms, such as acetyl or propionyl, or aromatic acid, such as benzoyl residue, or R'1 and R"1 taken together form a methylene radical whose carbon atom is optionally substituted by one or several radicals, which are identical or different, selected from alkyl radicals containing 1-4 carbon atoms, which taken together can form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and G2 represents protecting group chloroacetyl, methoxymethyl, 2,2,2-trichloroethoxycarbonyl, tert.butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, allyloxycarbonyl, benzyloxycarbonyl, where phenyl nucleus can be substituted  by halogen atom or alkyl radical with 1-4 carbon atoms or alkoxy-radical with 1-4 carbon atoms; or tert.butoxycarbonyl. 15. Compounds of general formula (VI'):   wherein R'1 and R"1, identical or different, represent residue of organic aliphatic acid containing 2-4 carbon atoms, such, as acetyl or propionyl or an aromatic acid, such as benzoyl residue, or R'1 and R"1 taken together form a methylene radical whose carbon atom is optionally substituted by one or several radicals, which are identical or different, selected from alkyl radicals containing 1-4 carbon atoms, which taken together can form an alicyclic radical containing 5 or 6 carbon atoms, and phenyl radicals, A represents hydrogen atom, radical of general formula (II) as claimed in claims 1,2,3 or protecting group G2 of aminofunction. 16. A process for preparing a compound of general formula (V):   wherein R2 is carboxyl; alkoxycarbonyl, alkyl part of which comprises 1-4 carbon atoms; N-alkylaminocarbonyl, alkyl part of which comprises 1-4 carbon atoms; or hydroxymethyl or alkoxymethyl; and R' and R", identical or different, are hydrogen atom or residue of organic aliphatic acid containing 2-4 carbon atoms, such as acetyl or propionyl or aromatic acid, such as benzoyl residue, or R' and R" taken together form a methylene radical whose carbon atom is optionally substituted by one or several radicals, which are identical or different, selected from alkyl radicals containing 1-4 carbon atoms, which taken together can form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and G1 represents hydrogen atom or protecting group G2  for amino-function, characterised in that, depending on nature of introduced radical R2, which was desired to get, non-organic base, alcoholate of alkali metal, alkylamine or borhydride of alkali metal is brought into reaction with a compound of general formula (VIII):   wherein R'1, R"1 and G2  are determined above, than, if necessary, substitute radicals R'1 and R"1 and protecting group G2 with hydrogen atom. 17. A process for preparing of compounds of general formula (V):   wherein R2 is carboxyl; alkoxycarbonyl, alkyl part of which comprises 1-4 carbon atoms; N-alkylaminocarbonyl, alkyl part of which comprises 1-4 carbon atoms; or hydroxymethyl; or alkoxymethyl; and R and R", identical or different, are hydrogen atom or residue of organic aliphatic acid containing 2-4 carbon atoms, such as acetyl or propionyl or aromatic acid, such as benzoyl residue; or R' and R" taken together form a methylene radical whose carbon atom is optionally substituted by one or several radicals, which are identical or different, selected from alkyl radicals containing 1-4 carbon atoms, which taken together can form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals; and G1 represents hydrogen atom or protecting group G2  for amino-function, characterised in that, the protecting group G2 of product of general formula (VIII):   wherein R'1, R"1 and G2  are determined above, are substituted with hydrogen atom, then, depending on nature of radical R2, which was desired to get, non-organic base, alcoholate of alkali metal, alkylamine or borhydride of alkali metal is brought into reaction with a received product, after that, if necessary, radicals R'1 and R"1 are substituted with hydrogen atom.