RU2000131167A

RU2000131167A - METHOD FOR STEROCHEMICALLY CONTROLLED OBTAINING OF ISOMERICALLY PURE HIGHLY SUBSTITUTED ASACYCLIC COMPOUNDS

Info

Publication number: RU2000131167A
Application number: RU2000131167/04A
Authority: RU
Inventors: Михель РЕГГЕЛИН; Тимо ХАЙНРИХ; Бернд ЮНКЕР; Йохен Антель; Ульф Пройшофф
Original assignee: Солвей Фармасьютикалс Гмбх
Priority date: 1998-05-13
Filing date: 1999-05-10
Publication date: 2003-01-27

Claims

1. The method of stereochemically controlled obtaining compounds of General formula Ia '

where R ¹ R ² CH group at the 5-position of the cyclic fragment and the hydroxy group in the 3-position of the cyclic element are in trans position relative to each other and where the substituent R ⁴ in the 4-position and the hydroxy group in the 3-position of the cyclic fragment are in cis -position relative to each other and where
n is 0 or 1;
R ¹ means hydrogen, C ₁ -C ₆ -alkyl or phenyl-C ₁ -C ₆ -alkyl, optionally once to three times substituted in the phenyl ring with lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, and
R ² means hydrogen, or
R ¹ and R ² together mean a methylene group linked by a double bond, which may be substituted with C ₁ -C ₅ -alkyl or phenyl-C ₁ -C ₅ -alkyl, if necessary, once to three times lower alkyl substituted in the phenyl ring, lower haloalkyl, lower alkoxy or lower haloalkoxy;
R ³ means hydrogen and
R ⁴ means hydrogen, lower alkyl or phenyl lower alkyl, optionally one- or multiple-substituted by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or
R ³ and R ⁴ also together mean a C ₂ alkylene chain or a C ₃ -C ₆ alkylene chain, optionally containing from 1 to 3 double bonds, which can be connected by a C ₁ -C ₂ alkylene bridge, in the case of mono or disubstituted lower alkyl,
R ⁵ means hydrogen, lower alkyl, hydroxy, lower alkoxy, or phenyl lower alkyl or phenyl lower alkoxy, optionally once to thrice substituted by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy and
R ⁶ means hydrogen and
R ⁷ means hydrogen and
R ⁸ means hydrogen, a cyano, carboxy group (optionally esterified with cycloaliphatic or linear or branched aliphatic C ₁ -C ₆ alcohols, optionally containing from one to three double bonds and which, if necessary, can be once to three times substituted with halogen or a lower alkoxy group or phenyl lower alcohols, optionally up to three times substituted in the phenyl ring with lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkyl sigruppoy) carbonylamino (optionally mono-substituted on nitrogen C ₃ -C ₈ -nikloalkil-lower alkanoyl or a linear or branched aliphatic C ₁ -C ₆ -alkanoyl, which, if necessary, may be monosubstituted to trisubstituted by halogen, or substituted lower alkoxy, or phenyl-lower alkanailom, if necessary, mono- to trisubstituted in the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or mono- or disubstituted on the nitrogen C ₃ -C ₈ -tsikloa keel-lower alkyl or linear or branched aliphatic C ₁ -C ₆ -alkyl, which, if necessary, may be monosubstituted to trisubstituted by halogen or lower alkoxy, or phenyl-lower alkyl, optionally mono- to trisubstituted in the phenyl ring with lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or substituted on the nitrogen with a suitable protecting group), if necessary, from once to four times unsaturated mono- or bicyclic systems with 3 to 10 carbon atoms in a cycle in which cyclic carbon atoms can be substituted once with up to three times with nitrogen, oxygen and / or sulfur, and the ring system can be substituted up to three times with three times lower alkyl, lower haloalkyl, lower alkoxy, hydroxy, halogen or a lower alkylene chain which is bonded by an oxygen atom to two adjacent carbon atoms of the ring system, or may also, if necessary, contain from one to three double bonds linear or branched C ₁ -C _{1 2} -alkyl, which can be substituted once to three times by halogen, hydroxy, lower alkoxy, carboxy, (if necessary, esterified with cycloaliphatic or linear or branched aliphatic C ₁ -C ₆ alcohols, if necessary, containing from one to three double bonds, and which, if necessary, can be substituted once by up to three times with halogen or a lower alkoxy group, or phenyl lower alcohols, if necessary, once up to three times substituted by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy), cyano, mercapto, lower alkylthio, amino, lower alkylamino, carbonylamino (optionally monosubstituted with nitrogen, C ₃ -C ₈ cycloalkyl lower alkanoyl or linear or branched aliphatic C ₁ -C ₆ alkanoyl, which, if necessary, can be substituted once or three times with halogen or a lower alkoxy group, or phenyl lower alkanoyl, if necessary, once up to three times substituted in phenyl co lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy groups, or mono- or disubstituted on nitrogen with C ₃ -C ₈ -cycloalkyl lower alkyl or linear or branched aliphatic C ₁ -C ₆ -alkyl, which, if necessary, can be substituted up to three times once with halogen or a lower alkoxy group, or phenyl lower alkyl, optionally one to three times substituted in the phenyl ring with lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or substituted у at nitrogen with a suitable protective group), if necessary, once to four times unsaturated mono- or bicyclic system with 3 to 10 carbon atoms in a cycle in which cyclic carbon atoms can be replaced up to three times by nitrogen, oxygen and / or sulfur and ring the system can be substituted once or three times by lower alkyl, lower haloalkyl, lower alkoxy, hydroxy, halogen or lower alkylene chains, which are linked by an oxygen atom to two adjacent ring carbon atoms howl system, or
R ⁵ and R ⁸ together with the carbon atoms to which they are bonded can form, if necessary, containing from 1 to 3 double bonds a mono- or bicyclic system with 5 to 10 carbon atoms in a cycle in which carbon atoms not containing R substituents ⁵ and R ⁸ can be substituted up to three times once with sulfur, oxygen and / or nitrogen and which, if necessary, can be substituted up to three times with lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, hydroxy, halogen or lower alkylene c I drink, which is linked by an oxygen atom with two adjacent carbon atoms of the ring system, or
R ⁶ and R ⁷ together may also form a bond and
R ⁵ and R ⁸ together with the carbon atoms to which they are attached can form an aromatic C ₆ ring system, which can be condensed with its 2 to 4 carbon atoms into a bicyclic system containing only 8 to 10 ring carbon atoms from 3 to 5 by double bonds, the carbon atoms of this C ₆ -C ₁₀ cyclic system not containing R ⁵ or R ⁸ substituents, can be replaced up to three times with sulfur, oxygen and / or nitrogen, and this C ₆ -C ₁₀ ring the system, if necessary, can be once up to three times substituted by lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, hydroxy, halogen or lower alkylene chain, which is linked by an oxygen atom to two adjacent carbon atoms of the ring system, and
R ⁹ means hydrogen, lower alkyl, phenyl lower alkyl, which, if necessary, is once to three times substituted in the phenyl ring with lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or a protective amino group, or
R ⁸ and R ⁹ together can form a C ₃ -C ₄ alkylene chain and their acid addition salts, and, if necessary, the existing reactive groups in the compounds of formula Ia ′ can be blocked with suitable protecting groups, characterized in that
a) a compound of General formula II

where R ³ and R ⁴ have the above meanings, R ¹⁰¹ has the meanings given above for R ¹ , with the exception of the methylene group, optionally substituted, Ar is phenyl, if necessary, once to three times substituted by lower alkyl, R ¹⁰ means lower alkyl or phenyl, if necessary, once substituted in the phenyl ring with lower alkyl or hydroxy-group protected by a suitable protecting group or, phenyl-lower alkyl, if necessary, once substituted in the phenyl ring with lower alkyl and R ¹¹⁰¹ it is a strong protective group, it is subsequently reacted with a base suitable for its deprotonation, an organometallic compound of the general formula VII
XM ² (OR ¹² ) ₃ VII
where X is halogen, M ² is a tetravalent transition metal, and R ¹² is lower alkyl, phenyl or phenyl lower alkyl, and a stereoisomer of a compound of general formula VIII

where R ⁵ , R ⁶ , R ⁷ and n have the above meanings, R ⁸⁰¹ has the meanings of R ⁸ , wherein in all cases the reactive groups are, if necessary, blocked by base-resistant protecting groups, R ⁹⁰¹ is hydrogen or together with R ⁸⁰¹ means a C ₃ -C ₄ alkylene chain and R ₁₃ means a protective amino group which, upon cleavage, leaves nucleophilic nitrogen to form a stereoisomer of a compound of general formula IX

where R ¹⁰¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸⁰¹ , R ⁹⁰¹ , R ¹⁰ , R ¹¹⁰¹ , R ¹² , R ¹³ , n, Ar and M ² have the above meanings,
b) the resulting compound of formula IX by treatment with a reagent suitable for removing the group R ¹³ is converted to a compound of general formula Xa

where R ¹⁰¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸⁰¹ , R ⁹⁰¹ , R ¹⁰ , n and Ar have the above meanings and R ¹¹ is hydrogen or a silyl protecting group, and if R ⁹⁰¹ is hydrogen, the nitrogen atom in the main cyclic fragment of the resulting compound of formula Xa is blocked with a base protecting group and, if necessary, the still present silyl protecting group R ^{11 is} cleaved, and
c) to obtain a compound of general formula Ia

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸⁰¹ and n have the above meanings and R ⁹⁰² is a protective group, resistant to bases, or together with R ⁸⁰¹ forms C ₃ - C ₄ alkylene chain,
ca) the obtained compound of formula Xa or the compound obtained by cleavage of the silyl protecting group R ¹¹ is treated with a reagent suitable for the reductive cleavage of the sulfonimidoylalkyl bond to obtain a compound of general formula Ib

where R ¹⁰¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸⁰¹ , R ⁹⁰² and n are as defined above, or
cb) in the obtained compound of formula Xa, where R ^{101 is} not hydrogen, the sulfonimidoylalkyl bond after electrophilic activation of the sulfonimidoyl unit is cleaved under the conditions of base-initiated elimination to obtain a compound of general formula IC

where R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸⁰¹ , R ⁹⁰² and n are as defined above and R ¹⁰² is C ₁ -C ₅ alkyl or phenyl lower alkyl, optionally, single or repeatedly substituted in the phenyl ring with lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy groups, the lower alkyl chain of which may contain from 1 to 5 carbon atoms, and if desired, all protective groups in the compound of formula Ia are again cleaved and, if desired, if I need to reacting with a reagent capable of N-alkylation or amide formation, or blocked with a protective amino group to obtain a compound of formula Ia '.

2. The method according to claim 1 for the preparation of compounds of general formula Ib, as well as those obtained from them by cleavage, in any case, of the existing protective groups, and reaction, in any case, of free NH-groups in the 1-position of the cyclic fragment with a reagent capable of N- alkylation or to the formation of an amide, or by blocking in any case these free NH groups with the protective amino groups of the compounds of claim 1.

3. The method according to claim 1, wherein a base group that is not stable to the base is used as a protective amino group of R ¹³ in the compounds of formula VIII, and a base is used as a reagent to remove the protective group of R ¹³ .

4. The method according to claim 3, wherein the base-unstable protecting group is a fluoren-9-yl-methyloxycarbonyl residue.

5. The method according to p. 4, where piperidine is used as the base.

6. The method according to p. 1, where, at least in stage a), toluene is used as a solvent.

7. The method according to p. 1, where in step ca), as the reagent for the reductive cleavage of the sulfonimidoylalkyl bond in the compounds of general formula Xa, samarium- (II) iodide is used.

8. The method according to p. 1, where in the compounds of general formulas Ia ', Ia, Ib, Ic, II, IX and Xa, each R ⁴ is different from hydrogen.

9. The method of claim 1, wherein tert is used as the silyl protecting group R ¹¹⁰¹ . β-butyldimethylsilyl or trimethylsilyl.

10. The method according to p. 1 to obtain compounds of General formula Ia ', where R ⁸ means hydrogen, lower alkyl, phenyl, phenyl lower alkyl or lower alkoxy lower alkyl, or R ⁶ and R ⁷ together form a bond and R ⁵ and R ⁸ together with the carbon atoms to which they are connected form an aromatic C ₆ ring system, or where R ⁸ together with R ⁹ form a C ₃ -C ₄ alkylene chain.

11. The compounds of general formula Xa according to claim 1, as well as the compounds formed from the compounds of formula Ia by removing, if necessary, the protective groups, and the acid addition salts of the free amines of formula Xa, where each sulfur-containing substituent is in the 5-position and the hydroxy group is 3 the -position of the cyclic fragment are in a trans position relative to each other and where the substituent R ⁴ at the 4-position and the hydroxy group in the 3-position of the cyclic fragment are in the cis position relative to each other.

12. The compounds of general formula Xa according to claim 11, which contain a secondary nitrogen atom in a cyclic moiety which is protected by tert. a butoxycarbonyl protecting group.

13. The compounds of general formula Xa according to claim 12, wherein R ⁹⁰¹ is hydrogen or together with R ⁸⁰¹ forms a C ₃ -C ₄ alkylene chain.

14. The use of samarium- (II) iodide for the reductive desulfurization of alkyl-sulfonimidoyl compounds of the general formula Xa from claim 1.

15. The use of 2-oxide (R _s ) -4 (S) -isopropyl-2-para-toluoyl-4,5-dihydro [1,2λ ⁶ , 3] oxathiazole, 2-oxide (S _s ) -4 (S ) -isopropyl-2-para-toluoyl-4,5-dihydro [1,2λ ⁶ , 3] oxathiazole, 2-oxide (R _s ) -4 (R) -isopropyl-2-para-toluoyl-4,5- dihydro [1,2λ ⁶ , 3] oxathiazole and 2-oxide (S _s ) -4 (R) -isopropyl-2-para-toluoyl-4,5-dihydro [1,2λ ⁶ , 3] oxathiazole in stereochemically controlled methods for preparing azacyclic compounds according to claim 1.

16. Use of [S _s , N (1S)] -N- [1 - ((tert-butyldimethylsilyl) oxy) methyl] -2-methylpropyl] -S-methyl-S- (4-methylphenyl) sulfoxyimide and [R _s , N (1R)] -N- [1 - ((tert-butyldimethylsilyl) oxy) methyl] -2-methylpropyl] -S-methyl-S- (4-methylphenyl) sulfoxyimide in a stereochemically controlled method for producing azacyclic compounds under item 1.