FI113771B - Enantiomerically pure (1S, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] nonane - Google Patents

Description

113771

Enantiomerically pure (1S, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] nonane

The invention relates to an enantiomerically pure (1S, 6S) -2-5 oxa-5,8-diazabicyclo [4.3.0] nonane of formula VIc

B

OF

H ....... H (V, C)

HN O

This compound is useful as an intermediate, e.g. in the preparation of certain carboxylic acid derivatives of 1,4-dihydro-4-oxo-3-quinoline-10 which can be used in various antimicrobial preparations and as feed additives.

EP-A-0 350 733 discloses quinolone and naphthyridone carboxylic acids having the 7-position substituted by a bicyclic amine residue.

The aforesaid 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives have the general formula (I) F n -CO 3 - (I) yl: wherein ·, 20 A is CH, CF, CC 1, C-OCH 3, C -CH 3, N, 1 X 1 is H, halogen, NH 2, CH 3, *. R 1 is C 1-3 alkyl, FCH 2 CH 2 -, cyclopropyl, optionally 1 to 3 halogen substituted phenyl, or A and R 1 together may represent C; -O-CH 2 -CH (CH 3) - bridge, • ♦>,; R 2 is H, optionally hydroxy, halo, or amino substituted C 1-3 alkyl or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, B is a group the formula is

OF

H ........) - (- H

Wherein N is O and R4 is H, C1-3 alkyl, C2-5 oxoalkyl, CH2-CO-C6H5, CH2CH2-CO2R ', RO2C-CH = C-CO2R', -CH = CH- CO 2 R 'or CH 2 CH 2 CN or 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, wherein R' is hydrogen or C 1-3 alkyl.

The compounds of formula (I) and their pharmaceutically acceptable hydrates and acid addition salts, as well as the time metal, alkaline earth metal, silver and guanidinium salts of the basic carboxylic acids, are highly antibacterial. In particular, the compounds of formula (I) in question are characterized in that; , ·, They also strongly affect resting and resistant pathogens.

For the preparation of enantiomerically pure compounds of the formula (I) as defined above, a compound of the formula (V) O x, 10 F JL i / coor 2 · I i T m · ·. : χ ^ Α ^ Ν R1 * * •,; wherein A, R 1, R 2 and X 1 have the same meaning as above and X 2 is a halogen, especially fluorine or chlorine, is reacted, optionally in the presence of an acid-binding agent, with an enantiomerically pure compound with formula 5 (VI c)

B

OF

B......

ΗΝχ

The resulting reaction product of formula (I) may optionally be further reacted with a compound of formula (IIIa) R4-X3 (IIIa) wherein X3 is halogen, especially chlorine, bromine or iodine, and R4 is C2-5 oxoalkyl, CH2-CO-C6H5, CH2CH2CO2R 'or CH2CH2-CN wherein R' is hydrogen or C1-3 alkyl, or a Michael acceptor such as acetylene dicarboxylic acid alkyl esters, propiolate alkyl esters or a compound having formula is (IV) • t • 1> 1 1: ch2 = ch-r5 (iv),

• I

• ft where R 5 is C 0 CH 3, CO 2 R 'or CN.

For example, when 6,8-difluoro · ;;; η 1 - (2,4-difluorophenyl) -1,4-dihydro-7 - ([1S, 6R] -2-oxa-η 5,8-diazabicyclo [4.3.0] non-8- yl) -4-oxo-3-quinolinecarboxylic acid: boxylic acid and acetylenedicarboxylic acid diethyl ester, the reaction scheme can be represented by the following »· '30 scheme: • 1» • »1 1 1 *« »• 4 113771

O

COOH

HsT j il 1 + c2h5o2c-cec-co2c2h5 -► <y

F

o

Fv ^ N ^ COOH

C02C2H5 T Γ j I O / -Ν ^ ΤΉ C2H502C-CH = C ^ <1 f V f k_ ° H ΠΓ

F

The enantiomerically pure compounds used as starting materials are novel and can be prepared by various methods: 1. The racemic intermediate is reacted with the enantiomerically pure auxiliary reagent, the resulting diastereoisomers are separated, for example, by chromatography, and the desired diastereomer is cleaved again, 10 Help Group.

J 2. The bicyclic amine '1 (VIc) of the invention is novel as an enantiomerically pure compound. It may be prepared by the following processes: 2.1. Racemic Bicyclic Amine (a): 11 N 1 (a), », ·,: where R 4 is H and Y is O,> · * · 113771 5 may be reacted with an enantiomerically pure acid such as carboxylic acid or sulfonic acid such as N-acetyl -L-glutamic acid, N-benzoyl-L-alanine, 3-bromocamphor-9-sulfonic acid, camphor-3-carboxylic acid, 5 cis-camphoric acid, camphor-10-sulfonic acid, 0,0'-dibenzoyl tartaric acid, D- or With L-tartaric acid, mandelic acid, α-methoxyphenylacetic acid, 1-phenylethanesulfonic acid, α-phenylsuccinic acid, to form a mixture of diastereomeric salts which can be fractionally crystallized by separation (Resolution 1 Opt.). The molar ratio of amine to enantiomerically pure acid can vary within wide limits. By treating these salts with alkali metal or alkaline earth metal hydroxides, enantiomerically pure amines can be liberated.

2.2. By a similar procedure to that described in section 2.1, the above enantiomerically pure acids can undergo the racemate separation of the basic intermediates obtained in the preparation of racemic bicyclic amines. An example of such a basic intermediate is:

B

ς ·: (Y33N-CHrO <c): where Y is 0.

2.3. Both racemic amines (a) and basic intermediates (c) can be optionally chromatographically separated after chiral support by acylation (see, e.g., G. Blaschke, Angew. Chem. 92, 14: [1980]).

, · 2.4. Both the racemic amines (a) and the basic intermediates (c) can be chemically attached to the acyl radicals to form diastereomeric mixtures, ·,; which can be separated by distillation, crystallization or chromatographic purification into diastereomerically pure acyl derivatives, from which the enantiomerically pure amines are isolated by saponification. Examples of reagents that can be coupled with chiral acyl residues include: α-methoxy-α-trifluoromethylphenylacetyl chloride, men-5-methyl isocyanate, D- or L-α-phenylethyl isocyanate, chloroformic acid methyl ester, camphor-10-sulfo-acid.

2.5. In the synthesis of bicyclic amines (a), chiral protecting groups may also be attached instead of non-chiral protecting groups. In this way, diastereomers which are separable are obtained.

2.6. Enantiomerically pure amines (VIc) can also be prepared from enantiomerically pure precursors, such as [R, R] or [S, S] -3,4-dihydroxypyrrolidine, which should be protected by a nitrogen atom.

As an example of the synthesis of an enantiomerically pure amine starting from an enantiomerically pure 1-benzyl-3,4-dihydroxypyrrolidine, the following reaction scheme can be presented:

H0, OH HO OH HO OCH2CH, OH

^ n n

N N N

· I I I

Bzl CO., LTD

0 R R

• »» »· 1 ·

TosO OCH2CH2OTos / \ / - \

—T O N-Bzl O N-H

Y V> o

I N

"| I

\ R CO H

R

20 * 113771 7 R = for example (CH3) 3CO, a: H2, Pd / activated carbon b: acylation c: NaH, BrCH2COOC2H5 or c: CH2 = CH-CH2Br, NaH, dd: L1BH4 or d: O3, NaBH4, e: tosyl chloride, NEt3, f: benzylamine, xylene, reflux g: hydrolysis h: H2, Pd / activated carbon 10 Reaction of a compound of formula (V) with a compound of formula (VIc), which may also be in the form of a salt, e.g. is preferably carried out in a diluent such as dimethylsulfoxide, Ν, Ν-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric trisamide, sulfolane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, pyridine. Mixtures of these diluents may also be used.

All common inorganic and organic acid binding agents can be used as acid binders. These preferably include alkali metal hydroxides, dit, alkali metal carbonates, organic amines and amidines. Particularly preferred are: tri- (25-ethylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or excess amine used (VI c).

, · Reaction temperatures can be varied within wide limits. In general, the reaction is carried out at a temperature of: 30 ° C to 200 ° C, preferably 80 ° C to 180 ° C.

The reaction can be carried out under normal pressure, but also under elevated pressure. Generally, pressures of about 100 to about 10,000 kPa, preferably 100 to 1,000 kPa, are used.

* In carrying out this process, 1 to 15 moles, preferably 1 to 6 moles, of the compound of formula (VIc) are used per mole of the compound of the formula :: 35 (V).

t * 113771 8

The starting compounds of formulas (IIIa) and (IV) are known. Examples include: chloroacetone, 4-chloro-2-butanone, 5-chloro-2-pentanone, 1-bromo-2-butanone, phenacyl chloride, acrylic-5-acid methyl ester, acrylic acid ethyl ester, acrylonitrile, methyl vinyl carboxylic acid, acetyl acetic acid, ri, Propyl Acid Methyl Ester, Propyl Acid Ethyl Ester.

The reaction of a compound of formula (I) with a compound of formula 10 (IIIa) is preferably carried out in a diluent such as dimethylsulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric acid trisamide, sulfolane, acetonitrile, water, alcohol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine in the presence of an acid binding agent. Mixtures of these diluents may also be used.

All common inorganic and organic acid-binding agents can be used as acid binding agents. They preferably include alkali metal hydroxides, alkali metal carbonates, organic amines and amides. Particularly preferred are: triethylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), or excess t · '.. t 25 the amine used (VI c).

Γ, Reaction temperatures can be varied within wide limits. Generally, the reaction is carried out at a temperature of 20 to 200 ° C, preferably 60 to 130 ° C.

The reaction may be carried out under normal pressure but. 30 at elevated pressure. Generally pressures of about 100 to 10,000 kPa, preferably 100 to 1,000 kPa, are used.

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

The reaction of the compound of formula (I) with the Michael acceptor (IV) is preferably carried out in a diluent such as acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, an alcohol such as methanol, ethanol, n-propanol or isopropanol. or glyco-limonomethyl ether.

5 Reaction temperatures can be varied within wide limits. Generally, the reaction is carried out at a temperature of about 20 to 150 ° C, preferably 40 to 100 ° C.

The reaction can be carried out under normal pressure but also under elevated pressure. Generally, pressures of about 100 to about 10,000 kPa, preferably 100 to 1,000 kPa, are used.

In carrying out this process, preferably 1 to 5 moles, preferably 1 to 2 moles, of compound of formula (IV) are used per mole of the compound of formula (I).

Acid addition salts of compounds of formula (I) are prepared in conventional manner, for example, by dissolving betaine in aqueous acid and precipitating the salt as a water-miscible organic solvent such as methanol, ethanol, acetone, acetonitrile. Equivalent amounts of betaine and acid in water or an alcohol such as glycol monomethyl ether may also be heated and the mixture then evaporated to dryness or filtered; > t the precipitated salt. Pharmaceutically acceptable salts include, for example, hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, '··>' citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, galacturonic acid, salts of glutamic acid or aspartic acid.

The alkali metal or alkaline earth metal salts of the carboxylic acids of formula (I) are prepared, for example, by dissolving betaine in an excess of an alkali metal or alkaline earth metal hydroxide solution, filtering off the insoluble betaine and evaporating the filtrate to dryness.

The pharmaceutically acceptable salts are sodium, potassium or calcium salts. By reacting an alkali metal or alkaline earth alkali salt with a suitable silver salt such as silver nitrate, the corresponding silver salts are obtained.

The compounds of formula (I) are potent anti-biotically active compounds with low toxicity and a broad spectrum activity against Gram-positive and Gram-negative bacteria, especially entero-bacteria; above all, they also act on bacteria that are resistant to various antibiotics, such as penicillins, cephalosporins, aminoglycosides, sulfonamides, tetracyclines.

These valuable properties allow their use as chemotherapeutic active ingredients in medicine and as preservatives for inorganic and organic materials, especially as preservatives for all kinds of organic substances such as polymers, lubricants, dyes, fibers, leather, paper and wood, food and water.

The compounds of formula (I) act on a very broad spectrum of microorganisms. They can help to prevent and / or cure the diseases caused by Gram-negative and Gram-positive bacteria and bacterial-like microorganisms and / or to cure these diseases.

. · Compounds of formula (I) are characterized by: • 25 enhanced activity on resting and resistant: microorganisms. Resting bacteria, namely:; for bacteria that cannot be shown to have any growth, the compounds appear to be at significantly lower concentrations than the agents known hitherto. This • ^ 30 applies not only to the amount of material used but also to the killing rate. Such results could be observed in gram-positive and -negative bacteria, especially in the following: Staphylococcus aureus, Pseudomonas ae- '. ruginosa, Enterococcus faecalis and Escherichia coli.

Also, with respect to bacteria susceptible to the 11377111 lower grade, particularly resistant to Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis, the compounds of formula (I) have shown a surprising improvement in efficacy.

Particularly effective are the compounds of formula (I) against bacteria and bacterial-like microorganisms. They are thus particularly suitable for use in human and veterinary medicine for the prevention and chemotherapy of local and systemic infections caused by these microorganisms.

The compounds are also suitable for the control of protozoa and worms.

The compounds of formula (I) may be used in a variety of pharmaceutical preparations. Preferred pharmaceutical formulations include tablets, dra-ges, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, lotions, lotions, and sprays.

The following results demonstrate the surprising advantages of the 20 enantiomerically pure isomeric compound of formula VIc to the corresponding:,: racemic intermediate obtained by the racemic intermediate; ; compared to the point. Table 1 shows the minimum inhibitory concentration values (pg / ml) obtained by agar dilution using a · · 25 method in a Denley Multipoint inoculator. United Sensitest agar. In Table 1, Compound I is the isomer obtained by the novel compound of formula VIc, and * · '* Compound II is the corresponding racemic compound known from U.S. Patent 94,251.

30 Table 1 i

Fv rsJv ^ ^ 0H ° C

113771 12

Compound II I

H H

i H Vh U> o>

H H

5 Kanta BAY W 9140 BAY 10-9551 (trans.ras) (IS, 6S) E.coli Neumann 0.03 0.015

Klebs.pneum.63 0.125 0.03 10 Psdm.aeruginose

Walter 2 1

Staph.aureus 133 0.06 0.03

Enteroc. faecalis ICB 27101 0.5 0.125 Bacteroides fragilis DSM 2151 0.06 1

Preparation of compound of formula (VIc) and other prodrugs

Example A

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

B

:: (.

: w as: ¾ v> 25 1) trans-1-benzoyl-3-bromo-4- (2-hydroxyethoxy) -. To a solution of pyrrolidine 1-benzoyl-3-pyrroline (95 g, 0.55 mol) in ethylene glycol (380 g) at room temperature is added 101 g (0.57 mol) in portions of 5 g over 2 hours. . ·. N-bromosuccinimide. Then stir overnight at room, ·,; at room temperature, the mixture is poured into water, extracted with methylene chloride, dried over magnesium sulfate and evaporated. The residue (188 g) is chromatographed on silica gel using ethyl acetate.

Yield: 136.5 g (78% of theory), content: 99% (by GC).

2) trans-1-benzoyl-3-bromo-4- (2-tosyloxyethoxy) pyrrolidine 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 are dissolved in 750 ml of toluene and a solution of tosyl chloride (60 g, 0.31 mol) in toluene (450 ml) is added dropwise. The mixture is stirred for 2 days at room temperature, water is added to the mixture, the aqueous phase is separated and extracted with toluene. The toluene solutions are washed with 10% hydrochloric acid, dried over magnesium sulfate and evaporated, the residue dissolved in ethyl acetate and filtered on silica gel. The filtrate is evaporated.

Yield: 125 g (91% of theory).

By thin layer chromatography, the compound is homogeneous.

3) cis-8-benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane: trans-1-benzoyl-3-bromo-4- (2-tosyloxyethoxy): - pyrrolidine (124 g, 0.265 mol) is heated overnight under reflux with benzylamine (86 g, 0.8 mol) in 1.5 l xylene. Benzylamine salts for filtration ·. ; and the filtrate is evaporated to dryness.

t ·· * 'Yield of crude product: 91.2 g.

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

* I I

·· ;; 30 cis-8-Benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] cyclo [4.3.0] nonane (91 g, 0.265 mol) is heated at reflux overnight with concentrated hydrochloric acid (2000 ml) and water (140 ml). From the cooled mixture, the filtrate is filtered off, the benzoic acid is removed, the filtrate is evaporated to half volume, made alkaline with potassium carbonate, extracted with chloroform, the extract is dried over potassium carbonate, evaporated and distilled.

Yield: 30.7 g (48.8% of theory), b.p. 134-142 ° C / 60 Pa.

5 Concentration by GC: 92%.

5) cis-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane (26 g, 0.11 mol, 92%) is hydrogenated in a mixture of ethanol (180 ml) and concentrated hydrochloric acid (19 ml) in the presence of 10% Pd / activated carbon catalyst (3 g) at 100 ° C under 10 MPa H2 pressure. The catalyst is filtered off, the filtrate is evaporated and the precipitated crystals are dried in a desiccator over phosphorus pentoxide.

Yield: 17.1 g (77% of theory), m.p. 244-250 ° C. Example B

Enantiomeric resolution of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane to 150.1 g (1 mol) of D (-) tartaric acid in 700 ml of 20 methanol A solution of cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane (218.3 g, 1 'mol) in methanol (300 ml) at 0 ° C. Allow the solution to slowly cool to about 49 ° C until the solution begins to cloud and add 1 / 1,6S-5-benzyl: 25 lit-2-oxa-5,8-diazabicyclo [4.3. 0] nonane D-tartrate crystals, it is stirred at this temperature for 30 minutes to form crystals, and then the mixture is slowly cooled to 0-3 ° C. The crystals are filtered and washed with a mixture of ethanol (200 ml) and methanol 30 (100 ml) cooled to 0 ° C and then with ethanol (3 x 300 ml) and the product is air dried.

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

174.5-176.5 ° C, <<35 ee> 97% (1-phenylethyl isocyanate derivative: HPLC analysis), 15-13771 [α] 23 D = + 24.0 ° (c = 1, methanol).

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

Yield: 140.0 g (89% recovery), m.p. 176-177 ° C, 5 [α] 23 D = + 25.2 ° (c = 1, methanol).

The methanolic mother liquor of the first crystallization is evaporated in a rotary evaporator. The syrupy residue (236 g) is dissolved in water (500 mL), 6N NaOH solution is added to pH 12-13 and the solution is extracted with toluene-10 (3 x 360 mL), the extract is dried over sodium carbonate and evaporated in vacuo. The residual brown oil (113.1 g) containing 97% cis-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane by gas chromatography is used without purification of the IS, 6R enantiomer. -15 mystery.

The crude, enriched IS, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane (113.1 g, 0.518 mol) is dissolved in methanol (155 mL) and the solution is added dropwise to L (+). of boiling tartaric acid (77.8 g, 0.518 mol) in methanol (363 ml). Even during drip, crystalline whey is gradually formed. Stirring at 60 ° C is continued for an additional 1 hour, then the mixture is slowly cooled to 0 ° C over 2 hours. The crystals are filtered off, washed with ethanol / methanol (2: 1) cooled to 0 ° C and then 3 x 25 times with ethanol. The crystals are air-dry.

Yield: 145.5 g (79% of theory) IS, 6R-5-benzyl; 2-oxa-5,8-diazabicyclo [4.3.0] nonane L-tartrate, m.p.

174.5-176.5 ° C, ee > 97% (HPLC analysis of 1-phenylethyl isocyanate derivative), [α] 23 D = -24.0 ° (c = 1, methanol).

ß. * Release of the enantiomerically pure bases: 144 g (0.39 mol) of IS, 6R-5-benzyl-2-ox-. .,? -5,8-diazabicyclo [4.3.0] nonane-L-tartrate solvent • »·; 35 ml of water (250 ml) and 175 ml (1.05 L · mole) of 6N NaOH solution are added. The separated oil is dissolved in toluene (500 ml), the organic phase is separated and the aqueous phase is extracted with toluene (3 x 250 ml). The combined organic phases are dried over sodium carbonate, filtered and evaporated in a rotary evaporator. The residue is distilled under a Greater 5 vacuum using a 20 cm Vigreux column.

Yield: 81.6 g (96% of theory) of IS, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane, b.p. 120-139 ° C / 4 -7 Pa, concentration: 100% as determined by gas chromatography, 10 density: δ = 1.113 g / ml, [α] 23d = -60.9 ° (undiluted), distillation residue: 0.12 g.

In a similar manner, 139.0 g (0.376 mol) of 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-15 tartrate are obtained in a yield of 76.0 g (93% of theory) of 1R, 6S-5-benzyl-2-yl-oxa-5,8-diazabicyclo [4.3.0] nonane.

[α] 23 D = + 61.2 ° (undiluted).

The cis-5-benzyl-2-oxa-5,8-diazabicyclo [4. 3. The enantiomeric separation of trans-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane can also be performed analogously to the enantiomeric resolution of 0] nonane R, R and S, S-5-benzyl -2-oxa-5,8-diazabicyclo [4.3.0] nonane.

Example C

; : 25 1) 3S, 4S-4-Allyloxy-3-hydroxypyrrolidine-1; * carboxylic acid tert-butyl ester »·

A mixture of 80% NaH (16.5 g, 0.55 mol) and anhydrous dioxane (500 mL) is added dropwise at 60 ° C to a solution of S, S-3,4-dihydroxy-30 dissolved in anhydrous dioxane. pyrrolidine-1-carboxylic acid tert-butyl ester (DE-A

• »*; * 3,403,194) (107, g g, 0.53 mol) solution. The mixture is stirred for * * 4 hours at 60 ° C, then 64 g (0.53 mol) of allyl bromide are added dropwise. It is then stirred for 3 hours at 60 ° C. The mixture is evaporated and the residue is dissolved in a mixture of water (200 ml · 5 ml) and methanol (600 ml). The solution is extracted with pentane (3 x 200 mL), the methanol is evaporated in a rotary evaporator, the residue is diluted with water (200 mL) and extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulfate, evaporated and the residue is dissolved in tert-butyl methyl ether (200 mL). 9 g (44 mmol) of the educt crystallizes from solution 5 overnight. The ethereal solution is evaporated and the residue is distilled.

Yield: 83 g (80% calculated on the recovered educt and diallyl ether), b.p. 149 ° C / 70 Pa to 159 ° C / 09 Pa.

The distillate contains 5% educt and 4% diallyl ether.

The pentane extract gives 17 g of a mixture containing 15% of the desired product and 84% of diallyl ether.

[α] 23 D = -10.5 ° (c = 1, methanol).

2) 3S, 4S-3-Hydroxy-4- (2-hydroxyethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester 64 g (0.24 mol, 91%) 3S, 4S-4-Allyloxy The 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester is dissolved in methanol (250 mL) cooled to 0 ° C and ozone is passed through the solution until a solution of potassium iodide in the aft-wash bottle gives the ozone reaction and shows complete reaction. The ozone traces in the reaction mixture are removed by passing to the mixture: nitrogen, then the resulting ozone is reduced at 0 ° C: 25 g of sodium borohydride (18 g) added in 1 g portion; · You. It is then stirred overnight at room temperature, mixture; evaporate, dilute with water, add 20 g of potassium carbonate and extract with methylene chloride (5 x 100 ml). The organic solutions are dried over magnesium sulfate. 30 la and evaporated to dryness.

Yield: 65.8 g (100% of theory). The product is 91% as determined by gas chromatography. t: [α] 20 D = -15.2 ° (c = 0.97, methanol).

·, (3) 3S, 4S-1-tert-Butoxycarbonyl-3-tosyloxy-4-yl 35 (2-tosyloxyethoxy) pyrrolidine in 2.7 g (10 mmol, 91%) of 3S, 4S-3 -hydroxy-4- 113771 18 (2-Hydroxyethoxy) pyrrolidine-1-carboxylic acid 1-tert-butyl ester in methylene chloride (30 ml) is added 6 ml of 45% NaOH solution and 0.1 g of benzyltriethylammonium chloride and then to the mixture a solution of to-5 alkyl chloride (2.86 g, 20 mmol) in methylene chloride (10 mL) is added dropwise with cooling. Stirring is then continued for another hour at room temperature, the mixture is poured into water (20 ml), the organic phase is separated off and the aqueous phase is extracted with methylene chloride. The organic phases are dried over magnesium sulfate 10 and evaporated.

Yield: 5 g (90% of theory). The product is thin-layer chromatographic uniform.

4) IS, 6R-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-8-carboxylic acid tert-butyl ester 3S, 4S-1-tert-butoxycarbonyl-3-tosyloxy- 4- (2-tosyloxyethoxy) pyrrolidine (87 g, 156 mmol) is heated under reflux with benzylamine (58 g, 0.54 mol) in 1 liter of xylene overnight. The mixture is cooled, the precipitated benzylamine salts are filtered off and the filtrate is evaporated.

Yield: 43 g (58% of theory). The product is 67% gas chromatographically determined.

5) IS, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane; : 25 IS, 6R-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0] -; Nonane-8-carboxylic acid tert-butyl ester (43 g, 90 mmol) is heated to reflux in a mixture of concentrated hydrochloric acid (35 mL) and water (35 mL) until the evolution of carbon dioxide ceases. The mixture is made alkaline with ka-30 lime carbonate, extracted with chloroform, the organic solutions are dried over magnesium sulfate and distilled twice; test through a 20 cm Vigreux column.

; Yield: 11.1 g (55% of theory), b.p. 108-115 ° C / 7 Pa, 35 [α] 26D = -58.3 ° (undiluted).

i9 113771

Example D

1) 3R, 4R-4-Allyloxy-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

The reaction is carried out analogously to Example C 1) 5 starting from R, R-3,4-dihydroxypyrrolidine-1-carboxylic acid tert-butyl ester.

Kp. : 145 ° C / 10 Pa [α] 23 = +9.5 (c = 1.0, methanol)

The product is 95% as determined by gas chromatography.

2) 3R, 4R-3-Hydroxy-4- (2-hydroxyethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester

The reaction is carried out analogously to the 3R, 4R-4-allyloxy-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester of Example C 2).

Yield: 99% of theory (0.175 mole charge) [α] 20 D = +16.5 (c = 0.94, methanol).

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

The reaction is carried out analogously to Example C3) 20 starting from 3R, 4R-3-hydroxy-4- (2-hydroxyethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester.

* · '' Yield: quantitative (0.11 mol charge).

4) 1R, 6S-5-Benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-8-carboxylic acid tert-butyl ester :: The reaction is carried out analogously to Example C4). starting with 3R, 4R-1-tert-butoxycarbonyl-3-tosyloxy-4- (2-tosyloxyethoxy) pyrrolidine.

Yield: 40% of theory (0.1 mole charge).

5) 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [30.0] [4.3.0] nonane • * * *; The reaction is carried out analogously to Example C5) V starting from 1R, 6S-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane-8-carboxylic acid tert-butyl ester. Yield: 63% of theory (40mmol charge), b.p. 35-120 ° C / 6 Pa. The product is 95% as determined by gas chromatography.

20-13771 [α] 23 D = + 58.5 ° (undiluted).

Example E

1) IS, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride 5 IS, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane (7.5 g, 34.4 mmol) is hydrogenated in a mixture of ethanol (200 mL) and concentrated hydrochloric acid (7 mL) in the presence of 10% Pd / activated carbon catalyst (1 g) at 100 ° C. pressure. The catalyst is filtered and washed 10 times with water. The aqueous filtrate is evaporated to give a crystalline residue. The crystals are thoroughly rubbed in ethanol, the crystals are filtered and air dried.

Yield: 4.6 g (66.5% of theory), m.p. Mp 233-235 ° C.

2) IS, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane IS, 6R-5-benzyl-2-oxa-5,8-diazabicyclo [4.3.0] nonane (59 g, 0.27 mol) is hydrogenated in ethanol (500 ml) in the presence of 10% Pd / activated carbon catalyst (5 g) at 120 ° C and 12 MPa. The catalyst is filtered off, the filtrate is evaporated and the residue is distilled.

Yield: 32.9 g (95% of theory), b.p. 65 ° C / 3 Pa.

: Rotation [?] 28d = + 8.2 ° (undiluted).

: ee value 2 99.5% (derivative prepared with Mosher reagent).

25 Example F

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

The reaction is carried out analogously to that described in Example E1) starting from 1R, 6S-5-benzyl-2-oxa-5,8-diacetyl-sabicyclo [4.3.0] nonane.

Yield: 77% of theory (23.8 molar charge), mp 230-232 ° C.

• ·

t I

2) 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane I The reaction is carried out analogously to that described in Example E 2) starting with 1R, 6S-5-benzyl- 2-oxa-5,8-diacetyl • sabicyclo [4.3.0] nonane.

113771 21

Yield: 93.3% of theory (1.58 molar charge), b.p. 63-65 ° C / 3 Pa.

Rotation: [α] 23 D = -8.4 ° (undiluted) ee value> 99.5% (with derivative prepared with Mosher reagent).

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

Example G

1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane di-10 hydrobromide 1) 1R, 6S-5- (1R-Phenylethyl) -8-tosyl-2-oxa-5,8- diazabicyclo [4.3.0] nonane trans-3-bromo-1-tosyl-4- (2-tosyloxyethoxy) pyrrolidine (101.8 g, 0.196 mol) and R - (+) - 1-phenyl-15-ethylamine (72 g) , 0.584 mol) is refluxed in xylene (900 ml) overnight. The cooled solution is washed with 2N NaOH solution, dried over potassium carbonate, potassium carbonate is removed and the solution is evaporated. As the residue cools, crystals are separated which are filtered off and recrystallized from a mixture of washing gasoline (750 ml) and n-butanol (200 ml).

Yield: 15 g (39.6% of theoretical optically pure material), m.p .: 188 ° C, δ Rotation: [α] 28 D = + 103.7 ° (c = 1, CHCl 3).

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

• · I

hydrogenate the diazabicyclo [4.3.0] nonane (13 g, 33.6 mmol) in ethanol (200 mL) in the presence of 10% Pd / activated carbon catalyst (2.5 g) at 100 ° C at 10 MPa pai-7 neessa. The catalyst is filtered off, the filtrate is evaporated and the residue is crystallized from toluene (30 ml).

Yield: 7.5 g (79% of theory), m.p. Mp: 160-161 ° C,

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

35 3) 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrobromide 113771 22 1R, 6S-8-tosyl-2-oxa-5,8-diazabicyclo [4.3.0] no - nane (7 g, 24.8 mmol) is dissolved in 33% HBr glacial acetic acid (25 mL), 5 g of phenol is added and the mixture is stirred overnight at room temperature. The mixture 5 is diluted with diisopropyl ether, the crystallized salt is filtered and air dried.

Yield: 5.5 g.

Gas chromatography analysis of the derivative prepared with Mosher reagent shows only one of the 10 detectable enantiomers (ee> 99.5%).

Example H

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

fvAA <C00H

F A

15 1) 2-Bromo-3,4,5,6-tetrafluorobenzoyl chloride 365 g (1.33 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoic acid [Tetrahedron 2-3, 4719 (1967)]. add 2 liters to 1! · Thionyl chloride and the mixture is refluxed for 11 hours. 20 cooling until gas evolution ceases. Excess * thionyl chloride is removed in vacuo and the residue is distilled.

'** ·' Yield: 330 g (85% of theory), b.p. 81-85 ° C / 300-500 Pa.

2) (2-Bromo-3,4,5,6-tetrafluorobenzoyl) malonic, 1,1'-acid diethyl ester V, 15.9 g (0.167 mol) of magnesium chloride are added 150. · Ml of anhydrous acetonitrile (dried with zeolite) and '26.9 g (0.167 mol) of malonic acid diethyl ester are added dropwise with cooling. The mixture is cooled to 0 ° C, 46 ml (33.7 g, 0.33 mol) of triethylamine are added dropwise and the mixture is stirred for a further 30 minutes. 48.9 g (0.168 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoyl chloride are then added dropwise, stirring is continued for another hour at 0 ° C and the mixture is allowed to warm to room temperature overnight. To the mixture is added 100 ml of 5N hydrochloric acid, the mixture is extracted 3 times with methylene chloride, dried over sodium sulfate and evaporated to the dry state in a vacuum.

Yield: 62.7 g of crude product.

3) (2-Bromo-3,4,5,6-tetrafluorobenzoyl) -acetic acid ethyl ester 10 g of crude (2-bromo-3,4,5,6-tetrafluorobenzoyl) malonic acid diethyl ester are mixed with 150 ml of water, 0.6 g of 4-toluenesulfonic acid and the mixture is refluxed for 6 hours. The mixture is extracted with methylene chloride, the extract is washed with water, dried over sodium sulfate and evaporated to dryness.

Yield: 46 g of crude product, b.p. (probe balloon): 150-160 ° C (oven) / 300 Pa, mass spectrum: m / e 342 (M +), 297 (M + -OC 2 H 5), 263 (M + -Br), 257, 255 (M + -CH 2 CO 2 ), 235 (263 - 28).

4) 2- (2-Bromo-3,4,5,6-tetrafluorobenzoyl) -3-ethoxyacrylic acid ethyl ester ·, · Crude (2-bromo-3,4,5,6-tetrafluorobenzoyl) -1: acetic acid ethyl ester (45 g) adding acetic anhydride (32.2 g, 0.31 mol) and orthomic acid triethyl ethyl; 25 ter (28.4 g, 0.19 mol) and the mixture is heated under reflux for 2 hours. Excess reagent is removed first under vacuum and then under high vacuum (bath temperature 120-130 ° C) and the crude product is used in the next reaction step.

Yield: 50.7 g of crude product.

5) 2- (2-Bromo-3,4,5,6-tetrafluorobenzoyl) -3- *: cyclopropylaminoacrylic acid ethyl ester *. To the crude product obtained in Step 4) (50.7 g) in ethanol (90 ml) is added dropwise, under ice-cooling, 8.6 g (0.15 mol) of cyclopropylamine, the mixture is stirred at room temperature and then left overnight at room temperature, cool again, filter the crystals, wash with cold ethanol and dry.

Yield: 29 g (42% in four steps), m.p. 103-105 ° C

(Ethanol).

5 6) 5-Bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester 2- (2-bromo-3,4,5,6-tetrafluorobenzoyl) - To a mixture of 3-cyclopropylaminoacrylic acid ethyl ester (28 g, 68 mmol) and DMF (88 mL) is added 6.9 g (164 mmol) of sodium 10 fluoride and the mixture is heated under reflux for 6 hours. The mixture is cooled, poured into ice water, the precipitated precipitate (red) is filtered off, washed with copious water and dried at 80 ° C in a convection oven.

Yield: 27.3 g of crude product, m.p. 150-175 ° C; mp. after crystallization from glycol monomethyl ether; 187-191 ° C.

7) 5-Bromo-1-cyclopropyl-6,7,8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 26.7 g (68 mmol) of crude 5-bromo-1- Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid ethyl ester is added to a mixture of acetic acid (165 mL), water (110 mL) and concentrated sulfuric acid (18 mL) reflux for 2 hours. After cooling, the reaction mixture is poured into ice water, the precipitate precipitated is filtered off, washed with plenty of water and dried at 80 ° C in a convection oven.

Yield: 19.7 g (80% of theory), m.p. Mp: 208-210 ° C

: (decomposes); mp. after crystallization from glycol monomethyl ether: 212-214 ° C (dec.); 1 H-NMR (DMSO): 8.73 (s, 1H in C-2), 4.16 (m, 1H, cyclo, ···, propyl), 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).

The preparation of the compounds of formula (I) is analogous to that described in the following examples.

'! t ·! ; 35 - · »·

Example 1 "113771

ΔO

O

Ps ^ VyCOOH

trans-1 H -cyclopropyl-6,8-difluoro-1,4-dihydro-7- (cis-5-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) ) -4-Oxo-3-quinolinecarboxylic acid 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.43 g, 5 mmol) is heated at reflux for 1 hour. acetonitrile (15 mL) and dimethylformamide (75 mL) in the presence of 1,4-diazabicyclo [2.2.2] octane (0.67 g, 6 mmol) in 93% cis-2-oxa-5 , 8-diazabicyclo [4.3.0] nonane (0.74 g, 5.4 mmol). The suspension is evaporated to dryness, the residue is triturated with water, the precipitate is filtered off and dried at 80 ° C in vacuo.

*, Yield: 1.67 g (85.4% of theory), m.p. 210-212 ° C

(breaks down).

»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 - 20 quinolinecarboxylic acid hydrochloride I 1.6 g (4 mmol) of the product of Step A are dissolved in a 1: 1 mixture of hydrochloric acid and water (12 0 ml) at 60 ° C, evaporated to dryness and the residue is stirred Ethanol, the precipitate is filtered off and dried at 90 ° C under vacuum.

Iti · 25 where.

Yield: 1.57 g. mp. : 300-303 ° C (dec.), Tlc (HPLC): 97%.

• »* ··· 'C. Analogously to Example 1A, the following is obtained:; : From 1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] nonane 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1R, 6S) -2-oxa-5,8-di-# 113771 26 azabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid, m.p. 204-206 ° C (dec.).

D. In analogy to Example 1B, 1-cyclopropyl-6,8-difluoro-1,4-5-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] is obtained from the betaine of Example 1C. non-8-yl-4-oxo-3-quinolinecarboxylic acid hydrochloride, m.p. 324-325 ° C (dec), [α] 24 D = -241 ° (c = 0.59, water).

E. In analogy to Example 1A, 10 IS, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane is obtained from 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (IS , 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid, m.p. 204-206 ° C (dec.), [(X) 25d = + 248 ° (c = 0.57, DMF).

F. In analogy to Example 1B, the betaine from Example 10E is obtained from 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 hydrochloride, m.p. 323 ° C (dec.), 20 [α] 25 = + 238 ° (c = 0.5, water).

Example 2

; O

·: ·; f ^ COOH

Cl A

• ·

I I I

In analogy to Example 1, 8-chlorine is obtained - * !!! From 25 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, m.p. 180-185 ° C (dec.).

30 B. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-

»· I

'' 7- (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-113771 27 3-quinolinecarboxylic acid hydrochloride, m.p. 227-232 ° C (dec.).

C. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4- oxo-3-quinolinecarboxylic acid, m.p. 186-188 ° C (dec.), [Α] 26 D = -269 ° (c = 0.5, DMF) D. 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1R) , 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid hydrochloride, m.p. 278-280 ° C (dec), [α] 24 D = -208 ° (c = 0.5, water).

E. 8-chloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-7- (IS, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo- so-3-quinolinecarboxylic acid, m.p. 188-190 ° C (decomp.), 15 [α] 25 D = + 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-yl) -4-oxo- m.p. 3-quinolinecarboxylic acid hydrochloride, m.p. 292-294 ° C (dec), 20 [α] 27 D = + 193 ° (c = 0.5, water).

Example 3

: O

Analogously to Example 1A, 25 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained: * 1 ' · 1 A. 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (cis-2- ... 1-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4- oxo-3-quinolinecarboxylic acid, mp 246-249 ° C (decomposes) (glycolimone: 30 from methyl ether).

* 113771 28 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-quinolinecarboxylic acid, m.p. 243-245 ° C (dec.), 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-quinolinecarboxylic acid hydrochloride, m.p. 300 ° C (dec.), [Α] 23 D = -99 ° (c = 0.5, water).

Example 4 F 0

r N

H'NVisF A

10

In analogy to Example 1A, the following is obtained from 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-7-15 (cis-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid, m.p. 210-216 CC (dec.).

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, m.p. 234-237 ° C (dec.); [Α] 20 [tt] 24D = -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, m.p. 236-237 ° C (decomp.), Λmax = + 282 ° (c = 0.5, dmf).

25 »» »t a 1 a * a» »»> »*» a * a 113771 29

Example 5

NH 2 O

F COOH

H-n ^ s f A

A. To 4.1 g (10 mmol) of the product of Example 4A 40 in 5 ml of pyridine are added 5 ml of liquid ammonia and the mixture is heated in an autoclave at 130 ° C for 10 hours. After cooling, the precipitate is filtered, washed with water and dried at 100 ° C in a convection oven. The crude product (2 g) is purified by crystallization from glycol monomethyl ether-10, yielding yellow crystals.

Yield: 1.3 g (31% of theory) of 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-quinolinecarboxylic acid, m.p. 233-240 ° C (dec.).

B. Similarly, using the product of Example 4B, 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro is obtained. ro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4- (oxo-3-quinolinecarboxylic acid, m.p. 212-214 ° C (dec), 20 [α] 25 D = -260 ° (c = 0.5, DMF).

'! C. Analogously using the product of Example 4, 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; -so-3-quinolinecarboxylic acid, m.p. 213-215 ° C (dec), 25 [α] 26 D = + 261 ° (c = 0.5, DMF), mass spectrum: m / e 406 (M +, 95%), 346, 249, 98, 41, 28 (100%).

»K 113771 30

Example 6

Br O

F .JkJLcOOH h> 0 F λ

HN r * H

362 mg (1 mmol) of 5-bromo-1-cyclopropyl-6,7,8-tri-5-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated to reflux with acetonitrile (3 mL) and dimethylformamide (1, 5 ml) in a mixture of 1,4-diazabicyclo [2.2.2] octane (220 mg, 2 mmol) and 1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] nonane dihydrochloride for 1.5 hours 10 din (220 mg, 1.1 mmol). The suspension is cooled, the precipitate is filtered, triturated with water (30 ml), filtered and dried at 90 ° C under high vacuum.

Yield: 320 mg (68% of theory) of 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diaza-15-bicyclo) [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid, m.p. : 2 63 - 2 64 ° C,: ·. [α] D = + 251 ° (c = 0.3, CH 2 Cl 2).

Example 7

: O

'*' F - X.COOH

I ·:

CH3-co-ch-nV F A

; · 20; To 1.56 g (4 mmol) of the product of Example 1A in dimethylformamide (30 mL) are added chloroacetone (0.82 g, 8.8 mmol) and triethylamine (1.05 g, 10.4 mmol) and a mixture of The mixture is heated for 3 hours at 50-80 ° C. The resulting yellow * * * '·' · 25 solution is evaporated to dryness at 80 ° C / 1.5 kPa, the oily residue 113771 31 is triturated with water until a solid product is obtained. It is filtered, washed with water and crystallized from glyco-limonomethyl ether.

Yield: 830 mg (47% of theory) of 1-cyclopropyl-6,8-5-difluoro-1,4-dihydro-4-oxo-7- (cis-5- [2-oxopropyl] -2-oxa-5,8 -diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid, m.p. 192-193 ° C (dec.).

Example 8

O

Fy ^ vJLcOOH

ch-ch co ^ ^. ^ T? k.0 10 1.56 g (4 mmol) of the product of Example 1A are refluxed in 50 ml of ethanol with methyl vinyl ketone (1.8 g, 25.6 mmol) for 3 hours. The suspension is evaporated to dryness at 70 ° C / 1.2 kPa, the residue is triturated with water and the precipitate is recrystallized from glycol monomethyl ether.

, Yield: 1.33 g (72% of theory) of 1-cyclopropyl-6,8- • difluoro-1,4-dihydro-4-oxo-7- (cis-5- [3-oxo-1-butyl] - '· * 2-Oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -3-quinolinecarboxylic acid, m.p. 188-189 ° C (dec.).

Example 9

O O

F y ^ A ^ COOH

^ F A

cis 780 mg (2 mmol) of 1-cyclopropyl-7- (cis-2,8-diaza-25-bicyclo [4.3.0] non-8-yl) -6,8-difluoro-1,4-dihydro- 4-Oxo-3-quinolinecarboxylic acid is heated to reflux.

* I

113771 32 in ethanol (15 mL) with ethyl propolis acid (500 mg, 5 mmol) for 1 hour. The suspension is cooled, the precipitate is filtered off, washed with ethanol (2S ml) and dried at 80 ° C under high vacuum. Yield: 880 mg (90% of theory-5) 1-cyclopropyl-7- [2- (trans-2-ethoxycarbonyl-vinyl) -cis-2,8-diazabicyclo [4.3.0] non-8-yl) - 6,8-Difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p.

244-246 ° C.

In analogy to Example 9, the corresponding starting compounds are obtained: t> 113771 33

ro (—I

u

K

u in o

II

u r-9 Γ ”Ö co + X - oo U n \ _ m O = \ Z- <] ^« \ / .u 00> = \ Cuo ™ ^ / \ w 1 2 3 X- {v <- - A _ //

'-. ® S * O

- - "T

X z-7 X * - </ - II <.

U ^ U

• / "'' rr! U ---

• <S

: O o)

. Ή 4J

X w

, * <S * H

u •> 1 · * * 0 B u

- · + J * H JL

..: λ w ^ • ιιϋ cd) § I. „Ho

M

.... fc) rH

* I »· 2 {3 • 1 · 113771 34 3> ^ 'm y D o δ δ 8 .. ^ in« ί ιιΰ ρ ο tl H J Ο «S s S r9 ä fe Γ • S Ä? T *?

V

E E ---—-

> o O

s R

«O w H \, V— \ ON os cj

4J n _ / Vr> 1 S 2 <N

ω 0 = <2 <J .rjoor-O

5 \ _ / & t o O Os rn 5 to £ -in ^ ^ § * H _ / - * B. zV * * “° 0 ° m I r- ^ r1 ___ <o L / \ Ό W> <B <A . / ^ S K z-7 X X ffi «e - 0) w, c II U- U tu $ U <u u u / ^ Λ U * -

OF

5 O «s £ K .¾ S u ju H> - * u a m: g 'Sm * oj ^ * Φ Ä ö) \' H« $ £ »4J M ^

* W

'. 0) _____ tsp)

"B

• Öi '· Π · *,: H g rH CN n

, «M I — I I— {M

. . q w

· ,,, · <H

i *

O

113771 35

Example 14

h HERE

CH302C j ρΝ / γΛ'Ν

/ =%> V α A

407.5 g (1 mmol) of 8-chloro-1-cyclopropyl-6-fluoro-5'-1,4-dihydro-7- (1S, 6R-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid (from Example 2E) is refluxed in methanol (10 mL) with propiolate methyl ester (210 mg, 2.5 mmol) for 1 hour. The mixture is evaporated and the isolated crude product (450 mg) is crystallized from acetonitrile (4 ml).

Yield: 8-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) -IS, 6R-2-oxa-5,8-di-azabicyclo [4.3. .0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid, m.p. 153-156 ° C (dec), 15 [α] 28 = + 36 ° (c = 0.5, CHCl 3).

Example 15

F O

: f sJvVC00H

H JT Jj ch3o2c H / = cvV τ λ * “cis

In analogy to Example 14, the compound of Example 4A gives 1-cyclopropyl-5,6,8-trifluoro-1,4-di: * hydro-7- [5- (trans-2-methoxycarbonylvinyl) -cis -2-oxa-1 · 5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid, m.p. 169-170 (decomposed) (from glycol mono: methyl ether).

* »· 25

O

113771 36

Example 16

FN ** SVA ^ C00H

h X Γ T

CH302C f / = v%, J a

H ^ 0 H

Analogously to Example 14, the E-1-5 junction of Example 1 gives 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- [5- (trans-2-methoxycarbonyl-vinyl) -IS, 6R-2-oxa -5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3-quinolinecarboxylic acid, m.p. 230-234 ° C (dec.) (From glycol monomethyl ether), 10 [α] 28 D = -27 ° (c = 0.5, CHCl 3).

Example 17

Br O

F nJsvA, cooh

H TTT

ch3o2c! B

l / -V%, T A

X1. In analogy to Example 14, the compound of Example 6 gives 5-bromo-1-cyclopropyl-6,8-difluoro-1,1,4-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, m.p. 158-160 ° C (decomposition) (isopropyl .. list), V. 20 [α] 25 D = + 8 ° (C = 0.27, CHCl 3).

F O

Example 18 113771 37

co2c2h5 L jl JJ

/ H rNy ^ N C2H502C —CH = C ^ ') L) F

N P ^ TT H

To 818 mg (2 mmol) of 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-7- (1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] - 5 Non-8-yl) -4-oxo-3-quinolinecarboxylic acid (from Example 4B) In 15 ml of ethanol is added 680 mg (4 mmol) of acetylenedicarboxylic acid diethyl ester and the mixture is treated in an ultrasonic bath at 30 ° C for 1 hour. The suspension is filtered, the precipitate washed with ethanol and dried at 70 ° C under high vacuum.

Yield: 890 mg (77% of theory) of 1-cyclopropyl-7- [5- (1,2-bis-ethoxycarbonyl-vinyl) -1R, 6S-2-oxa-5,8-diazabicyclo [4.3.0] non-8- yl] -5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 220-222 ° C (ha-15) (from glycol monomethyl ether); [α] 25 D = (c = 0.5, CHCl 3).

Example 19

O

j c2Hs02c rt * 7

f A

, I trans, rac.

; · 1

In analogy to Example 9, 1-cyclopropyl: 6,8-difluoro-1,4-dihydro-7- (trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4 Oxo-3-quinolinecarboxylic acid gives 1-cyclopropyl-7- [5- (trans-2-ethoxycarbonyl-vinyl] -1,371,738-yl] trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl ) - 6.8-Difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. : 266-268 ° C (dec.) (From glycol monomethyl ether).

Example 20

O

F W ^ \ yA / COOH

CH3OOCh r-

^^ „0 r A

. 1 trans, rac.

In analogy to Example 9, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -4-oxo-3- quinolinecarboxylic acid is reacted with propionic acid methyl ester to give 1-cyclopropyl-7- [5- (trans-2-methoxycarbonylvinyl) trans-2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl ) -6,8-Difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 275-277 ° C (dec.).

15 »» »» ·%% »·» ·

Claims (2)

113771 Patent Tivaatimus Enantiomeeripuhdas (IS, 6S) -2-oxa-5,8-diethabicyclo [4.3.0] nonaani, jolla on kaava VI c 5 HN H ........ ί - ^ - Ή <VIc > HN_f O 10 Enantiomerically pure (IS, 6S) -2-oxa-5,8-diazabicyclo [4.3.0] nonane of formula VI c * H N j H ....... H (VIc) 'H N