Method of 1,8-benzo(b)naphthyridine derivatives synthesis

专利摘要:
The invention relates to benzo (c) naphthyridine derivatives, in particular the preparation of compounds of the general formula (I) O F HalС10) OH R where R is H, alkyl fluoroalkyl, cyclopropyl, alkoxy, alkylamino or a protected amino group, Na - F, Cl, RI - H or Hal Ri - F, as semiconductors for the synthesis of biologically active substances. The goal is to create new useful intermediates. Synthesis is carried out by saponification or acidic hydrolysis of a C1-4 alkyl ester of the corresponding acid. Yo
公开号:SU1748646A3
申请号:SU904742812
申请日:1990-01-15
公开日:1992-07-15
发明作者:Антуан Мишель；Барро Мишель；Деконклуа Жан-Франсуа；Жирар Филипп；Пико Ги
申请人:Лаборатуар Роже Беллон (Фирма)；
IPC主号:

专利说明:

. The invention relates to methods for producing new derivatives of 1,8-benzo (c) naphthyridine of the general formula
where R is hydrogen, linear or branched C1-C4-alkyl, fluoroalkyl, cyclopropyl, which are intermediate compounds in the synthesis of biologically active Substances with antibacterial activity.
The purpose of the invention is the development on the basis of well-known methods of a method for producing new intermediate compounds used in the synthesis of biologically active substances with valuable pharmacological properties,
Example 1. Suspension of 15 g of 8-chloro-Zatoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [v] naphthyridine in 150 cm ^{3 of} acetic acid and 150 cm ^{3 of} 17.5% aqueous solution of hydrochloric acid is heated to 100 ° C with stirring for 4 hours. After cooling to a temperature of about 20 ° C, the product is dehydrated, washed with 150 cm ^{3 of} ethanol, then 2 times with 100 cm ^{3 of} ethyl
1748646AZ alkoxygroup, alkylamino or protective group ;.
Hal - fluorine or chlorine:
I, hydrogen or Hal and R, are simultaneously fluorine.
pour in 100 cm ^{3 of} water. The precipitate is dehydrated, washed 3 times with 20 cm ^{3 of} water. After recrystallization in a mixture of 30 cm ^{3 of} dimethylformamide and 30 cm ³ ethanol, 1.31 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [v] naphthyridine-3-carbonic acid are obtained acid in the form of a yellow solid, which melts at 284-285 ° ^.
Example 7. A suspension of 2.78 g of 3-ethoxycarbonyl-7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8-benzo [c] naphthyridine in 30 cm ³ 17.5% hydrochloric acid and 30 cm ^{3 of} acetic acid are heated at 100 ° C for 1 hour. After cooling to 20 ° C, the reaction mixture is poured into 100 cm ^{3 of} water. The precipitate formed is dehydrated, washed 3 times with 30 cm ^{3 of} water and 2 times with 5 cm ^{3 of} ethanol. Recrystallization in 100 cm ^{3 of} dimethylformamide with 20% ethanol gives 2.08 g of 7.8-difluoro-1-methoxy-4-oxo-1,4-dihydro-1,8benzo [v] naphthyridine-3-carboxylic acid in the form of a solid yellow substance with a melting point of 325-327 ° C.
Example 8. A suspension of 8 g of 3-ethoxycar15 ro-1,8-benzo [in] naphthyridine in 80 cm ^{3 of a} 17.5% aqueous solution of hydrochloric acid and 80 cm ^{3 of} acetic acid is heated with stirring at 100 ° C for 1, 5 hours. After cooling to 20 ° C, the solid is dehydrated and washed 6 times with 100 cm ^{3 of} water. After recrystallization in 160 cm ^{3 of} dimethylformamide, 6.44 g of 7.8-difluoro-1-methyl-4-oxo-1,8-benzo [v] naphthyridine-3 carboxylic acid is obtained as a yellow solid, which decomposes at 360 ° C.
PRI me R 9. A suspension of 4 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-okro-1,4-dihydro-1,8-benzene [in] naphthyridine in 30 cm ³ UK30 ether. 12.7 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-1,8-benzo [v] naphthyridine-3-carboxylic acid are obtained in the form of a beige solid powder which sublimates at 400 450 ° C.
Example 2. The process is carried out analogously to example 1, but take 10.5 g of 8-chloro-7-fluoro-3-ethoxycarbonyl-1-ethyl-4-oxo-1,4-dihydro-1,8-benzo [v] naphthyridine.
9.3 g of 8-chloro-1-ethyl-7-fluoro-4-U oxo-1,4-dihydro-1,8-benzo [v] naphthyridine 3-carboxylic acid are obtained in the form of a beige solid, which melts when 380 ° C.
Example 3. Suspension of 16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-M-formyl-M-methyl-1-amine-4-oxo-1,4-dihydro-1,8-benzo [in ] naphthyridine in 164 cm ³ of acetic acid and 164cm ³ 17.5% aqueous solution of hydrochloric acid was heated to 100 ° C in 20 teche- of 4 hours while stirring. After cooling to 10 ° C., 1.65 cm ^{3 of a} 30% sodium hydroxide solution are added at 10-20 ° C. The product is dehydrated, washed 3 times with 150 cm ³ .______, ________________ _____________ _{g of} water, 3 times with 150 cm ^{3 of} ethanol and 3 times with 150 25 bonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydride .. cm ³ ethyl ether. 13.64 g of 8- - on ^ ... 3 pso / are obtained.
chloro-7-fluoro-1-methylamino-4-oxo-1,4-dig idro-1,8-benzo [c] naphthyridine-3-carboxylic acid as a yellow solid, which melts at 354-356 ° С. I
PRI me R 4. Carry out the process under the conditions of example 1, but take 6.1 g of 8-chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8 -benzo (c) naphthyridine. 4.85 g of 8-chloro-1-cyclopropyl-7-I fluoro-4-oxo-1,4-dihydro-1,8-benzo [c] naphthyridine-3-carboxylic acid are obtained in as a yellow solid, which melts at 330 ° C. ... ··.
Example 5. A suspension of 1.88 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [v] naphthyridine in 10 cm ³ ethanol, 5 cm ^{3 of} water and 15 cm ^{3 of} 2N aqueous potassium hydroxide are heated to 75 ° C with stirring for 1 hour. To the resulting solution, 2 cm ^{3 of} acetic acid are added. The resulting precipitate is dehydrated. promyvayutZraza 10cm ³ of water, 'zrazy 10cm ³ of ethanol. . After recrystallization in 50 cm ^{3 of} dimethylformamide, 1.7 g of 8-chloro-7-fluoro-4- are obtained! oxo-1-tert-butyl-1,4-dihydro-1,8-benzo [c] naphthyridine-3-carboxylic acid as a yellow solid, which melts at 398 ° C. ¹
PRI me R.6. Suspension 1.95 g of 1-cyclo-! propyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [c] naphthyridine in 20 cm ^{3 of} 17.5% hydrochloric acid is heated at 100 ° C for 1 h 30 min After cooling to 20 ° С, the reaction mixture of acetic acid and 30 cm ^{3 of} 50% hydrochloric acid is heated for 2 h at 100 ° С. After cooling to 20 ° C, 100 cm ^{3 of} water are added. The precipitate formed is dehydrated, washed 3 times with 50 cm ^{3 of} water and recrystallized in 80 cm ^{3 of} dimethylformamide. 3.4 g of 7.8.9 trifluoro-1-methyl-4-oxo-1,4-dihydro-1,8-b-benzo [c] naphthyridine-3-carboxylic acid are obtained as a colorless solid, which melts at 350 -352 ° C.
Example. 6,7,8-Trifluoro-1-methoxy4-oxo-1,4-dihydro-1,8-benzo [v] naphthyridine-3-carboxylic acid was prepared under the conditions of Example 9, but 9 g of 3-ethoxycarbonyl-6 were taken, 7,8-trifluoro-1-methoxy-4-oxo-
1,4-dihydro-1,8-benzo [c] naphthyridine. 7.7 g of 6.7.8-trifluoro-1-methoxy-4-oxo- are obtained.
1.4- dihydro-1,8-benzo [c] naphthyridine / 3-carboxylic acid as a solid ve-
174.8646 beige, which melts at 322 ° C.
PRI me R 11. Carry out the process analogously to example 9, but take 1.8 g of 1-cyclopropyl-Zetoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydride-1,8-benzo [in ] naphthyridine. 1.1 g of 1-cyclopropyl-7,8,9-trifluoro-4-oxo-G, 4-d and g and d-o -1, 8 - benzo [c] naphthyridine-are obtained. 3-carboxylic acid as a yellow solid, which melts at 304 ° C.
Example 12. A suspension of 6 g of 8-chloro-Zetoxycarbonyl-1-ethoxymethyl-7-fluoro-4oxo-1,4-dihydro-1,8-benzo [c] naphthyridine in 120 cm ^{3 of} water, 120 cm ^{3 of} ethanol and 47, 5 cm ^{3 of} 15 N aqueous potassium hydroxide is heated with stirring at 75 ° C. for 2.5 hours. A light insoluble residue is removed by filtration at this temperature. After cooling to 20 ° C., 6 cm ^{3 of} acetic acid was added to the filtrate. The resulting precipitate is dehydrated, washed 3 times with 20 cm ³ odes and recrystallized with 60 cm ^{3 of} dimethylformamide. 4 g of 8-chloro-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [c] naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 285 ° C.
PRI me R 13. A suspension of 5.75 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [c] naf + iridine in 60 cm ³ 17, 5% hydrochloric acid is heated with stirring at 100 ° C for 30 minutes. After cooling to 20 ° C, the insoluble part is dehydrated, washed 3 times with 20 cm ^{3 of} ethanol and 3 times with 20 cm ^{3 of} ethyl ether. 3.05 g of 8-chloro-7-fluoro-4-oxo-1,4-dihydro-1,8-benzo [v] naphthyridine-3-carboxylic acid are obtained in the form of a beige solid, which decomposes at 416 ° C. .
Example 14. A suspension of 8 g of 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-1,8-benzo [c] naphthyridine in 80 cm ^{3 of} 17.5% hydrochloric acid acids and 80 cm ^{3 of} acetic acid are heated with stirring at 100 ° C for 1.5 hours. After cooling to 20 ° C, the insoluble part is dehydrated, washed 3 times with 20 cm ^{3 of} water and recrystallized in 50 cm ^{3 of} dimethylformamide. '6.3 g of 1-ethyl-7.8-difluoro-4-oxo-1.4-50 dihydro-1,8-benzo [c] naphthyridine-3-carbon are obtained
Editor A. Ogar hydrochloric acid as a yellow solid that melts at 330 ° C.
PRI me R 15. 8-Chloro-7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4-dihydro-1,8-benzo [c] naphthyridine-3-carboxylic acid is obtained in the conditions of example 9, but take 2.2 g of 8-chloro-Zetoxycarbonyl-7-fluoro-1- (2-fluoroethyl) -4-oxo-1,4 dihydro-1,8-benzo [v] naphthyridine. After two recrystallizations in 10 cm ^{3 of} dimethylformamide, 1.4 g of 8-chloro-7-fluoro-1- (2-fluoroethyl) -. 4-oxo1,4-dihydro-1,8-benzo [v] naphthyridine- 3-carboxylic acid as a yellow solid, which melts at 310 ° C.

权利要求:
Claims (1)
[1]
Claim
A method of producing derivatives of 1,8benzo (c) naphthyridine of the general formula
COOH where R is hydrogen, linear or branched StoC ^ -alkyl, fluoroalkyl, cyclopropyl, alkoxy, alkylamino or a protective group;
. Hal is fluorine or chlorine; ''
Ri is hydrogen or Hal and Ri are simultaneously fluorine, characterized in that the ester of the general formula o
С00А1 And where R; Ri and Hal have the indicated meanings;
Aik - linear or branched CiCd-alkyl, is subjected to hydrolysis in an acidic medium or saponification.
.Priority by signs: 01/16/89 at R-hydrogen, linear or branched Ci-Cd-alkyl, cyclopropyl, alkylamino or a protective group, Ri - hydrogen, Hal - chlorine.
07/28/89, when R is hydrogen, linear or branched Ci-Cd alkyl, cyclopropyl, alkoxy, alkylamino or a protective group, Ri is hydrogen, Hal is fluorine.

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引用文献:

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US4229456A|1977-07-18|1980-10-21|Merck & Co., Inc.|Substituted naphthyridinones and processes for their preparations|

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CS274601B2|1983-07-27|1991-09-15|Dainippon Pharmaceutical Co|Method of 1,8-naphthyridine derivative production|

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AU623473B2|1989-01-16|1992-05-14|Laboratoire Roger Bellon|New benzonaphthyridine derivatives and their preparation|

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NZ232091A|1989-01-16|1990-12-21|Bellon Labor Sa Roger|7-fluoro-8--4-oxo-1,4-dihydro-benzonaphthyridine-3-carboxylic acid derivatives, preparation and pharmaceutical compositions thereof|NZ232091A|1989-01-16|1990-12-21|Bellon Labor Sa Roger|7-fluoro-8--4-oxo-1,4-dihydro-benzonaphthyridine-3-carboxylic acid derivatives, preparation and pharmaceutical compositions thereof|

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AU623473B2|1989-01-16|1992-05-14|Laboratoire Roger Bellon|New benzonaphthyridine derivatives and their preparation|

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FR2682384B1|1991-10-10|1995-04-07|Bellon Laboratoires|PROCESS FOR THE PREPARATION OF BENZONAPHTYRIDINES.|

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FR2682378B1|1991-10-10|1995-04-07|Bellon Laboratoires|NOVEL DERIVATIVES OF FLUOROQUINOLEINE ACID CARBOXYLIC-3 AND THEIR PREPARATION.|

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FR2703681B1|1993-04-08|1995-05-12|Bellon Labor Sa Roger|PROCESS FOR PREPARING FLUORO-6-HALOGENO-2 QUINOLEINE|

法律状态:
2007-12-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20060116 |

优先权:

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申请号 | 申请日 | 专利标题

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FR898900430A|FR2641783B1|1989-01-16|1989-01-16|NOVEL BENZONAPHTYRIDINE-1,8 DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM|

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FR8910219A|FR2650276B1|1989-07-28|1989-07-28|NOVEL BENZONAPHTYRIDINE-1,8 DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM|

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