Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention initially relates to 3-azabicyclo [3. l.OJhexane with a two
• the present invention furthermore relates to processes for the preparation of these compounds starting from chlororenamines or bicyclic nitriles and to modification by customary deprotection. Finally, the present invention relates to the use of the new aminoazabicyclohexanes for the preparation of quinolones 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- naphthyridine-3-carboxylic acid and its salts and, if appropriate, a subsequent modification by deprotection.
• 6-amino-3-azabicyclo [3.1.0] hexane is used as the diamine component for the production of gyrase inhibitors (see WO 91/02526, US Pat. No. 5,164,402, EP-A 413 455, Synlett 1996, 1097. US-A 5 298 629, WO 93/18001 and Synlett 1996. 1100).
• the more accessible 6-exo amine is preferably used.
• 6-amino group is always generated after the cyclopropanation step by converting a functional group.
• compounds with mono-protected 6-amino groups are used.
• the amino group is already present in the molecule in the cyclopropanation step.
• the amino group is initially protected by two protective groups such as. B. protected benzyl or allyl residues, which can be split off later or after incorporation of the new aminoazabicyclohexanes in quinolone or naphthyridine carboxylic acid derivatives.
• this path has proven to be a practical approach to 6-amino-3-azabicyclo [3.1.0] hexane derivatives with a free amino group in the 6-position.
• Chlorenamines or bicyclic nitriles which can be prepared therefrom are chosen as starting materials in the new processes.
• Chlororenamines only provide the 6-endo-amino-3-azabicyclo [3.1.0] hexanes, and from the bicyclic nitriles both 6-endo- and 6-exo-amino-3-azabicyclo [3.1.0] hexanes are accessible .
• the present invention relates to new 6-amino-3-azabicyclo [3.1.0] hexanes of the formula
• R ' is preferably hydrogen.
• Optionally substituted C 6 -C 10 -aryl can be, for example, C 6 -C 10 -aryl which is unsubstituted or substituted by 1 to 3 identical or different substituents.
• substituents are C 1 -C 4 -alkyl and C.
• endo- (I) or exo- (I) which are identified in the following as endo- (I) or exo- (I) if a more precise description is required.
• R 1 , R 2 and R 3 in the formulas endo- (I) and exo- (I) correspond to the radicals given for formula (I).
• the present invention further relates to a process for the preparation of compounds of the formula endo- (I), which is characterized in that a
• R 3 has the same scope as R 1 and R 2 , but can be different from R 1 and R 2 ,
• R 1 , R 2 and R 3 have the meaning given for formula (II),
• R 1 , R 2 and R 3 have the meaning given above for formula (II).
• This method of the present invention is distinguished by a very high stereoselectivity.
• the substituted 4-aminotetrahydropyridine used can preferably be 1-benzyl-4-dibenzylamino-1, 2,5,6-tetrahydropyridine and 1-benzyl-4-diallylamino-1, 2, 5, 6-tetra-hydropyridine.
• the reaction mixture obtained in the chlorination can also be used as such, i.e. can be used without isolating the chlororenamine of the formula (II).
• the -CC alkyl alcoholates are generally used together with a solvent, preferably in an alcoholic solution, for example dissolved in the alcohol which corresponds to the respective alcoholate residue.
• a solvent preferably in an alcoholic solution, for example dissolved in the alcohol which corresponds to the respective alcoholate residue.
• the system is preferably sodium methanolate / methanol, which can be easily produced from elemental sodium and excess methanol. Preferably a two to four fold molar excess of alcoholate is used with respect to the chlororenamine.
• the reaction often proceeds at room temperature at a sufficient rate. It can be accelerated by heating to 50 to 60 ° C, for example.
• the N, O-acetal of the formula (III) obtained can be isolated and purified by, for example, first stripping off the solvent and extracting the remaining residue with a solvent, for example a hydrocarbon and the N, O-acetal of the formula (III) is obtained from the extract, for example by crystallization or distillation in vacuo.
• Acetal of formula (III) against hydrogen come e.g. Hydrides in question such as lithium aluminum hydride or diisobutyl aluminum hydride. Suitable solvents for this exchange reaction are, for example, ethers, preference is given to tetrahydrofuran. N, O-acetals of formula (III) and hydride transfer agents can e.g. be used in a molar ratio of 1: 1.2 to 1: 4. The reaction is preferred in one
• the exchange reaction with the hydride transfer agent can e.g. carry out such that the hydride transfer agent is suspended in a suitable
• Suspending agent submitted added dropwise a solution of the N, O-acetal of formula (III), after the end of the reaction, the suspension and solvent that the The residue is hydrolyzed, the solid constituents of the mixture then present are separated off, the remaining aqueous phase is extracted and the amine of the formula endo- (I) is isolated from the extract.
• Suspending agent for the hydride transfer agent For alkaline hydrolysis e.g. an aqueous alkali hydroxide solution in question, wherein the reaction mixture can optionally be poured into aqueous mineral acid beforehand.
• the extraction of the aqueous phase can e.g. perform with ethers such as diethyl ether.
• Suitable methods for isolating the amine of the formula endo- (I) are, for example, crystallization from a non-polar solvent such as pentane or distillation under reduced pressure.
• the present invention also relates to a process for the preparation of compounds of the formula endo- (I), which is characterized in that a chlororenamine of the formula
• R 3 has the same scope as R 1 and R 2 , but can be different from R 1 and R 2 , reacted directly with a hydride transfer agent, the resulting primary product is subjected to acidic hydrolysis and the amine of the formula endo- (I) is liberated. This process also proceeds with high stereoselectivity to form the endo-amine isomers of the formula endo- (I).
• This implementation can e.g. in acetonitrile or an acetonitrile-water mixture (e.g. 9: 1 to 2.5: 1) with heating to e.g. Carry out 40 to 70 ° C.
• hydride transfer agents e.g. Complex hydrides resistant to water and acetonitrile are suitable. Sodium boron tetrahydride is preferred.
• Chlororenamine and hydride transfer agents can e.g. in a molar ratio of 1: 5 to 1:10.
• the amine adduct formed primarily is split by hydrolysis with acid, preferably hydrochloric acid.
• the amine of the formula endo- (I) is subsequently mixed with alkali, e.g. released by adding aqueous alkali such as dilute potassium hydroxide solution.
• the present invention further relates to a process for the preparation of amines of the formula (I), which is characterized in that a bicyclic nitrile of the formula
• alkali metal in liquid ammonia, optionally in a mixture with a mono- or dialkylamine.
• the alkyl groups of these amines preferably contain 1 to 4 carbon atoms.
• Ethylamine is preferably used. This process can be used to stereoselectively prepare 6-amino-3-azabicyclo [3.1.0] hexane derivatives of the formulas endo- (I) and exo- (I)
• R 1 and R 2 have the meaning given for formula (I) and
• Bicyclic nitriles of the formula (IV) are obtainable, for example, in accordance with tetrahedron 51 ⁇ 3507 (1995) from chlororenamines or analogously to the procedure described there.
• the nitrile group in the nitrile of the formula (IV) can be replaced by hydrogen with an alkali metal in liquid ammonia or in a mixture of ammonia and a mono- or dialkylamine, preferably ethylamine.
• the nitrile and the alkali metal can be used in a molar ratio of e.g. 1: 3 to 1: 8 can be implemented. A ratio of 1: 5 to 1: 7 is preferred.
• the 6-exo-amine isomer of the formula exo- (I) mentioned is generally present in a proportion of (80 ⁇ 10)%; it can be obtained as a pure compound by crystallization or other separation methods. It corresponds to a 3-azabicyclo [3.1.0] hexane with a protective group bearing an amine group in the 6-exo position; it is a derivative of
• the present invention further encompasses the modification of the bicycles of the formula obtained via chlororenamines of the formula (II) or from nitriles of the formula (IV)
• R 1 , R 2 and R 3 can have the meaning given in the formulas (II) and (IV), by customary splitting off of protective groups.
• a hydrogenation treatment for the deprotection reaction from an amine of the formula (I) there are, for example, a hydrogenation treatment, a reaction with chloroformic acid C 2 -C -alkenyl ester and subsequent acidic hydrolysis, a reaction with chloroformic acid CrC 4 alkyl ester to give a urethane and its cleavage with halo-trialkylsilane or a deallylation with tetrakis (triaryl) phosphine palladium and a CH acid such as N, N'-dialkylbarbituric acid.
• the hydrating treatment can be done e.g. B. with hydrogen in the presence of a noble metal catalyst.
• Suitable catalysts are, for example, elemental palladium, in particular elemental palladium on a support such as carbon, aluminum oxide, silicon dioxide or silicates.
• the hydrogenating treatment can optionally be carried out in a solvent. Alcohols such as methanol are suitable for this purpose, to which tertiary amines such as triethylamine can optionally be added.
• the other reaction conditions for this hydrogenating treatment for example pressure, temperature etc.
• all benzyl groups can be reductively removed by hydrogen. This creates an amine of the formula
• R 6 represents hydrogen
• a selective removal of the N (3) -CH (R ') - Ar group in an amine of the formula (I) can be carried out, for example, by reaction with C 2 -C -alkenyl chloroformate and subsequent acidic hydrolysis of the urethane formed.
• a benzyl group on ⁇ (3) in the amine and chloroformic acid vinyl ester are particularly suitable for this.
• This conversion to urethane is preferably carried out in a solvent. Examples are dichloromethane, chloroform and acetonitrile,
• Chloroform is preferred. Chloroformic acid vinyl ester and amine can be used, for example, in a molar ratio of (1.1 to 1.2): 1. Reaction temperatures in A range of 40 to 60 ° C and reaction times of 1 to 3 hours generally lead to good results.
• a selective removal of the N (3) -CH (R ') - Ar group in an amine of the formula (I) can also be carried out by reaction with C 1 -C 4 -chloroformate and subsequent reaction with a halotrialkylsilane.
• a benzyl group on N (3) in the amine and methyl chloroformate and the cleavage of the resulting urethane with trimethylsilyl iodide are particularly suitable for this.
• the conversion to the urethane is preferably carried out in a solvent. Examples are dichloromethane and chloroform mixed with pyridine. Chloroform / pyridine in the ratio (4 to 6): 1 is preferred.
• Chloroformic acid methyl ester and amine can e.g. in a molar ratio of (1.5 to 2): 1. Reaction temperatures in the range of 40 to 60 ° C and reaction times of 3 to 6 hours generally led. too good
• the coproduct benzyl chloride can be separated off and the urethane can be purified by distillation in vacuo. Under the conditions described, dibenzylamine hydrochloride is formed as a by-product.
• the methoxycarbonyl group in the urethane is split off with halotrialkylsilane, in particular trimethylsilyl iodide, preferably in a solvent such as
• Halotrialkylsilane can e.g. be used in a 4 to 6-fold molar excess. I.a. the reaction is complete after 5 to 8 hours. It is then expedient to hydrolyze with acid. Good results are achieved with a methanolic hydrogen chloride solution. The amine of the formula (I) is then released by working up with alkali.
• molar ratios can also be chosen differently.
• Chlorinated hydrocarbons such as methylene chloride are suitable as solvents for this.
• Tetrakis (triphenylphosphine) palladium used, in a ratio of 1: (3.0 to 3.5): (0.01 to 0.03).
• the present invention also relates to the use of the new compounds of the formula (I) for the preparation of quinolone and naphthyridinecarboxylic acid derivatives with, if appropriate, subsequent modification of the 6-amino radical by deprotection.
• 6-amino radical for example, 7- (6-endo-amino-3-azabicyclo [3.1.0] hex-3- yl) -6-fluoro-1 - (2,4-difluorophenyl) - 1,4-dihydro-4- oxo-1, 8-naphthyridine-3-carboxylic acid and its salts accessible.
• the 7- (6-endo-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-l- (2,4-difluorophenyl) -l, 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid and its salts are distinguished from the corresponding 6-exo-amine isomers by a significantly lower neurotoxicity.
• Ammonium salt transferred and this isolated after evaporation of the solvent.
• a solution of the ammonium salt obtained after evaporation of the solvent in 30 ml of methanol was debenzylated with hydrogen in the presence of 0.1 g Pd / C catalyst (10% Pd). The catalyst was then filtered off and the solvent was removed in vacuo.
• the diamine of the formula (V) with R 6 -COOCH 3 was obtained by treating the residue with 0.65 g of sodium carbonate and distilling the mixture in a Kugelrohr at 150 ° C./1.3'10 "3 mbar. This was obtained by sublimation at 'mbar purified 70 ° C / 1.3 10 "3. 0.04 g of the diamine with a melting point of 76 ° C. was obtained. This corresponded to a yield of 66% of theory.
• Ammonia was passed at -78 ° C into a mixture of 20 ml of ethylamine and 0.14 g of lithium. After the beginning of blue coloration, the inflow of ammonia was stopped and the mixture was stirred at this temperature until the lithium had completely dissolved. Then the solution was warmed to 0 ° C. After the excess ammonia had been evaporated, 40 ml of ethylamine and 1.0 g of 6-endo-dibenzylamino-3-azabicyclo [3.1.0] hexane-6-carbonitrile were added. A color change from red to yellow-green indicates the end of reductive debenzylation. Excess lithium was then destroyed by adding ammonium chloride.
• the compound produced had a significantly lower neurotoxicity than the corresponding exo-6-amino compound.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Indole Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=7837780

Family Applications (1)

Country Status (12)

Families Citing this family (3)

Family Cites Families (5)

• 1997
  • 1997-08-02 DE DE19733439A patent/DE19733439A1/de not_active Withdrawn
• 1998
  • 1998-07-21 JP JP2000505127A patent/JP2001512101A/ja active Pending
  • 1998-07-21 EP EP98937579A patent/EP1000026A1/de not_active Withdrawn
  • 1998-07-21 AU AU86321/98A patent/AU8632198A/en not_active Abandoned
  • 1998-07-21 IL IL13405898A patent/IL134058A0/xx unknown
  • 1998-07-21 CA CA002298509A patent/CA2298509A1/en not_active Abandoned
  • 1998-07-21 PL PL98338349A patent/PL338349A1/xx unknown
  • 1998-07-21 KR KR1020007001100A patent/KR20010022512A/ko not_active Application Discontinuation
  • 1998-07-21 WO PCT/EP1998/004542 patent/WO1999006368A1/de not_active Application Discontinuation
  • 1998-07-21 HU HU0002895A patent/HUP0002895A3/hu unknown
  • 1998-07-21 CN CN98807850A patent/CN1265650A/zh active Pending
  • 1998-07-21 US US09/463,867 patent/US6310216B1/en not_active Expired - Fee Related

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events