SU1360584A3 - Method of producing naphthyrydine quinoline- or benzoxazine carbolic acids or their pharmaceutically acceptable salts of acid addition - Google Patents

Abstract

The invention relates to naphthyridine-, quinoline- or benzoxazine-carboxylic acid derivatives, in particular the compounds (I) of the general formula YC CH C - C (O) -C-C (O) OR ,, z6 x-C-CH-g -sn (I) where T. is RI; N-CCP5 X × MCH.); (СН2) .- 1СНг. I - “C CH -Cn-CH2, or / (W-7 Cr5Kb, p CCHoJ V ssng) / (c); le-: o-ny - u); s (b)); X - CH; CC1; CF, N, C-OH; C O - C, alkyl; p 1,2,3 or 4; , 2,3 or 4, and p + n. in the amount of 2.3.4 or.; five; p 0.1 or 2; n 1 or 2 .; i R, H; , Rj Н, СН or R Н, С-С-alkyl, С + Hydroxy-alkyl, trifluoroethyl, at Rj I С, -С4-alkyl or С, -С-alkoxy-; or C —C3 alkyl when, and Z is the value of a, with n + n 3; or CjHj; R4 C-C-alkyl, C2-C4-hydroxyalkyl, trifluoroethyl alkyl, or C-C-alkyl, when X C-OH in which hydrogen and R in the NR group can be mixed with a ring-forming radical - CHRg- CHRj, where or C, -C j-alkyl; or C-Pd-alkyl, or their pharmaceutically acceptable salts with antibacterial properties. The goal is to obtain more active compounds of the above class. The synthesis of compounds (I) is carried out by treating the corresponding chlorine or fluorine-substituted naphthyridinecarboxylic or quinolinecarboxylic acid with the corresponding amine. Compounds of compound (I) are reduced either in free form or in the form of an acid addition salt. Tests of compounds (I) show that they have a high antibacterial activity with a minimally used concentration of 0.1 µg / ml, which allows reducing the therapeutic dose for the organism. 3 tab. S W with G5 O SL 00 4 CM

Description

13605842

din-3-carboxylic acid, mp. 251-253 C,

Calculated,%: C 57.13; H 6.20; N. 15.68.

C, t 21 L 1 / - H, 0 Found,%: C 57.19; H 6.03; N 15.85.

EXAMPLE 3 1-EHYL-7- 3- (ethyl Example 1. 7-TZ- (Aminomethyl) -ig amino) methyl -1-pyrrolidinylJ-6-fluoro-I-pyrrolidinyl J-1- ethyl-6-fluoro-1,4-1,4-dihydro-4-oxy-1,8-naphthyridine-3-dihydro-4-OKCO-1, 8-naphthyridine-3-carboxylic acid.

boic acid, 1.00 g (3.69 mmol) 7-chloro-1-ethyl Mixture 2.00 g (7.39 mmol) 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthy-l-ethyl-6-fluoropl, 4-dihydro-4-oxo-1, 8-15 rdin-3-carboxylic acid, 100 ml naphthyridine-3-carboxylic acid, acetonitrile, and 1.42 g ( 11.08 mmol)

This invention relates to a process for the preparation of new naphthyridinquinoline; or benzoxazinecarboxylic acids with antibacterial properties.

 The purpose of the invention is the synthesis of compounds with high antibacterial activity.

250 ml of acetonitrile and 2.22 g (22.17 mmol) of 3-pyrrolidine methane amine (J.Org.Chem. 1961, 26.4955) ,. stirred at room temperature c. for 4 days. The reaction mixture is filtered and the precipitate is dissolved in 500 ml of ammonium hydroxide at pH 10.5. This solution is filtered and the solvent is removed under reduced pressure. The product is rinsed 2 times with 10 ml of water, then with ethanol - ether (1: 1) to dryness.

1.64 g of 7-HZ- (aminomethyl) -l-pyr-ididinyl-l-ethyl-6-fluoropl, 4-di-30 hydro-4-OKCo-l, 6-naphthyridine-3-carboxylic acid are obtained. m.p. 217-218.5 ° C.

Calculated,%: C 55.97; H 5.87; N 16.32,

C ,, F jFN.Oj 1 / 2НгО

Found,%: C 55.89; H 5.66; N 16.33.

Example 2. 1-Ethyl-6-fluoro-1,4-dihydro-7- {3- (methylamino) methyl-lN-ethyl-3-pyropolydine methanamine is stirred at room temperature for 3 days. Then the reaction 20 mixture is filtered and the precipitate is washed with water, ethanol with water (1: 3) and ether to dryness.

0.715 g of 1-ethyl-7- {3- (ethylamino) methylJ-1-pyrrolidinylJ-6-25 fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained, t mp.229.5-223.5 ° C.

Calculated,%: C 58.94; H 6.45; N 15.27; HjO 1.20.

C, 8 23FN4n3-0,24H20

Found,%: C 58.28; H 6.85; N 14.90; 0.80,

TG p and m 8 p 4, I-Ethyl-6-fluoro-1,4-DIGIDRO-4-OXO-7- (3- (propylamino) methyl-1-pyrrolidinyl -1,8-propylnaphthyridine- 3-carboxylic acid.

Almost a solution of 0.82 g (3.0 mmol) of 7-chloro-1-ztil-6-fluoro-1,4-DIHIDRO-4-OK-pyrrolidinyl-4-oxo-1, 8-naphthrin-40 8 naphthyridine-3 -carboxylic acid-3-carboxylic acid, you and 1.4 g (10 mmol) of N-propyl-3-pyr1, 00 g (3.69 mmol) of 7-chloro-1-3-ethyl-rolidine methane amine in 50 ml of acetonitrile are heated at boiling under reflux for 4 hours. Solution 6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 40 ml of acetonitrile and 1.27 g (11.08 mmol) N-methyl-3-pyrrolidine-methanamine is stirred at room temperature for 3 days. The reaction mixture is filtered and the precipitate is dissolved in an aqueous solution of ammonium hydroxide at pH 11, the solution is filtered and the solvent is removed under reduced pressure. The product is washed with 5 ml of water, 10 ml of ethanol - zfir (1: 1) and ether to dryness.

0.571 g of 1-eth1-6-fluoro-1,4-dihydro-7-GZ- (methylamino) methylJ-1-pyrrolidinyl} -4-oxo-1,8-naphthyri 45 are obtained.

the solvent is distilled off under vacuum, the residue

50

dissolved in water, filtered through a layer of glass fiber to clarify, and the filtrate was adjusted to pH 1.8 by adding 6 M hydrochloric acid. The resulting clear solution is lyophilized and the residue is recrystallized from ethanol. 400 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- {3- (propylamino) methyl -1-pyrrolidinyl J-1, 8-propylnaphthyridine-3-carboxylic acid are obtained, t .pl. 281-283 C, in the form of hydrochloride,

EXAMPLE 5, 1-Ethyl-6-fluoro, 4-DIHYDRO-7- / 3- {(1-methylethyl) amino

N-ethyl-3-pyprolidine methane is stirred at room temperature for 3 days. Then the reaction mixture is filtered and the precipitate is rinsed with water, ethanol - water (1: 3) and ether to dry residue.

0.715 g of 1-ethyl-7- {3- (ethylamino) methyl-1-pyrrolidinyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained, t. 222.5-231.5 ° C.

Calculated,%: C 58.94; H 6.45; N 15.27; HjO 1.20.

C, 8 23FN4n3-0,24H20

Found,%: C 58.28; H 6.85; N 14.90; 0.80,

TG p and m 8 p 4, I-Ethyl-6-fluoro-1,4-DIGIDRO-4-OXO-7- (3- (propylamino) methyl-1-pyrrolidinyl -1,8-propylnaphthyridine- 3-carboxylic acid.

Almost a solution of 0.82 g (3.0 mmol) 7-chloro-1-methyl-6-fluoro-1,4-DIGIDRO-4-OK5

the solvent is distilled off under vacuum, the residue

0

dissolved in water, filtered through a layer of glass fiber to clarify, and the filtrate was adjusted to pH 1.8 by adding 6 M hydrochloric acid. The resulting clear solution is lyophilized and the residue is recrystallized from ethanol. 400 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- {3- (propylamino) methyl -1-pyrrolidinyl J-1, 8-propylnaphthyridine-3-carboxylic acid are obtained, t .pl. 281-283 C, in the form of hydrochloride,

Example 5, 1-Ethyl-6-fluoro, 4-DIHYDRO-7- / 3- {(1-methylethyl) amino me31360584

thyl} -1-pyrrolidinyl / -4-OKCO-I, 8-naphtha is taken up in 10 ml of water, ethanol is ethyl thiridine-3-carboxylic acid (1: 1) and ether to the dry residue.

Almost a solution of 0.82 g (3.0 mol) 7-chloro-1-ethyl-6-fluoro-1,4-DIHIDRO-4-OXO-, 8-naphthyridine-3-carboxylic acid and 1.4 g (10 mmol) N- (2-nponmi) -3-pyrrolidine-methanamine in 50 ml of acetonitrile is heated at boiling with

ten

With constant refrigeration for 1 hour. The solvent is distilled off in vacuo, the residue is dissolved in water, filtered through a layer of glass fiber to clarify and the filtrate is brought to pH 2.0

Obtain 1.13 g of 7-GZ- (amknomethyl) - g 1-pyrrolidinyl -1-ethyl-6-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid, i.e. 234-23b.

Calculated,%: C 60.27; H 6.13; N 12.40.

...- j.} ..h.

Found,%: C 60.63; H 5.85; N 12.01.

PRI me R 8. 1-Ethyl-6-fluoro-1,4 by the addition of 6M hydrochloric acid - 15 dihydro-7- {3- (methyl-amino) methyl-pyr

slots The resulting clear solution is lyophilized and the residue is recrystallized from ethanol.

200 mg of 1-ethyl-6-fluoro-1,4-ridinyl} -4-oxo-3-quinol-1-carboxylic acid are obtained.

A mixture of 1.00 g (3.95 mmol) of 1-ethyl-6,7-difluoro-1,4-DIHIDRO-4-OXO-3-CI-

25

dimethylformamide, 75 ml of acetonitrile and 1.35 g (11.85 mmol) of N-methyl-3-pyrrolidine-methanamine are heated to a boil overnight. The reaction mixture is cooled to room temperature and filtered. The precipitate is washed with water, ethanol - ether (1: 3) and ether to dry residue.

1.17 g of 1-ethyl-6-fluoro-1,4-dihydro-7- / 3- (1-methylethyl) amino-methanol-carboxylic acid, 10 ml of N, N-tyl-1-pyrrolidinyl / -4-OXO are obtained. -1,8-naphthyridine-3-carbonic acid, m.p. 302-304 ° C, in the form of hydrochloride.

Example 8 p 6. (Cyclopropylamino) methyl J-1-pyrrolidinyl -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

Almost a solution of 0.82 g (3.0 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-DIHIDRO-4oxo-1, 8-naphthyridine-3-carboxylic acid - 30 dihydro-7- {3 - (methylamino) methyl -1-lots and 1.4 g (10 mmol) of cyclopropyl-pyrrolidinylJ-4-oxo-3-quinolinecarboxylic acid, mp.247-250 ° C.

Calculated,%: C 60.66; H 6.50; N 11, 79. 35 C gH FN303-l / 2 HjO

Found,%: C 60.69; H 6.30; N 11.82.

Example 8 p 9. 1-Ethyl-7- {3- (methyl-amino) methyl-1-pyrrolidinyl-6-fluoro-3-pyrrolidine-methanamine in 50 ml of acetonitrile is heated under reflux for 2 hours. The solvent It is distilled off in vacuo, the residue is dissolved in water, filtered through a layer of glass fiber to clarify and the filtrate is adjusted to pH 2.0 by the addition of 6 M hydrochloric acid. The resulting clear plant is 40 1,4-dihydro-4-oxo-3-quinolinecarbonyl

the thief is lyophilized and the residue is recrystallized from ethanol.

600 mg of 7- {3- (cyclopropylamino) methyl -1-pyrrolidinide I-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained, t. square 271-274 ° C, in the form of hydrochloride.

Pr and p 7. (Aminomethyl) - 1-pyrrolidinyl J-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid.

A mixture of 1.00 g (3.95 mmol) of 6,7-difluoro-1-ethyl-1,4-DIHIDRO-4-OXO-3-CHIVA acid.

A mixture of 2.70 g (10.0 mmol) of 7-chloro-1-methyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 60 ml of ft45 picoline and 3.85 g (30, 0 mmol) N-ethyl-3-pyrrolidine-methanamine is heated at reflux overnight. The reaction mixture is cooled to room temperature.

50 add 100 ml of concentrated ammonium hydroxide. The solvents are distilled off under reduced pressure. A solution of 200 ml of dichloromethane ether (1: 3) is added. The resulting precipitate of noline-carboxylic acid, 40 ml of aceto-55 is filtered off, rinsed with ethanol-nitrile and 1.28 g (12.75 mmol) of 3-pyr-ester (1: 3) and ether until dry, osrolidine-methanamine is stirred at tata.

room temperature overnight. 1.87 g of 1-ethyl-7- {3- (ethyl- the reaction mixture is filtered, the precipitate is amino) m & -1-pyrrolidinyl-6-fluoro. 1.13 g of 7-HZ- (amknomethyl) are obtained - g 1- pyrrolidinyl -1-ethyl-6-fluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid, i.e. 234-23b.

Calculated,%: C 60.27; H 6.13; N 12.40.

...- j.} ..h.

Found,%: C 60.63; H 5.85; N 12.01.

Example 8. 1-Ethyl-6-fluoro-1,4-ridinyl} -4-oxo-3-quinol-1-carboxylic acid.

A mixture of 1.00 g (3.95 mmol) of 1-ethyl-6,7-difluoro-1,4-DIHIDRO-4-OXO-3-CI-

dimethylformamide, 75 ml of acetonitrile and 1.35 g (11.85 mmol) of N-methyl-3-pyrrolidine-methanamine are heated to a boil overnight. The reaction mixture is cooled to room temperature and filtered. The precipitate is washed with water, ethanol - ether (1: 3) and ether to dry residue.

1.17 g of 1-ethyl-6-fluoro-1,4-lincarboxylic acid are obtained, 10 ml of N, N-

your acid.

A mixture of 2.70 g (10.0 mmol) of 7-chloro-1-methyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 60 ml of ft45 picoline and 3.85 g (30, 0 mmol) N-ethyl-3-pyrrolidine-methanamine is heated at reflux overnight. The reaction mixture is cooled to room temperature.

50 add 100 ml of concentrated ammonium hydroxide. The solvents are distilled off under reduced pressure. A solution of 200 ml of dichloromethane 51360584 is added.

1,4-dihydro-4-oxo-3-quinolinecarbonyl Calculated,%: C 60.15; H 6.11; N11.08.

howl acid, so pl. 248-252 p.

Calculated,%: C 58.81; H 7.00; N 10.83.

C.5H24 ™ ZOZ Found,%: C 58.70; H 6.53; N 10.85.

EXAMPLE 10 7-GZ- (Aminomethyl) 1-pyrrolidinyl -1-ethyl-6, 8-difluoro-1 o lidinyl-6,8-difluoro-1- (2-fluoroethyl) -1.4 -dihydro-4-oxo-3-quinolinecarboxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, so pl. 221-223 ° C (Pa). 7- {3- (Ethylamino) methyl - -pyrrolidinyl} -6,8-difluoro-1-ethenyl-1,4-diC gH jF jOj

Found,%: C 59.85; H 6.17; N11.08.

The following compounds are prepared analogously:

7- {3- (Ethylamino) methyl-1-pyrric acid.

A mixture of 0.50 g (1.84 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid, 5 ml of ace-15 hydro 4-oxo-3-quinoline-carboxylic acid - tonitrile, 0.28 g (1.84 mmol), 1.8 lots, so pl. 2 7-220 ° C (116).

1-Methyl-7- 3- C (ethylamino) methyl) -I-pyrrolidinyl} -6,8-difluoro-, 4-dihyd

Diazabicyclo 5.4. OJ undec-7-ene and 0.19 g (1.94 mmol) of 3-pyrrolidine methane-amine are heated at reflux for 1 hour, 20

ro-4-oxo-3-quinoline carboxylic acid, so pl. 238-240 0 (Ive).

Example 12. 1-Ethyl-6,8-difluoro-1,4-digidro-7- / 3- (2-hydroxyethyl) amino methyl -1-pyrrolidinyl / -4-oxo6, 7,8-trifluoro-4-oxoquinoline -3-carboxylic acid, 5 ml of acetonitrile, 0.28 g (1.84 mmol), 1.8-diazabicyclo 5.4.0 undec-7-ene, and 0.28 g (1.94 mmol) 2- The (3-pyropolyde methyl) amine ethanol is refluxed for 1 hour and then stirred overnight while the mixture is stirred at room temperature overnight. The reaction mixture is filtered and the precipitate is rinsed with ethyl ether.

0.56 g (aminomethyl) - 25 3-quinoline carboxylic acid is obtained. 1-pyrrolidinyl 1-ethyl-6,8-difluoro-Mixture 0.50 g (1.84 mmol) of 1-ethyl 1; 4-dihydro-4-oxo-3-quinoline-carboxylic acid, m.p. 219-221 s.

The following compounds are prepared analogously: 30

(Aminomethyl) -1-pyrrolidinsh1 - 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, m.p. 224-226 ° C (10a).

(Aminomethyl) -1-pyrrolidinyl - 5 natal temperature. The reaction mixture is 6,8-difluoro-1-ethenyl-1,4-dihydro-4-filtered and the precipitate is rinsed with ether

oxo-3-quinolinecarboxylic acid, to the dry residue,

m.p. 204-208 0 (106). 0.5 grams of 1-ethyl-6,8-difluoro-Pp is obtained. 1-ethyl-7- {3- (ethyl-1,4-dihydro-7- (3- (2-hydroxyeth-1) amino) methyl 1-pyrrolidinyl} -6,8-di- 40 amino methyl} - pyrrolidinyl / -4-oxofluoro-1, 4-dihydro-4-oxo-3-quinoline-

boom acid

A mixture of 22.50 g (83.03 mmol) of 1-ethyl-1,4-DIGIDRO-4-OXO-6,7,8-trifluoro-3-quinoline-carboxylic acid, 225 ml of acetonitrile, 11.25 g (87 , 08 mmol) N-ethyl-3-pyrrolidine-methanamine and 12.6 g (83.03 mmol) of 1,8-diazabicyclo 5.4.0 undec-7-ene are heated under reflux for 1 hour. Then they are stirred at room 45

3-quinolinecarboxylic. acids, so pl. 215-216 ° C.

When using N- (2,2,2-triphyphorethyl) -3-pyrrolidine-methanamine, 1-ethyl-6,8-difluoro-1,4-dihyd-PO-4-OXO-7- / 3- { (2,2,2-trifluoroethyl) amino methyl -1-pyrrolidinyl / -3-quinoline-carboxylic acid, m.p. 182-183 ° C (12a).

Using three equivalents of N- (2-propyl) -3-pyropolydine methane-amine in the absence of 1,8-diazabicyclo 5.4.0 undec-7-ene, 1 g of ethyl 7- / 3- (1-methylethyl) is obtained. Amino methyl g I-1-pyrrolidinyl / -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 198-200 ° C (126).

50

temperature overnight. The solid is filtered off and promoted with ether.

26.33 g of 1-eth1-7- 3- (e-tilamino) methyl U-1-pyrrolidinyl 1- 6,8-difluoro-I, 4-DIHYDRO-4-OXO-3-CHI-nolinecarboxylic acid are obtained, t “PL.208-.

Calculated,%: C 60.15; H 6.11; N11.08.

Found,%: C 59.85; H 6.17; N11.08.

The following compounds are prepared analogously:

7- {3- (Ethylamino) methylJ-1-pyrro1-methyl-7- 3- C (ethylamino) methyl) - I-pyrrolidinyl} -6,8-difluoro-, 4-dihydro-4-oxo-3-quinoline-carboxylic acid, so pl. 238-240 0 (Ive).

Example 12. 1-Ethyl-6,8-difluoro-1,4-digidro-7- / 3- (2-hydroxyethyl) amino methyl -1-pyrrolidinyl / -4-oxo6, 7,8-trifluoro-4-oxoquinoline -3-carboxylic acid, 5 ml of acetonitrile, 0.28 g (1.84 mmol), 1.8-diazabicyclo 5.4.0 undec-7-ene, and 0.28 g (1.94 mmol) 2- (3-pyropolyde methyl) amine of ethanol is refluxed for 1 h and then stirred overnight with a com-quinoline-carboxylic acid. A mixture of 0.50 g (1.84 mmol) of 1-ethyl1, 4-dihydro-7- / 3- (2-hydroxyeth1) amino methyl} - -pyrrolidinyl / -4-oxo

3-quinolinecarboxylic. acids, so pl. 215-216 ° C.

When using N- (2,2,2-triphyphorethyl) -3-pyrrolidine-methanamine, 1-ethyl-6,8-difluoro-1,4-dihyd-PO-4-OXO-7- / 3- { (2,2,2-trifluoroethyl) amino methyl -1-pyrrolidinyl / -3-quinoline-carboxylic acid, m.p. 182-183 ° C (12a).

Using three equivalents of N- (2-propyl) -3-pyropolydine methane-amine in the absence of 1,8-diazabicyclo 5.4.0 undec-7-ene, 1 g of ethyl 7- / 3- (1-methylethyl) is obtained. Amino Methyl I-1-pyrrolidinyl / -6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, m.p. 198-200 ° C (126).

PRI me R 13. (Aminometsh1) - 1-piperidinyl -1-ethyl-6-fluoro-1,4-di

hydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

A mixture of 0.52 g (0.19 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 150 ml of acetonitrile and 0, 66 g (5.76 mmol) of 4-aminomethylpiperidine is stirred at room temperature for 4 days. The reaction mixture is d for 4 hours and the ethanol is distilled off and the precipitate is dissolved in water in vacuo. The residue is diluted to

100 ml with water and adjusted to 0H. sodium hydroxide to pH 7.3. After oho ammonia, pH 10.5. The solution is filtered and the solvent is distilled off under reduced pressure. Product is promyshayut

Clarification to 5 ° C The precipitate is removed.

water, then ether to dry residue. After filtration, follow up.

This gives 1.23 g (aminomethyl) -1-piperidinyl J-1-ethyl-6-fluoro-1,4-di-hydro-4-OKCo-1, 8-naphthyridine-3-carboxylic acid, m.p. . 120-22 C.

Calculated,%: C 57.72; H 6.15; N16.08.

C HjtFN Oj- ЗНгО

Found,%: p. 57.72; H 6.00; N 15.80.

Example 14. (Aminomethyl), - I-piperidinyl -1-ethyl-6-fluoro-1,4-di-hydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

20

water, ethanol, ether and dried in vacuo.

Obtain 0.6 g of 7- (3-amino-1-pyrrolidinyl) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinolinecarboxylic acid, m.p. 240-242 ° C.

Example 16. 7- (3-Amino-1-azetidinyl) -I-ethyl-6-fluoro-1,4-digidro-4-ox-o-1,8-naphthyridine-3-carboxylic acid 25

Suspension 0.81 g (3.0 mmol) 7-chloro-1-ethyl-6-fluoro-1,4-DIHIDRO-4-OK-CO-I, 8-naphthyridine-3-carboxylic acid, 1.0 g (6.0 mmol) 1,1-dimetsh1- A mixture of 1.04 g (3.84 mmol) of 7-chloroso ethyl (3-azetidinyl) carbamate, 1.0 g of 1-ethyl-6-fluoro-1 , 4-dihydro-4-oxo-1,8- (10 1- {mol) triethylamine and 50 ml acenaphthyridine-3-carboxylic acid, 100 ml acetonitrile and 1.32 g, (11.5 mmol) 3- aminomethylpyridine is stirred at room temperature for 4 days. The reaction mixture is filtered and the precipitate is dissolved in aqueous ammonia, pH 10.5. The solution is filtered and the solvent is distilled off under reduced pressure. The product was purified. The turbid solution was clarified with a filter with water, then with ether until dry, and the filtrate was adjusted to pH 7.3 dock with a pressure of 1.0N. sodium hydroxide.

1.23 g (aminomethyl) is obtained. - The resulting precipitate is removed by filter-1-piperidinyl-α-ethyl-6-fluoro-1,4-dihydrogenation, washed successively with hydro-4-oxo-1,8-naphthyridine-3- carboxy s with water, ethanol and ether, and dried

in a vacuum.

Obtain 0.2 g of 7- (3-amino-1-azetidinyl) -1-ethyl-6-fluoro-I, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 50, t .pl. 260-262 C.

Using 1,1-dimethyl (3-azetidinylmethyl) carbamate, 7- (3-aminomersh1) -1-azetidinyl-l-ethyl-6-fluoropl, 4-dihydro-4-oxo-1,835

The tonitrile is heated at reflux for 4 hours. The solvent is distilled off in vacuo and the residue is dissolved in IO ml of trifluoroacetic acid. The solution is stirred at room temperature for 1 hour, the solvent is distilled off in vacuo and the residue is dissolved in water.

New acid, so pl. 120-122 C.

Calculated,%: C 57.72; H 6.15; N16.08.

C, H, j, FN 03-3H20.

Found,%: C 57.72; H 6.00; N 15.80.

Example 15: 7- (3-A1, 1-o-pyrrolidinyl) -1-ethyl-6.8-difluoro-1, A-di-hydro-4-oxo-3-quinolinecarboxylic acid .55 naphthyridine-3-carboxylic acid,

A suspension of 0.81 g (3.00 mmol) of 1 - mp. 239-240 C (16a). ethyl 1,4-dihydro-b, 7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, Example 17: I-Ethyl-6-fluoro-1.41, 28 g (10 mmol ) 3-acetylaminopirdo-dihydro-7- 3- (methylamino) methyl-4-oxidine (Patent SP1A No. 4341784 and 1.5 g (15 mmol) of triethylamine in 50 ml of acetonitrile are boiled under reflux for 4 hours. The solvent It is distilled off in vacuo and the residue is dissolved in 50 ml of 6.0 M hydrochloric acid-ethanol (1: 1). The mixture is heated under reflux until 5 ° C the precipitate is removed

Suspension 0.81 g (3.0 mmol) 7-chloro-1-ethyl-6-fluoro-1,4-DIHIDRO-4-OK-CO-I, 8-naphthyridine-3-carboxylic acid, 1.0 g (6.0 mmol) 1,1-dimesh1- ethyl- (3-azetidinyl) carbamate, 1.0 g (10 1- {mol) of triethylamine and 50 ml of acetic acid. The solution is clarified by filtration and the filtrate is brought to pH 7.3 by the addition of 1.0 n. sodium hydroxide.

The tonitrile is heated at reflux for 4 hours. The solvent is distilled off in vacuo and the residue is dissolved in IO ml of trifluoroacetic acid. The solution is stirred at room temperature for 1 hour, the solvent is distilled off in vacuo and the residue is dissolved in water.

91

co-1,8-naphthyridine-3-carboxylic acid.

A suspension of 0.81 g (3.0 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-DIHIDRO-4-OK-co-1., 8-neftyridin-3-carbonoBoy acid, 0.9 g (9.0 mmol) of N-methyl-3-azetidine methane amine and 30 ml of acetonitrile are refluxed for 6 hours. The reaction mixture is cooled to 5 ° C. The filtered solid is rinsed with acetonitrile and ether and dried in vacuo. The dried solid is suspended in 70 ml of water and basified to pH 11.0 after filtration through a layer of glass fiber to clarify, the filtrate is acidified to pH 7.4 by addition of 1.0 M hydrochloric acid.

lots. The resulting precipitate is removed by 20 pyrrolidinyl-7-oxo-7H-pyrido (,

2,3-de) -1,4-benzoxazin-6-kaEboxylic acid, so pl. 235-237.5 ° C.

Calculated,%: C 59.37; H 6.03; N 10.93.

C 5H FN304 l / 2 Found: C 59.34; H 5.78; N 10.95.

When using N-ethyl-3-azethi-EXAMPLE 20 (Ethyl-amidin-methanamide, 1-ethyl-7- (3-but) methyl -1-pyrrolidinyl-1 -9-fluoro-2,3-methylaminomethyl) is obtained. -1-azetidinyl-6-fluoro-zo dihydro-3-methyl-7-oxo-7H-pyrido (1,

filtering, sequentially, with water, 2-propanol, ether and sumat in vacuum.

270 mg of 1-ethyl-6-fluoro-1,4-dihydro-7- 3- (methylamino) -methyl} -25 4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained, m.p. 180-182 ° C.

1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, so pl. 208-210 C (17a).

The reaction of N-ethyl-3-azetidine methane-amine with 1-ethyl-1,4-dihydro-4-oxy-6, 7, 8-trifluoro-3-quinolinecarboxylic acid gives 1-ethyl-7- (3-ethylamino; methyl } -1-azetidinyl-6,8-difluoro-1,4-1-dihydro-4-oxo-3-quinoline-carboxylic acid, mp 208-21 ° C (176).

Example 18. (Aminomethyl) l-pyrrolidinyl-9-fluorop-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (l, 2,3-de) -1,4-benzoxazin-6-carboxylic acid.

0.75 g (0.27 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (1,2,3-de) -1,4-benzoxazin-6 -carboxylic acid, 40 ml of acetonitrile and 0.80 g (8.0 mmol) of 3-pyrrolidine methane-amine are refluxed overnight. The solvent is distilled off under reduced pressure and the residue is triturated with 40 ml of ethanol-ether (1: 1).

Obtain 0.90 g of (aminomethyl) -55 Х HSRHOLIN- or naphthyridine-γ-pyrrolidinyl-9-fluoro-2,3-dihydrone acid, 10 ml of solvent 3-methyl-7-pkso-7H-t1irido (1.2 , 3-de) - (acetonitrile or / j-picoline), one-154-benzoxazin-6 -carboxylic acid, the equivalent equivalent of 1,8-diazabicyclo m.p., 213-216 C..4.0 undec-7-ene and 1.05 equivalent to 0584

ten

Example 19. 9-Fluoro-2,3-dihydro-Z-methyl-1O- {3- (methylamino) methyl-J-1-pyrrolidinyl-7-oxo-7H-pyrido (1, 2,3-de) - 1,4-benzoxazin-6-carboxylic acid.

0.75 g (2.7 mmol) of 9.1O-difluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido (1,2,3-de) -1,4-benzoxazin-6 -carboxylic acid, 40 ml of acetonitrile and 0.91 (0.80 mmol) of N-methyl-3-pyrrolidine-methanamine are refluxed overnight. The solvent is distilled off under reduced pressure and the residue is triturated with 95% ethanol and with ether to dryness.

0.63 g of 9-fluoro-2,3-dihydro-3-methyl-10- 3- (methylamino) methylJ10 is obtained.

20 pyrrolidinyl-7-oxo-7H-pyrido (,

2,3-de) -I, 4-benzoxazin-6-carboxylic acid.

0.75 g (2.7 mmol) of 9,0-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (1,2,3-de) -1,4-benzoxazine -6-carboxylic acid, 40 ml of acetonitrile and 1.03 g (8.00 mmol) of K-ethyl 1-3-pyrrolidine methanamine are refluxed overnight. The reaction mixture is cooled in an ice bath and then filtered. The precipitate is washed with ethanol - ether (4: 1), and then with ether to the dry residue.

0.86 g of 10- {3- (ethylam-5-but) methyl 3-1-pyrrolidinyl-9-fluoro-2,3-dihydro-3-ethyl-7-oxo-7H-pyrido (1,2,3- de) -1,4-benzoxazin-6-carboxylic acid, T..PL. 221-224 S.

Calculated,%: C 60.29; H 6.33; 0 N 10.55.

CioHj FNjO - 1/2

Found,%: C 60.45; H 6.21; N 10.80.

EXAMPLE 21 A mixture of 1 g of an amine haloide is refluxed for a predetermined time, then stirred overnight at room temperature. The product is filtered and washed with ethyl ether to dryness. The required amines can also be prepared according to the procedure described in J. Heterocyclis Chem. 1983, 20,321, 439.

According to this method, the following compounds are obtained:

1-Ztil-6-fluoro-1,4-DIHIDRO-7-5 methyl octahydropyrrolo (3,4-c) pyrrol-2-yl-4-oxo-1,8 naphthyridine 3-carboxylic acid (21)

1-Ethyl-6 fluoro-1,4-dihydro-7-octa-hydropyrrolo (3,4-c) pyrrol-2-ylJ-4-oxo-1,8-naphthyridine-3 carboxylic acid (21a)

1-Ethyl-6-fluoro-1,4-DIHIDRO-7-octa-hydro-1H-pyrrolo (3,4-c) pyridin-2-yl-4-oxo-1,8-naphthyridine-3-carboxylic acid

A suspension of 0.8 g (3.0 mmol) of 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid in 40 ml of acetonitrile is processed 0.80 g (6 , 3 mmol) 2,7-diazacipot4.4J

35

acid (216)

I-Ethyl-6-fluoro-I, 4-dihydro-7-5-non-25 nonane, and the mixture is stirred for 2 days; tiloctahydropyrrolo (3,4-c) pyrrol-2-at room temperature, boiled

-4-oxo-3-quinolinecarboxylic acid under reflux for 1.5 h, oht (21c) is laden and filtered.

1-Ethyl-6-fluoro-1,4-dihydro-7-octa-1.17 g of the target compound, shehydropyrrolo (3,4-c) pyrrol-2-ylJ-4-OK-30, are obtained, m.p. 234-240 0 (decomp.). co-3 quinoline carboxylic acid (21 g) Calculated,%: C 60.47; H 5.61;

1-Ethyl-6-fluoro-1,4-dihydro-7-octa-hydro-1H-pyrrolo (3,4-c) pyridine-2-pc - 4-oxo-3-quinoline-carboxylic acid (21d)

1-Ethyl-6,8-difluoro-1,4-DIHIDRO-7-5-methyl-octagropyrrolo (3,4-c) pyrrol-2-yl-4-oxo-3-quinolinecarboxylic acid, m.p. 213-214 C (21e)

1-Ethyl-6,8-difluoro-1,4-DIHIDRO-7-40 octahydropyrrolo (3,4-c) pyrrol-2-yl-4-oxo-3-quinoline-carboxylic acid (21g)

1-Ethyl-6,8-difluoro-1,4-DIHIDRO-7 octahydro-1H-pyrrolo (3,4-c) pyridine- f ec-7-ella and 5.42 g (20 mmol) of 2- yl) -4-oxo-3-quinolinecarboxylic acid.-1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1, 8-naphthyridine-3-carboxylic acid. After stirring for 23 hours at room temperature

N 11.13.

C U N C P

B d .J. Uj

Found,%: C 60.17; H 5.46; N 11.11.

PRI me R 24. 1-Ethyl-6-fluoro-1,4-DIHIDRO-7- (7-methyl-2,7-diazaspiro 4. 4 non-2-yl) -4-oxo-1, 8-naphthyridine-3-carboxylic acid.

A stirred suspension of 4.40 g (20.7 mmol) of 2-methyl-2,7-diazaspiro 4.4 nonane dihydrochloride in 200 ml of acetonitrile is treated with 9.42 g (62 mmol) of 1,8-diazabicyclo 5.4.0} unlot (21z)

Example 22. 1-Ethyl-6-fluoro-1,4-dihydro-7-2.7-diazaspiro (4,4) non-2yl-4-oxo-1, 8 naphthyridine-3-carbono-50 precipitated product filter out howling acid hydrochloride.

A suspension of 1.10 g (4.00 mmol) of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-digentro-1,8-naphthyridine-3-carboxylic acid in 40 ml of acrylonitrile is treated 1.10 g (8.7 mmol) of 2,7-diazaspiro 4 .4 nonane and the mixture is stirred at room temperature for 4.5 hours. Crude solid stock55

It is taken up in acetonitrile and ether and recrystallized from ethanol.

3.99 g of the expected compound are obtained, m.p. 252-254 C (decomp.).

Using 2,8-diazaspiro 5.5 undecane dihydrochloride, 1-ethyl-6-fluoro-1,4-DIHYDRO-7- (2,8-diazas-57-dec-2-yl) 4-oxo-1 is obtained, 8-naphthi5

0

Stir, mix with 10 ml of water, filter, dissolve in 100 ml of 6 M ammonium hydroxide and lyophilize to obtain 0.53 g of solid, which is diluted with hydrochloric acid, filtered, lyophilized, and crystallized from ethanol-water.

Obtain 0.26 g of the title compound, m.p. above 300 ° C.

Calculated,%: C 54.47; H 5.59; N 14.12; C1 8.94.

C, 8R ,, N, C1FO,

Found,%: C 54.14; H 5.60; N 13.85; C1 8.68.

Example 23 1-Ethyl-6,8-difluoro-1,4-DIHIDRO-7- (2,7-diazaspiro 4.4 non-2-yl) -4-oxo-3-quinoline-carboxylic acid.

A suspension of 0.8 g (3.0 mmol) of 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid in 40 ml of acetonitrile is processed 0.80 g (6 , 3 mmol) 2,7-diazacipot4.4J

f Ec-7-ella and 5.42 g (20 mmol) was added. 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-diN 11.13.

C U N C P

B d .J. Uj

Found,%: C 60.17; H 5.46; N 11.11.

PRI me R 24. 1-Ethyl-6-fluoro-1,4-DIHIDRO-7- (7-methyl-2,7-diazaspiro 4. 4 non-2-yl) -4-oxo-1, 8-naphthyridine-3-carboxylic acid.

A stirred suspension of 4.40 g (20.7 mmol) of 2-methyl-2,7-diazaspiro 4.4 nonane dihydrochloride in 9 ml of acetonitrile is treated with 9.42 g (62 mmol) of 1,8-diazabicyclo 5.4.0} the entrained product is filtered,

It is taken up in acetonitrile and ether and recrystallized from ethanol.

3.99 g of the expected compound are obtained, m.p. 252-254 C (decomp.).

Using 2,8-diazaspiro 5.5 undecane dihydrochloride, 1-ethyl-6-fluoro-1,4-DIHYDRO-7- (2,8-diazas-57-dec-2-yl) 4-oxo-1 is obtained, 8-nafti13

EXAMPLE 27 9-Fluoro-2,3-dihydro-3-methyl-1 O- (7-methyl-2,7-diazaspiro C 4,4) non-2-yl) -7-oxo-7H-pyrido (, 2,3-de) -1,4-benzoxazin-6-carboxylic acid,

Suspension 0.42 g (1.97 mmol) 2-metsh1-2,7-diazaspiro G4.4 nonane dihydrochloride in 25 ml of acetonitrile obridine-3 - carboxylic acid, so pl. 188-192 ° С (decomp.) (24a).

Example 25. Ethyl-6-fluoro-1,4-dihydro-7-C7-methyl-2,7-diazaspypo 4.4 ion-2-yl) -4-oxo-3-quinolinecarboxylic acid.

A suspension of 0.65 g (3.05 mmol) of 2-methyl-2,7-diazaspiro 4.4 nonane dihydrochloride in 40 ml of acetonitrile work 0.85 g (5.80 mmol) of 1.8-dip 1 , 33 g (9.0 mmol) 1,8-day-diazabicyclo 5.4.0 undec-7-ene and doazabicyclo 5.4.01 undex-7-ene and add 0.52 g (1.85 mmol) 9,10-dibavil 0.76 g (3.0 mmol) of 1-ethyl-fluoro-2,3-dihydro-3-methyl-7-oxo-1H6, 7-difluoro-1,4-diHYDRO-4 -OXO-3-CHINO-pyrido- (1,2,3-de) -1,4-benzoxazin-6-lincarboxylic acid. The mixture is boiled with 15 carboxylic acid. The mixture was stirred at reflux overnight. The hot solution is filtered. After crystallization at room temperature, the product is filtered and washed with acetonitrile.

0.72 g of the expected compound is obtained, m.p. 239-241 C (decomp.).

Calculated,%: C 64.33; H 6.48; N 11.25.

C ,, H2, N, FOj

2 hours at room temperature and then refluxed overnight. The product, which crystallizes upon cooling, is extracted with acetonitrile and recrystallized from acetonitrile.

0.45 g of the expected compound is obtained, m.p. 227-230 ° C (decomp.). Calculated,%: C 63.15; H 5.55;

25 N 10.52.

W fo

11 22- 3 Increased,%: C 64.25; H 6.50; N 11,27.-Naida no,%: C 63.13; H 5.73;

Example 26. 1-Etil-6,8-difluoro-N 10.51.

1,4-dihydro-7- (7-methyl-2,7-diazaspi-EXAMPLE 28 1-Ethyl-6-fluoro-1,4-.4 non-2-yl) -4- oxo-3-quinoline-3H dihydro-7- (7-ethyl-2,7-diazaspiro 4.4 carboxylic acid, non-2-yl) -4-oxo-1,8-naphthyridine-S Suspension 0.64 g (3, 0 mmol) 2-methyl-2,7-diazaspiro 4.4 nonane dihydrochloride c. 40 ml of acetonitrile carboxylic acid.

The title compound is prepared analogously to Example 24, 1.33 g (9.0 mmol) of 1,8-di-gg of 1-ethyl-6-fluoro-7-chloro-4-oxo-, 4-azabicyclo 5.4.0 are reacted. undec-7-ene and added dihydro-1,8-naphthyridine-3-carboxylic acid, 0.81 g (3.0 mmol) of 1-methyl-6,7,8-acid with 2-ethyl-2,7 -diazaspiro 4.4 trifluoro-1,4-dihydro-4-oxo-3-quinolinone nonan dihydrochloride, mp 215-i carboxylic acid. The mixture is stirred - 217 ° C (decomp.).

4 minutes at room temperature, refluxed for 1.5 hours and stirred at room temperature overnight. The precipitate is filtered off and promoted with acetonitrile and ether.

Obtain 0.87 g of the target compound, so pl. 229-231 C (dec,). Calculated,%: C, 61.37; H 5.92; N 10.74. , Cj..O,

Found,%: C 61.20; H 5.88; N 10.75.

Using 2,8-diazaspiro 15.5 undecane dihydrochloride, 1-ethyl-gg dihydrochloride is obtained, m.p. 199-202 C 6,8-difluoro-1,4-dihydro-7- (2,8-diaza- (decomp.).

Spiro 5.5 undec-2-yl) -4-oxa (-3-quino- Calculated,%: C 62.21; H 6.22; lincarboxylic acid, mp. 267; N 10.36.

268T (decomp.) (26a).

14

0584

EXAMPLE 27 9-Fluoro-2,3-dihydro-3-methyl-1 O- (7-methyl-2,7-diazaspiro C 4,4) non-2-yl) -7-oxo-7H-pyrido (, 2,3-de) -1,4-benzoxazin-6-carboxylic acid,

Suspension 0.42 g (1.97 mmol) 2-metsh1-2,7-diazaspiro G4.4 nonane dihydrochloride in 25 ml of acetonitrile about

0.85 g (5.80 mmol) of 1,8-diazabicyclo 5.4.0 undec-7-ene is added and 0.52 g (1.85 mmol) of 9,10-dipyrido- (1,2 , 3-de) -1,4-benzoxazin-6-carboxylic acid. Mixing is mixing

2 hours at room temperature and then refluxed overnight. The product, which crystallizes upon cooling, is distilled with acetonitrile and recrystallized from acetonitrile.

0.45 g of the expected compound is obtained, m.p. 227-230 ° C (decomp.). Calculated,%: C 63.15; H 5.55;

N 10.52.

W fo

11 22- 3 Find out,%:

carboxylic acid.

The target compound is obtained analogously to example 24 as a result of the reaction; 40 Calculated,%: C, 61.84; H 6.49; N 14.42.

C, H ,, N, F03

 Found,%: C 61.68; H 6.17; N 14.20.

45 PRIOMER 29. -Etil-6z-8-difluoro-1,4-dihydro-7- (7-methyl-2,7-diazaspiro 4.4 non-2-yl) -4-oxo-3- quinoline carboxylic acid.

50

The target compound is prepared analogously to example 26 as a result of the reaction of 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with 2-ethyl-2,7-diazaspiro 4.4 nonane

CivHjsNjF Oj

 51360584 16

Found,%: C 62.24; H 6.15; 175 C, which is then hydrolyzed at

N 10.36, refluxed

Example 30, (Aminomethyl) -bn, hydrochloric acid, 4-thiazolyl -1-ethyl-6-fluoro-1,4-dihyd-Obtain the target compound, t, pl,

ro-4-oxo-3-quinoline carboxylic acidic acid, 230-234 s (times) lot. Calculated,%: C 56.50; H 4.46;

A suspension of 0.59 g (1.54 mmol) of these-N 11.63. 7-Bromoacetyl-1-ethyl-6-C, L-free ester, fluoro-, 4-dihydro-4-oxo-3-quinoline-C, H JJFOJS Found:%: C 56.26; H 4., 56;

bonic acid in 4 ml of K, L-dimethyl-N 11.40.

process formamide treatment 0.22 g Example 32. 7-G2- (Ethylaminome (1.67 mmol) acetamidothioacetamide, mn1) -4-thiazolyl -1-ethyl-6 fluoro-1., 4After stirring for 3 hours, dihydro-4- oxo-3-quinolinecarboxylic

the mixture is treated with 0.22 ml (1, 58 mmol) of 2 acids hydrochloride, triethylamine, stirred for 1 hour and mixed in 40 ml of ice water. The precipitate from the reaction of 7-bromo-acetylter ethyl ester, rinse with water, and s-tyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxostate to give 0.45 g of crude 3-quinolinecarboxylic acid with 2- ( Substances. Chromatography on a column of acetamyl-K-ethylamino) thioacetamide in

with 20 g of silica gel using chloro-o-ethanol, 1 form ethyl ester (9: 1) is obtained and crystallization of ethyl 7-2 (N-acethyl-N-ethyl amino) from ethanol, 0.37 g of ethyl Tyl-4-thiazolyl-6-fluoro-1,4-dihydr 7-H 2- (acetamidomethyl) -4-4-oxo-3-quinolinecarboxylic acid ester,

thiazolyl -1-ethyl-6-fluoro-1 54-dihydro-25t.pl. 160-161 C, which is then hydro4-oxo-3-quinolinecarboxylic acid, is lysable at reflux although hot melt. 230-233 C (Rael.). 6n hydrochloric, hydrochloric

A solution of 0.32 g (0.76 mmol) with ethyl acid to give the desired compound (acetamidomethyl) -4-ester, t, bm. 289 300 ° C (decomp.), Thiazolyl -1-ethyl-6-fluoro-1,4-dihydroso Calculated,%: C 51.81; H 4.73;

4-oxo-3-quinolinecarboxylic acid in N 10.07; C1 8.50, 3 ml of 6N hydrochloric acid C gH gN ClFOjS -0.3 H, jO stirred at the same time as boiling with reverse; Found,%: C 51.81; H 4.79;

fridge for 3 hours. MixtureN 10.09; C1 8.49.

ball to dryness and result, Example 33 33. 1-Ethyl-6-fluoro-1,4tiruyuschie solid suspendiran-dihydro-7- / 2 - {(2-hydroxyethyl) amino

they are dissolved in 5 ml of water and dissolved by the addition of methyl j-4-thiazolyl-4-oxo-3-quinoline in 1N. sodium hydroxide to pH 11. carboxylic acid hydrochloride. After filtration, the product is precipitated As in Example 30, as a result

adding 1n. hydrochloride preparation of 7-bromoacetyl acid ethyl ester to pH 6.2, filtered, washed with 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3 with water and dried., a quinolinecarboxylic acid with 2-tN- (2 Get 0.22 g of (aminomethyl) -acetoxyethyl) -K-acetylamino-thioacet4-thiazolyl -1-ethyl-6-fluoro-1, 4-dihyd-amide in ethanol get ethyl

ro-4-oxo-3-quinolinecarboxylic acid-45ether 1-ethyl-6-fluoro-1,4-dihydro-7- / 2 tons, mp, 249-254 ° С (decomp.). (2-au, eTOKCH3Tmi) -N-acetylamino

Froze (Methylamino-methylj-4-thiazolyl / -4-oxo-3-quinolinmethyl) -4-thiazolyl -1-ethyl-6-fluoro-1,4-carboxylic acid, m.p. 148-152 ° C

the dihydro-4-oxo-3-quinolish sarbonone which is re-converted into hydrochloric acid, the substance melts at 164-165 ° C,

Analogously to example 30, as a result, it is hydrolyzed at reflux.

reactions of ethyl 7-bromoacetate 1-cooler 6n. hydrochloric

1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-acid, giving the desired compound,

quinolinecarboxylic acid with 2- (H-ace-m.p. decl. of methyl-H-methylamino) thioacetamide in etagg Calculated,%: C 50.76; H 4.02;

Nol get ethyl ester 1-ethyl-6-N 9,87. fluorine -7-2- (L-acetyl-K-methylamino- N FC104P tyl) -4-thiazol., 4-DIHYDRO-4-OXO- Found,%; C 50.36; H 4.50;

3-quinoline carboxylic acid, m.p.173-N 9.66.

Example 34, 7-G2- (1-aminoethyl 4-thiazolyl-α-ethyl-6-fluoro-1,4-dihydro-4-oxCo-3-quinolinecarboxylic acid.

Analogously to Example 30, the reaction of 7-bromo-acetyl-1-ethyl-b-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid ethyl ester with 2- (acetylamino) thiopropionamide in ethanol gives ethyl ether 7 -f2- 1- (I-acetylamino) ethnl-4-thiazolyl - 1-ethyl-6-fluoro-1,4-DIHIDRO-4-OXO-3-quinolinecarboxylic acid, m.p., - 236-238 ° C which is hydrolyzed at reflux of 6N. hydrochloric acid to give the title compound, mp.246- (decomp.).

Calculated,%: C 55.94; H 4.53; N 11.51.

C H NjFOjS 0,2 HjO

Naidon,%: C 55.92; H 4.51; N11.68,

Example 35 (Aminomethyl) 4-thiazolyl J-1-ethyl-b, 8-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid.

To 800 mg (1.99 mmol) of 7-bromoacetyl-1-Ztnl-6,8-difluoro-I, 4-dihydro-4-oxo-3-quinoline-carboxylic acid in a mixture of K, K-dimethylforma and ethanol, add 446 mg (1.0 eq.) 2- (N-6eH zyloxycarbonyl) aminothiacetamide. The mixture is stirred for 72 hours at room temperature. The mixture was added to ice water and the solid was filtered off, yielding 0.92 g of 1-ethyl-6,8-difluoro-1,4-dihyd-. RO-4-OXO-7- / 2- {(phenylmethoxy) carbonyl aminomethyl} -4-thiazolyl-3-quinolinecarboxylic acid, m.p. 185-190 ° C. Without further purification, the solid is treated with bromis.

hydrofluoric acid in U1SSUN difluoro-1,4-dihydro-7- {2- (methylamyte overnight and poured into ether - ethyl acetate. A solid is obtained by filtration, which is dissolved in aqueous ammonia at pH 10.8. Concentrating this mixture up to one third of the volume and filtration gives O, 46 g (aminomethyl) -4-thiazolyl -1-ethyl-6,8-difluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid, mp 199 -203 ° s.

The following compounds are prepared analogously:

I-Ethyl-6,8-difluoro-1,4 dihydro-7-. {2- (methylamino) methyl-4-thiazolyl but) methyl-4-thiazolyl-4-oxo-3-quinoline-carboxylic acid in 30 ml of dry methanol was added 300 mg (2 equiv. Of tert-butyl acetate). After 24 hours

The gQ is heated to reflux and the mixture is cooled, diluted with water, adjusted to pH 6.0 and filtered.

Get 31 About mg 1-ethyl-6-fluoro-1,4 dihydro-8-methoxy-7-f 2- (methylamino)

gg methyl-4-thiazolyl-4-OKCO-Z-quinoline-carboxylic acid, so pl. 164-166 C. Similarly, receive (aminomethyl) -4-thiazolyl -1 Ztil-6-fluoro-1, 4 dihydro-8-methoxy-4-oxo-3-quinolIn0

five

0

five

0

five

0

4-oxo-3-quinolinecarboxylic Acid, m.p. 172-174 ° C (decomp.) (35a)

 (Ethylamino) methyl -4-thiazolyl} -. 1-ethyl-6,8-difluoro-1,4-DIHIDRO-4-OXO-3-quinolinecarboxylic acid, m.p. 155-157 C (356)

(/) 1 1-methyl-4-thiazolyl 3-6,8-difluoro-1 (2-fluoroethyl) -1,4-DIHIDRO-4-oxo-3-quinoline-carboxylic acid, m.p. 216-218 ° С (35в)

6,8-Difluoro-1 - (2-fluoroethyl) -1,4-di-hydro-7-f (not GIL amino) methyl 4-thiazoyl-4-oxo - 3-quinoline carboxylic acid, m.p. 214-2 | 5 C (35g)

(Ethylamino) methyl-4-thiazolyl J-6, 8-difluoro-1 - (2-fluoroethyl) -, 4-dihydro-4-oxo-3-quinoline-carboxylic acid, m.p. 197-201 C (35d)

(Aminomethyl) -4-thiazolyl-1-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H pyrido (G, 253-de) 1,4-benzoxazine-6-carboxylic acid, m.p. 229-231 C (35e)

PRI me R 36. 7-12- (Aminomethyl) -4-thiazolyl -1-ethyl 1-6-fluoro-1,4-dihydro-8-methylamino-4-oxo-3-quinoline carboxylic acid .

To 500 mg (1.37 mmol) of (Amino methyl) -4-thiazolyl J-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3 quinoline-carboxylic acid, add 15 ml of 50 % aqueous methylamine. The mixture is heated at 50 ° C for 72 hours. The solution is adjusted to pH 6.5 and filtered.

350 mg of (aminomethyl) 4-thiazolyl -1-ethyl-6-fluoro-1,4-dihydro-8-methylamino-4-oxo-3-quinoline-carboxylic acid are obtained, m.p. 194-195 ° C.

Example 37. 1-Ethyl-6-fluoro-I, 4-dihydro-9-methoxy, 7- {2- (methylamino) methyl-4-thiazolyl-4-oxo-3-quinoline-carboxylic acid.

To 500 mg (1.32 mmol) of 1-ethyl-6, difluoro-1,4-dihydro-7- {2- (methylamino) methyl-4-thiazolyl-4-oxo-3-quinolinecarboxylic acid in 30 ml dry methanol, 300 mg (2 eq.) of tert-butyl acetate was added. After 24 hours

The gQ is heated to reflux and the mixture is cooled, diluted with water, adjusted to pH 6.0 and filtered.

Get 31 About mg 1-ethyl-6-fluoro-1,4 dihydro-8-methoxy-7-f 2- (methylamino)

gg methyl-4-thiazolyl-4-OKCO-Z-quinoline-carboxylic acid, so pl. 164-166 C. In an analogous manner, (aminomethyl) -4-thiazolyl -1 Ztil-6-fluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinol-carboxylic acid, m.p. (37a).

- Example 38. 1-Ethyl-6-fluoro-1,4-dihydro-8-hydroxy-7-2f (methylamino); methyl-4-thiazolyl} -4-oxo-3-quinoline-carboxylic acid.

To 700 mg (1.79 mmol) of 1-ethyl-6-fluoro-1,4-dihydro-8-methoxy-7- {2-L (meoxo-3-quinolinecarboxylic acid, so pl. 192-194 C (different).

A solution of 0.87 g (2.17 mmol) of ethyl 7-C4- (azidomethyl) -2-t azolylT-1-ethyl-6-fluoro 1,4-dihydrooxo-3-quinolinecarboxylic acid in 125 ml of acetic acid - mixing with Oh, 10 g of 10% palladium on coal

tylamino) methyl-4-thiazolyl} -4-oxo-3-ig as a catalyst and for

20

quinolinecarboxylic acid is added 8 ml of hydrobromic acid in acetic acid. The mixture is heated to 70 ° C. After 4 hours, another 8 ml of hydrobromic acid is added. Mixture 15 is stirred overnight. The solid is collected, dissolved in aqueous ammonia and concentrated to a quarter of the volume. By filtration, 580 mg of 1-ethyl-6-fluoro, 4-dihydro-8-hydroxy-7- {2-f (methylamino) methyl-4-thiazolium j-4-oco-3-quinoline carboxylic acid are obtained, mp. 242-246 C.

Similarly, (aminomethyl) -4-thiazole 1 J-1-ethyl-6-fluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline-carboxylic acid, m.p. 275-277 ° C (38a).

Example 39 (Aminomethyl) -2-thiazolyl} -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A solution of 0.16 g (0.5 mmol) of ethyl-1-ethyl-6-fluoro-7-thiocarbamoyl-1,4-digi po-4-oxy-3-xinol-lacuparboxylate U 0.32 g (2.5 mmol) of 1,3-dichloroacetate in 3 ml of N, K-dimethylformamide is heated for 3.5 hours on a steam bath. By diluting the cooled reaction mixture with ethyl acetate, a receive. O, 12 g of product which is recrystallized from chloroform-ethyl acetate to obtain 0.08 g of 7- (4- (chloromethyl) -2-thiazolyl -1-ethyl-1 -6-fluoro-1,4-dngydro-4 ethyl ester -oxo-3-quinolinecarboxylic acid, mp 214-215 C (decomp.).

A mixture of 1.10 g (2.78 mmol) of (chloromethyl) -2-thiazolyl -1-ethyl-6-fluoro-1,4-dihydro-4-ox-3-quinolinecarboxylic acid ethyl ester and .0.50 g (7.6 mmol) of sodium azide in 50 ml of K, M-dimethylformamide is heated on the steam bath for 4 hours. After evaporation to an almost dry residue, 50 ml of water is added to give 1.01 g of product, which is crystallized from ethanol, in order to obtain 0.91 g of (azidomethyl) -2-thiazolyl -1-ethyl-6-fluoro-I, 4-dihydro-41 ethyl ester, the gaseous gas is bubbled in for 5 hours. After filtration, evaporation of the solvent and trituration with an effluent, 0.77 g of ethyl 7-4-amino ester of tyl -2-thio to 6-fluoro-1,4-DIHYDRO-4-OXO-3-CHINOLI of carboxylic acid are obtained.

A solution of 0.70 g (1.87 mmol) of this ether (aminomethyl) -2-thiyl 1} ethyl 1-ethyl-6-fluoro-1,4-DIHYDRO-4-O co-3-quinolinecarboxylic acid c. 15 ml 6n. hydrochloric acid is heated on the steam bath for 2.25 hours. After adding 15 ml of water

25 the mixture is cooled to 0 ° C and filtered. The solid is suspended in 8 water, dissolved at pH II in 2n. sodium hydroxide and re-precipitated by adding 2 n. hydrochloric acid

30 acids to pH 6. The product (0.37 g) is crystallized twice from K, N-dimeti formamide.

Obtain 0.19 g (aminometi 2-thiazole1 -1-ethyl-6-fluoro-1,4-dichl

“G 4-oxo-3-quinolinecarboxylic acid, mp 222-226 C (decomp.).

Example 40. 1-Ethyl-6-fluoro-1 dihydric-7- {4- (methylamino) methyl -2 thiazolyl V-4-oxo-3-quinoline carboxylic acid.

A solution of 0.61 g (1.54 mmol) of 7- (4-chloromethyl-2-thiaz-lyl) -1-ethyl-6-fluoro-1,4-DIGIDRO-4-O oxo-3-quinoline-carboxylic acid ethyl ester at

45 20 ml 6n. hydrochloric acid is refluxed for 2 hours and evaporated to a residue. The resulting solid is suspended in hot water,

50 PyioT and dried, yielding 0.48 g of product 7- (4-chlorometsh-2-thiazolyl-1-ethyl-6-fluoro-1,4-DIHYDRO-4-OXO-3-quinoline-carboxylic acid product).

A solution of 0.40 g of 7- (4-chloromethyl-2

55 thiazolyl-1-ethkl-6-fluoro-1,4-dihydr 4-oxo-3-quinolinecarboxylic acid in 100 ml of 40% aqueous methyl are stirred at room temperature overnight and evaporated to

40

oxo-3-quinolinecarboxylic acid, m.p. 192-194 C (decomp.).

A solution of 0.87 g (2.17 mmol) of ethyl 7-C4- (azidomethyl) -2-thiazolyl-1-ethyl-6-fluoro 1,4-dihydro-oxo-3-quinolinecarboxylic acid in 125 ml of acetic acid acid-mixed with Oh, 10 g of 10% palladium on carbon in

as a catalyst and for

five

1.5 hours of gaseous hydrogen. After filtration, evaporation of the solvent, and trituration with ether, 0.77 g of ethyl ethyl 4-aminomethyl-2-thi-ethyl-6-fluoro-1, 4-DIHYDRO-4-OXO-3-CHINOLIN-carboxylic acid are obtained.

A solution of 0.70 g (1.87 mmol) of ethyl (aminomethyl) -2-thiazolyl} -1-ethyl-6-fluoro-1,4-DIHYDRO-4-OK-so-3-quinolinecarboxylic acid ethyl ester c. 15 ml 6n. hydrochloric acid is heated on the steam bath for 2.25 hours. After adding 15 ml of water

5, the mixture is cooled to 0 ° C and filtered. The solid is suspended in 8 ml of water, dissolved at pH II in 2n. sodium hydroxide and re-precipitated by adding 2 n. hydrochloric

0 acid to pH 6. The product (0.37 g) is crystallized twice from K, N-dimethylformamide.

0.19 g of (aminomethyl) -2-thiazole 1 -1-ethyl-6-fluoro-1,4-dichloro 4-oxo-3-quinolinecarboxylic acid is obtained, mp 222-226 ° C (decomp.).

Example 40. 1-Ethyl-6-fluoro-1,4-dihydrc-7- {4- (methylamino) methyl -2-thiazolyl V-4-oxo-3-quinoline-carboxylic acid.

A solution of 0.61 g (1.54 mmol) of 7- (4-chloromethyl-2-thiazolyl) -1-ethyl-6-fluoro-1,4-DIGIDRO-4-OK-oxo-3-quinolinecarboxylic ethyl ester acid in

5 20 ml 6n. The hydrochloric acid is refluxed for 2 hours and evaporated to a residue. The resulting solid is suspended in hot water, PyoT® and dried, yielding 0.48 g of the crude product 7- (4-chlorometh-1-2-thiazolyl) -1-ethyl-6-fluoro-1,4-DIHYDRO-4- OXO-3-quinolinecarboxylic acid.

A solution of 0.40 g of 7- (4-chloromethyl-25 thiazolyl) -1-etl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid in 100 ml of 40% aqueous methylamine is stirred at room temperature. temperature overnight and evaporated to

0

21

dry residue. The resulting solid is crystallized from water.

Obtain 0.33 g of the target compound, mp. 216-218 ° C (decomp.).

Calculated,%: C 55.94; H 4.53; N 1.1.51. C, "NgFOgS -0.2 HjO

Found,%: C 55.92; H 4.41; N 11.18.

EXAMPLE 41 7- (2-Amino-4-pyrimidinyl) -1-ethyl 1-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

To 900 mg (2.5 mmol) of 7- (2-dimethylaminoetheneshl) ethyl 1-ethyl-6-fluoro-1,4-DIGIDRO-4-OXO 3-quinolinecarboxylic acid ethyl ester in 15 ml of tert-butanol at 50 C was added -580 mg (2.5 eq.) Of guanvidine hydrochloride, which was pretreated with 1.35 g (5 eq.) Of tert-butyl acetate at 50 ° C in tert-butanol for 30 minutes. The final mixture is stirred for 24 hours at 60 ° C. It is poured into 8% aqueous acetic acid and extracted into chloroform. Chloroform is extracted three times with water, dried over magnesium sulfate and concentrated

riruyut. The residue is purified by hydro-4-oxo-3-quinoline-carbonic acid chromatography in a column. The lots are (aminomethyl) -4-py35

 295 mg of 7- (2-amino-4-pyrimidinyl) -1-ethyl-6-fluoro-I, 4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, mp 245-247 ° C.

Example 42. (Aminomethyl) -4-pyrimidinyl -1-e-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

To 1.5 g (4.1 mmol) of ethyl ester 40 of 7- (2-dimethylaminoethenyl) carbon 1-1-ethyl-6,8-difluoro-1,4-dihydro-A-oxo-3-quinoline of carboxylic acid in 35 ml of tert-butanol, a mixture of 2.49 g (2.5 eq.) 2-N- (benzyl- 45 V hydroxycarbonyl) amino-acetamide hydrochloride a and 1.15 g (2.5 eq. .) tert-butylate calcium in 50 ml of tert-butanol. ; After 4 hours, 452 mg of tert-bu -.i: ridinyl -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, m.p. 206-208 С (426).

From 2-N- (benzyloxycarbonyl) methyl-amino-acetamidine hydrochloride and 7- (2-dimethylaminoethenyl) carbonyl-1-ethyl-1-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester similarly, (methylamino) methyl} -4-pyrimidyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained, m.p. 238-239 with (42v).

Tests of the activity of the compounds are shown in the table.

Synthesis of raw materials.

7-acetyl-1-ethyl-6-fluoro-1, 4-dihydro-4-oxy-3-quinoline- ethyl ester. tilatkali extra. Mixture of per-gg carboxylic acid.

stir at 60 ° C overnight. A solution of 26.4 g (0.17 mmol) of the 3-acetone is poured into dilute hydrochloric acid and extracted with dichloromethane. Dichloromethane is concentrated. The residue is purified by column chromatography to obtain 530 mg of 1-ethyl6, 8-difluoro-.1,4-dihydro-4-oxo-7- / 2-: {(phenylmethoxy) carbonyl aminomethyl 4-pyrimidinyl / -3-quinolinecarbonyl

Tyl-4; -fluoroaniline; and 34.6 ml (0.35 mol) of I, 3-propanedithiol in 2.5 l of chloroform are cooled to. 55 Gaseous hydrogen chloride bubbled into the.-Stirred solution; for 15 minutes at 5-10 ° C, the reaction mixture was warmed to room temperature while stirring

22

0

about

acid as a yellow solid, so pl. 195-19b C, This mother-j al is then treated with hydrobromic acid in acetic acid for 3 hours. The mixture is poured into ethyl acetate-diethyl ether. The solid is filtered off and then dissolved in aqueous ammonia (pH 10.8). This mixture is concentrated to a quarter of the volume and the solid is filtered off.

173 mg of 7-G2- (aminomesh1) -4-pyrimidinyl3-1-ethyl-6,8-difluoro-1,4-5 dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, m.p. 285-289 sec.

Similarly, 7- (2-amino-4-pyrimidinyl) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, m.p. 285-286 0 (42 a) using guanidine hydrochloride and 7- (2-dimethylamino-ethenyl) carbonyl-1-ethyl-6,8-difluoro-I, 4-dihydro-4-oxo-3-quinolincarbono- ethyl ethyl ester 5 howl acid.

In addition, from 2-N- (benzyl-Oxycarbonyl) amino-acetamidine hydrochloride and 7- (2-dimetsh-amino-ethenyl) carbonyl-1-ethyl-6-.fluoro-1,4-di5 ethyl ester

0 5

Ridinyl -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, so pl. 206-208 С (426).

From 2-N- (benzyloxycarbonyl) methyl-amino-acetamidine hydrochloride and 7- (2-dimethylaminoethenyl) carbonyl-1-ethyl-1-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester similarly, (methylamino) methyl} -4-pyrimidyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained, m.p. 238-239 with (42v).

Tests of the activity of the compounds are shown in the table.

Synthesis of raw materials.

7-acetyl-1-ethyl-6 ethyl ester 26.4 g (0.17 mmol) of 3-acetyl-4; -fluoroaniline; and 34.6 ml (0.35 mol) of I, 3-propanedithiol in 2.5 l of chloroform are cooled to. Hydrogen chloride gas bubbled into the.-Stirred solution for 15 minutes at 5-10 ° C, the reaction mixture was warmed to room temperature while stirring

over night The solvent is distilled off in vacuum at 60 ° C. The solid residue is taken up twice in 800 ml of toluene and stripped in vacuum at 60 ° C. The solid material is dissolved in 1.5 ml of chloroform, twice washed with 200 ml of saturated sodium bicarbonate solution, twice with 200 ml of water, and dried with magnesium sulfate. Removal of the solvent in vacuo gives a brown oil containing 4-fluoro-3- (2-methy-1-1,3-dithian-2-yl) benzamine. This oil is dissolved in 1,2-l toluene and 34.4 ml (0.17 mol) of ethoxymethylenemalonic acid diethyl ester are added. Toluene is distilled off within 2 hours while

the temperature at the top of the column will not reach 120-125 ° C, Brown oil containing 4-fluoro-3- (2-methyl-1, 3-dithian-2-yl) phenylaminomethylene propanedioic acid diethyl ester directly in 500 ml of Dauterm product A, preheated to 250 s. The temperature of the mixture is again raised to 250 ° C and heated for 15 minutes. After cooling, the mixture is slowly poured into 2 liters of pentane and stirred vigorously overnight. The solid is collected, thoroughly washed with pentane and dried, yielding 40 g of a light brown solid — 6-fluoro-1,4-dihydro-7- (2-methyl-1,3-dithian-2- ethyl ethyl ester). yl) -4-oxo-3-quinolinecarboxylic acid. Without further purification, this material is treated with 75.3 g (0.55 mol) of potassium carbonate and 43.6 m (0.55 mol) of ethyl iodide in 2.7 l of N, N-dimethylformamide and npi 85 ° C overnight. The solvent is distilled off in vacuo at 65 ° C. The residue is dissolved in 2 liters of chloroform, washed thoroughly with water and dried over magnesium sulfate. Removal of the solvent in vacuo afforded 48.2 g of a light brown solid — 1-ethyl-6-fluoro-1,4-dihydro-7- (2-methyl-1, 3-dithian-2-yl) ethyl ester. 4-oxo-3-quinolinecarboxylic acid. Without further purification, this material is dissolved in 1 liter of 80% acetonitrile - water and added over 30 minutes at room temperature under a nitrogen atmosphere to a well-stirred suspension of 1-1-ethyl-6-fluoro-1,4 -dihydro-4-suspension 28.9 g (0.13 mol) -methoxide of mercury-oxo-3-quinolinecarboxylic acid, ty and 72.9 g (0.27 mol) of mercury chloride in 2 l of 80% acetonitrile - water. The reaction mixture is heated

t, pl, 176-179 C.

Ethyl ester with 7- (2-dimethyl-ethenyl) carbonip-1-ethyl-6,8-difluoro

boil under reflux for 6 hours under nitrogen, cool to room temperature and filter through a pad of celite. The filter layer was washed with 3 liters of 1: 1 dichloromethane-hexane. The organic phase of the filtrate is separated, twice washed with 500 ml of 5 M ammonium acetate solution, twice with 500 ml of water and dried

magnesium sulfate. The solvent is distilled off in vacuo, the solid residue is stirred overnight in 1.5 liters of diethyl ether. Solid

Collect, rinse thoroughly with diethyl ether and dry.

23.4 g of 7-acetyl-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained.

t, pl. 106-108 ° С,

7-Bromapetshl-1-ethyl-6-fluoro, 4-dihydro-4-oxo-3-quinoline ethyl ester. carboxylic acid.

A solution of 2.45 g (8.0 mmol) of 7-acetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 50 ml of acetic acid is treated with 0.46 g of potassium bromate, and then 3.8 ml of hydrobromic.:

the acids are added dropwise over 0.5 hour. The mixture is stirred for 24 hours at room temperature and poured into 200 ml of ice water. The precipitate is filtered off, rinsed with water and su. 2.87 g of ethyl ether are obtained.

7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic

acid.

7- (2-dimethylamino-ethenyl) carbonyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester.

K 2.0 g (6.5 mmol) ethyl

7-acetyl-1-ethyl 1-6-fluoro 1,4-dihydro-4-oxo-3-quinolinecarboxylic ester in 50 ml of dimersformamide was added 1.71 g ml (, 25 eq.) of bis-tert-butoxydimethylaminomethane.

The mixture is heated for 18 hours at 70 ° C, then concentrated. The residue is treated with ether and filtered,

Poluagot: 1, 95 g of ethyl 7- (2-dimethylaminoethenyl) carbon 1-1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid,

t, pl, 176-179 C.

7- (2-dimethylamino-ethenyl) carbonip-1-ethyl-6,8-difluoro 1, 4-digvodo 4-oxo-3-quinoline-carboxylic acid ethyl ester.

K5.00g (15.3 mmol) of 7-acetyl-1-ethyl-6,8-difluoro-1, 4-Diggcro-4-oxo-3-quinoline-carboxylic acid ethyl ester n 65 ml of dimethyl forms and 4 , 27 ml (1.3 eq.) Of bis-tert-butoxy-dimethylaminomethane. The mixture was adjusted overnight, then concentrated. The solid is suspended in ethyl ether and filtered.

4.88 g of 7- (2-dimethyl-aminoethenyl) carbonyl-1-ethyl 1-6.8-difluoro-1,4-dihydro-4-oxo-3-quinoline: carboxylic acid, are obtained; mp 175-177 ° C.

7-Cyano-1,4-dihydro-1-ethyl-6-fluoro-3-quinolinecarboxylic acid ethyl ester.

to a suspension of 2.78 g (10 mmol) of 7-amino-1,4-dihydro-1-etip-6-fluoro-3-quinolinecarboxylic acid ethyl ester .. in 40 ml of 1N. HC1 at 8 ° C was added a solution of 0.72 g (10.5 ml) of sodium nitrite and 5 ml of water in portions, maintaining the temperature by 8 ° C. To a solution of 1.07 g (.12 mmol) of cyanvide, copper (I), 2.28 g (35 mmol) of potassium cyanide and 25 ml of water at 45-50 ° C, add a solution of diazonium for 10 minutes. The foam mixture is heated with stirring at 50-60 ° C. for 1.25 hours, then treated with 10 ml of 29% ammonium hydroxide and stirred at 50 ° C for. . 20 minutes. The solution is cooled with ice. The solid is collected by filtration and recrystallized. -. from acetonitrile.

Obtain 0.28 g of the desired compound, i.p. 205-207 0.

The acetonitrile filtrate was evaporated to a dry residue, which was triturated with ethers to give an additional 0.63 g of product.

1-ethyl-6-fluoro-7-thiocarbamoyl, 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester.

Hydrogen sulfide is passed through a solution of 1.50 g (5.2 mmol) of ethyl 7-cyano-1-ethyl-6-ftpr-4-: oxo-3-quinolinecarboxylic acid in 25 ml of pyridine and 1 ml of triethylamine for 5 hours. After stirring at night in a closed flask, the precipitated solid is filtered off.

Rinse with pyridine and ether and dry.

Obtain 1, 28 g yellowish Tsejj-. of the substance of the title compound. mp.198-199 C (de).

Calculated.%.: C 55.88; H 4.69; N 8.68; S. 9.95. C.yH ..

Q Found,%: C 55.77; H 4.78; N 8.43; S 10.15.

7-Acetyl 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarbonate krslot. 5 2,6-Difluoroacetophenone.

To 64.19 g (455 mmol} of 2,6-difluoro-benzonitrile in 300 ml of diethyl ether are added over 1 hour at -78 ° C 650 ml. 1.6 M methyl lithium 0 (2.0 eq.) .. The mixture was stirred at -78 ° C for 2.5 hours and then treated with 250 ml of 6N hydrochloric acid. The reaction mixture was made up and left to rise to 5 to room temperature overnight. The layers were separated. The aqueous layer was washed with dichloromethane. and the dichloromethane layers are combined, dried and concentrated to an oil, which is purified by chromatography on a column of silica gel.

61 g of 2,6-difluoroaceto, phenone are obtained in the form of a light yellow liquid W (liquid film), ... 1709; 1622,

Jd

2,6-Difluoro-3-nitroacetophenone.

17.0 g (109 mmol) of 2,6-difluoroacetophenone was slowly added to 100 ml of concentrated sulfuric acid over 20 minutes, incubating at a temperature of -10 ° C. To this solution, at -5 ° C, add a mixture of 20 ml of concentrated sulfuric acid and 6.5 ml of 70%

nitric acid, pre-mixed with. The nitrous mixture is added at a rate sufficient to maintain the reaction temperature at 5 seconds. Then the reaction mixture is stirred for 20 minutes and poured onto ice. The mixture is extracted twice with dichloromethane. Dichloromethane is dried and concentrated to an oil, which is purified by column chromatography.

Preparation of 14.8 g of 2,6-difluoro-3-nitroacetophenone as a pale yellow oil, IR (liquid film),. cm × 1715; 1620; 1590; 1540; 1350.

40

50

Diethyl ester 3 acetyl-2,4-difluoroanilinomethylenemalonic acid.

To 18.1 (90.0 mmol) of 2,5-difluoro-3-nitroacetophenone is added methanol, Rane's nickel skeletal catalyst, and hydrogen gas. When the mixture takes away the theoretical amount of hydrogen, it is filtered in excess diethylmethylenemalonate. The methanol is distilled off. The mixture is treated with toluene, which is then distilled to half the volume. The mixture is then concentrated in vacuo and the residue is stirred with ether - pentane, to obtain 24.4 g of 3-acetal 11-2,4-difluoroanilino methylenemalonic acid diethyl ether, m.p. 82-84 ° C.

7-acetyl 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester.

14.4 g (42.2 mmol) of 3-acetyl-2,4-difluoro-anilinomethylenemalonic acid cyethyl ester are added to 380 ml of the product Dauaterm A boiling under reflux in 3 portions. The reaction mixture is stirred in for 30 minutes After cooling, all of this is treated with 500 ml of pentane. The solid is filtered off and promoted with ether - pentane.

7.9 g of 7-acetyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (m.p. 267-270 C) are obtained, which is used without further purification.

K 22.3 g (76.6 mmol). ethyl acetate 7 acetyl-6, 8-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid in 900 ml of dimethylformamide was added 25.6 g (2.5 eq.) of potassium carbonate and 22 ml of ethyl iodide . The mixture is stirred overnight at 45 ° C and then concentrated. The residue is dissolved in water and extracted with dichloromethane, the dichloromethane is concentrated. The residual oil is purified by column chromatography. .

10.5 g of 7-acetyl-1-ethyl-6,8-difluoro-1,4-di-hydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained, mp 29-130 ° C.

lots, dissolved in 100 ml of dimethylK 400 ml (1.23 mmol) of this material g formamide, at room temperature, 5 ml of 6N is added to the rial. hydrochloric acid. The mixture is stirred for 2 hours and hydrogen acid and a suspension of pe- 13, Og (2.4 eq.) 1-bromo-2-fluoroethane are added. stirred overnight at 85 ° C and the Mixture is stirred overnight filtered. at 50 ° C, concentrated and divided

310 mg of 7-acetyl-1-ethyl-6,8-difluoro-1,4 digidro-4-oxo-3-quinoline-carboxylic acid, m.p. 2505GS, are obtained

1-Etenyl-6,7,8-trifluoro-1,8-di-hydro-4-oxo-3-quinoline-carboxylic acid.

Similarly, when treating 6,7,8 trifluoro-, 4-digi, Dro-4-oxo-3-quinoline-carboxylic acid ethyl ester with dibromoethane, ethyl is obtained. I-ethenyl-6,7,8-trifluoro-1,4-digtsdro-4-oxo-3-quinolinecarboxylic ester

acids, so pl. 134-135 C. Subsequent hydrolysis of hydrochloric acid gives 1-ethenyl-6,7,8-trifluoro-I, 4-digtsro-4-oxo-3-quinoline-carboxylic acid, mp 186-187 ° C.

7- (Bromoacetyl -1-ethyl-6,8-difluoro1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

0.18 g of potassium bromate was added to 1.12 g (3.80 mmol) of 7-acetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4oxo-3-quinoline-carboxylic acid in 30 ml of acetic acid. and 1.48 ml of 48% hydrobromic acid. The mixture is stirred for 24 hours at.

The mixture is concentrated to half the volume and 20 ml of water are added. The solid is filtered off.

1.3 g of 7-bromoacetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo3 quinolinecarboxylic acid are obtained, m.p. 212-215 ° C.

Similarly, 7- (bromacetil) -6,8-difluoro-1 - (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinolish sarboxylic acid is obtained.

acid, mp. 173-175 ° C, and 10- (bromo-acetyl-9: tfluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (1,2,3-de) -1,4-benzoxazin-6-carboxylic acid, mp 224-223 ° C.

7-Acetyl-6,8-difluoro-1- (2-fluoro-ethyl) -1,4-dihydro-4-oxo-3-quinoline-carboxylic acid.

To 1.62 g (34.0 mmol) of sodium hydride {50% dispersion in the washed

oil) in 250 ml of dimethylformamide 10.0 g (34 mmol) of 7-acetal-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester was added.

29

between water and dichloromethane. Then dichloromethane is concentrated. The residue is purified by column chromatography.

3.75 g of 7-acetyl-6,8-difluoro-1 - (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinoline-carboxylic acid ethyl ester are obtained, mp 155-156 ° WITH. This material is hydrolyzed 2n. hydrochloric acid and 2-propanol as a cosolvent.

2.95 g of 7-acetyl-b, 8-difluoro-1- (2-fluoroethyl) -1,4-dihydro 4-oxo-3-choline-carboxylic acid, m.p. 215-21b C.

6,7,8-Trifluoro-1- (2-fluoroethyl J-1,4-DI-hydro-4-oxo-3-quinoline-carboxylic acid.

Similarly, 6,7,8-trifluoro-1,4-di-hydro-4-oxo-3-quinoline-carboxylic acid, 2 ethyl esters are converted to 6.7 58-trifluoro-1 - (2-fluoroethyl) -1,4 -di-hydro-4-lxo-3-quinoline carboxylic acid, mp 207-21 ° C.

10-Acetyl-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-1-Tirido (1, 2,3-de) -1,4-benzoxazy-1-6-carboxylic acid.

15

1-b-Fluoro-2- 2- (2-methyl-1,3-dioxalan-2-yl) propoxy-3-nitrophenyl} istanone.

To 35.45 g (0.230 mol) of 2-hydroxymethyl-2-methyl-1,3-dioxalane, 0.78 g of HjO in 300 ml of tetrahydrofuran at -18 ° C are added 100 ml of 2, 3M n-butyl - lithi. The solution is heated to -40 ° C and 2.6 difluoro-3-nitroacetophenone in 200 ml of tetrahydrofuran is added to 46.35 g (0.230 mol) at 0 ° C. The reaction mixture is stirred for 30 minutes, then poured into 1000 ethyl acetate, loaded with ammonium chloride (1: 1). Solution filter: 5 that through aims. The layers are separated. The aqueous layer is extracted three times with 500 ml of ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate. The solvent is distilled off under reduced pressure. The product is chromatographed on silica gel using hexane-ether (4: 1).

41.2 g of 1- {6-fluoro-2 - (- mets-1-1, 3-diox. Alan-2-pc of proxy-3-nitrophenyl ethanone are obtained.

1 - C2-Acetyl-3-ethanol-1 - (2-acet 1) - fluoro-6-nitrophenoxy -2-propanone.

2.2 g (7.35 mmol) 1- {b-fluoro- (2-methyl-1,3-dioxolan-2-Sh1)

1360584.30

propoxy-3-nitrophenyl} ethanone and 360 ml of water - hydrochloric acid - acetic acid (100: 10: 250) are stirred overnight. The solvent solution is distilled off under reduced pressure, the residue is taken up in dichloromethane and re-washed with water. The organic layer is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is ground in pgntane - Etj0 (3: 1).

1.78 g of 1- (2-acetyl-3-fluoro-b-nitrophenoxy 2-propanone, mp. 64-65 ° C. is obtained.

1 - (7-fluoro-2,3-dihydro-3-methyl-2H-1, 4-benzoxazin-6-yl) -ethanone.

A mixture of 4.98 g (19.5 mmol) of 1- (2-acetyl-3-fluoro-6-nitrophenoxy) -2-propanol, .100 ml of 95% ethanol and 1 g of Rane's skeletal nickel catalyst was shaken in an atmosphere of hydrogen at 4.5 CHO Pa at room temperature for 18 h. The reaction mixture is filtered and the solvent is distilled off under reduced pressure. The residue is chromatographed on silica gel with hexane-ether (1: 1).

2.76 g of 1- (7-fluoro-3,4-di-hydro-3-methyl-2H-1,4-benzoxazin-6-yl) ethanone is obtained.

4- (8-Acetyl-7-fluoro-2,3-dihydro. 2-methyl-4H-1,4-benzoxazin-4-yl) methylene -2,2-dimethyl-1, Z-dioxane-4, 6- dione.

A mixture of 3.66 g (17.19 mmol) of 1- (7-fluoro-3, 4-digidro-3-methyl-2H-1, 4-benzoxazin-8-yl) ethanone, 100 ml of methanol and 3 , 91 g (21, O mmol 4- (methoxymethylene) -2,2-dimethyl-1, 3-dioxane-4, 6-dione is stirred overnight at room temperature. The reaction mixture is filtered and the solvent is distilled off under reduced pressure. The crystals are triturated with pentane.

4.30 g of 4- (8-acetyl-7-fluoro-2, 3-dihydro-3-megyl-4H-1, 4-ben-, zoxazin-4-yl) methylene -2,2-dimethyl- 1 is obtained , Z-dioxane-4,6-dione, mp.18425

thirty

35

40

45

50

55

185 C.

10-Atstsh1-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido- (l, 2,3-de) - 1,4-benzoxazin-6-carboxylic acid.

A mixture of 7.22 g (19.87 MMOLB) 4- (8-acetyl-7-fluoro-2,3-dihydro-3-me-TIL-2H-1,4-benzoxazin-4-yl) methylene 55

185 C.

10-Atstsh1-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido- (l, 2,3-de) - 1,4-benzoxazin-6-carboxylic acid.

A mixture of 7.22 g (19.87 MMOLB) 4- (8-acetyl-7-fluoro-2,3-dihydro-3-me-TIL-2H-1,4-benzoxazin-4-yl) methylene 31 .1360584 32

2,2-dimethyl-1,3-dioxane-4,6-dione 68.68 g of N-methyl-l- (phenylmethyl) -3 and 72.2 g of polyphosphoric acid are heated at 65 ° C for 2 hours. The reaction mixture cooled and poured onto ice. The crystals are filtered and triturated with ethyl ether.

3.45 g of 10-acetyl-9-fluoro-2,3-dihydro-3-metsh1-7-oxo-7H-pyri, pyrrolidine methanamine are obtained in the form of an oil, which is used without further purification in the next stage.

N-methyl-3-pyrrolidinomethanamine.

A mixture of 67.28 g (0.32 mol) of N-methyl-1 - (phenylmethyl) -3-pyrrolidine-methanamine, 3 g of 20% palladium per ugda- (1,2,3-de) -1.4 benzoxazin-6-carol and 600 ml of methanol shake

Bonovy acid, t.tsl.258-259 C.

N-methyl-3-pyrrolidinomethanamine.

N-Methyl-5-oxo-1- (phenylmethyl} -3-pyridine carboxamide.

in a hydrogen atmosphere under a pressure of 4.5 10 Pa and at room temperature for 18 hours. Another 3 g of 20% palladium on carbon and a hydroxide mixture A mixture of 100 g (0.43 molj methyl over 5 seconds) is added. After the continuous 5-oxo-1- (phenyl-methyl) sulphate, another 3.0 g of 20% pyrrolidinecarboxylic acid, 500 ml of palladium-carbon and the hydrogenation of methanol and 100 g (3.2 mol of methylamine) are added. continue for another 4.5 hours. The catalyst is heated at 1OO C for filtering and the filtrate is evaporated for 16 hours in a reactor under pressure. The reaction is under reduced pressure. the ammonia and methanol are distilled off under reduced pressure are rectified under vacuum conditions (72-76 ° C, 10.5 mm Hg), yielding 8.32 g of N-methyl-3-pyrrolncin-methanes - on them. The residue is taken up in dichloromethane and washed with 3x100 ml of 1N sodium hydroxide. The organic layer is dried over magnesium sulfate. The solvent is distilled off under reduced pressure.

88.3 g of N-MeTHn-5-OKCO-1- (phenylmethyl) -3-pyrrolidinecarbox are obtained. A mixture of 200 g (0.86 mol) of methyl 5-OKCO-I- (phenylmethyl) pyramid is obtained in the form of a white solid. 30 rolidinecarboxylic acid, 1000 ml

va, t, pl. 82.5-83.0 C.

Calculated,%: C, 67.22; .H, 6.94; N 12.06.

C.jH ..

Found,%: C, 66.98; H 6.69; N 12.02.

This material is used in the next step.

H-Methyl-1- (phenylmethyl) -3-zirrolidinemethanamine.

To a suspension of 37.40 g (1.00 mol) of lithium aluminum hydride in 1000 ml of tetrahydrofuran, a solution of 88.3 g (0.380 mol) of M.tmethyl35 is added dropwise.

methanol and 200 g (4.4 mol) of ethyl, amine are heated for 17.2 hours in the reactor under pressure. The P mixture is cooled and the excess ethyl amine and methanol are distilled off under reduced pressure. The residue is taken up in dichloromethane and circulated 3x150 ml of 1N. sodium hydroxide. The organic layer is dried over magnesium sulphate. 40 The solvent was distilled off under reduced pressure.

Obtain 104.6 g of N-ethip-5-oxo (fenshetil) -3-pyrrolidinecarboxam and in the form of a white solid

3-oxo-1- (fensh1metsh1) -3-pyrrolindine- 45 (m.p. 97-99 ° C) used on

Icarboxamide in tetrahydrofuran under nitrogen. The reaction mixture was heated at reflux overnight. The reaction flask was cooled in an ice bath and 37.4 ml of water, 37.4 ml of 15% sodium hydroxide and 112.2 ml of water were added. The precipitated solid is filtered and washed with hot ethanol. The combined filtrates are concentrated, then dissolved in dichloromethane, filtered, dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give

subsequent stage.

N-Ethyl-1- (phenolmetsh1) -3-pyrrole dinmetanamine.

To a suspension of 108.68 g (2.860 mol 50 lithium aluminum hydride in 800 ml of tetra-hydrofuran, a solution of 194.5 g (0.790 mol) M-ethyl-5-oxo-1- (phenylmethyl) -3-pyrrolidine boxamide in 600 ml of tetrahydrofuran 55 under nitrogen atmosphere. The reaction mixture is heated under reflux for 4 hours. The reaction flask is cooled in an ice bath and 108 ml of water are added, 108 ml of 15% hydrochloric acid, pyrrolidinmethanamine is used as an oil, without further purification in the next stage.

N-methyl-3-pyrrolidinomethanamine.

A mixture of 67.28 g (0.32 mol) of N-methyl-1 - (phenylmethyl) -3-pyrrolidine-methanamine, 3 g of 20% palladium on carbon and 600 ml of methanol was shaken.

Continuing 6.5 seconds. After. another 3.0 g of 20% palladium on carbon is added and the hydrogenation is continued for another 4.5 hours. The catalyst is filtered off and the filtrate is evaporated. under reduced pressure. The rest is cancer

Typified under vacuum conditions (72-76 ° C, 10.5 mm Hg) to obtain 8.32 g of N-methyl-3-pyrrone-cin-methanes — na.N-Ethyl-3-pyrrolidine-methanamine.

H-Ethnl-5-oxo-1 - (phenylmethyl) -3-pyrrolidinecarboxamide.

A mixture of 200 g (0.86 mol) of methyl 5-OKCO-I- (phenylmethyl) -pyrrolidinecarboxylic acid, 1000 ml

rolidinecarboxylic acid, 1000 ml

methanol and 200 g (4.4 mol) of ethyl, amine is heated at 17.2 hours in the reactor under pressure. The reaction mixture is cooled and the excess ethyl amine and methanol are distilled off under reduced pressure. The residue is taken up in dichloromethane and sold 3x150 ml of 1N. sodium hydroxide. The organic layer is dried over magnesium sulphate. The solvent is distilled off under reduced pressure.

104.6 g of S-ethip-5-oxo1- (fenshetil) -3-pyrrolidinecarboxamide are obtained in the form of a white solid.

(m.p.97-99 ° C) used on

subsequent stage.

N-Ethyl-1- (phenolmetsh1) -3-pyrrolidinemethanamine.

To a suspension of 108.68 g (2.860 mol) of lithium aluminum hydride in 800 ml of tetrahydrofuran, a solution of 194.5 g (0.790 mol) of M-ethyl-5-oxo-1- (phenylmethyl) -3-pyrrolidinecarboxamide in 600 ml of tetrahydrofuran under nitrogen. The reaction mixture is boiled under reflux for 4 hours. The reaction flask is cooled in an ice bath and 108 ml of water are added, 108 ml of 15% hydrochloride 33136

sodium oxide and. 324 ml of water. The precipitated solid is filtered and washed with hot ethanol. The combined filtrates are concentrated, then dissolved in dichloromethane, filtered, dried over magnesium sulfate. The solvent is distilled off under reduced pressure.

151.9 g of K-etch1-1- (phenylmethyl) -3-pyrrolidine-methanamine are obtained in the form of an oil, which is used without further purification in the next stage.

N-Ethyl-3-pyrrolidinomethanamine.

A mixture of 151.65 g (0.695 mol) H-eth1-15 condenser for 2 hours.

1- (phenstmethyl) -3-pyrrolidine methane amine, 5 g of 20% palladium on carbon and 1100 ml of ethanol are shaken in a hydrogen atmosphere at 4.5 10 Pa and at room temperature for 21.6 hours. another 5 grams of 20% palladium on coal. The hydrogenation is continued for 24 hours. The catalyst is off-stream and the filtrate is evaporated under reduced pressure. The residue is rectified in vacuum

Hg).

g K-etsh1 -3-pyr20

25

35

(88-91 ° C, 11.5 mm; Get 66,0 rolidinemethanamine.

N- (2,2,2-trifluoroethyl) -3-pyrroli- 30

.Dinmethanamine.

5-OXO-1- (phenylmethyl) -N- (2,2,2 trifluoroethyl-3-pyrrolidinecarboxamnd.) A mixture of 21.9 g (0.100 mol) methyl-;

.5-oxo-1- (phenylmethyl) -3-pyrrolidine carboxylate in I50 ml of tetrahydrofuran is cooled to 0 ° C in an ice bath under nitrogen atmosphere and 24.32 g (0.150 mol) of carbonyldiimidazole is added. The reaction mixture is stirred for 0.5 hours at 0 ° C, then at room temperature for 0.5 hours. A solution of 13.55 g (O, 100 mol) is added. 2,2,2-trifluoroethnlamine hydrochloride , 15.22 g (0.100 mol) 45 1, 8-diazabicyclo 15 .4.0. undec-7-ene; and 100 ml of tetrahydrofuran. The reaction mixture is stirred overnight at room temperature. The solvent is distilled off under reduced pressure. The residue is taken up in dichloromethane and washed three times with sodium bicarbonate saturation (3 x X 150 ml). The organic layer is dried over magnesium sulfate and the solvent 55 is distilled off under reduced pressure. The product is purified by chromatography on a column of silica gel with ethyl acetate. ..

then stirred overnight at room temperature. The reaction mixture is cooled on an ice-bath and 3.2 ml of water, 3.2 ml of 1N sodium hydroxide and 9.6 ml are added to the precipitated salts and filtered off and washed with hot ethanol. The combined filtrates are concentrated under reduced pressure. The residue is taken up in dichloromethane, filtered and dried over magnesium sulfate. The solvent is distilled off under reduced pressure.

7.15 g of 1 - (Phenylmethyl N- (2,2,2-trifluoroethyl-3-pyrrolide methanamine) is obtained, which is used without further purification for further stud

N- (2,2,2-trifluoroethyl-3-pyrrole dinmethanamine.

A mixture of 7.15 g (26.3 mmol) of 1- (fnylmethyl) -N (2, 2, 2-trifluoromethane1 pyrrolidine methane amine, 100 ml of methane and 0.7 g of 20% palladium is shaken in the atmosphere Hydrogen pressure of 4 Pa and room temperature for 24 hours, the catalyst is filtered and the filtrate is kept under reduced pressure. The current is rectified in vacuum (63-65 ° C, 2.8 mm Hg) to give 2.5 N - (2,2,2-trifluoroethyl-3-pyrrolidanamine.

N-Propyl-3-pyrrolidinomethanamine

5-OXO-1- (phenylmethane) -N-propyl pyrrolidinecarboxamide.

To a solution of 10.96 g (50 mmol) of 5-OXO- - (phenylmethyl) -3-pyrrolide carboxylic acid in 150 ml of acetonitrile was added 9.73 g (60 mmol of 1,1-carbonyl diimidazole. The reaction mixture was heated to 60 ° C for 1 h, cooled to room temperature and treated with 4.13 g (70 mmol) of n-propylamine, After r

four

34

8.50 g of 5-oxo-- - (phenylmethyl) -N- (2,2,2-trifluoroethyl -3-pyrrolidinecarboxamide) are obtained, mp. 110-112 used in the next stage.

1 - (Fensch1metsh1) -K- (2,2,2-trifluoroethyl) -3-pyrrolidine methane amine.

A mixture of 8.50 g (28.3 mol) of 5-oxo-1 - (phenylmethyl) -K- (2,2, 2-trifluoroethyl 3-pyrrolidine-methanamine in 100 ml of tetrahydrofuran is added dropwise to 3.22 g (84, 9 mmol) lithium aluminum hydride in 50 ml of tetrahydrofuran. The reaction mixture is boiled with reverse 0

five

35

0

0 45 50 55.

then stirred overnight at room temperature. The reaction mixture was cooled in an ice bath and 3.2 ml of water, 3.2 ml of 15% sodium hydroxide and 9.6 ml of water were added. The precipitated salts are filtered and washed with hot ethanol. The combined filtrates are concentrated under reduced pressure. The residue is taken up in dichloromethane, filtered and dried over magnesium sulphate. The solvent is distilled off under reduced pressure.

7.15 g of 1 - (phenylmethyl) - N- (2,2,2-trifluoroethyl-3-pyrrolidine-methanamine) are obtained, which is used without further purification in a further step,

N- (2,2,2-trifluoroethyl-3-pyrrolidine methane amine).

A mixture of 7.15 g (26.3 mmol) of 1- (phenylmethyl) -N (2, 2, 2-trifluoromethyl) 1- 3-pyrrolidine-methanamine, 100 ml of methano-, la, and 0.7 g of 20% palladium on an angle of shaking under hydrogen at 4, Pa and at room temperature for 24 hours, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is rectified in vacuum (63-65 ° C, 2.8 mm Hg) to give 2.55 g N- (2,2,2-trifluoroethyl-3-pyrrolidine methane amine.

N-Propyl-3-pyrrolidinomethanamine.

5-OXO-1- (phenylmethane) -N-propyl-3-pyrrolidinecarboxamide.

To a solution of 10.96 g (50 mmol) of 5-OXO- - (phenylmethyl) -3-pyrrolidine-. carboxylic acid in 150 ml of acetonitrile was added 9.73 g (60 mmol) of 1,1 -carbonyldiimidazole. The reaction mixture is heated to 60 ° C for 1 h, cooled to room temperature and treated with 4.13 g (70 mmol) of n-propylamine, After over 351

stirring for 2 hours, the solvent is distilled off in vacuo and the residue is divided between ether and water. The organic layer is washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered and evaporated in vacuo to give 12.0 g of 5-OXO-1- (phenylmethyl) -N-propyl-3-pyrrolidinecarboxamide, mp. 86- 87 ° C.

1 - (Phenylmethyl) -N-propyl-3-pyrrolidinemethanamine,

To suspension of 8.2 g. (0.2 mol) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran, 12.0 g (45.6 mmol) of solid 5-OXO- - (phenylmethyl) -N-propyl-3-pyrrolidinecarboxamide are added in portions. After the addition is complete, the reaction mixture is stirred at room temperature for 18 hours and then heated under reflux for 2 hours. After cooling to room temperature, the mixture is treated by adding dropwise successively 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml of water, titration is carried out during the final addition to obtain a granulated precipitate. The solid was removed by filtration, washed with terahydrofuran and the filtrate evaporated in vacuo.

9.6 g of 1- (phenylmetersh1) -K-prop1-3-3-pyrrolidine methane amine are obtained in the form of a heavy syrup used in the next step without further purification.

N-propyl-3-pyrrolidinomethanamine.

A mixture of 14.0 g (60.0 mmol) of 1- (phenylmethyl) -N-propyl-3-pyrrolidine namin, 1.0 g of 20% palladium on carbon and 140 ml of methanol is shaken in; an atmosphere of hydrogen under pressure of 4.510 Pa and at room temperature for 24 hours. The catalyst is removed by filtration through celite and the filtrate is concentrated and distilled in vacuo to give 7.1 g of N-npo drank-3-pyrrolidine-methanamine, boiling point 4 5b C / 0, 25 mmHg , / N-Cyclopropyl-Z-pyrrolidinamine.

5-OXO-1- (phenylmethyl) -N-cyclopropyl-3-pyrrolidinecarboxamide.

To a solution of 16.4 g (75 mmol) of 5-oxo-1- (phenylmethyl) -3-pyrrolidine-carboxylic acid in 150 ml of acetonitrile was added 13.8 g (85 mmol) of 1.1

584

36

carbonyldiimzazol. The reaction mixture is heated to 1 h, cooled to room temperature and 4.85 g (85 mmol) of cyclopropylamine are treated. The reaction mixture was stirred at room temperature for 18 hours, the solvent was distilled off in vacuo and the residue was partitioned.

0 between chloroform and water. The organic layer is washed with water, 1N, hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g

5 5-oxo-1 - (phenylmethyl) -N-cyclopropyl-3-pyrrolidinecarboxamide, m.p1.94-96 ° C.

1- (Phenylmethyl) -N-cyclopropyl-3-pyrrolidine-methanamine.

0 To suspension 8.2 g (0.20 mol)

lithium aluminum hydride in 150 ml of dry: tetravdrofuran 18.0 g (70.0 mmol) of solid 5-5-OXO-1- (phenylmetersh1) -Y-cyclopropyl 5 3-pyrrolvdincarboxamchda are added in portions. After the addition is complete, the reaction mixture is stirred at room temperature for 18 hours and then for 2 hours at reflux.

0 After cooling to room temperature, the mixture is treated by adding dropwise 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml of water, in the course of the final addition, the titration is carried out to obtain a granulated precipitate. The solid is removed by filtration, washed with tetrahydrofuran and the filtrate is evaporated.

0 ett in vacuum.

16 O g I- (phenipmethyl) -N-cyclopropyl-3-pyrrolidine methane amine is obtained in the form of a heavy oil used in the next stage without further purification.

N-Cyclopropyl-3-pyrrolidine-methane, amine.

A mixture of 13.6 g (59.0 mmol) of 1- (phenylmethyl) -N-cyclopropyl-3-pyrrolidine methaneamine, 0.5 g of 20% palladium on carbon and 140 ml of methanol was shaken in a hydrogen atmosphere under 5 pressure of 4.54 O Pa n at room temperature for 24 hours. The catalyst is removed by filtration through celite, the filtrate is concentrated and rec-g; Typify in vacuo.

five

0

6.3 g of N-cyclopropyl-3-pyrrolidine-methanamine are obtained, t, bp.88- 90 ° C / 13 mm Hg.

N- (2-Propyl-3-pyrrolidine methangg amine.

5-OXO-1 - (phenylmeteIIp) -N- (2-propyl-3-pyrrolicin-carboxamide.

To a solution of 16.4 g (75.0 mmol) of 5-OXO-1- (phenylmetsch1) -3-pyrrolidine-carboxylic acid in 150 ml of acetonitrile was added 13.8 g (85.0 mmol) of 1/1 -carbonyldiimidazole. The reaction mixture is heated for 1 hour to 60 ° C., cooled to room temperature, and treated with 5.0 g (85 mmol) of isopropamine. The reaction mixture is stirred at room temperature for 18 hours, the solvent is distilled off in vacuo and the residue is divided between chloroform and water. The organic layer is washed with water, 1N. hydrochloric acid, dried over magnesium sulphate and evaporated in vacuo e.

18.6 g of 5-goxo-1- (phenylmethyl) -N- (2-propyl} -3-pyrrolidinecarboxamide, m.p. 122-124 C are obtained.

1- (Phenylmetip) -N- (2-Propyl) -3-pyrrolidinemethanamine.

To a suspension of 8.2 g (0.2 mol) of lithium aluminum hydride in 150 ml of excess tetrahydrofuran, 18.3 g (70.0 mmol) of solid 5-oxo-1- (fensh1methyl) -M- (2- propyl) -3-pyrrolidinecarboxam1zd. After the addition is complete, the reaction mixture is stirred at room temperature for 18 hours and then heated under reflux for 2 hours. After cooling to room temperature, the mixture is treated by adding 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml of water sequentially, during the final addition, the titration is carried out to obtain a granulated precipitate. The solid was removed by filtration, washed with tetrahydrofuran and the filtrate was evaporated in vacuo.

15.6 g of 1- (fensh1methyl) -N- (2-propyl) -3-pyrrolvdinmethanamine is obtained in the injected heavy syrup used in the next stage without further purification.

N- (2-propyl} -3-pyrrolidine-methane; amine.

A mixture of 13.4 g (58.0 mmol) of 1-phenylmethyl-N- (2-propyl) -3-pyrroladin methane-amine, 1.0 g of 20% palladium per

coal and 130 ml of methanol is shaken in a hydrogen atmosphere at 4.5 Yu-Pa and at room temperature for .24 hours. The catalyst is removed by filtration through celite, the filtrate is concentrated and rectified in vacuo. 6.3 g of K- (2-prop 1) -3-pyrrolidine methanamine are obtained, bp 58-60 C /

/ 3.5 mmHg

2- (3-Pyrrolidinmethyl) aminovJ ethanol.

N- (2-Hydroxyethyl) -5-oxo-1t (phenipmethyl) -3-pyrrolidinecarboxamide.

A mixture of 46.7 g (1200 mol) of methyl 5-OXO- - (phenylmethyl) -3-pyrrolidinecarboxylic acid, 36.7 g (1600 mol) of 2-lminethanol and 500 ml of methanol is refluxed overnight. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The residue is taken up in dichloromethane and extracted with 3x100 ml of 1N sodium hydroxide. The aqueous layer was adjusted to pH 5, extracted with dichloromethane (3x150 ml), then the pH was adjusted to 8, and again extracted with dichloromethane (3x150 ml).

The aqueous layer is concentrated under reduced pressure. The resulting suspension is stirred in dichloromethane. Layers are filtered. The combined organic, -layers are dried over magnesium sulphate, the solvent is removed under reduced pressure.

47.9 g of N- (2-hydroxyl ethyl) -5-oxo-1-phenylmethyl -3-pyrrolidine carboxamide are obtained in the form of an oil, which is used in the next stage without further purification.

2-1 (Phenylmethyl) -3-pyrrolidinyl methyl amino / ethanol. A mixture of 46.66 g (0.178 mol) of N- (2-hydroxyethyl) -5-oxo-2- (phenylmethyl) -3-pyrrolidinecarboxamide in 200 ml of tetrahydrofuran is added dropwise to a suspension of 20.25 g (0.534 mol) of lithium aluminum hydride in 150 ml tetrahydrofuran. The reaction mixture was boiled under reflux for 3 hours and cooled in an ice bath. Then, 20 ml of water, 20 ml of 15% sodium hydroxide are successively added.

and 60 ml of water. The reaction mixture. filtered and the precipitate is rinsed with ethanol. The filtrate is concentrated under reduced pressure, the residue is taken up in dichloromethane, and dried over sulfate

magni. The solvent is removed under reduced pressure.

. 32.3 g of 2- (ll- (feng-sh-methyl) -3-pyrrolidinyl methyl amig / are obtained. . ethanol as an oil, used in the next step without further purification.

2- (3-Pyrrolidinylmethyl) amino7 ethanol.

Mixture. 32.32 g (phenylmeth1-sh 3-pyrrolidinyl 1methyl} amino / ethanol, 330 ml of methanol and 3 g of 20% palladium on carbon are shaken in a hydrogen atmosphere at 4.5-10 Pa and at room temperature for 18 hours The solvents are then removed under reduced pressure. The residue is rectified in vacuo.

1.43 g of 2- (3-pyrrolidinylmethyl) amino ethanol are obtained, bp 129-131 0 / 1.5 mm Hg.

1, 1-Dimepslethyl 1 - (diphenylmethyl) -3-azetidinyl 1carbamate.

A solution of 12.2 g (51.2 mmol) of 1- (diphenylmethyl) -3-azetidinamine in a mixture of 34 ml of water and 100 ml of tert-butanol was added dropwise to 11.4 g (52 mmol) of di-tert-butyl dicarbonate.

After the addition is complete, the reaction is then 18 hours at room temperature. The mixture is heated for 1 hour at 60 ° C, then 18 hours at room temperature. The reaction mixture is diluted with water and extracted with chloroform. The chloroform layer is washed with water, dried over magnesium sulphate, filtered and evaporated in vacuo.

14.3 g of 1,1-dimethylethyl- - 1 - (diphenylmethyl) -3-az-ethidinyl carbate, 1448-155 0, are obtained.

1.1-Dimethylethyl- (3-azetidinyl) carbamate.

A solution of 14.2 g (42.0 mmol), 1-dimethylstil- - (diphenylmethyl) -3-azetidinyl carbamate in 100 ml of tetrahydrofuran is embedded in 2 g of 20% palladium and on coal in a hydrogen atmosphere at 4,5.-10 Pa for 24 hours. The reaction mixture is filtered through Celite and the solvent is distilled off in vacuo. The residue is triturated several times with hexane to give 6.5 g of insoluble residue in the vce 6.5, 1g of di-methylethyl- (3-acetidinyl) carbamate, mp 138-140 ° C.

1 - (Diphenylmethyl) -3-azetidine methane-amine.

Suspension 5.7 g (0.15 mol) of lithium aluminum hydride in 200 ml of cyxoroV

re. Thereafter, the reaction mixture is diluted with water and extracted with chloroform. The organic layer is washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo, floor: and 14.2 g of 1, 1-dimethylethyl (diphenylmethyl) -3-azetidinyl} methyl} carbamate.

1,1-Dimethyl- (3-azetidinylmetesh1) 40 carbamate.

A solution of 13.7 g (38.9 mmol) of 1,1-dimethylethyl 1 (diphenylmethyl) -3-azetidinyl methyl carbamate in i50 ml of tetrahydrofuran is shaken with 2 g of 45 20% palladium on carbon in a hydrogen atmosphere at 4.5 -I O Pa for 24 hours. The reaction mixture was filtered through Celite and the solvent was distilled off in vacuo. The residue is repeatedly digested with hexane,

As an insoluble residue, 6.8. G i, 1-dimesh1- (3-azetidinsh1methyl) carbamate is obtained as a viscous oil, used without additional purification.

1- (Diphenylmethyl) -N-methyl-3-azetidinecarboxamide.

K. a solution of 7.5 g (28 mmol) of 1- (diphenylmethyl azetidine-3-carboxylic

0

tetrahydrofuran is treated portionwise by adding 18.6 g (75 mmol) of solid 3-cyano-1 - (diphenylmethine-p) azetidine. After the addition is complete, the reaction mass is stirred at room temperature for 2 hours, boiled for 4 hours under reflux and stirred for 18 hours at room temperature. The reaction mixture was decomposed by sequential addition of 6 ml of water, 6 ml of 15% sodium hydroxide and 18 ml of water, and the titration was carried out to obtain a granulated precipitate. HeopraHii4ecKm i precipitate is removed by filtration, washed with tetrahydrofuran and evaporated in vacuo.

16.9 g of 1 - (diphenylmethylJ-3-azetidine methanamine) are obtained in the form of a heavy oil.

1,1-Dimethylstil 1 - (diphenylmethyl - 3-azetidinyl methium carmate).

To a solution of 12.0 g (47 mmol) of 1- (diphenylmethyl) -3-azeta-silane-methane amine, 5 2.08 g (52 mmol) of sodium hydroxide in 34 ml of water and 100 ml of tert-butanol. m, P, 4 g (52 mmol) of di-tert-butyl carbonate. The reaction mixture is heated for 1 hour at 60 ° C.

five

0

re. Thereafter, the reaction mixture is diluted with water and extracted with chloroform. The organic layer is washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo, floor: and 14.2 g of 1, 1-dimethylethyl (diphenylmethyl) -3-azetidinyl} methyl} carbamate.

1,1-Dimethyl- (3-azetidinylmetesh1) carbamate.

A solution of 13.7 g (38.9 mmol) of 1,1-dimethylethyl 1 (diphenylmethyl) -3-azetidinyl methyl carbamate in i50 ml of tetrahydrofuran is shaken with 2 g of 20% palladium on carbon in a hydrogen atmosphere at 4.5 - I O Pa for 24 hours. The reaction mixture is filtered through Celite and the solvent is distilled off in vacuo. The residue is rubbed several times with hexane,

As an insoluble residue, 6.8. G i, 1-dimesh1- (3-azetidinsh1methyl) carbamate is obtained as a viscous oil, used without additional purification.

1- (Diphenylmethyl) -N-methyl-3-azetidinecarboxamide.

K. a solution of 7.5 g (28 mmol) of 1- (diphenylmethyl azetidine-3-carboxylic

I

Acids in 75 ml of acetonitrile are added 6.0 (37 mmol) Ijl -carbonyldi-midazol. The reaction mixture is heated for 2 hours and after that, remove 3, .1 i g (30.9 mmol) of triethylamine in succession and 2, 08 g (30.8 mmol) of methylamine hydrochloride. The reaction mixture was stirred for another 1 hour. The solvent was distilled off in vacuo. The residue is dissolved in chloroform. After scrubbing with water and drying over magnesium sulphate, the chloroform layer is evaporated in vacuo.

9.0 g of 1- (difensh1metsh1) N-methyl-3-azetidinecarboxamide are obtained, mp. 103-107 ° C.

1- (Diphenylmethyl) -N-methyl-3-azeti dinmethanamine.

To a suspension of 3.2 g (85 mmol) of lithium aluminum hydride in 50 ml of tetrahydrofuran is added dropwise a solution of 8.5 g (28 mmol) of l-difvnyl-methyl-N-methyl-3-azethidine carbohydrate in 50 ml of dry tetrahydrofuran After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled to room temperature and decomposed by the sequential addition of 3.4 ml of water, 3.4 ml of 15% aqueous sodium hydroxide and 10.2 ml of water are titrated to obtain a granulated sediment. The inorganic precipitate is removed by filtration, washed with tetrahydrofuran and evaporated in vacuo. The precipitate was dissolved in chloroform, dried over magnesium sulfate, filtered, and evaporated in vacuo.

7.0 g of 1- (methyl 1-methyl) -N-methyl-3-azedine methane-amine are obtained in the form of heavy syrup, which is used without subsequent purification.

N-Methyl-3-azetidininemethanamine.

A solution of 5.7 g (2 mmol) of 1 - diphenylnyl-C-K-methyl-3-az single tanamine in 100 ml of methanol is shaken with 2.0 g of 20% -Hdro palladium on carbon in a hydrogen atmosphere at 4.5 -10 Pa for 18h. The reaction mixture was filtered through celite and the solvent was distilled off in vacuo. The residue is triturated several times with hexane.

An insoluble residue is obtained — 2.3 g of N-methyl-3-azetilinemethanamine as a heavy syrup, using go without further purification.

42

1 - (Diphenylmethyl) -Y-ethyl-3-azedine-carboxamide.

To a solution of 7.5 g (28 mmol) of 1- (dr-phenylmethyl) azetidine-Scarboxylic acid in 75 ml of acetonitrile was added 6.0 g (37 mmol of j 1,1 -carbonyl-dimidazole. The reaction mixture was heated at 60 ° C 3.1 g for 2 hours and successively

(30.8 mmol) of triethylamine and 2.52 g (30.8 mmol) of ztilamine hydrochloride. The reaction mixture was stirred for another 1 h, the solvent was distilled off in vacuo and the residue was dissolved in chloroform. After washing with water and drying over magnesium sulfate, the chloroform layer is evaporated in vacuo.

 Get it. 9.4 g. 1- (diphenylmethyl) - L-ethyl-3-azetidinecarboxamide, m.p. 91-93 C.

1 - (Diphenylmethyl) -N-ethyl-3-azetidinine methane amine.

To a suspension of 3.2 g (85 mmol) of lithium aluminum hydride in 50 ml of dry tetrahydrofuran is added dropwise a solution of 8.5 g (28.0 mmol) of 1- (diphenylmethyl) -N-etst-3-azetidinecarboxamide in 50 ml of dry tetrahydrofuran. After the addition is complete, the reaction mixture is boiled under reflux for 2 hours, cooled to room temperature and decomposed

by sequential addition of 3.4 ml of water, 3.4 ml of 15% aqueous sodium hydroxide and 10.2 ml of water, the titration is carried out to obtain a granulated precipitate. Inorganic sediment

was removed by filtration, washed with tetrahydrofuran and evaporated in vacuo.

6.7 g of 1- (diphenylmethyl) -N-ethyl-3-azetidine methane amine are obtained in the form of heavy syrup, used without

further purification.

L-Etsh1-3-azetidininmetanamin. A solution of 6.4 g (23 mmol) of 1- (diphenylmethyl) -N-ethyl-3-azetidinine methane-amine in 100 ml of methanol shaken-.

with 2.0 g of 20% palladium on carbon in a hydrogen atmosphere at 4, for 18 hours. The reaction mixture is filtered through Celite and the solvent is distilled off in vacuo. The residue is triturated several times with hexane.

An insoluble precipitate of 1.6 g of N-ethyl-3-azetidinine-methanamine is obtained,

 13605

in the form of heavy syrup, used without further purification.

2-Methyl-2,7-diazaspiro 4.4 nonane-1,3-8-trion.

A solution of 20.3 g (0.084 mol; 3-to-to-3-to-5-oxo-3-pyrrolidine acetic acid ethyl ester in 40 ml of 40% aqueous methylamine is stirred overnight at room temperature IQ, then placed on an oil bath and gradually heated to within 30 minutes, ensuring the distillation of volatile substances from the open flask. The crude product is crystallized from zanol.

Obtain 12.56 g of the title compound, mp. 201-204 C.

Vyisleno,%: C, 52.74; H 5.53; .

15

N

15.38

С „Н ..N, 0

2.0

.

Found,%: C 52.87; H 5.60; N 15.25.

7-Benzyl-2-methyl-2,7-diazaspiro 4.4 nonane-1,3,8-trion.25

A solution of 1.82 g (10 mmol) of 2-methyl-2,7-diazaspiro 4.4 nonane-1,3-8-trione in 20 ml of% M-dimethyl-Aramid is gradually added in a nitrogen atmosphere to 0.050 g (10 4 mmol). DL of 50% sodium hydride oil suspension, previously washed twice with toluene, and covered with 10 ml of K, K-dimethylformamide. After stirring for 1 hour, add. 1.40 g (11 mmol) of benzyl chloride and stirring continued overnight at room temperature. After condensing to a small volume in vacuo, the residue is diluted. 40 with 40 ml of water and extracted twice with dichloromethane. The combined organic phase is washed with water, dried over magnesium sulphate and evaporated.

35

.Cl,

Found,%: C 59.37; H 7.98; N 9., 03; 01 23.09.

2-Methyl-2,7-diazaspiro G4.4 nonane dihydrochloride.

A solution of 7-benzyl-2-methyl-2,7-diazaspiro 4.4 nonane pvdrochloride in 150 ml of methanol with 1.0 g of 20% palladium on coal is hydrogenated at 4.5-10 Pa for 2 days. After filtration, the filtrate is concentrated to a thick syrup, which crystallizes upon addition of acetonitrile.

11.50 g of the title compound softened at and melting at 168-170 ° C is obtained.

Calculated,%: C 45.08; H 8.51; N 3,5; C1 33.27. .

Cjh

Found.%: C 45.24; H 8.77; N 13.18; 01 33.26.

2-Ethyl-2,7-diazaspiro 4.4 nonane-I, 3,8-trion.

Suspension 24.33 g (0.100 mmol)

getting a solid. Crystals- 45 ethyl ester of 3-ethoxycarbonyl-5oxo-3-pyrrolidine acetic acid in excess of 2n. the sodium hydroxide is stirred for 3 hours at room temperature, acidified with dilute chlorine

1.74 g of the title compound is obtained from toluene-hexane, mp 157-158 C ... -

 Calculated,%: C 66.16; H 5.92;

N 10.27. .

C.jH ..

Found,%: C, 66.45; H 5.79; N 10.09.

2-Kenzyl-7-metsh1-2,7-diazaspiro-4.4 nonane dihydrochloride.

A solution of 1.36 g (5.0 mmol) of 7-benzyl-2-methyl-2,7-diazaspiro 4. Nan-1,3,8-trione in 50 ml of tetrahydrofuran is added dropwise to the suspension

Q

five

.0

five

O 0

five

84

0.95 g (25 mmolJ of lithium aluminum hydride in 30 ml of tetrahydrofuran). The mixture is stirred overnight at room temperature, refluxed for 1 h, cooled and 0.95 ml of water is added dropwise , 95 ml of a 15% sodium hydroxide solution and 2.8 ml of water. After removing the inorganic substance by filtration, the filtrate is concentrated in vacuo to give a syrup, which is dissolved in isopropanol and treated with excess 6N hydrogen chloride in isopropanol. 0.97 is obtained by crystallization. g target compound, mp. 233-234 ° C.

ViñisloD: C 59.40; H 7.98; N 9.24; C1 23.38.

.Cl,

Found,%: C 59.37; H 7.98; N 9., 03; 01 23.09.

2-Methyl-2,7-diazaspiro G4.4 nonane dihydrochloride.

A solution of 7-benzyl-2-methyl-2,7-diazaspiro 4.4 nonane pvdrochloride in 150 ml of methanol with 1.0 g of 20% palladium on coal is hydrogenated at 4.5-10 Pa for 2 days. After filtration, the filtrate is concentrated to a thick syrup, which crystallizes upon addition of acetonitrile.

11.50 g of the title compound softened at and melting at 168-170 ° C is obtained.

Calculated,%: C 45.08; H 8.51; N 3,5; C1 33.27. .

Cjh

Found.%: C 45.24; H 8.77; N 13.18; 01 33.26.

2-Ethyl-2,7-diazaspiro 4.4 nonane-I, 3,8-trion.

Suspension 24.33 g (0.100 mmol)

ethyl ester of 3-ethoxycarbonyl-5oxo-3-pyrrolidinoacetic acid in excess of 2n. The sodium hydroxide is stirred for 3 hours at room temperature, acidified with dilute hydrochloric acid and evaporated in vacuo to a dry residue. The product 3-carboxy-5-oxo-3-pyrrolidinacetic acid is taken in isopropyl alcohol, separated from the insoluble

filter sodium chloride, concentrate to a syrup and dissolve in 100 ml of 70% ethylamine. The solution is gradually heated in an oil bath until the fly-off tolerance is allowed 5

sneeze substances and then withstand

230-240 ° C for iO min. After cooling, the product is crystallized from isopropyl alcohol.

10.12 g of the expected compound are obtained, mp 168-169 ° C.

Calculated,%: C 55.09; H 6.17; N 14.28.

Se N, 2Y, Oz

Found,%: C 55.03; H 5.84; N 14.01.

2-Etsh1-7-benzyl-2,7-diazaspiro 4.4 nonane-1,3,8-trion.

A suspension of sodium hydride (2.20 g of a 60% oil suspension (0.055 mol), washed with toluene) in 50 ml of K, N-dimethylformamide is gradually treated with a solution of 10.0 g (0.051 mol) of 2-ethyl-2.7 -diazaspiro 4.4 nonan-1,3,8-trione in 100 ml of K, L-dimethylformamide. After stirring for 15 minutes, 6.4 ml (0.055 mol) of benzyl chloride was added dropwise and the mixture was stirred overnight, concentrated in vacuo and shaken with water — methylene chloride. The organic layer is dried, evaporated and the product is crystallized from toluene - hexane.

Obtain 11.11 g of the title compound, mpg. 1 25-1 26.5 C.

. Calculated,%: C 67.11; H 6.34; N 9.79.

C ,, H, gN, 03

Found,%: C 67.41; H 6.33; N 9.79.

2-Benzyl-7-ethyl-2,7-diazaspio-L4.4Jnonane dihydrochloride.

A solution of 11.00 g (0.0385 mol) of 2-ethyl-7-benzyl-2,7-diazaspiro 4.4} nonane-1,3,3-trione in 100 ml of rofuran tetrahydrate is added dropwise to a sous- , 00 g (0.158 mol) lithium-aluminum, o; read in 250 ml of tetrahydrofuran. After stirring overnight, the mixture was boiled under reflux for 1 h, cooled, and 6 ml of water, 6 ml of I5% sodium hydroxide and 18 ml of water were added dropwise. The neoric solid is filtered and the filtrate is concentrated in a mixture, taken up in ether, dried over magnesium sulfate and re-evaporated. The resulting syrup is dissolved in y-isopropyl alcohol and is processed also with a 1-fold hydrogen chloride in isopropyl alcohol.

46

0

0

five

9.63 g of the title compound are obtained, m.p. 196-98 C (decomp.)

Calculated,%: C 60,56; H 8.26; N 8.83; C1 22.35. i

1S H 2 Found: C, 60.51; H 9.06; N 8.69; C1 22.26.

2-ETHYL-2,7-diazaspiro4.4} nonane dihydrochloride.

. The solution is 9.50 g (0.030 molj 2-benzyl-7-ethyl-2,7-diazaspiro4.4JHO-nal dihydrochloride in 100 ml of methanol is hydrogenated with 1.0 g of 20% palladium-5 di on coal as a catalyst i at 4.5-10 Pa for 22 hours. After filtration, the solution is concentrated to a syrup and crystallized from acetonitrile.

6.66 g of the expected compound are obtained, m.p. 168-172 C.

Calculated,%: C, 47.58; H 8.86; N 12.33; C1 31.21.

.Cl,

Found,%: C 47.70; H 8.58; N 12.39; C1 30.92.

When used as agents for the treatment of bacterial infections, the proposed compounds are prescribed for administration with an initial dose, from 3 to 40 mg per 1 kg of body weight daily (preferably from 6 to 14 mg, per 1 kg of mass). The dose depends on the patient and the compound used. The treatment should be started with smaller doses, gradually using it until the optimum effect is achieved. The total daily dose may be divided and administered in portions per Q over the course of a day.

Pharmacokinetics.

Biopharmaceutical profile - 1 ethyl-7- {3- (eth1amino) methyl J-1-pyrrolidinyl1-6,8-difluoro-1,4-dihydro-5 4-oxo-3-quinolink: arboxylic acid (RD 114843, RR 764 -00147).

For the bioavailability study, a suitable oral absorption model for this series of compounds in-Q is dogs.

Microbiological and chemical (high performance chromatography) assays for RD 114843 are fully developed and available for use.

5 ™ "

Preliminary pharmacokinetic studies in dogs and dogs have shown that RD 114843 is well absorbed when administered orally (RO)

five

and is present in the blood long enough

The concentration level C of the compound in the blood of mice after a single dose (50 mg / kg) is given in tabLo2,

The concentration of compound C in the blood of dogs (4 dogs were used) after administration of one dose (25 mg / kg) is given in tabLoZ.

Pharmacological research

Studies have shown that C1-934 (RD 1148.43) can be used as an antibacterial agent for oral administration. In dogs, with IV infusion of 30 mg / kg and an oral dose of 100 mg / kg, some cardiovascular manifestations and pulmonary exposure after IV ampoules in doses greater than 10 mg / kg. The estimated dose of RD 114843 for a person is significantly lower and ranges from 100 to 400 mg, Toe, 1.4-5.7 mg / kg (orally twice a day).

Action RD 114843 in CNS Survey RR 740-01396. Oral and subcutaneous doses of 300 mg / kg do not have a noticeable CNS effect on mice.

Evaluation of the activity of RD 114843 (experiments on mice) in the reverse screening test (MAST), RR 840-01397

RD 114843 does not have a noticeable activity in the MAST test (PO and SC doses of 10, 30 and 100 mg / kg), no effects were found that could interfere with further biological assessments.

The absence of anti-irritant effects of RD 114843, RR 740-01308 RD 114843 does not have an effect similar to an anxiolytic drug (experiments on rats).

Pulmonary safety studies on intravenous administration RD 114843, RR 640-01395,

When administered in doses that provide a therapeutic effect, RD 114843 does not have any harmful pulmonary effects. At higher IV doses, the compound causes a noticeable drop in blood pressure, respiratory rate and tidal volume, leading to death. In this test, two dogs were given increasing IV doses at 10-minute intervals — 1.0; 3.0; 10.0; 30.0 and 100 mg / kg, bringing the total dose to 144.0 mg / kg.Pos-

There was no effect on administration of 1.0 and 3.0 mg / kg IV atf pool. After 0 mg / kg (14 microns in total / kg), the respiratory rate, minute volume and heart rate changed markedly. One dog died after a dose of 30 mg / kg, and a friend after a dose of 100 mg / kg (44

and 144 mg / kg, respectively).

With an infusion of 2.4 mg / kg / min to 144 mg / kg over 60 minutes, there was a period of relative drop in mean arterial pressure and heart rate, an increase in respiratory rate and minute volume. These changes were less significant than the changes that were observed after taking pills.

Autonomous assessment of synthetic antibacterial agent RD 114843, RR 740-01394 „

A locomotised dog RD 114843 under anesthesia does not have

caused noticeable cardiovascular or autonomic effects during elevation; IV doses of 3 and 10 mg / kg; at 30 mg / kg he moderately antagonized sympathetic irritations, it is not

prevents its use as a synthetic antibacterial agent

Cardiovascular risk assessment of synthetic antibacterial RD 114843 in dogs with increased intravenous and oral doses, RR 740-01393

RD 114843 in doses of 3 and 10 mg / kg IV and 10 and 30 mg / kg RO did not have a noticeable effect on the cardiovascular system of conscious dogs5 A slight increase in heart rate and blood pressure occurred after 100 mg / kg RO, After

injections of 30 mg / kg IV and 100 mg / kg PO, ventricular ectopy and vomiting were noted.

Hemodynamic effect of synthetic antibacterial agent

RD 114843 on dogs under anesthesia .RR 740-01392

An increase in IV doses of RD 114843 from 1.0 to 30 mg / kg did not have a noticeable hemodynamic effect on dogs,

anesthetized phenobarbitalo

The effect of synthetic antibacterial RD 114843 on blood pressure and heart rate in rats that are conscious and

491

having a normal pressure, RR 740-01321.

RD 114843 did not cause noticeable changes in rats with normal pressure; no adverse side effects were noted.

The lipid-regulating effect of anti-infective agent RD 114843, RR 740-01287,

RD 114843 did not affect rats with natural or diet-induced hyperlipidemia; no lipid regulative effect

Ex vivo studies of platelet aggregation under the influence of synthetic antibacterial aggregate RR 740-01274

RD 114843 had no significant effect on platelet aggregation ex vivo in rats

Exposure to RD 114843 of a synthetic antibacterial agent in a pharmacological hazard test, RR 740-01313.

An oral dose of 1000 mg / kg of RD 11484 to male bees caused depression, which lasted four days. Half of the 10 mice injected with a dose of 1000 mg / kg died for five days, one on the 3rd, and four on the 4th day. No effects were observed with the introduction of 100 mg / kg or 1.0 mg / kg RD 114843,

Studies of chemotherapeutic tolerance RD 114843, RR-MEMO 750-00170.

The results showed that RD 114843, administered orally to female mice at doses of 1000 mg / kg, was reasonably well tolerated by them for 14 days, two of 40 mice died, one. - on the 4th, friend - on the 6th day.

Doses recommended for people

On the basis of the high antibacterial activity of the compounds (the minimum inhibitory concentration (HQ) of 0.1 Kg / mp) for the patient's body, the therapeutic dose is 100-400 mg boi.do orally in the form of coated tablets.

Claims (1)

Invention Formula Method for preparing naphthyrndine quinoline- or benzoxazinecarboxylic acids of general formula 50 o C0 N R H or where Z is R R N-CCR.R,), (SNRL / (CR, R,) / ("2) .. men,) N (mn,), L (mn,) N - R, (CH2) ( H-VZ CH; -CH-CH five 0 0 five o five five X-cn, C1, CF, c-one, so-, alkyl or nitrogen; fluorine; 1,2,3 or 4; 1,2,3 or 4, with n + n totaling 2,3,4 or 5; p .0.1 or 2; 1 or 2; hydrogen; ethyl; hydrogen, methyl or ethyl; hydrogen, C, -C-alkyl, hydroxyalkyl, trifluoroethyl R / CO, where Ry is C, -C-alksh1 or C, -C-alkoxy; J is hydrogen or C (-C3 alkyl) provided that when X is N and Z is a group X (CIS) „  MSN, Y - n P P 1 - RJRJ R. R  2 n where, R is methyl or ethyl, and 4 C, -C-alkyl, C-C-hydroxyalkyl, or trifluoroethyl; Ry is hydrogen or C —C-alkyl, R is hydrogen or C -C-alkyl when X is a C-OH group, the indicated hydrogen of the C-OH group and the indicated R, 2 N-R2 groups can be replaced by the ring-forming radical -CH-CH, where R J is hydrogen.  . „Or S., - С, -клкш1, Kg к - 9 and R 3 hydrogen or C ,, - Sz-alkyl or their pharmaceutically acceptable salts. of the addition of acid, about tl and Table 2