Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-18
2001-10-30
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06310216
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates firstly to 3-azabicyclo[3.1.0]hexanes with an amino function carrying two protective groups in position 6. The present invention further relates to processes for the preparation of these compounds starting from chloroenamines or bicyclic nitriles, and the modification by cleaving off the protective groups in a customary manner. Finally, the present invention relates to the use of the novel aminioazabicyclohexanes for the preparation of quinolone- and naphthyridinecarboxylic acid derivatives such as 7-(6-amino-3-azabicyclo[3.1.0]hexyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naph-thyridine-3-carboxylic acid and salts thereof, and optionally to subsequent modification by cleaving off the protective groups.
It is known that 6-amino-3-azabicyclo[3.1.0]hexanes is used as diamine component for the preparation of gyrase inhibitors (cf. WO 91/02526, U.S. Pat. No. 5,164,402, EP-A 413 455, Synlett 1996, 1097. U.S. Pat. No. 5,298,629, WO 93/18001 and Synlett 1996, 1100). In the process, preference is given to using the more readily available 6-exo-amine.
In the syntheses of 6-exo- and 6-endo-amino-3-azabicyclo[3.1.0]hexane to date, the 6-amino group is always obtained alter the cyclopropanation step by converting a functional group. Here, compounds with monoprotected 6-amino groups are used in each case.
In the invention presented below, the amino group is already present in the molecule in the cyclopropanation step. However, the amino group is initially protected by two protective groups, such as, for example, benzyl or allyl radicals, which can be cleaved off later or following incorporation of the novel aminoazabicyclohexanes into quinolone- or naphthyridinecarboxylic acid derivatives. Despite an opposing opinion expressed in the literature (cf. Synlett 1996, 1100), this route is therefore a practical way of also obtaining 6-amino-3-azabicyclo[3.1.0]hexane derivatives having a free amino group in position 6. The starting materials chosen in the novel process are chloroenamines or else bicyclic nitriles preparable therefrom. Chloroenamines give exclusively the 6-endo-amino-3-azabicyclo[3.1.0]hexanes, whilst either 6-endo- or 6-exo-aminio-3-azabicyclo[3.1.0]hexanes are obtainable from the bicyclic nitriles.
The present invention relates to novel 6-amino-3-azabicyclo[3.1.0]hexanes of the formula
in which
R
1
and R
2
independently of one another are C
3
-C
4
-alkenyl or Ar—CH(R′)— where R′=hydrogen or C
1
-C
4
-alkyl and Ar=optionally substituted C
6
-C
10
-aryl and
R
3
is hydrogen, C
3
-C
4
-alkenyl, Ar—CH(R′)— where R′=hydrogen or C
1
-C
4
-alkyl and Ar=optionally substituted C
6
-C
10
-aryl or COOR
4
where R
4
=C
1
-C
4
-alkyl or C
2
-C
4
-alkenyl.
R′ is preferably hydrogen.
The optionally substituted C
6
-C
10
-aryl can, for example, be unsubstituted C
6
-C
10
-aryl or C
6
-C
10
-aryl substituted with from 1 to 3 identical or different substituents. Suitable substituents are, for example, C
1
-C
4
-alkyl and C
1
-C
4
-alkoxy.
In preferred compounds of the formula (I), R
1
and R
2
are identical and are allyl or benzyl and R
3
is hydrogen, allyl, benzyl, COOCH
3
or COOCH═CH
2
.
The discussed compounds of the formula (I) have two stereoisomers of the formulae
which, should a more accurate name be needed below, are referred to as endo-(I) and exo-(I) respectively. R
1
, R
2
and R
3
in the formulae endo-(I) and exo-(I) correspond to the radicals given for formula (I).
The present invention also relates to a process for the preparation of compounds of the formula endo-(I), which is characterized in that a chloroenamines of the formula
in which
R
1
and R
2
are identical and are C
3
-C
4
-alkenyl or Ar—CH(R′)— where R′=hydrogen or C
1
-C
4
-alkyl and Ar=optionally substituted C
6
-C
10
-aryl, and
R
3
has the same scope of meaning as R
1
and R
2
, but can be different from R
1
and R
2
,
is reacted with a C
1
-C
4
-alkyl alkoxide, to give an N,O-acetal of the formula (III),
in which
R
1
, R
2
and R
3
are as defined for formula (II),
the latter is treated with a hydride conversion agent, giving an amine of the formula
in which
R
1
, R
2
and R
3
are as defined above for formula (II).
This process of the present invention is characterized by very high stereoselectivity. The cyclopropane formation from the chloroenamines of the formula (II) and subsequent substitution in the N,O-acetals of the formula (III), which have a tertiary acetalic amine unit, always lead to endo-amine derivatives of the formula endo-(I).
Chloroenamines of the formula (II) can be obtained in a known manner or analogously thereto, for example by reacting 1-[C
3
-C
4
-alkenyl or Ar—CH(R′) where R′=hydrogen or C
1
-C
4
-alkyl and Ar=optionally substituted C
6
-C
10
-aryl]-4-di-[C
3
-C
4
-alkenyl or Ar—CH(R′)— where R′=hydrogen or C
1
-C
4
-alkyl and Ar=optionally substituted C
6
-C
10
-aryl-]amino-1,2,5,6-tetrahydropyridine with N-chlorosuccinimide (see Tetrahedron 51, 3507 (1995)).
In the process, the substituted 4-aminotetrahydropyridine used may preferably be 1-benzyl-4-dibenzylamino-1,2,5,6-tetrahydropyridine and 1-benzyl-4-diallylamino-1,2,5,6-tetrahydropyridine. The reaction mixture produced in the chlorination can also be further used as such, i.e. without isolation of the chloroenamines of the formula (II).
The C
1
-C
4
-alkyl alkoxides are generally used together with a solvent, preferably in alcoholic solution, for example dissolved in an alcohol which corresponds to the respective alkoxide radical. Preference is given to the sodium methoxide/methanol system, which can be prepared very simply from elemental sodium and excess methanol. Preference is given to using a two- to fourfold molar excess of alkoxide with respect to the chloroenaminie. The reaction often proceeds at a sufficient rate at room temperature. It can be speeded up by heating to e.g. 50 to 60° C.
When reaction with the C
1
-C
4
-alkyl alkoxide is complete, the resulting N,O-acetal of the formula (III) can be isolated and purified by, for example, firstly stripping off the solvent, extracting the residue which remains with a solvent, e.g. a hydrocarbon, and isolating the N,O-acetal of the formula (III) from the extract, e.g. by crystallization or distillation under reduced pressure.
Particularly when, during the reaction of a chloroenamines of the formula (II) with a C
1
-C
4
-alkyl alkoxide, the chloroenamines of the formula (II) is added as a powder to a solution of a C
1
-C
4
-alkyl alkoxide in a C
1
-C
4
-alkyl alcohol, the 6-endo-amine isomer of the N,O-acetal [as shown in formula (III)] is exclusively obtained.
Suitable hydride conversion agents for substituting the C
1
-C
4
-alkoxy group in the N,O-acetal of the formula (III) by hydrogen are, for example, hydrides, such as lithium aluminium hydride or diisobutyl aluminium hydride. Suitable solvents for this substitution reaction arc, for example, ethers, preference being given to tetrahydrofuran. N,O-acetals of the formula (III) and hydride conversion agents can be used, for example, in a molar ratio of from 1:1.2 to 1:4. The reaction is preferably carried out in a temperature range from, for example, 50 to 70° C. It is generally completed within 3 to 5 hours.
The substitution reaction with the hydride conversion agent can be carried out, for example, by initially introducing the hydride conversion agent suspended in a suitable suspending agent, adding a solution of the N,O-acetal of the formula (III) dropwise, stripping off the suspending agent and solvent after the reaction is complete, hydrolyzing the residues, separating off the solid constituents from the mixture then present, extracting the aqueous phase which remains, and isolating the amine of the formula endo-(I) prepared from the extract.
The solvent used for the N,O-acetal of the formula
Dalhoff Axel
Goerz Torsten
Milch Gunther
Petersen Uwe
Schmuck Gabriele
Bayer Aktiengesellschaft
Eyl Diderico van
Gil Joseph C.
Henderson Richard E. L.
Ramsuer Robert W.
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