All About Drugs

Example 1 Z

8-cyano-1-cyclopropyl-6 ,7-difluoro-1 ,4-dihydro-4-oxo-3-quinoline-carboxylic acid ethyl ester

 

a 3-bromo-2 ,4,5-trifluoro-benzoate

To a mixture of 1460 ml of methanol and 340 g of triethylamine, 772 g of 3-bromo-2 ,4,5-trifluoro-benzoyl fluoride was added dropwise under ice cooling. There is one

Stirred for an hour at room temperature. The Reaktionsgemsich is concentrated, the residue dissolved in water and methylene chloride, and the aqueous phase was extracted with methylene chloride. After drying the organic phase over sodium sulfate, concentrated, and the residue was distilled in vacuum. This gives 752.4 g of 3-bromo-2 ,4,5-trifluoro-benzoic acid methyl ester of boiling point 122 ° C/20 mbar.

b. 3-Cyano-2 ,4,5-trifluoro-benzoic acid methyl ester:

269 ​​g of 3-bromo-2 ,4,5-trifluoro-benzoic acid methyl ester and 108 g of copper cyanide are heated to reflux in 400 ml of dimethylformamide for 5 hours. , All volatile components of the reaction mixture are then distilled off in vacuo. The distillate was then fractionated on a column. This gives 133 g of 3-cyano-2 ,4,5-trifluoro-benzoate of boiling point 88-89 ° C / 0.01 mbar.

c. 3-Cyano-2 ,4,5-trifluoro-benzoic acid

A solution of 156 g of 3-cyano-2 ,4,5-trifluoro-benzoate in 960 ml of glacial acetic acid, 140 ml of water and 69 ml concentrated sulfuric acid is heated for 8 hours under reflux. Then the acetic acid is distilled off under vacuum and the residue treated with water. Of failed-ne solid is filtered off, washed with water and dried. Obtained

118.6 g of 3-cyano-2 ,4,5-trifluoro-benzoic acid as a white solid, mp 187-190 ° C.

d 3-cyano-2 ,4,5-trifluoro-benzoyl chloride:

111 g of 3-cyano-2 ,4,5-trifluoro-benzoic acid and 84 g of oxalyl chloride are stirred in 930 ml of dry methylene chloride with the addition of a few drops of dimethylformamide for 5 hours at room temperature. The methylene chloride is evaporated and the residue distilled in vacuo. This gives 117.6 g of 3-cyano-2 ,4,5-trifluoro-benzoyl chloride as a yellow oil.

e 2 – (3-cyano-2 ,4,5-trifluoro-benzoyl)-3-dimethylamino-acrylic acid ethyl ester:

To a solution of 36.5 g of 3-dimethylamino-acrylate and 26.5 g of triethylamine in 140 ml toluene, a solution of 55 g 3-cyano-2, 4,5 – trifluoro-benzoyl chloride are added dropwise in 50 ml of toluene so that the temperature 50-55 ° C remains. Then stirred for 2 hours at 50 ° C.

The reaction mixture is concentrated in vacuo and used without further

Processing used in the next step. f 2 – (3-cyano-2 ,4,5-trifluoro-benzoyl)-3-cyclopropylamino-acrylic acid ethyl ester:

To the reaction product of step e 30 g of glacial acetic acid are added dropwise at 20 ° C. A solution of 15.75 g of cyclopropyl amine in 30 ml of toluene is added dropwise. The mixture is stirred at 30 ° C for 1 hour. Are then added 200 ml of water, stirred 15 minutes, the organic phase is separated off and shakes it again with 100 ml of water. The organic phase is dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained is a set-without further purification in the next step.

g 8-cyano-l-cyclopropyl-6 ,7-difluoro-l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester:

The reaction product from stage f and 27.6 g of potassium carbonate are stirred in 80 ml dimethylformamide for 16 hours at room temperature. The reaction mixture is then poured into 750 ml ice water, the solid filtered off with suction and washed with 80 ml cold methanol. After drying, 47 g of 8 – cyano-l-cyclopropyl-6 ,7-difluoro-l ,4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester, mp 209-211 ° C.

Example 2 Z

2,4-dichloro-5-fluoro-l ,3-dimethylbenzene

 

a solvent-free

In 124 g of 3,5-dimethyl-fluorobenzene 1 g of anhydrous iron (III) chloride are pre-loaded and launched with the speed of chlorine (about 4 h), with which the reaction. This is initially slightly exothermic (temperature increase from 24 to 32 ° C) and is maintained by cooling below 30 ° C. After addition of 120 g of chlorine, the mixture is determined. According to GC analysis are 33.4% monochloro compound, formed 58.4% desired product and 5%> overchlorinated connections. The hydrogen chloride is removed and the reaction mixture is then distilled in a column in a water jet vacuum:

In the run 49 g of 2-chloro-5-fluoro-l ,3-dimethylbenzene obtained at 72-74 ° C/22 mbar. After 5 g of an intermediate fraction proceed at 105 ° C/22 mbar 75 g of 2,4 – dichloro-5-fluoro-l ,3-dimethylbenzene via, Melting range: 64 – 65 ° C.

b in 1,2-dichloroethane

1 kg of 3,5-dimethyl-fluorobenzene and 15 g of anhydrous iron (III) chloride are placed in 1 1 1 ,2-dichloroethane and chlorine is introduced in the same extent as the reaction proceeds (about 4 h). The reaction is initially exothermic (temperature rise from 24 to 32 ° C) and is kept below 30 ° C by cooling. After the introduction of 1200 g of chlorine are according to GC analysis 4% monochloro compound, 81.1% and 13.3% desired product overchlorinated connections emerged. After distilling off the solvent and the hydrogen chloride is distilled in a column in a water jet vacuum:

In the run 40 g of 2-chloro-5-fluoro-l ,3-dimethylbenzene receive. After some intermediate run going at 127-128 ° C/50 mbar 1115 g of 2,4-dichloro-5-fTuor-l ,3-dimethyl-ethylbenzene over.

Example 3 Z

2,4-dichloro-5-fluoro-3-dichloromethyl-l-trichloromethylbenzene

 

In a photochlorination using chlorine inlet and outlet for the hydrogen chloride to a scrubber and a light source in the vicinity of the chlorine inlet tube, 1890 g of 2,4-dichloro-5-fluoro-l ,3-dimethylbenzene pre-loaded and at 140 to 150 ° C. Chlorine metered. Within 30 hours 3850 g of chlorine are introduced. The content of the desired product according to GC analysis is 71.1% and the proportion of connections minderchlorierten 27.7%. The DestiUaton a 60 cm column with Wilson spirals provides a flow of 1142 g, which can be reused in the chlorination. The main fraction at 160-168 ° C / 0.2 mbar gives 2200 g of 2,4-dichloro-5-fluoro-3-dichloromethyl-l-trichloro-methyl benzene having a melting range of 74-76 ° C. After one recrystallization

Sample from methanol, the melting point 81-82 ° C.

Example Z 4

2,4-dichloro-5-fluoro-3-formyl-benzoic acid

 

In a 2500 ml stirred apparatus with gas discharge are presented 95% sulfuric acid at 70 ° C. and under stirring, 500 g of molten added dropwise 2,4-dichloro-5-fluoro-3-dichloromethyl-1 trichloromethylbenzene. It is after a short while hydrochloric development. Is metered during a 2 h and stirred until the evolution of gas after. After cooling to 20 ° C., the mixture is discharged ice to 4 kg and the precipitated solid is filtered off with suction. The product is after-washed with water and dried.

Yield: 310 g, melting range: 172-174 ° C

Example Z 5

2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid

 

In a stirred reactor 80 g of hydroxylamine hydrochloride in 500 ml of ethanol are charged and added dropwise 200 ml of 45% strength sodium hydroxide solution and then with 40 – 200 g of 2,4-dichloro-5-fluoro-3-formyl-benzoic acid added 45.degree.The reaction is slightly exothermic and it is stirred for 5 h at 60 ° C. After cooling to

Room temperature is provided by the dropwise addition of hydrochloric acid to pH <3, the product taken up in tert-butyl methyl ether, the organic phase separated and the solvent distilled off. The residue obtained 185 g of 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl benzoic acid, melting range: 190 – 194 ° C.

Example No. 6

2,4-dichloro-3-cyano-5-benzoyl-fιuor

 

In a stirred vessel with metering and gas outlet via a reflux condenser to a scrubber 600 ml of thionyl chloride are introduced and registered at 20 ° C. 210 g of 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl benzoic acid in the proportion as hydrochloric developed and sulfur dioxide. After the addition the mixture is heated until the gas evolution under reflux. Mixture is then distilled, and boiling in the range of 142-145 ° C/10 mbar, 149 g of 2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride (98.1% purity by GC) Melting range: 73-75 ° C.

Example No. 7

3-Cyano-2 ,4,5-trifluoro-benzoyl

 

50 g of potassium fluoride are suspended in 120 ml of tetramethylene sulfone and at 15 mbar for drying distilled (ca. 20 mL).Then, 50.4 g of 2,4 – dichloro-3-cyano-5-fluoro-benzoyl chloride was added and stirred at an internal temperature with exclusion of moisture for 12 hours at 180 ° C. Are removed by vacuum distillation to 32.9 g of 3-cyano-2 ,4,5-trifluoro-benzoyl fluoride in the boiling range of 98 –

Obtain 100 ° C/12 mbar.

Example No. 8

3-Cyano-2 ,4,5-trifluoro-benzoyl chloride

 

76.6 g of 3-cyano-2 ,4,5-trifluoro-benzoyl fluoride together with 1 g of anhydrous

Aluminum chloride introduced at 60-65 ° C and then added dropwise 25 g of silicon tetrachloride gas in the course of development. After the evolution of gas at 65 ° C is distilled in a vacuum. Boiling range 120-122 ° C/14 mbar, 73.2 g of 3 – cyano-2 ,4,5-trifluoro-benzoyl chloride over.

Example No. 9

1 – (toluene-4-sulfonyl-pyrroline

 

In a 20 1 HC4-HWS boilers are 2.016 kg (17.6 mol)

Submitted methanesulfonyl chloride in dichloromethane and 12 1 at -10 ° C internal temperature under strong cooling (-34 ° C) solution of 705 g (8.0 mol) of 2-butene-l ,4-diol in 1.944 kg (2.68 1 , 19.2 mol) of triethylamine was added dropwise over 30 minutes. A yellow suspension stirred for 1 hour at -10 ° C and then treated with 4 1 of water, the temperature rises to 0 ° C.The suspension is warmed to room temperature, stirred for 10 minutes at room temperature and then fed in a 30 1 separating funnel. The phases are stirred separately (good phase separation) and the aqueous phase extracted with 2 1 of dichloromethane. The combined dichloromethane phases are presented in a pre-cooled 20 1 HC4 vessel and kept at 0 ° C.

In another 20-1 HC4 boiler distillation 1.37 kg (8.0 mol) toluenesulfonamide be submitted in 6 1 toluene. It is mixed with 3.2 kg of 45% sodium hydroxide solution, 0.8 1 of water and 130.5 g Tetrabutylammomiimhydrogensulfat, heated to 40 ° C maximum temperature inside and creates a vacuum. Then, the previously obtained

Dichloromethane (15.2 1) was added dropwise over 1.5 hours while the dichloromethane was removed by distillation at 450 mbar (bath temperature: 60 ° C). During the distillation is foaming. In the end, a solution is available at an internal temperature of 33-40 ° C. After the addition of dichloromethane is distilled off, until barely distillate is (duration: about 85 minutes; internal temperature 40 ° C at 60 ° C bath temperature at the end). The vessel contents will be warm transferred to a separating funnel and rinsed the tank with water and 5 1 2 1 toluene at 50 ° C. Before phase separation, the solids are extracted in the intermediate phase and washed with 0.5 1 of toluene. The organic phase is extracted with 2.4 1 of water, separated and evaporated to dryness on a rotary evaporator. The solid residue (1758 g) is suspended in 50 ° C bath temperature in 1.6 1 of methanol, the suspension is transferred into a 10 1-flanged flask and the flask rinsed with diisopropyl 2,4 1. The mixture is heated to reflux temperature (59 ° C) and stirred for 30 minutes under reflux. The suspension is cooled to 0 ° C., stirred at 0 ° C for 1 hour and extracted with 0.8 1 of a cold mixture of ether Methanol/Diisopropyl-: washed (1 1.5). The crystals are dried under a nitrogen atmosphere at 50 ° C/400 mbar.

Yield: 1456 g (81.5% of theory)

Example Z 10

3 – (toluene-4-sulfonylV6-oxa-3-aza-bicvclo [3.1.0] hexane

^{o “|” h “CH3}

334.5 g (1.5 mol) of l-(toluene-4-sulphonyl)-pyrroline are dissolved in 1.5 1 of dichloromethane at room temperature and over 15 minutes with a suspension of 408 g (approx. 1.65 to 1, 77 mol) of 70-75% m-chloroperbenzoic acid in 900 ml of dichloromethane (cools added in manufacturing from). The mixture is heated under reflux for 16 hr (test for

Peroxide with KI / starch paper shows yet to peroxide), the suspension was cooled to 5 ° C, sucks the precipitated m-chlorobenzoic acid and washed with 300 ml of dichloromethane (peroxide with Precipitation: negative; precipitate was discarded). The filtrate is to destroy excess peroxide with 300 ml of 10% sodium sulfite solution, washed twice (test for peroxide runs now negative), extracted with 300 ml of saturated sodium bicarbonate solution, washed with water, dried with sodium sulfate and about a quarter of the volume evaporated. Again on test peroxide: negative. The mixture is concentrated and the solid residue is stirred with ice cooling, 400 ml of isopropanol, the precipitate filtered off and dried at 70 ° C in vacuum.

Yield: 295 g (82.3%),

Mp: 136-139 ° C,

TLC (dichloromethane methanol 98:2): 1 HK (Jodkammer)

Example CLOSED

^{trans-3-Hydroxy-4-(2-hydroxy-ethylamino-l-(‘toluene-4-sulfonyl’)} pyrrolidine

 

643.7 g (2.65 mol) 3 – (Toluoι-4-sulfonyl)-6-oxa-3-aza-bicyclo [3.1.0] hexane to 318.5 ml with ethanolamine in 4 1 of isopropanol at reflux for 16 hours cooked. After TLC monitoring, further 35.1 ml (total 5.86 mol) of ethanolamine added to the mixture and boiled again until the next morning. The mixture is filtered hot with suction and the filtrate concentrated on a rotary evaporator to 3.5 ltr. After seeding and stirring at room temperature for 3.5 1 diisopropyl ether are added, and stirred at 0 ° C for 6 hours. The precipitated crystals are filtered off, with 250 ml of a mixture of isopropanol / diisopropyl ether (1: 1) and washed 2 times with 300 ml of diisopropyl ether and dried overnight under high vacuum.

Yield: 663.7 g (83% of theory), content: 96.1% (area% by HPLC). Example Z 12

trans-toluene-4-sulfonic acid {2 – [[4-hydroxy-l-(toluene-4-sulfonyl)-pyrrolidin-3-yl] – ftoluol-4-sulfonyl)-amino]-ethyl ester)

 

552 g (1.837 mol) of trans-3-hydroxy-4-(2-hydroxy-ethylamino)-l-(toluene-4-sulfonyl) – pyrrolidine are dissolved under argon in 1.65 1 tetrahydrofuran and 0.8 1 of pyridine dissolved and at -10 ° C in portions 700 g (3.675 mol) p-toluenesulfonyl chloride are added thereto. The mixture is then stirred at this temperature for 16 hours. The work is done by adding 4.3 18.5 1% aqueous hydrochloric acid, extraction twice with dichloromethane (3 1, 2 1), washing the combined organic phases with saturated Natriurnhydrogencarbonatlösung (3 1, 2 1), drying over sodium sulfate, extracting and distilling off the solvent in vacuo. The residue is dried overnight at the oil pump and crude in the next reaction. There were 1093 g as a hard foam (content [area% by HPLC]: 80% Tris-tosyl-product and 13% tetra-tosyl-product, yield see next step). Example Z 13

rac. trans-5 ,8-bis-tosyl-2-oxa-5 .6-diazabicyclor4 .3.01 nonane

 

1092 g of crude trans-toluene-4-sulfonic acid {2 – [[4-hydroxy-l-(toluene-4-sulfonyl) – pyrrolidin-3-yl] – (toluene-4-sulfonyl)-amino]-ethyl} were dissolved in tetrahydrofuran and 9.4 1 at 0-3 ° C with 1.4 1 of a 1.43 molar solution of sodium hydroxide in

Methanol reacted. After half an hour at this temperature, 2.1 1 of water and 430 ml of diluted (2:1) was added to the mixture and acetic acid with previously isolated crystals of trans-toluene-4-sulfonic acid {2 – [[4-hydroxy-l – (toluene-4-sulfo-phenyl)-pyrrolidin-3-yl] – (toluene-4-sulfonyl)-amino] ethyl}-seeded. The suspension is stirred overnight at 0 to -4 ° C. The next morning, the crystals are filtered off, washed twice with 400 ml of cold mixture of tetrahydrofuran / water (4:1) and dried at 3 mbar at 50 ° C overnight.

Yield: 503 g of white crystals (62.7%> of theory over 2 steps), content: 99.7% (area% by HPLC). Example Z 14

Preparative chromatographic resolution of racemic rac. trans-5.8-bis-tosyl-2-oxa-5.6-diazabicyclor4.3.0] nonane

The chromatography of the racemate at room temperature in a column (inner diameter 75 mm), which with 870 g of a chiral stationary phase (kie-selgelgebundenes poly (N-methacryloyl-L-leucine-d menthylamide) based on the mer captomodifizierten silica Polygosil 100 , 10 microns; see EP-A 0 379 917) is filled (bed height: 38 cm). Detection is carried out using a UV detector at 254 nm

For the sample application using a solution of a concentration of 100 g of rac. trans-5 ,8-bis-tosyl-2-oxa-5 ,6-diazabicyclo [4.3.0] nonane in 3000 ml of tetrahydrofuran. A Trenncyclus is carried out under the following conditions: with the aid of a pump is required for 2 min at a flow of 50 ml / min, a part of the sample solution and the same time at a flow rate of 50 ml / min, pure n-heptane to the column.

Thereafter eluted at a flow rate of 100 ml / min 18 minutes with a mixture of n-Heptan/Tetrahydrofuran (3/2 vol / vol). This is followed for 3 minutes at a flow of 100 ml / min elution with pure tetrahydrofuran. Thereafter, further eluted with n-Heptan/Tetrahydro-furan (3/2 vol / vol). This cycle is repeated several times.

The first eluted enantiomer is the (lS, 6R) -5,8-bis-tosyl-2-oxa-5 ,6-diazabicyclo-[4.3.0] nonane, which is isolated by concentration. The eluate of the more retarding enantiomers is largely evaporated in vacuo, and the precipitated crystals are filtered off with suction and dried. From the separation of 179 g of racemate in this

As 86.1 g (96.2% of theory) of the enantiomer (lS, 6S) -5,8-bis-tosyl-2-oxa-5, 6 – diazabicyclo [4.3.0] nonane having a purity of> 99 % ee. Example Z 15

(LR, 6R-2-oxa-5.6-diazabicvclo [4.3.0] nonane dihydrobromide

 

38.3 g (87 mmol) of (lS, 6R) -5,8-bis-tosyl-2-oxa-5 ,6-diazabicyclo [4.3.0] nonane in 500 ml of 33 -% HBr / glacial acetic acid 10 g added anisole and heated for 4 hours at 60 ° C (bath). After standing overnight, the suspension is cooled, the precipitate filtered, with

100 ml of abs. Ethanol and dried at 70 ° C under high vacuum.

Yield: 23.5 g (93%) of white solid product, mp 309-310 ° C (dec.), DC (dichloromethane/methanol/17% aq ammonia 30:8:1.): 1 HK

[Α] _D: + 0.6 ° (c = 0.53, H ₂ O) (fluctuating).

Example Z 16

(LS.6S-2-oxa-5.6-diazabicvclor4.3.01nonan-Dihvdrobromid

 

Z is analogous to Example 15 from (lS, 6S) -5,8-bis-tosyl-2-oxa-5 ,6-diazabicyclo [4.3.0] no-nan (1S, 6S)-2-oxa-5, 6-diazabicyclo [4.3.0] nonane dihydrobromide receive. Example Z 17

(1 R.6R-2-oxa-5.8-diazabicvclo [4.3.Olnonan

 

1 Method: 5,8 g (20 mmol) of (lS, 6R)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane dihydro-drobromid are suspended in 100 ml of isopropanol at room temperature with 2.4 g ( 42.9 mmol) and powdered potassium hydroxide while leaving about 1 hour in an ultrasonic bath. The suspension is cooled in an ice bath, filtered, washed with isopropanol and the undissolved salt, the filtrate was concentrated and distilled in a Kugelrohr oven at 150-230 ° C oven temperature and 0.7 mbar. Obtained 2.25 g (87.9% of theory) of a viscous oil which crystallizes. [Α] _D -21.3 ° (c = 0.92, CHC1 ₃₎ Accordingly, this reaction can be carried out in ethanol.

2 Method: A homosexual genie catalyzed mixture of (lR, 6R)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane dihydrobromide and 620 mg (11 mmol) of powdered potassium hydroxide is dry in a Kugelrohr apparatus at 0.2 mbar and increasing oven temperature to 250 ° C distilled. Obtained 490 mg (76.6% of theory) of (lR, 6R) -2 – oxa-5 ,8-diazabicyclo [4.3.0] nonane as a viscous oil which slowly crystallized.

3 Method: 100 g of moist, pretreated cation exchanger (Dowex 50WX, H ⁺ – form, 100-200 mesh, capacity: 5.1 meq / g of dry or 1.7 meq / mL) are charged into a column with about 200 ml 1 N HC1 activated and washed neutral with water 3 1. A solution of 2.9 g (10 mmol) of (lS, 6R)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane

Dihydrobromide in 15 ml of water is added to the ion exchanger, and then washed with 2 1 water, and eluted with approximately 1 1 1 N ammonia solution. The eluate is evaporated. concentrated. Yield: 1.3 g of a viscous oil (quantitative), DC (dichloromethane/methanol/17% NH ₃ 30:8:1): 1 HK, GC: 99.6% (area).

Example Z 18

(LS.6SV2-oxa-5.8-diazabicvclor4.3.01nonan

 

Z is analogous to Example 17 from (lS, 6S)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane-di-hydrobromide the free base (lS, 6S)-2-oxa-5 ,8-diazabicyclo [ 4.3.0] nonane made.

Example Z 19

2 – (2,4-dichloro-3-cyano-5-fluoro-benzoyl)-3-dimethylamino-acrylic acid ethyl ester

 

To a solution of 626 g (4.372 mol) of 3-dimethylamino-acrylate and 591 g (4.572 mol) of ethyl-diisopropyl-amine (Hunigs base) in 1060 ml of dichloromethane, a solution of 1075 g starting at room temperature 2,4-dichloro -3-cyano-5-fluoro-benzoyl chloride (94% pure, corresponding to 1010.5 g = 4.00 mol) was dropped in 850 ml of dichloromethane. The temperature rises to 50-55 ° C (dropwise addition about 90 minutes). Then stirred for 2 hours at 50 ° C and the reaction mixture was used without further purification in the next step.

Example Z 20

2 – (2,4-dichloro-3-Cyano-5-fluoro-benzoyl-3-cvclopropylamino-acrylate

 

To the reaction mixture from the above step 306 g (5.1 mol) of glacial acetic acid are added dropwise under cooling at about 15 ° C. Then, with further cooling at 10-15 ° C. 267.3 g (4.68 mol) of cyclopropyl amine is added dropwise. Immediately after which the reaction mixture is mixed with 1300 ml of water under ice-cooling and 15 minutes stirred well. The dichloromethane layer was separated and used in the next step.

Example 21 Z

7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1.4-dihydro-4-oxo-3-chinolincarbonsäureethyl ester

 

To a heated to 60-70 ° C suspension of 353 g (2.554 mol) of potassium carbonate in 850 ml of N-methylpyrrolidone, the dichloromethane phase is dropped from the precursor (about 90 minutes). During the addition of the dichloromethane at the same time

Reaction mixture was distilled off. Then the reaction mixture for 5 Vz hours at 60-70 ° C is well stirred. The mixture is cooled to about 50 ° C. and distilled under a vacuum of about 250 mbar residual dichloromethane from. At room temperature is added dropwise 107 ml 30% hydrochloric acid under ice cooling, then to obtain a pH of 5-6 is set. Then, 2,200 ml of water are added under ice cooling. The reaction mixture is thoroughly stirred for 15 minutes, the solid was then filtered off and washed on the filter twice with 1000 ml of water and extracted three times with 1000 ml of ethanol and then dried in a vacuum oven at 60 ° C.

Yield: 1200 g (89.6% of theory).

This product can be purified, if desired by, the solid is stirred in 2000 ml of ethanol for 30 minutes at reflux. You filtered hot with suction, washed with 500 ml of ethanol and dried at 60 ° C in vacuum. Melting point: 180-182 ° C.

Η-NMR (400 MHz, CDC1 _3): d = 1.2 to 1.27 (m, 2H), 1.41 (t, 3H), 1.5-1.56 (m, 2H), 4, 1 to 4.8 (m, 1H), 4.40 (q, 2H), 8.44 (d, J = 8.2 Hz, H), 8.64 (s, 1H) ppm.

Example Z 22

7-chloro-8-cyano-1-cvclopropyl-6-fluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid

 

33.8 g (0.1 mol) of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-3-quinolinecarboxylate dissolved in a mixture of 100 ml of acetic acid, 20 ml water and 10 ml concentrated sulfuric acid was heated for 3 hours under reflux. After cooling, the mixture is poured onto 100 ml of ice water, the precipitate filtered off, washed with water and ethanol and dried at 60 ° C in vacuum.

Yield: 29.6 g (96% of theory),

Mp 216-21 C. (with decomposition)

Example 1

 

A 8-Cyano-l-cvclopropyl-6-fluoro-7-((lS.6S-2-oxa-5.8-diazabicvclo [4.3.0] non-8-yl – 1 ,4-dihydro-4-oxo-3 -quinoline carboxylic acid

1.00 g (3.26 mmol) of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated with 501 mg (3.91 mmol) of ( lS, 6S)-2-oxa-5 ,8-diazabicyclo [4.3.0] nonane and 0.9 ml of triethylamine in 30 ml of acetonitrile was stirred at 40-45 ° C under argon for 25 hours. All volatile components in vacuo. removed and the residue recrystallized from ethanol. Yield: 1.22 g (94%)

Melting point: 294 ° C. (with decomposition)

B) ^{8-Cyano-l-cyclopropyl-6-fluoro-7-(‘(lS.6S-2-oxa-5} ,8-diazabicvclo [4.3.01nonan-8-YLV 1.4-dihydro-4-oxo-3- quinoline carboxylic acid Hvdrochlorid

200 mg (0.63 mmol) of 8-cyano-l-cyclopropyl-6 ,7-difluoro-l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester to be 97 mg (0.75 mmol) of (lS, 6S)-2-oxa-5, 8 – diazabicyclo [4.3.0] nonane and 0.17 ml of triethylamine in 3 ml of acetonitrile was stirred at 40-45 ° C for 2 hours under argon. All volatile components in vacuo. removed, the residue treated with water, insolubles filtered off and the filtrate was extracted with dichloromethane. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. a. The resulting residue is dissolved in 6 ml of tetrahydrofuran and 2 ml of water and 30 mg (0.72 mmol) of lithium hydroxide monohydrate was added. After 16 hours of stirring at room temperature, acidified with dilute hydrochloric acid and the resulting precipitate was filtered off with suction and dried. Yield: 155 mg (57%) Melting point:> 300 ° C

C) 8-Cyano-l-cvclopropyl-6-fluoro-7-((lS, 6S-2-oxa-5.8-diazabicvclo [4.3.01non-8 yiyi.4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride

1 g (2.5 mmol) of 8-cyano-l-cyclopropyl-6-fluoro-7-((lS, 6S)-2-oxa-5 ,8-diazabicyclo [4.3.0] non-8-yl )-l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid is suspended in 20 ml of water was added to the suspension, 10 ml hydrochloric acid and stirred for In at room temperature for 3 hours. The resulting precipitate is filtered off, washed with ethanol and dried at 80 ° C under high vacuum.

Yield: 987 mg (90.6% of theory), Melting point: 314-316 ° C. (with decomposition).

D) 8-Cyano-l-cvclopropyl-6-fluoro-7-(iS, 6S)-2-oxa-5.8-diazabicyclo [4.3.0] non-8-YLV 1 ,4-dihydro-4-oxo-3 -quinoline carboxylic acid hydrochloride

86.4 g (217 mmol) of 8-cyano-l-cyclopropyl-6-fluoro-7-((lS, 6S)-2-oxa-5, 8 – diazabicyclo [4.3.0] non-8-yl) – l ,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved at room temperature in 963 ml of water and 239 ml of 1 N aqueous sodium hydroxide solution. After filtration and washing with 200 ml of water is added to 477 ml in aqueous hydrochloric acid and the precipitated crystals placed at 95 ° C to 100 ° C in solution. The solution is cooled overnight, the precipitated crystals are filtered off with suction and washed three times with 500 ml of water and dried in vacuum.

Yield 90 g (94.7% of theory), content:> 99% (area% by HPLC) 99.6% ee. [] _D ^23: -112 ° (c = 0.29, N NaOH).

 

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Tetrahedron Lett 2009, 50(21): 2525

A novel approach to Finafloxacin hydrochloride (BAY35-3377) Pages 2525-2528 Jian Hong, Zonghua Zhang, Huoxing Lei, Haiying Cheng, Yufang Hu, Wanliang Yang, Yinglin Liang, Debasis Das, Shu-Hui Chen, Ge Li

Finafloxacin hydrochloride, an important clinical compound was synthesized by a novel synthetic approach. An active intermediate ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate 19 was prepared by a new route. The chiral (S,S′)-N-Boc 10 was derived from protected pyrrolidine and the absolute stereochemistry was established by X-ray analysis.

http://www.sciencedirect.com/science/article/pii/S0040403909005875

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