KR100266888B1 - Precursors of Quinolone- and Naphthyridone-Carboxylic Acid Derivatives - Google Patents

Abstract

The present invention relates to precursors of novel quinolone- and naphthyridone carboxylic acid derivatives.

Description

Precursors of Quinolone- and Naphthyridone-Carboxylic Acid Derivatives

The present invention relates to novel quinolone- and naphthyridone-carboxylic acid derivatives, methods for their preparation and antimicrobial and feed additives containing them.

Quinolone- and naphthyridone-carboxylic acids wherein the 7 position is substituted with a bicyclic amine group are already disclosed in European Patent Publication No. 0,350,733.

The present invention relates to novel quinolone- and naphthyridone-carboxylic acid derivatives, methods for their preparation and antimicrobial and feed additives containing them.

The present invention relates to the novel compounds of formula (1) and their pharmaceutically usable hydrates and acid addition salts, as well as alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts of basic carboxylic acids.

Where

A represents CH, CF, CCl, C-OCH ₃ , C-CH ₃ or N,

X ¹ represents H, halogen, NH ₂ or CH ₃ ,

R ¹ represents phenyl which may be mono- or trisubstituted by C ₁ -C ₃ -alkyl, FCH ₂ CH _2- , cyclopropyl or halogen, or A and R ¹ together represent CO-CH ₂ -CH ( CH ₃ )-can represent a bridge of structure,

R ² represents C ₁ -C ₃ -alkyl which may be substituted by H, hydroxyl, halogen or amino or represents 5-methyl-2-oxo-1,3-diosol-4-yl-methyl ,

B is the following formula

In which Y represents O or CH ₂ , and R ³ represents C ₂ -C ₅ -oxoalkyl, CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH═C—CO ₂ R ′, —CH═CH—CO ₂ R ′ or CH ₂ CH ₂ —CN, wherein R ′ represents hydrogen or C ₁ -C ₃ -alkyl, R ⁴ is H, C ₁ -C ₃ -alkyl, C ₂ -C ₅ -oxoalkyl, CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH = C- CO ₂ R ′, —CH═CH—CO ₂ R ′ or CH ₂ CH ₂ —CN or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, where , R 'represents hydrogen or C ₁ -C ₃ -alkyl.

This compound has high antibacterial activity. The compounds according to the invention are particularly distinguished in that they have high activity against resting and resistant microorganisms.

Preferred compounds of formula (1) are

A represents CH, CF, CCl, C-OCH ₃ or N,

X ¹ represents H, F, Cl, Br, NH ₂ or CH ₃ ,

R ¹ may represent C ₂ H ₅ , cyclopropyl or 2,4-difluorophenyl, or A and R ¹ together may represent a bridge of the structure CO—CH ₂ —CH (CH ₃ ) —,

R ² represents H, CH ₃ , C ₂ H ₅ or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl,

B is of the formula

Wherein Y represents O or CH ₂ , and R ³ represents CH ₂ -CO-CH ₃ , CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO-CH ₃ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ CH = C-CO ₂ R', -CH = CH-CO ₂ R 'or CH ₂ CH ₂ -CN, wherein R' is C ₁ -C _2- Alkyl, R ⁴ is H, C ₁ -C ₃ -alkyl, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, CH ₂ -CO-CH ₃ , CH ₂ -CO -C ₆ H ₅ , CH ₂ CH ₂ -CO-CH ₃ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH = C-CO ₂ R', -CH = CH-CO ₂ R 'or CH ₂ CH ₂ -CN, wherein R 'is a compound representing C ₁ -C ₂ -alkyl.

Particularly preferred compounds of formula (1) are

A represents CH, CF, CCl, C-OH ₃ or N,

X ¹ represents H, F, Cl, Br, NH ₂ or CH ₃ ,

R ¹ may represent C ₂ H ₅ , cyclopropyl or 2,4-difluorophenyl, or A and R ¹ together may represent a bridge of the structure CO—CH ₂ —CH (CH ₃ ) —,

R ² represents H, CH ₃ or C ₂ H ₅ ,

B is of the formula

or

In which Y represents O or CH ₂ , and R ⁴ represents H, C ₁ -C ₃ -alkyl, 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, CH ₂ -CO-CH ₃ , CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO-CH ₃ , CH ₂ CH ₂ CO ₂ R ', R'O ₂ C-CH = C-CO ₂ R' , -CH = CH-CO ₂ R 'or CH ₂ CH ₂ -CN, wherein R' is a compound representing C ₁ -C ₂ -alkyl.

A, X ¹ , R ¹ and R ² are as defined above, and B is

Wherein the compound of formula (1) according to the invention wherein R ³ and Y are as defined above is a compound of formula (2), preferably in the presence of an acid binder It can obtain by reacting with a compound [method A].

R ³ -X ³

In the above formulas,

A, Y, X ¹ , R ¹ and R ² are as defined above,

R ³ represents C ₂ -C ₅ -oxoalkyl, CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ -CO ₂ R 'or CH ₂ CH ₂ -CN, wherein R' is hydrogen or C _1- C ₃ -alkyl,

X ³ represents halogen, in particular chlorine, bromine or iodine.

A, X ¹ , R ¹ and R ² are as defined above, and B is

Wherein Y is as defined above and R ³ is CH ₂ CH ₂ -CO-CH ₃ , CH ₂ CH ₂ -CO ₂ R ', R'O ₂ C-CH = C-CO ₂ R ', -CH = CH-CO ₂ R' or CH ₂ CH ₂ -CN, wherein R 'represents hydrogen or C ₁ -C ₃ -alkyl, the compound of formula (1) The compound of formula (2) can be obtained by reacting with a Michael acceptor such as dialkyl acetylenedicarboxylate, alkyl propiolate or a compound of formula (4) [Method B].

<Formula 2>

CH ₂ = CH-R ⁵

In the above formulas,

A, X ¹ , R ¹ , R ² and Y are as defined above,

R ⁵ represents COCH ₃ , CO ₂ R ′ or CN.

The pure enantiomer of the compound of formula (1) reacts the compound of formula (5) with the pure enantiomer of the compound of formula (6) in the presence of an acid scavenger, if appropriate

or

(In the above formulas,

A, R ¹ , R ² and X ¹ are as defined above,

X ² represents halogen, in particular fluorine or chlorine,

Y represents O or CH ₂ ,

R ^{4 ′} represents H or C ₁ -C ₃ -alkyl),

The reaction product is optionally prepared by further reaction with a Michael acceptor, such as a compound of formula (3a) or a dialkyl acetylenedicarboxylate, alkyl propiolate or a compound of formula (4) [method C].

R ^{4 '} -X ³

<Formula 4>

CH ₂ = CH-R ⁵

In the above formulas,

X ³ is as defined above,

R ^{4 '} represents C ₂ -C ₅ -oxoalkyl, CH ₂ -CO-C ₆ H ₅ , CH ₂ CH ₂ CO ₂ R' or CH ₂ CH ₂ -CN, wherein R 'is hydrogen or C ₁ -C ₃ -alkyl,

R ⁵ represents COCH ₃ , CO ₂ R ′ or CN.

For example, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and [S, S] -2,8-dia In the case of using xabicyclo [4.3.0] nonane as starting material, the reaction process can be represented by the following reaction formula.

For example, 6,8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7-([1S, 6R)]-2-oxa-5,8- When diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid and diethyl acetylenedicarboxylate are used as starting materials, the reaction process can be represented by the following scheme. .

The racemic compounds of formula (2) used as starting materials are mostly known. Pure enantiomers of the compound of formula (2) are novel compounds and can be obtained by various methods as follows.

1. The racemic intermediate of formula (2) is reacted with an enantiomerically pure adjuvant, the resulting diastereoisomers are separated, for example by chromatography, and the chiral auxiliaries are removed again from the desired diastereomers. . As an example, the following reaction can be shown.

2. Bicyclic amines (Formula 6) are novel enantiomerically pure compounds. These can be manufactured by the following method.

2.1. R ⁴ is H or C ₁ -C ₃ - rache miche a bicyclic amine of the formula alkyl (7a)

Enantiomerically pure acids such as N-acetyl-L-glutamic acid, N-benzoyl-L-alanine, 3-bromocamphor-9-sulfonic acid, camphor-3-carboxylic acid, cis-camphoric acid , Such as camphor-10-sulfonic acid, O, O'-dibenzoyl-tartaric acid, D- or L-tartaric acid, mandelic acid, α-methoxy-phenylacetic acid, 1-phenyl-ethanesulfonic acid or α-phenyl-succinic acid By reacting with carboxylic acid or sulfonic acid, a mixture of diastereomeric salts can be obtained, and the mixture can be separated by fractional crystallization to give diastereomeric pure salts [P. Newman, Optical Resolution Procedures for Chemical Compounds]. , Vol. 1]. The molar ratio between amine and enantiomerically pure acid can vary over a relatively wide range. Treatment of these salts with alkali metal or alkaline earth metal hydroxides can liberate enantiomerically pure amines.

2.2. In a manner similar to that described in 2.1, the cleavage of the basic intermediates produced during the preparation of racemic bicyclic amines can be carried out using the enantiomerically pure acids described above. Examples of basic intermediates of this kind are

There is this.

As an example of cleavage, in the following scheme, 8-benzyl-cis-2,8-diazabicyclo [4.3.0] nonane is separated into enantiomers via tartarate, which is enantiomerically pure cis-2,8- Conversion to diazabicyclo [4.3.0] nonane.

2.3. Both racemic amines (Formula 7a) and basic intermediates (Formula 7b)-(Formula 7e) can be acylated, if appropriate, and then separated by chromatography with a chiral support material [e.g. G. Blaschke), Angew. Chem. 92 , 14 (1980)].

2.4. Racemic amines (Formula 7a) and basic intermediates (Formula 7b), (Formula 7c) and (Formula 7e) are all converted to diastereomeric mixtures by chemical bonding with chiral acyl groups, and the mixture is distilled, crystallized or Chromatography allows separation of diastereomerically pure acyl derivatives, from which the enantiomerically pure amines can be isolated by hydrolysis. Examples of reagents for binding to chiral acyl groups include α-methoxy-α-trifluoromethyl-phenylacetyl chloride, menthyl isocyanate, D- or L-α-phenyl-ethyl isocyanate, menthyl chloroformate or camphor Form-10-sulfonyl chloride.

2.5. In the course of the synthesis of bicyclic amines (formula 7a), chiral protecting groups can also be introduced instead of achiral protecting groups. In this method, separable diastereomers are obtained. For example, in the synthesis of cis-2,8-diazabicyclo [4.3.0] nonane, the benzyl group can be replaced with an R- or S-α-phenylethyl group.

2.6 Enantiomerically pure amines (Formula 6) are also derived from enantiomerically pure precursors such as, for example, [R, R]-or [S, S] -3,4-dihydroxy-pyrrolidine. Can be synthesized, in which case the precursor must be protected by nitrogen by a protecting group.

An example of synthesizing enantiomerically pure amines starting from enantiomerically pure 1-benzyl-3,4-dihydroxy-pyrrolidine can be represented by the following scheme.

In the above formulas,

R = for example (CH ₃ ) ₃ -CO,

a: H ₂ , Pd / A-carbon

b: acylation

c: NaH, BrCH ₂ COOC ₂ H ₅ or c: CH ₂ = CH-CH ₂ Br, NaH

d: LiBH ₄ or d: O ₃ , N _a BH ₄

e: tosyl chloride, NEt ₃

f: benzylamine, xylene, reflux

g: hydrolysis

h: H ₂ , Pd / A-carbon

Examples of the compound of formula (6) include the following compounds.

Cis-2,8-diazabicyclo [4.3.0] nonane,

Cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane,

Trans-2-oxa-5,8-diazabicyclo [4.3.0] nonane,

S, S-2,8-diazabicyclo [4.3.0] nonane,

IR, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane,

IS, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane,

IR, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane and

IS, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane

The reaction of the compound of formula (5) with the compound of formula (6), wherein the compounds of formula (6) can also be used in the form of their salts, for example in the form of hydrochlorides, is preferably dimethyl sulfoxide With alcohols such as N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoramide, sulfolane, acetonitrile, water, methanol, ethanol, n-propanol or isopropanol, glycol monomethyl ether or pyridine In the same diluent. Mixtures of these diluents can also be used.

Acid binders that can be used are all conventional inorganic and organic acid binders. Such binders preferably include alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Particularly suitable binders include triethylamine, 1,4-dazabicyclo- [2.2.2] octane (DABCO), 1.8-diazabicyclo [5.4.0] undec-7-ene (DBU) or excess amine ( Formula 6) is mentioned.

The reaction temperature can vary in a relatively wide range. In general, the reaction is carried out at about 20 to 200 ° C, preferably 80 to 180 ° C.

The reaction can be carried out at atmospheric pressure but can also be carried out at elevated pressure. It is generally carried out at a pressure of about 1 to 100 bar, preferably 1 to 10 bar.

In carrying out this process, 1 to 15 moles, preferably 1 to 6 moles of the compound of formula (6) are used per mole of compound of formula (5).

Examples of the compound of formula (2) which can be used as both racemates and pure enantiomers or pure diastereomeric compounds include the following compounds _.

<Formula 2>

<Formula 2>

<Formula 2>

<Formula 2>

<Formula 2>

Starting materials of formula (3) and formula (4) are known. Examples that may be mentioned include chloroacetone, 4-chloro-2-butanone, 5-chloro-2-pentanone, 1-bromo-2-butanone, phenacyl chloride, methyl acrylate, ethyl acrylate, Acrylonitrile, methyl vinyl ketone, dimethyl acetylene dicarboxylate, diethyl acetylene dicarboxylate, methyl propiolate and ethyl propiolate.

The reaction of the compound of formula (2) with the compound of formula (3) is preferably carried out in the presence of an acid binder, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoramide, It is carried out in diluents such as alcohols such as sulfolane, acetonitrile, water, methanol, ethanol, n-propanol or isopropanol, glycol monomethyl ether or pyridine. Mixtures of these compounds can also be used.

Acid binders that can be used are all conventional inorganic and organic acid binders. Such binders preferably include alkali metal hydroxides, alkali metal carbonates, organic amines and amidines. Particularly preferred binders which may be mentioned include triethylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1.8-diazabicyclo [5.4.0] undec-7-ene (DBU) or Excess amine (Formula 6) may be mentioned.

The reaction temperature can be varied within a relatively wide range. In general, the reaction is carried out at 20 to 200 ° C, preferably 60 to 130 ° C.

The reaction can be carried out at atmospheric pressure, but can also be carried out at elevated pressure. It is generally carried out at a pressure of about 1 to 100 bar, preferably 1 to 10 bar.

In carrying out this process, 1 to 15 moles, preferably 1 to 6 moles of the compound of formula (3) are used per mole of compound of formula (2).

The reaction of the compound of formula (2) according to method B with the Michael acceptor of formula (4) is preferably an alcohol such as acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, methanol, ethanol, propanol or isopropanol Or in a diluent such as glycol monomethyl ether.

The reaction temperature can be varied within a relatively wide range. In general, the reaction is carried out at about 20 ° C to about 150 ° C, preferably at 40 ° C to 100 ° C.

The reaction can be carried out at atmospheric pressure, but can also be carried out at elevated pressure. In general, the reaction is carried out at 1 to 100 bar, preferably 1 to 10 bar.

In carrying out the process according to the invention, 1 to 5 moles, preferably 1 to 2 moles of the compound of formula (4) are used per mole of compound of formula (2).

The process for preparing acid addition salts of the compounds according to the invention is carried out by conventional methods, for example by dissolving betaine in an aqueous acid and precipitating the salts with a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. . Equal amounts of betaine and acid may be heated in alcohol such as water or glycol monomethyl ether and then evaporated to dryness or the precipitated salts removed by suction filtration. Pharmaceutically available salts include, for example, hydrochloride, sulfate, acetate, glycolate, lactate, succinate, citrate, tartarate, methanesulfonate, 4-toluenesulfonate, galacturonate, gluconate, It is understood in the same sense as ambonate, glutamate or aspartate.

Alkali or alkaline earth metal salts of carboxylic acids according to the invention are obtained, for example, by dissolving betaine in an excess of alkali or alkaline earth metal hydroxide solution, filtering out undissolved betaine and evaporating the filtrate. Pharmaceutically suitable salts are sodium salts, potassium salts or calcium salts. By reacting the alkali or alkaline earth metal salts with a suitable silver salt such as silver nitrate, the corresponding silver salt is obtained.

In addition to the active substances mentioned in these examples, for example, the compounds shown in the table below (optionally in cis- or trans-form) can also be prepared by the methods described above.

The compounds according to the invention have potent antibiotic action and have low toxicity and are capable of gram-positive and gram-negative microorganisms, in particular enterobacteria and in particular, for example, penicillin, cephalosporin, aminoglycosides, sulfonamides and tetracyclines. It has a broad spectrum of antibiotic activity against microorganisms that are resistant to various antibiotics.

Such useful properties include the active substances for chemotherapy in medicine, and also for the preservation of inorganic and organic substances, in particular all kinds of organic substances such as polymers, lubricants, dyes, fibers, leather, paper and wood, food and water To enable their use.

The compounds according to the invention have activity against a wide range of microorganisms. With their help, gram negative and gram positive bacteria and bacterial like microorganisms can be suppressed and prevent, alleviate, alleviate and / or treat diseases caused by these pathogens.

Compounds according to the invention are distinguished by increased activity against resting and resistant microorganisms. In the case of resting bacteria, ie bacteria in which growth is not detected, the compound acts at concentrations much lower than the concentrations of substances known so far. This depends not only on the amount used, but also on the rate of destruction. Gram-positive and gram-negative bacteria, in particular Staphylococcus aureus , Pseudomonas aeruginosa , Enterococcus faecalis and Escherichia coli I could find it.

The compounds according to the invention also show a surprising increase in activity against bacteria which are classified as less sensitive to the substances to be compared, in particular resistant Staphylococcus orius, Escherichia coli, Pseudomonas oirozinosa and Enterococcus paecalis. Indicates.

The compounds according to the invention are particularly effective against bacteria and bacterial like microorganisms. Therefore, these compounds are very particularly suitable for medicaments for the prevention and treatment of local and systemic infections in humans and livestock caused by these pathogens.

These compounds are also suitable for inhibiting protozoa and parasites.

The compounds according to the invention can be used as various pharmaceutical preparations. Preferred pharmaceutical formulations which may be mentioned are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsifiers, pastes, ointments, gels, creams, lotions, powders and sprays.

The table below identifies the surprising advantages of the compounds according to the invention compared to cyprofloxacin in a mouse model infected with Staphylococcus erius.

Table: Activity against Staphylococcus Oillius infection in mice (mg / kg)

matter Oral administration Subcutaneous administration Cyprofloxacin Example 27 Example 29A Example 31 Example 33 Example 35 80 10 5 10 10 2.5 80 2.5 5 10 5 2.5

The compounds according to the invention as compared to known compounds which are structurally similar show an enhancement of antibiotic activity, especially in anaerobic microorganisms, as shown in the table below.

table

Bell Strain name compound A B C Bacteroides fragilis ES 25 0.25 One 8 DSM 2151 0.25 0.5 4 Clostridium perfringens 1024027 0.125 0.5 0.5 Tero night Edith Te Tai Ota five microns (Bact. Thetaiotaomicron) DSM 2079 0.5 2 8

A: Compound according to the present invention as in Example 2B

B: Compound described in European Patent No. 0,350,733

Where R = )

C: Cyprofloxacin

MIC value was measured by the dilution test method using the sensitivity test agar medium with a multipoint inoculator (product of Denley) (μg / ml).

Preparation Example of Precursor

Example A

[S, S] -2,8-diazabicyclo [4.3.0] nonane

1) [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane

Method I:

a) Separation of diastereomeric salts:

3.0 g (20 mmol) of D-(-)-tartaric acid are dissolved in 10 ml of dimethylformamide by heating to 80 ° C. and the solution is cis-8-benzyl-2,8-diazabicyclo in 3 ml of dimethylformamide [ 4.3.0] -nonane 2.16 g (10 mmol) solution. The mixture was stirred at 0 ° C. for 1 h and the product was removed by suction filtration and washed with dimethylformamide and methoxyethanol.

Yield: 1.93 g

Melting Point: 146-151 ℃

[a] _D ²³ = -19.3 ° (c = 1, H ₂ O).

Diastereomerically pure [S, S] -8-benzyl-2.8-diazabicyclo [4.3.0] nonane D-tartrate was obtained by recrystallization once from methoxyethanol.

[a] _D ²³ = -22.7 ° (c = 1, H ₂ O).

Melting Point: 148-154 ℃

b) free of base:

40 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane D-tartrate was dissolved in 250 ml of water and treated with 32 g of 45% sodium hydroxide solution. The precipitated oil was dissolved in 150 ml of tert-butyl methyl ether, the aqueous layer was extracted again with 150 ml of tert-butyl methyl ether, and the combined organic layers were dried over sodium sulfate and then concentrated. The residue was then distilled in vacuo.

Yield: 18.5 g of [S, S] -8-benzyl-2,8-diazabicyclo- [4.3.0] nonane

Boiling Point: 107-109 ℃ / 0.1 millibars

[a] _D ²⁴ = -17.3 ° (not diluted).

Method II:

75.0 g (0.5 mol) of L-(+)-tartaric acid are dissolved in 250 ml of dimethylformamide at 80 ° C. and 54.1 g (0.25 mol) of cis-8-benzyl-2,8-diazabicyclo [4.3.0] nonane ) Was added dropwise as a solution in 75 ml of dimethylformamide. The mixture was cooled slowly to 20 ° C. and the crystal suspension was stirred for 1 hour. Crystals ([R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane L-tartrate) were removed by suction filtration and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in 500 ml of water and finished as described in Method I using 63 g of 45% sodium hydroxide solution.

Yield: 25.2 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] -nonane

The product contains 3.6% of R, R-enantiomers. (Measured by gas chromatography after derivation using menthyl chloroformate)

The compound is reacted with D-(-)-tartaric acid according to Method I to give diastereomerically pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane D-tartrate Could get In this case, no recrystallization is necessary.

Method III:

73.6 g (0.34 mole) of cis-8-benzyl-2,8-diazabicyclo- [4.3.0] nonane as a solution in 111 ml of dimethylformamide L (+) in 343 ml of dimethylformamide at 80-90 ° C. -Dropwise to a solution of 102.9 g (0.685 mol) of tartaric acid. The mixture was seeded with [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane and slowly cooled to an internal temperature of 18 ° C. The crystals were removed by suction filtration and the filtrate was seeded with [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] -nonane L-tartrate and stirred until complete crystallization. (After concentration and liberation of the base as described in Method I, [S, S] -8-benzyl-2,8-biazabicyclo [4.3.0] nonane D-tartrate is purified with D-tartaric acid to give the mother liquor Can be obtained from The product was then suction filtered, washed with dimethylformamide and isopropanol and dried in air. Crystals were recrystallized from 88% ethanol. 52 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] -nonane L-tartrate trihydrate was obtained.

Melting Point: 201-204 ℃

[α] _D ²³ = + 5.2 ° (c = 1, H ₂ O)

The salt can liberate the base as described in Method I to obtain enantiomerically pure [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane.

Method IV:

a) [1S, 6R] -8-benzyl-7,9-di by enantiomeric separation of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane Preparation of oxo-2,8-diazabicyclo [4.3.0] nonane

This method is similar to Example B (method II / a) using D-(-)-tartaric acid as chiral coagent, the procedure is as follows.

Mother liquor from [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane L-tartrate (Example B, obtained from Methods II / a) and The washes were concentrated together, the residue was concentrated in water and the solution was extracted three times with toluene. The toluene layer was removed. The aqueous layer was treated with saturated sodium hydrogen carbonate solution until the pH was 7-8, and then extracted four times with methylene chloride. The combined methylene chloride layers were dried over magnesium sulfate and concentrated.

Yield: 14.4 g (60% of theory of originally used racemic cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane)

[a] _D ²³ = -4.5 ° (c = 5, ethanol).

14.4 g (59 mmol) of the compound were crystallized from 120 ml of ethanol similarly to Example B (method II / a) using 8.6 g (57 mmol) of D-(-)-tartaric acid.

Yield: 8.9 g of [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane D-tartrate (77% of theory)

After recrystallization from ethanol / glycol monomethyl ether mixture, it was further purified.

[a] _D ²³ = -59.3 ° (c = 0.5, 1N HCl).

5.0 g (12.7 mmol) of the diastereomerically pure tartrate produced in this way were converted to the free amine as described in Example B, Method II / a.

Yield: 3.0 g of [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane (96% of theory)

Melting Point: -22.2 ° C (c = 5, Ethanol)

Enantiomeric excess of 96.6% was determined by gas chromatography after derivation using menthyl chloroformate.

b) [S, S] -8-benzyl-2,8-diazabicyclo of [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane [4.3.0] reduction to nonan

This method was carried out in Example B (method II, except that [1S, 6R] -8-benzyl-7,9-dioxo-2,8-diazabicyclo- [4.3.0] nonane was used as starting material. similar to b).

The crude product produced after the finishing treatment was derived using menthyl chloroformate and proved to be [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane. Therefore racemization was observed during reduction.

2) [S, S] -2,8-diazabicyclo [4.3.0] nonane

28.4 g (0.131 mole) of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane was poured over 90 hours at 90 ° C. and 90 over 5.8 g of 5% activated carbon based palladium in 190 ml of methanol. Hydrogenated at bar. The catalyst was then removed by suction filtration and washed with methanol and the filtrate was concentrated on a rotary evaporator. The residue was distilled off without fractionation.

Yield: 15.0 g of [S, S] -2,8-diazabicyclo [4.3.0] nonane (90.5% of theory)

Boiling Point: 44-59 ℃ / 0.18 millibars

[α] _D ²² = -2.29 ° (not diluted).

ee:> 99% [measured by gas chromatography after derivation using Mosher's reagent]

Method V:

3.75 g (25 mmol) of L-(+)-tartaric acid were introduced at 80 ° C. in a solution in 50 ml of dimethylformamide and 10.82 g of cis-8-benzyl-2,8-diazabicyclo [4.3.0] nonane ( 50 mmol) was added dropwise as a solution in 15 ml of dimethylformamide. The mixture was seeded with [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] -nonane L-tartrate and stirred at about 72 ° C. for 1 hour to complete seed crystal formation. It was then slowly cooled to 15 ° C., the crystals were removed by suction filtration and washed twice with 13 ml of dimethylformamide in each case. The combined filtrates were heated to 80 ° C. and treated with additional 3.75 g (25 mmol) of L-(+)-tartaric acid. The mixture is further heated to 119 ° C. until a clear solution is formed and again seeded with [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] -nonane L-tartrate Cooled slowly. The crystals were removed by suction filtration, washed successively with dimethylformamide, 2-methoxy-ethanol and ethanol and dried in air.

Yield: 9.59 g

Melting Point: 188 to 192 ° C

Crystals were recrystallized from 95 ml of 80% ethanol. 8.00 g of [S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane L-tartrate trihydrate (76% of theory) were obtained by bubbling at 112 to 118 ° C. to melt. Later, it was restocked and melted again at 199 to 201 ° C.

[a] _D ²³ = -4.5 ° (c = 1, water).

ee: 98.05% (measured by gas chromatography after derivatization with menthyl chloroformate)

Example B

[R, R] -2,8-diazabicyclo [4.3.0] nonane

1) [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane

Method I:

Crystalline 49.2 g of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] -nonane, produced according to Example A, Method II, was washed with dimethylformamide and methoxyethanol And recrystallized from 300 ml of methoxyethanol. 45.6 g of ethanethiomerically pure [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane L-tartrate were obtained. (Enantiomer purity was measured by gas chromatography after derivation using menthyl chloroformate).

Melting Point: 121-124 ℃

[a] _D ²³ = + 22.3 ° (c = 1, H ₂ O).

44.5 g of salt was converted to the free base, as described in Example A, Method Ib. 20.2 g of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane were obtained.

Boiling Point: 107-111 ℃ / 0.04 millibars

[a] _D ²⁴ = -17.5 ° (not diluted).

Method II

a) [1R, 6S] -8-benzyl-7,9- by separation of the enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane Generation of Dioxo-2,8-diazabicyclo [4..3.0] nonane

24.1 g (98.8 mmol) of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane was stirred in a mixture of 410 ml of ethanol and 25 ml of acetonitrile in a three neck flask. Heated to reflux. Subsequently, 14.8 g (98.8 mmol) of L-(+)-tartaric acid were added once. After complete dissolution of all tartaric acid, heating was first stopped and the flask was left in an oil bath. When the system was cooled until the solution was no longer boiling, the stirrer was stopped. Crystallization and addition of seed crystals are carried out at a temperature of 50 ° C. After standing overnight and cooling at room temperature, the precipitated crystals were removed by suction filtration and washed with a small amount of ethanol / petroleum ether (1: 1) and dried at 80 ° C. for 2 hours.

Yield: 9.8 g of [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane L-tartrate (50% of theory)

[a] _D ²³ = + 47.7 ° (c = 0.5, 1N HCl).

The compound can be further purified by recrystallizing twice from a mixture of ethanol and glycol monomethyl ether.

[a] _D ²³ = +58.6 degrees (c = 0.5, 1N HCl).

¹ H-NMR (DMSO): 7.22-7.35 (2m, 2H, aryl-H); 4.55 (s, 2H, benzyl-CH ₂ ); 4.28 (s, 2H, tartaric acid-CH); 3.91 (d, 1 H, 1-CH); 2.97 (dd, 1H, 6-CH); 2.53-2.66 (m, 2H, 3-cH ₂ ); 1.78 and 1.68 (2m, 2H, 5-CH ₂ ); 1.42 and 1.28 ppm (2m, 2H, 4-CH ₂ )

Elemental Analysis for C ₁₈ H ₂₂ N ₂ O ₈ (394)

C H N O

Theoretical 54.4 5.6 7.1 32.5

Found 54.7 5.8 7.1 32.4

Determination of absolute coordination was performed by X-ray structural analysis.

3.6 g (9.1 mmol) of the diastereomerically pure tartrate produced in this way were dissolved in water to liberate the base and treated with saturated sodium hydrogen carbonate solution until the pH was 7-8. The aqueous solution was extracted four times with 20 ml of methylene chloride each time. The combined methylene chloride layers were dried over magnesium sulfate and concentrated.

Yield: 2.2 g of [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane (99% of theory)

Melting Point: 60-61 ℃

[a] _D ²³ = + 21.8 ° (c = 5, ethanol).

Enantiomeric excess (ee) of 93.8% was determined by gas chromatography after derivation using menthyl chloroformate.

b) [R, R] -8-benzyl-2,8-diazabicyclo of [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane [4.3.0] reduction to nonan

In a heating flask, 0.34 g (9 mmol) of lithium aluminum hydride was introduced under N ₂ in 18 ml of anhydrous tetrahydrofuran and [1R, 6S] -8-benzyl-7,9-dioxo-2,8-diazabi 0.73 g (3 mmol) of cyclo [4.3.0] nonane was added dropwise as a solution in 3 ml of anhydrous tetrahydrofuran. The mixture was then boiled for 16 hours under reflux condensation. The finishing operation was performed by dropwise addition of 0.34 ml of water, 0.34 ml of 10% sodium hydroxide solution and 1.02 ml of water in 10 ml of tetrahydrofuran. The precipitate was removed by suction filtration, washed with tetrahydrofuran and the filtrate was concentrated. 0.7 g of crude [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane remain (GC purity: 99%).

It was not possible to determine the specific racemization while determining the ethanethiomer purity by gas chromatography using menthyl chloroformate.

2) [R, R] -2,8-diazabicyclo [4.3.0] nonane

19.4 g (0.09 mol) of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane were hydrogenated according to the method of Examples A and 2.

Yield: 9.61 g of [R, R] -2,8-diazabicyclo [4.3.0] nonane (85% of theory)

Boiling Point: 45-58 ℃ / 0.08 millibars

[α] _D ²³ = + 2.30 ° (not diluted).

Example C

[S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane

1) [S, S] -8-benzyl-2-methyl-2,8-diazabicyclo [4.3.0] -nonane

[S, S] -8-benzyl-2,8-diazabicyclo [4.3.0] 43.2 g (0.2 mmol) nonane were treated with 20 ml of 37% formaldehyde solution, 40 ml of water and 24 g of acetic acid, and The mixture was hydrogenated over 2 g of 5% activated carbon based palladium at 20 ° C. and 20 bar for 10 hours. It was then removed by suction filtration with a catalyst, the filtrate was made alkaline with potassium carbonate and the product was extracted with tert-butyl methyl ether. After drying over magnesium sulfate, the mixture was concentrated and the residue was distilled in vacuo.

Yield: 14.8 g

Boiling Point: 114-124 ℃ / 0.14 millibars

2) [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane

12.9 g (56 mmol) of [S, S] -8-benzyl-2-methyl-2,8-diazabicyclo [4.3.0] nonane was dissolved in 5% activated carbon based palladium 1.1 at 90 ° C. and 90 bar in 90 ml of methanol. Hydrogenated on g. The mixture was then filtered, the filtrate was concentrated on a rotary evaporator and the residue was distilled in vacuo.

Yield: 5.5 g of ethanethiomerically pure [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane (determined by derivatization using Mosher Shiac)

Boiling Point: 78-81 ℃ / 14 Millibar

Example D

[R, R] -2-methyl-2,8-diazabicyclo [4.3.0] nonane

The title compound was prepared according to the method instructions described in Example C using 43.2 g (0.2 mole) of [R, R] -8-benzyl-2,8-diazabicyclo [4.3.0] nonane as starting material.

Yield: 4.9 g of [R, R] -2-methyl-2,8-diazabicyclo [4.3.0] -nonane

Boiling Point: 30-33 ℃ / 0.12 millibars

Example E

Cis-7,9-dioxo-8-([1S] -1-phenyl-ethyl) -2,8-diazabicyclo [4.3.0] nonane

1) N-([1S] -1-phenyl-ethyl) pyridine-2,3-dicarboximide

74.5 g (0.5 mol) of pyridine-2,3-dicarboxylic anhydride are first introduced at 20 ° C. in a solution in 500 ml of dioxane and 60.5 g (0.5 mol) of S-(-)-1-phenyl-ethylamine Was added dropwise as the temperature rose to 33 ° C. The mixture was further stirred for 1 hour, then concentrated on a rotary evaporator and the residual solvent was removed at 40 ° C / 0.1 millibars. The residue was dissolved in 245 g (2.4 mol) of acetic anhydride and the solution was treated with 4.9 g (0.06 mol) of anhydrous sodium acetate and stirred at 100 ° C. for 1 hour. After cooling, the mixture was poured onto 1 l of ice water with good stirring, and the precipitate was removed by suction filtration, washed with cold water and hexanes and dried in air. The crude product (114 g, melting point: 112-114 ° C.) was recrystallized from 285 ml of methanol.

Yield: 96.3 g (76%)

Melting Point: 115-117 ℃

[a] _D ²² = -46.9 ° (c = 2, ethanol).

2) cis-7,9-dioxo-8-([1S] -1-phenyl-ethyl) -2,8-diazabicyclo [4.3.0] nonane

79.7 g (0.316 mole) of N-([1S] -1-phenylethyl) -pyridine-2,3-dicarboximide on 10 g of 5% activated carbon based palladium in 600 ml of tetrahydrofuran at 90 ° C./100 bar. Hydrogenated. After the hydrogen uptake was complete the catalyst was filtered off and the filtrate was fully concentrated. 83.7 g of a viscous residue were obtained.

Purity: 95%

¹ H-NMR (CDCl ₃ , 200 MHz): 1.4-1.7 (m, 3H); 1.82 and 1.83 (2d, 3 H); 1.9-2.05 (m, 1 H); 2.28 (broad s, 1H); 2.54-2.86 (m, 3 H); 3.77 (d, 1 H); 5.39 (1, 1 H); 7.24-7.48 ppm (m, 5 H).

Example F

Cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane

1) trans-1-benzoyl-3-bromo-4- (2-hydroxyethoxy) -pyrrolidine

95 g (0.55 mol) of 1-benzoyl-3-pyrroline was dissolved in 380 g of ethylene glycol, and 101 g (0.57 mol) of N-bromosuccinimide was added in portions of 5 g over 2 hours. The mixture was then stirred overnight at room temperature, poured into water, extracted with methylene chloride, and the solution dried over magnesium sulfate and concentrated. 188 g of residue was chromatographed on silica gel with ethyl acetate.

Yield: 136.5 g (78% of theory)

Purity by GC: 99%

2) trans-1-benzoyl-3-bromo-4- (2-tosyloxyethoxy) -pyrrolidine

Toluene 92 g (0.239 mol) of trans-1-benzoyl-3-bromo-4- (2-hydroxyethoxy) -pyrrolidine, 32 g (0.316 mol) of triethylamine and 1 g of 4-dimethylaminopyridine It was dissolved in 750 ml and 60 g (0.31 mol) of tosyl chloride in 450 ml of toluene were added dropwise. The mixture was stirred at rt for 2 days, water was added, the aqueous layer was separated off and extracted with toluene. The toluene solution was washed with 10% hydrochloric acid, dried over magnesium sulfate, concentrated, the residue was dissolved in ethyl acetate and the solution was filtered through silica gel. The filtrate was concentrated.

Yield: 125 g (91% of theory)

Thin layer chromatograms represent homogeneous compounds.

3) cis-8-benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

124 g (0.265 mole) of trans-1-benzoyl-3-bromo-4- (2-tosyloxyethoxy) -pyrrolidine was reacted with 86 g (0.8 mole) of benzylamine in 1.5 l of xylene under reflux. Heated, the salt of benzylamine was removed by suction filtration and the filtrate was concentrated.

Crude yield: 91.2 g

4) cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

91 g (0.265 mole) of cis-8-benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane was heated under reflux with sun at 200 ml of concentrated hydrochloric acid and 140 ml of water. . After cooling, the benzoic acid is removed by suction filtration, the filtrate is concentrated to 1/2 volume, the solution is alkaline with potassium carbonate, extracted with chloroform, the extract is dried over potassium carbonate and concentrated to give a residue. Distilled.

Yield: 30.7 g (48.8% of theory)

Boiling Point: 134-142 ℃ / 0.6 millibars

Purity by GC: 92%

5) cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride

26 g (0.11 mole, 92%) of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane in 180 ml of ethanol and 19 ml of concentrated hydrochloric acid were 10% at 100 ° C. and 100 bar. Hydrogenated in 3 g of activated carbon based palladium. The catalyst was removed by suction filtration, the filtrate was concentrated and the separated crystals were dried in a drier over phosphorus pentoxide.

Yield: 17.1 g (77% of theory)

Melting Point: 244-250 ℃

Example G

Separation of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonan enantiomers

150.1 g (1 mol) of D-(-)-tartaric acid are first introduced in 700 ml of methanol at 60 to 65 ° C., and cis-5-benzyl-2-oxa-5,8-diazabicyclo- [4.3.0] 218.3 g (1 mol) of nonane was added dropwise as a solution in 300 ml of methanol. The mixture is then slowly cooled to about 49 ° C. until the solution becomes cloudy and the 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane D produced in the previous experiment. Seeded with crystals of tartrate and stirred at this temperature for 30 minutes for seed crystal formation, followed by slow cooling to 0-3 ° C. After removal by suction filtration, the solid was washed with a mixture of 200 ml of ethanol cooled to 0 ° C. and 100 ml of methanol, then in each case three times with 300 ml of ethanol, and the product was then dried in air.

Yield: 160.3 g of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo- [4.3.0] nonane tartrate (87% of theory)

Melting Point: 174.5 ~ 176.5 ℃

ee:> 97% (determined by HPLC analysis after derivatization with 1-phenyl-ethyl isocyanate)

[a] _D ²³ = + 24.0 ° (c = 1, methanol).

156.9 g of the first crystals were recrystallized from 1500 ml of methanol.

Yield: 140.0 g (89% recovery)

Melting Point: 176-177 ℃

[a] _D ²³ = + 25.2 ° (c = 1, methanol).

The methanolic mother liquor from the first crystallization was concentrated on a rotary evaporator. 236 g of syrup residue was dissolved in 500 ml of water, adjusted to pH 12-13 with 250 ml of 6N sodium hydroxide, extracted three times with 350 ml of toluene each time, the extract was dried over sodium carbonate and concentrated in vacuo. . Preparation of 1S, 6R-enantiomer 113.1 g of brown oil residue containing 97% cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane according to gas chromatography investigation Used without purification for.

Crude concentrate 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane 113.1 g (0.518 mol) was dissolved in 155 ml of methanol and L-(+ in 363 ml of methanol ) Was added dropwise to a boiling solution of 77.8 g (0.518 mol) of tartaric acid. Gradually magma formed during the enemy. The mixture was stirred at 60 ° C. for 1 hour and then slowly cooled to 0 ° C. over 2 hours. The crystals were filtered off with suction, washed with a mixture of ethanol and methanol (2: 1) cooled to 0 ° C. followed by three washes with ethanol. The product was then dried in air.

Yield: 145.5 g of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane L-tartrate (79% of theory)

Melting Point: 174.5 ~ 176.5 ℃

ee:> 97% (determined by HPLC analysis after derivatization with 1-phenyl-ethyl isocyanate)

[α] _D ²³ = -24.0 ° (c = 1, methanol)

Glass of enantiomerically pure base

144 g (0.39 mol) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane tartrate are dissolved in 250 ml of water and 175 ml (1.05 mol) of 6N sodium hydroxide solution ) Was added. The soaked oil was dissolved in 500 ml of toluene, the organic layer was separated off and the aqueous layer was further extracted three times with 250 ml of toluene in each case. The combined organic layers were dried over sodium carbonate, filtered and concentrated on a rotary evaporator. The residue was distilled through a 20 cm Vigreux column under high vacuum.

Yield: 81.6 g of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane (96% of theory)

Boiling Point: 120 to 139 ° C / 0.04 to 0.07 millibars

Purity: Measured by 100% by gas chromatography

Density: δ = 1.113 g / ml

[α] _D ²³ = -60.9˚ (not diluted)

Distillation residue: 0.12 g

In the same way, 76.0 g of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane (93% of theory) was replaced with 1R, 6S-5-benzyl-2-oxa- Obtained from 139.2 g (0.376 mol) of 5,8-diazabicyclo [4.3.0] nonane tartrate.

[α] _D ²³ = + 61.2˚ (not diluted)

Separation of the enantiomers described for cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane is also carried out with trans-5-benzyl-2-oxa-5,8-diazabicyclo Similarly using [4.3.0] nonane can be performed to obtain R, R- and S, S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane.

Example H

1) tert-butyl 3S, 4S-4-allyloxy-3-hydroxypyrrolidine-1-carboxylate

16.5 g (0.55 mole) of 80% NaH was first introduced into 500 ml of anhydrous dioxane and then hotly dissolved in tert-butyl S, S-3,4-dihydroxypyrrolidine-1-carboxylate in anhydrous dioxane. 107.5 g (0.53 mol) solution (German Patent Publication No. 3,403,194) was added dropwise at 60 ° C. The mixture was stirred at 60 ° C. for 1 hour and then 64 g (0.53 mol) of allyl bromide were added dropwise. The mixture was then stirred at 60 ° C. for 3 hours. It was concentrated and the residue was dissolved in 200 ml of water and 600 ml of methanol. The solution was extracted three times with 200 ml of pentane each time, methanol was removed on a rotary evaporator, the residue was diluted with 200 ml of water and the mixture was extracted with methylene chloride. The methylene chloride solution was dried over MgSO ₄ , concentrated and the residue was dissolved in 200 ml of tert-butyl methyl ether. 9 g (44 mmol) of starting material were crystallized overnight. The ether solution was concentrated and distilled.

Yield: 83 g (80% of theory with respect to recovered starting material and diallyl ether)

Boiling Point: 149 ° C / 0.7 Millibar to 159 ° C / 0.9 Millibar

The distillate contains 5% of the starting material and 4% of diallyl ether.

The pentane extract produced a mixture of 15% of the desired compound and 84% of diallyl ether.

[α] _D23 = -10.5 ° (c = 1, methanol)

2) tert-butyl 3S, 4S-3-hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylate

64 g (0.24 mol, 91%) of tert-butyl 3S, 4S-4-allyloxy-3-hydroxypyrrolidine-1-carboxylate are dissolved in 250 ml of methanol, cooled to 0 ° C. and potassium iodide The reaction was completed by passing ozone through the solution until the wash bottles containing the solution and connected in series indicated the generation of ozone. After the residue of ozone was reacted by the nitrogen stream, the resulting ozonate was reduced using 18 g of sodium hydrogen borate and added in portions by 1 g. The mixture was then stirred overnight at room temperature, concentrated, the residue was diluted with water, the mixture was treated with 20 g of potassium carbonate and extracted five times with 100 ml of methylene chloride each time. The organic solution was dried over magnesium sulfate and concentrated.

Yield: 65.8 g (100% of theory)

The product was 91% as determined by gas chromatography.

[α] _D ²⁰ = -15.2 ° (c = 0.97, methanol)

3) 3S, 4S-1-tert-butoxycarbonyl-3-tosyloxy-4- (2-tosyloxymethoxy) -pyrrolidine

2.7 g (10 mmol, 91%) of tert-butyl 3S, 4S-3-hydroxy-4- (2-hydroxymethoxy) -pyrrolidine-1-carboxylate were first added to 30 ml of methylene chloride, 6 ml of 45% sodium hydroxide solution and 0.1 g of benzyltriethylammonium chloride were added and then a solution of 2.86 g (20 mmol) of tosyl chloride in 10 ml of methylene chloride was added dropwise while cooling. The mixture was then stirred for an additional hour at room temperature, placed in 20 ml of water, the organic layer was separated off and the aqueous layer was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated.

Yield: 5 g (90% of theory)

The product was homogeneous when analyzed by thin layer chromatography.

4) tert-butyl 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo- [4.3.0] nonan-8-carboxylate

87 g (156 mmol) of 3S, 4S-1-tert-butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) -pyrrolidine was added to 58 g (0.54 mol) of benzylamine in 1 x of xylene ) Under heating at reflux. The mixture was cooled, the precipitated salt of benzylamine was removed by suction filtration and the residue was concentrated.

Yield: 43 g (58% of theory)

The product was 67% analyzed by gas chromatography.

5) 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

43 g (90 mmol) of tert-butyl 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-8-carboxylate in 35 ml of concentrated hydrochloric acid and 35 ml of water Heated under reflux until generation of carbon dioxide was complete. The mixture was made alkaline with potassium carbonate, extracted with chloroform, the organic solution was dried over MgSO ₄ , concentrated and the residue was distilled twice through a 20 cm Vigrex column.

Yield: 11.1 g (55% of theory)

Boiling Point: 108-115 ℃ / 0.07 millibars

[α] _D ²⁶ = -58.3˚ (not diluted)

Example I

One) tert-butyl 3R, 4R-4-allyloxy-3-hydroxypyrrolidine-1-carboxylate

The reaction was carried out analogously to Example H1) using tert-butyl R, R-3,4-dihydroxypyrrolidine-1-carboxylate.

Boiling Point: 145 ℃ / 0.1 millibars

[α] _D ²³ = + 9.5 ° (c = 1.0, methanol)

The product was 95% by gas chromatography.

2) tert-butyl 3R, 4R-3-hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylate

The reaction was carried out analogously to Example H2) using tert-butyl 3R, 4R-4-allyloxy-3-hydroxy-pyrrolidine-1-carboxylate.

Yield: 99% of theory (0.175 mol batch)

[α] _D ²⁰ = + 16.5 ° (c = 0.94, methanol)

3) 3R, 4R-1-tert-butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) -pyrrolidine

The reaction was carried out analogously to Example H3) using tert-butyl 3R, 4R-hydroxy-4- (2-hydroxyethoxy) -pyrrolidine-1-carboxylate.

Yield: quantitative (0.11 mole batch)

4) tert-butyl 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonan-8-carboxylate

The reaction was carried out analogously to Example H4) using 3R, 4R-1-tert-butoxy-carbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) -pyrrolidine.

Yield: 40% of theory (0.1 mol batch)

5) 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

The reaction was carried out analogously to Example H5) using tert-butyl 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonan-8-carboxylate.

Yield: 63% of theory (40 mmol batch)

Boiling Point: 120 ℃ / 0.06 Millibar

The product was 95% when analyzed by gas chromatography.

[α] _D ²³ = +58.5 (not diluted)

Example J

1) 1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride

1 g of 10% activated carbon based palladium in 200 ml of ethanol with 7.5 ml (34.4 mmol) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane added with 7 ml of concentrated hydrochloric acid Phase was hydrogenated at 100 ° C. and 100 bar. The catalyst was removed by suction filtration and washed several times with water. The aqueous filtrate was concentrated as the residue crystallized. The crystals were thoroughly saturated with ethanol, removed by suction filtration and dried in air.

Yield: 4.6 g (66.5% of theory)

Melting Point: 233-235 ℃

2) 1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane

59 g (0.27 mole) of 1S, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane was charged at 120 ° C. and 120 bar on 5 g of 10% activated carbon based palladium in 500 ml of ethanol. Hydrogenated. The catalyst was removed by suction filtration, the filtrate was concentrated and the residue was distilled off.

Yield: 32.9 g (95% of theory)

Boiling point: 65 ℃ / 0.03 millibars

Rotation: [α] _D ²⁸ = + 8.2˚ (not diluted)

ee: ≥99.5% (measured by derivation using Mosher reagents)

Example K

1) 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride

The reaction was carried out similarly to Example J1) using 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo- [4.3.0] nonane.

Yield: 77% of theory (23.8 mmol batch)

Melting Point: 230-232 ℃

2) 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane

The reaction was performed similarly to Example J2) using 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo- [4.3.0] nonane.

Yield: 93.3% of theory (1.58 mol batch)

Boiling Point: 63-65 ℃ / 0.03 Millibar

Rotation: [α] _D ²³ = -8.4˚ (not diluted)

ee: ≥99.5% (measured by derivation using Mosher reagents)

Similarly, 1R, 6R- or 1S, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane can be obtained.

Example L

1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrobromide

1) 1R, 6S-5- (1R-phenylethyl) -8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

101.8 g (0.196 mol) of trans-3-brom-1-tosyl-4- (2-tosyloxyethoxy) -pyrrolidine in 900 ml of xylene and 72 g (0.584) of R-(+)-1-phenylethylamine Mole) was heated at reflux overnight. The cold solution was washed with 2N sodium hydroxide, dried over potassium carbonate, the desiccant removed and the solvent concentrated. While cooling, the crystals were dipped from the residue removed by suction filtration and recrystallized from a mixture of 750 ml of petroleum ether and 200 ml of n-butanol.

Yield: 15 g (39.6% of optically pure material theory)

Melting Point: 188 ℃

Rotation: [α] _D ²⁸ = + 103.7˚ (c = 1, CHCl ₃ )

2) 1R, 6S-8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane

13 g (33.6 mmol) of 1R, 6S-5- (1R-phenylethyl) -8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane is 10% activated carbon based palladium in 200 ml of ethanol Hydrogenated at 100 ° C. and 100 bar over 2.5 g. The catalyst was removed by suction filtration, the filtrate was concentrated and the residue was recrystallized from 30 ml of toluene.

Yield: 7.5 g (79% of theory)

Melting Point: 160-161 ℃

Rotation: [α] _D ²³ = +17.5 ° (c = 1.21, CHCl ₃ )

3) 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrobromide

7 g (24.8 mmol) of 1R, 6S-8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane are dissolved in 25 ml of a 33% hydrogen bromide solution in glacial acetic acid and 5 g of phenol are added The mixture was stirred overnight at room temperature. Diluted with diisopropyl, the determined salt was removed by suction filtration and dried in air.

Yield: 5.5 g

Derivation with Mosher reagents and gas chromatography analysis showed only one detectable enantiomer (ee> 99.5%).

Example M

5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

1) 2-bromo-3,4,5,6-tetrafluoro-benzoyl chloride

365 g (1.33 mole) of 2-bromo-3,4,5,6-tetrafluorobenzoic acid [Tetrahedron 23 , 4719 (1967)] was added to 2 l of thionyl chloride, and the mixture was stopped until gas evolution ceased. Heated under reflux for 11 hours. Excess thionyl chloride was removed in vacuo and the residue was distilled off.

Yield: 330 g (85% of theory)

Boiling point: 81-85 ℃ / 3-5 millibars

2) diethyl (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -malonate

15.9 g (0.167 mole) of magnesium chloride was added to 150 ml of anhydrous acetonitrile (dried on zeolite) and 26.9 g (0.167 mole) of diethyl malonate was added dropwise while cooling. The mixture was cooled to 0 ° C, 46 ml (33.7 g = 0.33 mol) triethylamine were added dropwise and the mixture was stirred for 30 minutes. Then 48.9 g (0.168 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoyl chloride were added dropwise and the mixture was stirred at 0 ° C. for a further 1 hour and left at room temperature overnight. Treated with 100 ml of 5N hydrochloric acid and extracted three times with methylene chloride, the extract was dried over Na ₂ SO ₄ and concentrated in vacuo.

Crude product: 62.7 g

3) ethyl (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -acetate

60 g of crude diethyl (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -malonate are placed in 150 ml of water, treated with 0.6 g of 4-toluenesulfonic acid and the mixture is for 6 hours. Heated under reflux. Extract with methylene chloride, extracts were washed with water, dried over Na ₂ S0 ₄ and concentrated.

Crude product: 46 g

Boiling point (sample distillation in bulb tube): 150-160 ° C. (oven) / 3 millibar

Mass spectrum: m / e 342 (M ⁺ ), 297 (M ⁺ -OC ₂ H ₅ ), 263 (M ⁺ -Br), 257, 255 (M ⁺ -CH ₂ CO ₂ C ₂ H ₅ ), 235 ( 263-28).

4) Ethyl 2- (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -3-ethoxy-acrylate

45 g of crude ethyl (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -acetate were added to 32.2 g (0.31 mol) of acetic anhydride and 28.4 g (0.19 mol) of triethyl orthoformate, The mixture was heated under reflux for 2 hours. Excess reagent was first removed in vacuo followed by high vacuum (bath up to 120-130 ° C.) and the crude product reacted to the next step.

Crude product: 50.7 g

5) ethyl 2- (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -3-cyclopropylamino-acrylate

50.7 g of the crude product from step 4) were cooled on ice dropwise with 8.6 g (0.15 mole) of cyclopropylamine in 90 ml of ethanol, the mixture was stirred at room temperature, left overnight, cooled appropriately again, crystals Was removed by suction filtration, washed with cold ethanol and dried.

Yield: 29 g (42% over 4 steps)

Melting Point: 103-105 ° C (Recrystallized from Ethanol)

6) ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate

28 g (68 mmol) of ethyl 2- (2-bromo-3,4,5,6-tetrafluoro-benzoyl) -3-cyclopropylaminoacrylate were added to 6.9 g (164 mmol) of sodium fluoride in 88 ml of DMF. Heated at reflux for 6 h. After cooling the mixture, it was poured into water, and the soaked precipitate (red) was removed by suction filtration, washed with plenty of water and dried at 80 ° C. in a recirculated air oven.

Crude product: 27.3 g

Melting Point: 150-175 ℃

Recrystallized from glycol monomethyl ether.

Melting Point: 187-191 ℃

7) 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

165 ml of acetic acid, 26.7 g (68 mmol) of crude ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylate, Into a mixture of 110 ml of water and 18 ml of concentrated sulfuric acid was heated under reflux for 2 hours. The cooled reaction mixture was poured into ice water and the soaked precipitate was removed by suction filtration, washed with plenty of water and dried in a recirculated air oven at 80 ° C.

Yield: 19.7 g (80% of theory)

Melting Point: 208-210 ℃ (Decomposed)

Recrystallized from glycol monomethyl ether.

Melting Point: 212-214 ° C (Decomposed)

NMR ¹ H (DMSO): 8.73 s (1H, C-2), 4,16 m (1H, cyclopropyl), 1,2 m (4H, cyclopropyl) [ppm].

Mass spectrum: m / e 361 (M ⁺ -H ₂ O), 317 (M-CO ₂ ), 41 (100%, C ₃ H ₅ ).

Preparation of the Final Compound

Example 1

A. 1-Cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl-6,8-difluoro-1,4-dihydro-4 Oxo-3-quinolinecarboxylic acid

141.5 g (0.5 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added to 1,4-diazabicyclo- [2.2. 2] (+)-[S, S] -2.8-diazabicyclo [4.3.0] nonane (ee 99.5%) in a mixture of 1500 ml of acetonitrile and 750 ml of dimethylformamide in the presence of 55 g (0.5 mol) of octane Heated to reflux for 1 hour with 69.25 g (0.55 mol) of GC 99.8%). The suspension was cooled, the precipitate was removed by suction filtration, washed with water and then further stirred with 1 l of water (pH 7). The product was removed by suction filtration and dried at 60 ° C. in a recycle air oven.

Yield: 163.4 g (84% of theory)

Melting Point: 249-251 ℃ (Decomposed)

B. (-)-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4 -Dihydro-4-oxo-3-quinoline-carboxylic acid hydrochloride

1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4- 6.0 g (15.4 mmol) of oxo-3-quinolinecarboxylic acid were dissolved in 40 ml of semi-concentrated hydrochloric acid at 60 ° C. and the hydrochloride solution was filtered. The filtrate was concentrated to ½, cooled in ice and treated with 40 ml of ethanol. The yellow crystals were removed by suction filtration, washed with ethanol and dried at 60 ° C. in high vacuum to lighten the color. 5.51 g (84% of theory) of very pure hydrochloride were obtained.

For further purification, it was dissolved in 50 ml of water under heating. The yellow solution was treated with 5 ml of semi-concentrated hydrochloric acid, cooled in ice, the soaked crystals were removed by suction filtration, washed with ethanol, first dried at room temperature and then placed under high vacuum at 100 ° C.

Yield: 4.64 g (70.8% of theory)

Melting Point: 324-325 ℃ (Decomposed)

TLC (silica gel, dichloromethane / methanol / 17% aqueous ammonia = 30: 8: 1): homogeneous

Rf value: 0.3

[α] _D ^{25 :} -256 ° (c = 0.5, H ₂ O)

Purity (HPLC): 99.4%

C ₂₀ H ₂₁ F ₂ N ₃ O ₃ ^. Elemental Analysis for HCl (425.5)

C H N Cl

Theoretic: 56.4 5.2 9.9 8.3

Measured value: 56.3 5.4 9.8 8.3

Example 2

A. 8-Chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-di Hydro-4-oxo-3-quinoline-carboxylic acid

Two batches of the next size were run side by side and processed together.

180 g (0.6 mole) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was diluted with 1,4-diazabicyclo [2.2 .2] -octane (DABCO) (+)-[S, S] -2,8-diazabicyclo [4.3.] In a mixture of 900 ml of acetonitrile in the presence of 99 g (0.88 moles). 0] nonane was heated under reflux for 1 hour with 84 g (0.67 mol) (internal temperature: 90.5 ° C). The yellow solution was cooled and treated with seed crystals (from 5 ml of concentrated sample, the residue was stirred with acetonitrile). The mixture was stirred at about 3 ° C. for 2 hours and the immersion precipitates from both batches were quickly removed by suction filtration and washed with acetonitrile and placed in 1.5 l of ice water. After about 10 minutes the original thin, well stirred suspension became an agitated mass, which was further diluted with 150 ml of water. The precipitate was removed by suction filtration, washed with water and dried at 80 ° C. in a recycle air drying oven.

Yield: 402 g (82.7% of theory), pale yellow product

Melting Point: 193-196 ℃ (Decomposed)

Rf value (silica gel, methylene chloride / methanol / 17% aqueous NH ₃ = 30: 8: 1): 0.4

B. 8-Chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro 4-oxo-3-quinolinecarboxylic acid hydrochloride

8-chloro-1-cyclopropyl-7-([S, S] -2.8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo 13.1 g (32 mmol) of -3-quinolinecarboxylic acid were suspended in 50 ml of water and made into a solution by adding 50 ml of semi-concentrated hydrochloric acid. The mixture was filtered through glass frit, the filtrate was concentrated in vacuo and the residue was stirred using about 300 ml of absolute ethanol. The suspension was cooled in ice and the precipitate was removed by suction filtration, washed with ethanol and first dried at room temperature and then at 100 ° C. in vacuo.

Yield: 13.4 g (93.8% of theory)

Melting Point: 328-330 ℃ (Decomposed)

Rf value (silica gel, methylene chloride / methanol / 17% aqueous ammonia = 30: 8: 1): 0.4

Purity (HPLC): 99.9%

[α] _D ^{24 :} -164.4 ° (c = 0.45, H ₂ O)

C ₂₀ H ₂₁ ClFN ₃ O ₃ ^. Elemental Analysis for HCl (442.3)

C H N Cl

Theoretic: 54.3 5.0 9.5 16.0

Measured value: 54.3 5.0 9.5 16.0

C. For example, the following salts may also be similarly prepared.

8-chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-3-quinoline carboxylic acid methanesulfonate,

8-chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-3-quinoline carboxylic acid toluenesulfonate,

8-chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-3-quinoline carboxylic acid sulfate,

8-chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-3-quinoline carboxylic acid acetate

8-chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-3-quinoline carboxylic acid lactate,

8-chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-3-quinoline carboxylic acid citrate,

8-chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-3-quinoline carboxylic acid emcarbonate.

Example 3

The following compounds were prepared analogously to Example 1 using 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A. Cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 -Quinoline-carboxylic acid

Melting Point: 256-258 ℃ (decomposed)

B. 1-Cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo 3-quinoline-carboxylic acid hydrochloride

Melting Point:> 320 ° C (Decomposed)

[α] _D ^{26 :} -90.6 ° (c = 0.48, H ₂ O)

Example 4

A. 1,4-diazabicyclo 6 g (20 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [2.2.2] (+)-[S, S] -2,8-diazabicyclo [4.3.0 in 40 ml / N-methylpyrrolidone 20 ml of acetonitrile in the presence of 2.2 g (20 mmol) of octane ] Nonan was heated under reflux for 1 hour using 2.7 g (21.4 mmol) of nonane. The resulting suspension was cooled, the precipitate was removed by suction filtration, washed with acetonitrile and dried at 100 ° C./12 millibars.

Yield: 1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -5,6,8-trifluoro-1,4- 6.7 g of dihydro-4-oxo-3-quinolinecarboxylic acid (82.3% of theory)

Melting Point: 257-259 ℃ (decomposed)

Recrystallized from glycol monomethyl ether.

Melting Point: 260-265 ℃ (Decomposed)

B. 1.5 g (3.7 mmol) of product from Step A were placed in 6 ml of 1N hydrochloric acid. After a while, the hydrochloride distillate was removed by suction filtration, washed twice with 5 ml of ethanol each time and dried at 100 ° C./12 millibars.

Yield: 1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -5,6,8-trifluoro-1,4- 1.4 g of dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride (85.7% of theory)

Melting Point:> 310 ° C (Decomposed)

[α] _D ^{26 :} -272 ° (c = 0.5, H ₂ O)

Example 5

5.2 g (13 mmol) of the compound from Example 4A were treated with 15 ml of liquid ammonia in 80 ml of pyridine in an autoclave and heated at 130 ° C. for 12 hours. The mixture is then cooled, the autoclave is stopped, the mixture is concentrated and the residue is treated with acetonitrile in an ultrasonic bath. Undissolved precipitate is removed by suction filtration, the residue is dissolved in 150 ml of medicine under heating, the solution is filtered, the hydrochloride is precipitated using 10 ml of semi-concentrated hydrochloric acid, removed by suction filtration and recirculated air It dried at 100 degreeC in a drying oven. The resulting compound was suspended in 100 ml of glycol monomethyl ether at 110-115 ° C. and made into a solution by adding 38 ml of semi-concentrated hydrochloric acid. The solution was filtered at high temperature through glass frit, cooled and the cooled yellow crystals were removed by suction filtration, washed with ethanol and dried at 120 ° C./12 millibars.

Yield: 5-amino-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1, 2.5 g of 4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride (44% of theory)

Melting point:> 335 ° C (decomposed, already dark under 335 ° C)

[α] _D ^{28 :} -280.8 ° (c = 0.53, H ₂ O)

Example 6

1.4 g (5 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was dissolved in 15 ml of acetonitrile. The mixture was stirred and stirred at room temperature for 1 hour using 1.3 g (10.3 mmol) of (+)-[S, S] -2,8-diazabicyclo [4.3.0] nonane. After standing overnight, the precipitate was removed by suction filtration, washed with acetonitrile and chromatographed on silica gel (eluant: methylene chloride / methanol / 17% water soluble ammonia = 30: 8: 1, Rf value: 0.4) Purified. Resulting 1-cyclopropyl-7-([S, S] -diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-1,8 Naphthyridine-3-carboxylic acid was dissolved in 15 ml of semi-concentrated hydrochloric acid, the solution was evaporated and the residue was stirred with ethanol. The precipitate was removed by suction filtration, washed with ethanol and dried at 120 ° C./12 millibars.

Yield: 1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] nonan-8-yl) -6-fluoro-1,4-dihydro-4- 960 mg oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (47% of theory)

Melting Point: 345-346 ℃ (decomposed)

[α] _D ^{30 :} + 5.4 ° (c = 0.5, H ₂ O)

Example 7

The following compounds were prepared in analogy to Example 1 using (-)-[R, R] -2,8-diazabicyclo [4.3.0] nonane.

A. 1-cyclopropyl-7-([R, R] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro- 4-oxo-3-quinoline-carboxylic acid

Melting Point: 247-249 ℃ (Decomposed)

B. 1-Cyclopropyl-7-([R, R] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro- 4-oxo-3-quinoline-carboxylic acid hydrochloride

Melting Point: 322-326 ℃ (Decomposed)

Purity (HPLC): 99.4%

ee: 98.6%

[α] _D ^{24 :} + 250 ° (c = 0.5, H ₂ O)

Example 8

The following compounds were prepared analogously to Example 2 using (-)-[R, R] -2,8-diazabicyclo [4.3.0] nonane.

A. 8-Chloro-1-cyclopropyl-7-([R, R] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1.4-dihydro- 4-oxo-quinolinecarboxylic acid

Melting Point: 192-195 ℃ (Decomposed)

B. 8-Chloro-1-cyclopropyl-7-([R, R] -2,8-diazabicyclo- [4.3.0] non-8-yl) -6-fluoro-1,4-di Hydro-4-oxo-quinolinecarboxylic acid hydrochloride

Melting Point: 323-324 ℃ (Decomposed)

Purity (HPLC): 99.9%

[α] _D ^{24 :} + 164.5 ° (c = 0.53, H ₂ O)

C ₂₀ H ₂₁ ClFNO ₃ ^. Elemental Analysis for HCl (442.3)

C H N Cl

Theoretical 54.3 5.0 9.5 16.0

Found 54.2 5.0 9.5 16.1

Example 9

The following compounds were prepared with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and (-)-[R, R] -2,8-dia It was prepared similarly to Example 1 from xabicyclo- [4.3.0] nonane.

A. 1-Cyclopropyl-7-([R, R] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4-oxo 3-quinoline-carboxylic acid

Melting Point: 254-258 ℃ (decomposed)

B. 1-Cyclopropyl-7-([R, R] -2,8-diazabicyclo [4.3.0.] Non-8-yl) -6-fluoro-1,4-dihydro-4- Oxo-3-quinoline-carboxylic acid

Melting Point: Decomposes above 320 ℃

[α] _D ^{24 :} + 92.5 ° (c = 0.53, H ₂ O)

Example 10

A. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl)- 4-oxo-3-quinoline-carboxylic acid

1.43 g (5 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was mixed with 15 ml of acetonitrile and 75 ml of dimethylformamide. Heated under reflux for 1 hour with 0.74 g of 93% cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane in the presence of 0.67 g of 1,4-diazabicyclo [2.2.2] octane in I was. The suspension is concentrated, the residue is stirred with water, the precipitate is removed by suction filtration and dried in vacuo at 80 ° C.

Yield: 1.67 g (85.4% of theory)

Melting Point: 210-212 ℃ (decomposed)

B. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl)- 4-oxo-3-quinoline-carboxylic acid hydrochloride

1.6 g (4 mmol) of the compound from Step A are dissolved in 120 ml of semi-concentrated hydrochloric acid at 60 ° C., the solution is concentrated, the residue is stirred with ethanol and the precipitate is removed by suction filtration and at 90 ° C. in vacuo. Dried.

Yield: 1.57 g

Melting Point: 300-303 ℃ (Decomposed)

Purity (HPLC): 97%

C. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [., Which has a melting point of 204-206 ° C. (decomposed) 4.3.0] non-8-yl) 4-oxo-3-quinolin-carboxylic acid with Example 10A using 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane Similarly prepared.

D. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo having a melting point of 324-325 ° C. (decomposed) 4.3.0] non-8-yl) -4-oxo-3-quinolin-carboxylic acid was prepared similar to Example 10B using betaine.

[α] _D ^{24 :} −241 ° (c = 0.59, H ₂ O)

E. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo, having a melting point of 204-206 ° C. (decomposed) 4.3.0] Non-8-yl) -4-oxo-3-quinoline-carboxylic acid using Example 1A using 1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane Prepared similarly.

[α] _D ^{25 :} + 248 ° (c = 0.57, DMF)

F. 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.] Having a melting point of 323 ° C. (decomposed). 0] non-8-yl) -4-oxo-3-quinoline-carboxylic acid hydrochloride was prepared analogously to Example 10B using betaine from Example 10E.

[α] _D ^{26 :} + 238 ° (c = 0.5, H ₂ O)

Example 11

The following compounds were prepared analogously to Example 10 using 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl- 4-oxo-3-quinolinecarboxylic acid

Melting Point: 180-185 ℃ (Decomposed)

B. 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) 4-oxo-3-quinolinecarboxylic acid hydrochloride

Melting Point: 227-232 ℃ (decomposed)

C. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8- Mono) -4-oxo-3-quinolinecarboxylic acid

Melting Point: 186-188 ℃ (Decomposed)

[α] _D ^{26 :} -269 ° (c = 0.5, DHF)

D. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8- I) -4-oxo-3-quinolinecarboxylic acid hydrochloride

Melting Point: 278-280 ℃ (decomposed)

[α] _D ²⁴ : −208 ° (c = 0.5, H ₂ O)

E. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8- Mono) -4-oxo-3-quinolinecarboxylic acid

Melting Point: 188-190 ℃ (decomposed)

[α] _D ²⁵ : + 270 ° (c = 0.5, DMF)

F. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8- diazabicyclo [4.3.0] non-8- I) -4-oxo-3-quinolinecarboxylic acid hydrochloride

Melting Point: 292-294 ℃ (Decomposed)

[α] _D ²⁷ : + 193 ° (c = 0.5, H ₂ O)

Example 12

The following compounds were prepared analogously to Example 10A using 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo 3-quinoline-carboxylic acid

Melting Point: 246-249 ° C. (Decomposed) (Recrystallized from Glycol Monomethyl Ether)

B. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4 Oxo-3-quinoline-carboxylic acid

Melting Point: 243-245 ℃ (Decomposed)

C. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4 Oxo-3-quinoline-carboxylic acid hydrochloride

Melting Point: 300 ℃ (Decomposed)

[α] _D ²³ : -99 ° (c = 0.5, H ₂ O)

Example 13

The following compounds were prepared analogously to Example 10A using 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A. 1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl ) -4-oxo-3-quinolinecarboxylic acid

Melting Point: 210-216 ℃ (decomposed)

B. 1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8 -Yl) -4-oxo-3-quinolinecarboxylic acid

Melting Point: 234-237 ℃ (Decomposed)

[α] _D ²⁴ : -287 ° (c = 0.5, DMF)

C. 1-Cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8 -Yl) -4-oxo-3-quinolinecarboxylic acid

Melting Point: 236-237 ℃ (decomposed)

[α] _D ²⁴ : + 282 ° (c = 0.5, DMF)

Example 14

A. 4.1 g (10 mmol) of the compound from Example 13A were treated with 5 ml of liquid ammonia in 40 ml of pyridine and heated in an autoclave at 130 ° C. for 10 hours. After cooling, the precipitate was removed by suction filtration, washed with water and dried at 100 ° C. in a recycle air drying oven. 2 g of crude product were purified by recrystallization from glycol monomethyl ether.

Yield: 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non- 8-yl) -4-oxo-3-quinoline-carboxylic acid 1.3 g (31% of theory)

Melting Point: 233-240 ℃ (decomposed)

B. 5-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non -8-yl) -4-oxo-3-quinolinecarboxylic acid was similarly prepared using the compound from Example 13C.

Melting Point: 212-124 C (Decomposed)

[α] _D ²⁵ : -260 ° (c = 0.5, DMF)

C. 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non -8-yl) -4-oxo-3-quinolinecarboxylic acid was similarly prepared using the compound from Example 13C.

[α] _D ²⁶ : + 261 ° (c = 0.5, DMF)

Mass spectrum: m / e 406 (M ⁺ , 95%), 346, 249, 98, 41, 28 (100%)

Example 15

A. 7- (2-tert-butoxycarbonyl-2,8-diazabicyclo [4.3.0] non-8-yl) -1-cyclopropyl-6,8-difluoro-1,4- Dihydro-4-oxo-3-quinolinecarboxylic acid

1-clopropyl-7- (2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecar 7.8 g (20 mmol) of acid were dissolved in a mixture of 60 ml of dioxane / water (2: 1) and 20 ml of 1 N sodium hydroxide solution, the mixture was ice cooled and di-tert-butyl pyro-carbonate Treatment was by stirring using 5.24 g (24 mmol). The mixture was stirred at rt for 1 h and left overnight. The soaked precipitate was removed by suction filtration, washed with 250 ml of water and dried overnight at 50 ° C. in a recycle air drying oven.

Yield: 9.34 g (95.5% of theory)

Melting Point: 216-219 ℃ (decomposed)

B. 2S-methyl-1-butyl 7- (2-tert-butoxycarbonyl-2,8-diazabicyclo [4.3.0] non-8-yl) -1-cyclopropyl-6,8-di Fluoro-1,4-dihydro-4-oxo-quinolinecarboxylate

2.15 g (4.4 mmol) of the compound from Step A were suspended in 60 ml of tetrahydrofuran / water (1: 1) at room temperature and 1.65 g (5 mmol) cesium carbonate were added. The mixture was reacted at about 40 ° C. in an ultrasonic bath for 20 minutes, about 40 ml of solvent was distilled off at 40 ° C./12 millibars, and the remaining solution was lyophilized to obtain a slightly soluble crude cesium salt. 3.3 g of this salt was dissolved in 40 ml of dimethylformamide, treated with 1.4 g of S (+)-1-bromo-2-methyl-butane, and reacted overnight in an ultrasonic bath at 40-50 ° C. The resulting suspension was concentrated and the residue was treated with water and extracted with methylene chloride. After drying over sodium sulfate, the solution was concentrated and the residue was purified by chromatography (silica gel, eluent: methylene chloride / methanol 95: 5).

Yield: 950 mg (38% of theory)

Melting Point: 72-83 ℃ (decomposed)

C. 2S-methyl-1-butyl 1-cyclopropyl-7- (2,8-diazabicyclo- [4.3.0] non-8-yl) -6,8-difluoro-1,4-di Hydro-4-oxo-3-quinolinecarboxylate trifluoroacetate

570 mg (1 mmol) of the compound from Step B were dissolved in 3 ml of trifluoroacetic acid at room temperature and the solution was concentrated at 60 ° C./12 millibars. The resulting viscous oil was stirred with 5 ml of ether to give a solid product. It was removed by suction filtration, washed with ether and dried at 80 ° C. in high vacuum.

Yield: 450 mg (78% of theory)

Melting Point: 214-216 ° C (Decomposed)

[α] _D ²⁵ : + 2.8 ° (c = 0.5, DMF)

Example 16

1-cyclopropyl-7- (2,8-diazabicyclo- [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline 390 mg (1 mmol) of carboxylate are dissolved in a 40 mg solution of sodium hydroxide in 3 ml of water at room temperature in an ultrasonic bath, and the solution is diluted with 160 mg (1.1 mmol) solution of R-(+)-α-methyl-benzyl isocyanate. Ice-cold treatment. The soaked precipitate was removed by suction filtration, washed with dioxane and dried at 100 ° C. in high vacuum.

Yield: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (2- [1R-phenyl-ethyl-amino-carbonyl] -2,8-dia Xavicyclo [4.3.0] non-8-yl) -3-quinoline-carboxylate 530 mg (99% of theory)

Melting Point: 208-210 ℃ (decomposed)

[α] _D ²⁵ : -23.2˚ (c = 0.5, DMF)

The reaction product was separated into diastereomers by chromatography, and the carbamoyl group was again removed by acidic hydrolysis to obtain the compounds of Examples 1 and 7.

Example 17

1.52 g (5 mmol) of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate was dissolved in 30 ml of acetonitrile 1,4-dia Zacyclocyclo [2. 2.2] octane 550 mg (5 mmol) and (+)-[SS] -2.8-diazabicyclo- [4.3.0] nonane 760 mg (6 mmol) with 2 hours at 50 ° C. and 2 hours at 60 ° C. Reacted. After cooling, the resulting suspension was removed by suction filtration and the precipitate was washed with water and dried at 90 ° C. in vacuo.

Yield: ethyl 1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-di 0.99 g of hydro-4-oxo-3-quinolinecarboxylate (47.5% of theory)

Melting Point: 194-195 ° C. (Recrystallized from Acetonitrile)

[α] _D ²³ : -188.9 ° (c = 0.51, CHCl ₃ )

Example 18

9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] -benzoxacin-6-carboxylic acid 1.4 g (5 mmol) of 0.85 g (7.7 mmol) of 1,4-diazabicyclo [2.2.2] octane in 15 ml of acetonitrile / 7.5 ml of dimethylformamide, similar to Example 1, and (+)-[SS ] -2,8-diazabicyclo [4.3.0] nonane 0.7 g (5.6 mmol).

Yield: 10-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo 1.24 g of pyrido [1,2,3-dec] [1,4] benzoxac-6-carboxyl (64% of theory)

Melting Point: 265-268 ℃ (decomposed)

[α] _D : -232.2 ° C (c = 0.58, CHCl ₃ )

3S-10-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo- 7H-pyrido [1,2,3-dec] [1,4] benzoxacin-6-carboxylic acid was similarly obtained.

Example 19

1-Chloropropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid is reacted similarly to Example 1 and the reaction product is silica gel Purification was carried out by chromatography on chromatography (eluent: methylene chloride / methanol / 17% aqueous ammonia = 30: 8: 1).

1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4 having a melting point of 203-208 ° C. (decomposed) Dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

Got it.

[a] _D ²³ : -193 ° (c = 0.4, CHCl ₃ )

Example 20

The reaction was carried out similarly to Example 1A using 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give a melting point of 236-239 ° C. ( Decomposed) phosphorous 1-ethyl-7-([S, S] -2,8-diazabicyclo [4.3.0] -non-8-yl) -6,8-difluoro-1,4-dihydro -4 -oxo-3-quinolinecarboxylic acid was obtained (recrystallized from glycol monomethyl ether)

[α] _D ²³ : -186.3 ° (c = 0.3, CHCl ₃ )

Example 21

A. ethyl 7-([S, S] -2,8-diazabicyclo [4.3.0] non 8-yl) -1- (2,4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate

1.9 g (5) of ethyl 7-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate Millimoles) was added to 680 mg of [SS] -2,8-diazabicyclo [4.3.0] nonane in the presence of 560 mg (5 mmol) of 1,4-diazabicyclo [2.2.2] octane in 20 ml of acetonitrile. 5.4 mmol) was stirred at 10 ° C. for 3 hours. The suspension was removed by suction filtration, washed with water and dried. 0.35 g of product was obtained. The mother liquor was concentrated, the residue was stirred with water, the undissolved product was isolated and chromatographed on silica gel (eluant: dichloromethane / methanol / 17% aqueous ammonia) to further isolate 0.7 g of the product.

Total yield: 1.05 g (44% of theory)

Melting Point: 184-185 ℃ (Decomposed)

[α] _D ²³ : + 6.8 ° (c = 0.46, CHCl ₃ )

B. 7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -1- (2,4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, S-naphthyridine-3-carboxylic acid hydrochloride

0.8 g (1.7 mmol) of the compound from Step A were heated under reflux for 4 hours in a mixture of 10 ml of acetic acid and 8 ml of semi-diluted hydrochloric acid. The mixture was concentrated and the residue was stirred with traces of water, the precipitate was removed by suction filtration, washed with ice cold ethanol and dried.

Yield: 0.67 g (83% of theory)

Melting Point: 324-326 ℃ (decomposed)

[α] _D ²⁵ : + 10.8 ° (c = 0.37, DMF)

Example 22

0.56 g (2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate was dissolved in 3.5 ml of dimethyl sulfoxide [S, S] -2,8-diazabicyclo [4.3.0] nonane 0.38 g (3 mmol) and 0.45 g (4 mmol) 1,4-diazabicyclo [2.2.2] octane at 120 ° C. for 2 hours Heated. After cooling, the solvent was removed in high vacuum. The residue was dissolved using acetonitrile. The solid was separated off, washed with acetonitrile and dried at 60-80 ° C.

Yield: 1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-5- 0.5 g of methyl-4-oxo-3-quinolinecarboxylate (65% of theory)

Melting Point: 217-219 ℃ (decomposed)

[α] _D : -119 ° (c = 0.5, DMF)

Example 23

A. 837 mg (3 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid was charged with 10 ml of acetonitrile and dimethylform 1.1 g (10 mmol) of 1,4-diazabicyclo [2.2.2] octane and 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane-dihydro in a mixture of 5 ml of amide Heated under reflux for 2 hours using 665 mg (3.3 mmol) of chloride. The mixture was evaporated and the residue was stirred using 30 ml of water and the precipitate was removed by suction filtration and dried at 80 ° C. in vacuo.

Yield: 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8 -Yl) -4-oxo-3-quinoline-carboxylic acid 400 mg (34% of theory)

Melting Point: 213-214 ° C (Decomposed)

B. 0.4 g of betaine from Step A was dissolved in 5 ml of semiconcentrated hydrochloric acid at room temperature, the solution was concentrated and the residue was stirred with about 3 ml of ethanol. The precipitate was removed by suction filtration and dried at 80 ° C./12 millibars.

Yield: 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8 -Yl) -4-oxo-3-quinoline-carboxylic acid hydrochloride 290 mg (66% of theory)

Melting Point: 305-308 ° C (Decomposed)

[α] _D ²³ : -79 ° C (c = 0.52, H ₂ O)

Example 24

362 mg (1 mmol) of 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added to 3 ml of acetonitrile and dimethyl 220 mg (2 mmol) 1,4-diazabicyclo [2.2.2] octane and 1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydro in a mixture of 1.5 ml formamide Heated at reflux for 1.5 h with 220 mg (1.1 mmol) of chloride. The suspension is cooled and the precipitate is removed by suction filtration, stirred with 30 ml of water and dried at 90 ° C. in high vacuum.

Yield: 5-bromo-1-cyclopropyl-6.8-difluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non -8-yl) -4-oxo-3-quinolinecarboxylic acid 320 mg (68% of theory)

Melting Point: 263-264 ℃ (Decomposed)

[α] _D ³⁰ : + 251 ° (c = 0.3, CH ₃ Cl ₂ )

Example 25

The following compounds were prepared analogously to Example 1 using [S, S] -2-methyl-2,8-diazabicyclo [4.3.0] nonane.

A. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-([S, S] -2-methyl-2,8-diazobicyclo [4.3.0] non-8 -Yl) -4-oxo-3-quinolinecarboxylic acid

Melting Point: 230-233 ° C. (Decomposed) (Recrystallized from Glycol Monomethyl Ether)

B. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-([S, S] -2-methyl-2,8-diazobicyclo [4.3.0] non-8 -Yl) -4-oxo-3-quinolinecarboxylic acid hydrochloride

Melting Point: 258-260 ℃ (Decomposed)

[α] _D ²⁵ : -216.3˚ (c = 1, H ₂ O)

Example 26

The following compounds were prepared analogously to Example 1 using [R, R] -2-methyl-2,8-diazabicyclo [4.3.0] nonane.

A: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-([R, R] -2-methyl-2,8-diazabicyclo [4.3.0] non-8 -Yl) -4-oxo-3-quinolinecarboxylic acid

Melting point: 228-230 ° C (not decomposed) (recrystallized from glycol monomethyl ether)

B. 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-([R, R] -2-methyl-2,8-diazabicyclo [4.3.0] non-8 -Yl) -4-oxo-3-quinolinecarboxylic acid hydrochloride

Melting Point: 258-260 ℃ (Decomposed)

[α] _D ²⁵ : + 213.8 ° (c = 1, H ₂ O)

Example 27

1.95 g (5 mmol) of the compound from Example 1A were heated under reflux for 4 hours with 2.1 g (30 mmol) of methyl vinyl ketone in 50 ml of ethanol. The mixture was concentrated, the residue was stirred with water, the precipitate was removed by suction filtration, washed with ethanol and dried at 100 ° C./12 millibars.

Yield: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-oxo-7-([S, S] -2- [3-oxo-1-butyl] -2,8- Diazabicyclo [4.3.0] non-8-yl) -3-quinolincarboxylic acid 2.1 g (91.5% of theory)

Melting Point: 181-183 ° C. (Decomposed) (Recrystallized from Glycol Monomethyl Ether)

[α] _D ²⁴ : -120.7 ° (c = 0.57, CH ₃ Cl ₂ )

Example 28

1.95 g (5 mmol) of the compound from Example 1A were heated at 50-80 ° C. for 3 hours with 1.0 g (10.8 mmol) of chloroacetone and 1.3 g (13 mmol) of triethylamine in 30 ml of dimethylformamide. . The solution is concentrated, the residue is stirred with water (pH 6), the insoluble precipitate is removed by suction filtration, washed with water and dried at 100 ° C. in a recycle air drying oven (crude yield: 1.3 g), Recrystallized from glycol monomethyl ether.

Yield: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-([S, S] -2- [2-oxopropyl] -2,8-dia Xavicyclo [4.3.0] non-8-yl) -3-quinolincarboxylic acid 1.12 g (50% of theory)

Melting Point: 181-184 ℃ (Decomposed)

[α] _D ²³ : -72 ° (c = 0.55, CHCl ₂ )

Example 29

A. The compound from Example 2A was reacted similarly to the method of Example 27, yielding 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4- having a melting point of 107-109 ° C. Obtained oxo-7-([S, S] -2- [3-oxo-1-butyl] -2,8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid .

[α] _D ²³ : -53 ° (c = 0.67, CHCl ₃ )

Purity: 99.2% (HPLC)

B. Racemate 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-cis-2- [3-oxo-1-butyl having a melting point of 124-125 ° C. ] -2,8-diazabicyclo [4.3.0] -non-8-yl) -3-quinolincarboxylic acid to 8-chloro-1-cyclopropyl-7- (cis-2,8-diazabicyclo Similarly prepared using [4.3.0] -non-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid.

Example 30

1.56 g (4 mmol) of the compound from Example 10A were treated with 0.82 g (8.8 mmol) of chloroacetone and 1.05 g (10.4 mmol) of triethylamine in 30 ml of dimethylformamide and the mixture was treated at 50-80 ° C. for 3 hours. Heated during. The resulting yellow solution was concentrated at 80 ° C./15 millibars and the oily residue was stirred with water until it solidified. The solid product was removed by suction filtration, washed with water and recrystallized from glycol monomethyl ether.

Yield: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (cis-5- [2-oxopropyl] -2-oxa-5,8-dia Xavicyclo [4.3.0] non-8-yl) -3-quinolincarboxylic acid 830 mg (47% of theory)

Melting Point: 192-193 ℃ (Decomposed)

Example 31

1.56 g (4 mmol) of the compound from Example 10A were heated under reflux for 3 hours with 1.8 g (25.6 mmol) of methyl vinyl ketone in 50 ml of ethanol. The suspension was concentrated at 70 ° C./12 millibars and the residue was stirred with water and recrystallized from glycol monomethyl ether.

Yield: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (cis-5- [3-oxo-1-butyl] -2-oxa-5.8- 1.33 g of diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid (72% of theory)

Melting Point: 188-189 ℃ (Decomposed)

Example 32

1.95 g (4.8 mmol) of the compound from Example 2A were heated at reflux for 2 hours with 3 g (30 mmol) of ethyl acrylate in 30 ml of glycol monomethyl ether. The mixture was evaporated and the residue was stirred with water, the precipitate was removed by suction filtration, dried (crude product: 1.9 g) and recrystallized from glycol monomethyl ether.

Yield: 8-chloro-1-cyclopropyl-7-([S, S] -2- [2-ethoxy-carbonyl-ethyl] -2,8-diazabicyclo [4.3.0] non-8 -Yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (60% of theory)

Melting Point: 117-118 ℃ (Decomposed)

[α] _D ²⁸ : -103 ° (c = 0.49, DMF)

Purity: 99.6% (HPLC)

Example 33

1.95 g (4.8 mmol) of the compound from Example 2A were heated under reflux for 5 hours with 0.8 g (15 mmol) of acrylonitrile in 30 ml of ethanol. The mixture was evaporated and the residue was stirred with water, dried (crude product: 1.9 g) and recrystallized from glycol monomethyl ether.

Yield: 8-chloro-7-([S, S] -2- [2-cyanoethyl] -2,8-diazabicyclo [4.3.0] non-8-yl) -1-cyclopropyl- 1.6 g of 6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (73% of theory)

Melting Point: 153-155 ° C (decomposed)

[α] _D ²⁷ : -98.6˚ (c = 0.53, DMF)

Purity: 96% (HPLC)

Mass spectrum: m / e 458 (M ⁺ ), 250, 149 (100%, C ₉ H ₁₃ N ₂ ), 110, 49

Example 34

1.95 g (5 mmol) of the compound from Example 1A were stirred under reflux for 2 hours with 1.2 g (8 mmol) of dimethyl acetylenedicarboxylate in 60 ml of ethanol. The suspension is concentrated, the residue is stirred with water and the precipitate is removed by suction filtration and dried. 2.3 g of crude product were recrystallized from glycol monomethyl ether / dimethylformamide.

Yield: 1-cyclopropyl-7- [2- (1,2-methoxycarbonyl-vinyl) -1S, 6S-2,8-diazabicyclo [4.3.0] non-8-yl] -6 2 g of 8-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (74% of theory)

Melting Point: 262-264 ℃ (Decomposed)

[α] _D ²⁴ : + 28.8 ° (c = 0.24, CH ₂ Cl ₂ )

Example 35

The compound from Example 2A was reacted with dimethyl acetylenedicarboxylate similarly to Example 34. 8-chloro-1-cyclopropyl-7- [2- (1,2-bis-methoxycarbonyl-vinyl) -1S, 6S-2,8-diazabicyclo having a melting point of 210-212 ° C. [4.3. 0] non-8-yl] -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was obtained in 87% yield.

[α] _D ²⁴ : + 16.6 ° (c = 0.5, DMF)

Example 36

1-cyclopropyl-7- (cis-2,8-diazabicyclo- [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro-oxo-3-quinoline 780 mg (2 mmol) of carboxylic acid were heated under reflux with 500 mg (5 mmol) of ethyl propiolate in 15 ml of ethanol for 1 hour. The suspension is cooled, the precipitate is removed by suction filtration, washed with 25 ml of ethanol and dried at 80 ° C. in high vacuum.

Yield: 1-cyclopropyl-7- [2- (trans-2-ethoxycarbonylvinyl) -cis-2,8-diazabicyclo- [4.3.0] non-8-yl] -6,8 880 mg of difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (90% of theory)

Melting Point: 244-246 ℃

The following compounds were prepared analogously to Example 36 from the corresponding starting materials.

The following compounds were prepared analogously to Example 10 from the corresponding intermediate products.

Example 48

8-chloro-1-cyclopropyl-7-([S, S] -2,8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1,4-dihydro-4 -Oxo-3-quinolinecarboxylic acid was reacted with methyl propiolate in ethanol or methanol similarly to Example 36, yielding 8-chloro-1-cyclopropyl-6- with a melting point of 220-222 ° C. (decomposed). Fluoro-1,4-dihydro-7- [2- (trans-2-methoxycarbonyl-vinyl)-[S, S] -2,8-diazabicyclo- [4.3.0] non-8 -Yl) -4-oxo-3-quinolinecarboxylic acid was obtained.

[α] _D ²⁴ : + 8.2˚ (c = 0.5, CHCl ₃ )

Example 49

8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) 407.5 g (1 mmol) of 4-oxo-3-quinolinecarboxylic acid (compound from Example 11E) were heated under reflux for 1 hour with 210 mg (2.5 mmol) of methyl propiolate in 10 ml of methanol. The mixture was concentrated and 450 mg of the isolated crude product was recrystallized from 4 ml of acetonitrile.

Yield: 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) -1S, 6R-2-oxa- 5,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinolinecarboxylic acid

Melting Point: 153-156 ℃ (decomposed)

[α] _D ²⁸ : + 36 ° (c = 0.5, CHCl ₃ )

Example 50

The reaction with the compound of Example 13A was carried out similarly to Example 49, yielding 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro- having a melting point of 169-170 ° C. (decomposed). 7- [5- (trans-2-methoxycarbonyl-vinyl) -cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinoline Carboxylic acid was obtained (recrystallized from glycol monomethyl ether).

Example 51

The reaction with the compound of Example 10E was carried out similarly to Example 49, yielding 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- having a melting point of 230-234 ° C. (decomposed). [5- (trans-2-methoxycarbonyl-vinyl) -1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl] -4-oxo-3-quinoline Carboxylic acid was obtained (recrystallized from glycol monomethyl ether).

[α] _D ²⁸ : -27 ° (c = 0.5, CHCl ₃ )

Example 52

The reaction with the compound of Example 24 was carried out similarly to Example 49 to give 5-bromo-1-cyclopropyl-6,8-difluoro-1,4- with a melting point of 158-160 ° C. (decomposed). Dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) -1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl] -4- Oxo-3-quinolinecarboxylic acid was obtained (recrystallized from isopropanol).

[α] _D ²⁸ : + 8 ° (c = 0.27, CHCl ₃ )

Example 53

The reaction with the compound of Example 17 was carried out similarly to Example 36 to give methyl 1-cyclopropyl-7- [2- (trans-2-ethoxycarbonyl-vinyl) -1S, having a melting point of 168-169 ° C., 6S-2,8-diazabicyclo [4.3.0] non-8-yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate was obtained.

Example 54

1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] from Example 13B 818 mg (2 mmol) of non-8-yl) -4-oxo-3-quinolinecarboxylic acid were treated with 680 mg (4 mmol) of diethyl acetylene dicarboxylate in 15 ml of ethanol and the mixture was treated at 30 ° C. Treatment was performed for 1 hour in an ultrasonic bath. The suspension was removed by suction filtration and the precipitate was washed with ethanol and dried at 70 ° C. in high vacuum.

Yield: 1-cyclopropyl-7- [5- (1,2-bis-ethoxycarbonyl-vinyl) -1 R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non- 8-yl] -5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 890 mg (77% of theory)

Melting Point: 220-222 ° C. (Decomposed) (Recrystallized from Glycol Monomethyl Ether)

[α] _D ²⁵ : -57 ° (c = 0.5, CHCl ₃ )

Example 55

1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (trans-2-oxa-5,8-diaza [4.3.0] non-8-yl) -4-oxo The reaction with the 3-quinolinecarboxylic acid was carried out similarly to Example 36 to give 1-cyclopropyl-7- [5- (trans-2-ethoxy-carbonyl-vinyl] -trans-2-oxa-5, 8-diaza [4.3.0] non-8-yl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was obtained.

Melting point: 266-268 ° C. (decomposed) (recrystallized from glycol monomethyl ether)

Example 56

1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (trans-2-oxa-5,8-diaza [4.3.0] non-8-yl) -4-oxo The reaction of the 3-quinolinecarboxylic acid with methyl propiolate was carried out similarly to Example 36, yielding 1-cyclopropyl-7- [5- (trans-2-methoxy-carbonyl-vinyl) -trans- 2-Oxa-5,8-diaza [4.3.0] non-8-yl] -6,8-difluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid was obtained.

Melting Point: 275-277 ℃ (decomposed)

The compounds according to the invention have potent antibiotic action and have low toxicity and are capable of gram-positive and gram-negative microorganisms, in particular enterobacteria and in particular, for example, penicillin, cephalosporin, aminoglycosides, sulfonamides and tetracyclines. It has a broad spectrum of antibiotic activity against microorganisms that are resistant to various antibiotics.

Such useful properties include the active substances for chemotherapy in medicine, and also for the preservation of inorganic and organic substances, in particular all kinds of organic substances such as polymers, lubricants, dyes, fibers, leather, paper and wood, food and water To enable their use.

Claims (1)

Compounds of the formula or . Where Y is O or CH ₂ R ⁴ is H or C ₁ -C ₃ -alkyl.