Method of producing benzoheterocyclic compounds

专利摘要:
A process for preparing compounds of general formula (I> <IMAGE> wherein R<1> represents a hydrogen atom or a lower alkyl group; R<2> represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or a hydroxy group, or a lower alkanoyl group which may be substituted with a halogen atom; X represents a hydrogen atom or a halogen atom; n is an integer of 1 or 2; with the proviso that when n is 1, R<2> should not be a lower alkyl group substituted with a halogen atom, which comprises (a) cyclizing a compound of general formula (II> <IMAGE> wherein R<1>, R<2>, X and n have the same meanings as defined above; and R<3> and R<4>, which may be the same or different, each represents a lower alkyl group; with the proviso that when n is 1, R<2> should not be a lower alkyl group substituted with a halogen atom, or (b) cyclizing a compound of general formula (III> <IMAGE> wherein R<1>, R<2>, X and n have the same meanings as defined above and R<5> represents a lower alkyl group to form a compound of general formula (IV> <IMAGE> wherein R<1>, R<2>, R<5>, X and n have the same meanings as defined above, and then hydrolyzing this compound.
公开号:SU1428201A3
申请号:SU813367435
申请日:1981-12-17
公开日:1988-09-30
发明作者:Оцубо Юнитиро；Манабе Есиаки；Накагава Казуюки
申请人:Оцука Фармасьютикал Ко.,Лтд (Фирма)；
IPC主号:

专利说明:

(21) 3367435 / 23-04
(22) 12/17/81
(31) 179949/80; 152451/80
(32) 12/18/80; 25.09.81
(33) jp
(46) 09/30/88. Bul Number 36
(71) Otsuka Pharmaceutical Co., Ltd
(JP)
(72) Unitiro Otsubo, Yoshiaki Manabe and Kazuyuki Nakagawa (JP)
(53) 547.892.07 (088.8)
(56) Patent of Germany No. 2914258, cl. C 07 D 471/04, 1979.
(54) METHOD OF OBTAINING BENZO-HETEROCYCLIC COMPOUNDS
(57) The invention relates to benzo-heterocyclic compounds of the formula Il
X 1 .COOH
(CH2) LV
where R, f is H or an alkyl group Ci C /) RI H, an alkyl group which may be substituted with a halogen or hydroxy group, or a lower alkanoyl group which may be substituted with a halogen; X is H or halogen; n is an integer, 1 or 2, provided that n is 1, RI does not mean the alkyl group Ct-C, substituted by halogen, has antibacterial activity. In order to increase the yield and quality of the target product, the benzoheterocyclic compound of formula II
where R ;,, R, X and 11 above R group of the formula 0-C (0) -0) CH) -C (0) -0- C (R5) (R4) or a group of the formula - OH C (COORj) j, where Rj, R4 and Well each means a lower alkyl group, is cyclized by heating it in a solvent (distilenglycol-dimethyl ether, diphenyl ether or tetralin) at 100-200 C or less at lOO-ISO c, but in 1–20 mol of an acidic substance, Phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, conc. H.JS04 or polyphosphoric acid (PFC). Moreover, PFC is used in an amount that is 3–8 times (by weight) greater than the amount of the compound of formula II, and when Rg is a residue of formula (COOR5) j, where Ry has the indicated value. The compound obtained is hydrolyzed at a temperature of from room temperature to 200 ° C in the presence of a catalyst such as a base, a mineral or organic acid. 4 tab.
ABOUT)
with
4iib
TO)
CX)
Yu

S
The invention relates to an improved process for the preparation of benzoheterocyclic compounds of the general formula
soon
Vg-O
(CH2) LV,
where R is hydrogen or alkyl group Cf-C4)
RII is hydrogen, an alkyl group which may be substituted by halogen or hydroxy, or a lower alkanoyl group that may be substituted by halogen; X is hydrogen or halo; n is an integer, 1 or 2, provided that n is 1, then RJ cannot be lower alkyl
a group substituted by halogen having antibacterial activity
The purpose of the invention is to increase the yield and quality of the target product due to the implementation of the cyclization of new raw materials in certain parameters.
Example 1. a. 5- (4-Methyl-1-piperazinyl) -6-fluoro-1,2,3,4-tetrahyd roquinaldine (10 g, 0.038 mol) and isopropylidenyl methoxymethylene malonate (8 g, 0.043 mol) are mixed at room temperature and heated for 30. min at 100 s with stirring
Solids are recrystallized from chloroform-p-hexane to obtain 14.6 g (92%) of cyclic isopropyl-idyl (4-methyl-1-pip-rasinil) -6-fluoro-1,2,3, 4-tetrahydro-1-chi 11 aldinyl aminomethylenemal oxide, white crystals.
Calculated,%: C 63.29; H 6.76; N 10.07.
 CgjHsaO NjF
Found: C, 63.42; H, 6.59; N, 10.05.
b. Polyphosphoric acid (50 g), crawled from phosphorus pentoxide (25 g, 0.12 mol) and phosphoric acid (25 g, 0.26 mol), and cyclic isopropylidinyl (4-methyl-1-pi-Perazinyl) -6-fluoro-1,2,3,4-tetrahydro l-ch-aldynyllaminomethylenmenate
(14 g, 0.034 mol) obtained in the above step a is heated under stirring for 1 h. After cooling, water (60 mi) is added to the mixture to form a solution, which is then neutralized with a 20% aqueous solution of sodium hydroxide, extracted twice with chloroform (200 mp). After drying over anhydrous magnesium sulfate, the chloroform layer is concentrated to dryness. Methanol (40 mp) is added to the crystals thus obtained.
and activated carbon (0.5 g) and
the mixture is heated. After removing the activated carbon from the resulting solution and cooling, the resulting crystals are collected by filtration and 10.2 g (84.6%) of 8- (4-methyl-1-piperazinyl) -9-fluoro-5-methyl-6 are obtained. , 7-dihydro-1-oxo-1-H, 5H-benzo (1) quinolosin-2-carboxylic acid. White rhombic
262-263 S.
C 63.49, H 6.17,
crystals, so pl.
Calculated,%: N11.69.
C gyeijNjOsF
Found,%: C 63.42; H.6.25; . N 11.6G.
Example 2. In a manner similar to that described in Example 1, the compounds shown in Table 1 were obtained. 1, from the corresponding starting products.
B tab. 1, each compound is expressed in combination of the value of RijRj and X in the formula (1a), and the point of melting of the compound and its output in step b are given
Cun
RO -N

0
Methylenemalonate example
3. a. Diethylethoxy- (9 g, 0.041 mol) was added to 5- (4-formyl-1-piperazinyl) -. B-chloro-1,2,3,4-tetrahydroquinaldine (8.5 g, 0.02 mol) and the mixture is heated at 30 minutes, solid particles are obtained, which are then recrystallized from chloroform-n-hexane, and 12.7 g (92%) of diethylH-5- (4-formyl-1-piperizinyl) are obtained. ) b-chloro-1,2,3,4-tetrahydro-1-quinalindyl J-aminomethyl methyl methyl, white rhombic crystals.
314
Calculated,%: C 59.54; H 6.52; N 9.06.
C-ijHjoOjNiCl
Found,%: C 59.49, H 6.53,
N9.07.
b. Polyphosphoric acid (70 g) obtained from phosphorus pentoxide (35 g 0.17 mol) and phosphoric acid (35 g, 0.36 mol), and diethyl (4-formyl-1-piperazshch1) -6-chloro-1 , 2,3,4-tetrahydro-1-quin dish aminomethylenemalonate (12.5 g, 0.027 mol), obtained from step a, is heated at 140-150 ° C for 1 hour. After the reaction is complete, the reaction mixture is poured into ice water (200 g) and adjust the pH of the mixture to 6-7 with aqueous 10 N. Sodium hydroxide solution. The resulting precipitate is collected by filtration and added to concentrated hydrochloric acid (60 ml). The mixture is heated to 100-110 ° C. for 1 hour. After that, water (100 ml) is added to the reaction mixture and the resulting crystals are collected by filtration, washed with water and dried. Recrystallization from methanol gives 8.9 g (82.5%) of 8- (4-formyl-1-piperazinyl) 9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-6eH3o (ij a) quinolizin-2-carboxylic acid, white rhombic crystals, so pl. 262-265 0.
Calculated,%: C 58.54; H 5.17, N 10.78.
.Cl.
Found,%: C 58.43; H 5.24; N 10.70.
Example 4. In a manner similar to that described in Example 3, the compounds shown in Table 2 were prepared starting from the corresponding starting materials. In tab. 2, each compound is expressed in terms of a combination of values, R and X in the formula (1a), also shows mp, compounds
output at stage b.
soon
BGO
Example 5. a. 4- (4-Metsh1-1-piperazinyl) 5-fluoro-2-methylindindol (9.6 g, 0.039 mol) and isopropshtidenyl methoxymethylenemalonate (8 g, O, 043 mol) are mixed at room temperature
j
5 0 C O
five
0 5
0
five
01
and the mixture is heated under stirring for 30 minutes to obtain solid particles, which are then recrystallized from chloroform-N-hexane. 14 g of cycpinic isopropylidenyl (4-MeTHn-1-piperazinyl) -5-fluoro-2-metsh1-1-indoninyl aminomethylenemalonate are obtained.
Calculated,%: C 59.18; H-6.33; N 9.99.
C2 H26Nj04F
Found,%: C 59.31, H 6.16, N 9.88.
b. Polyphosphoric acid (50 g) obtained from phosphorus pentoxide (25 g, 0.12 mol) and phosphoric acid (25 g, 0.26 mol) and cyclic isopropylideneyl K - {4- (4-methyl-1-piperazinsh1 ) - 5-fluoro-2-methylindonyl-aminomethylene maponate (13.5 g, 0.03 mol), obtained in step a, is heated at 100 ° C for 1 h with stirring. Cooling is complete, water (60 ml) is added to the mixture and the resulting solution is neutralized with aqueous 20% sodium hydroxide solution, followed by extraction with chloroform twice (200 ml). The chloroform layer is dried over anhydrous magnesium sulphate and concentrated to dryness. Methanol (40 ml) and activated carbon (0.5 g) are added to the crystals thus obtained and the mixture is heated to form a solution. After removing the activated carbon by filtration and cooling, the resulting 11e crystals are collected to give (9.8 g) 9- (4-methyl-1-piperazinsh1) -8-fluoro-2-methyl-1,2-dihydro-6-oxopyrrolo- (3.2 1 ij) quinoline-5-carboxylic acid, white rhombic crystals, m.p., 242-244 ° C.
Calculated,%: C 62.59, H 5.84. N 12.17. . CijHjoN OjF
Found,%: C 62.51, H 5.88; N 12.12. ,
Example 6. In a manner similar to that described in Example 5, the compounds shown in Table 1 were obtained. 3, from the respective starting products,
in tab. 3, each compound is expressed under the combination of the radicals R, R2, and X in the formula (16) and is also shown in mp. compounds and exit stage b ..
Cun
R2-NQ; N
Example of tylenmamalonate (9
7. a. Diethyl ethoxymeg, 0.04 mol) was added to 4- (1-piperazins:) 5-chloro-2-methylINDOLINE (6.8 g, 0.027 mol) and the mixture was heated for 30 minutes to form solid particles. which are then recrystallized from chloroform-n-hexane to obtain 10.2 g (92%) of diethyl N-C4- (1-nHne-razinyl) -5-chloro-2-methylinzolinyl aminomethylenemalonate.
Calculated%: C 60.22-; H 6.12 N, 10.14.
Found,%: C 60.07; H 6.24; N 10.01.
b. Polyphosphoric acid (65 g) obtained from phosphorus pentoxide (32.5 g, 0.156 mol) and phosphoric acid (32.5 g, 0.332 mol) and diethyl N-f4- (1-piperazinyl) -5-chloro-2 -methyldinyl1-aminomethylenemalonate (10 g, 0.024 mol), obtained in step a, is heated at 140-150 C for 1 h. After completion of the reaction, the reaction mixture is poured into ice-cold water (200 g) and the pH of the mixture is adjusted to 6-7 with aqueous 10N sodium hydroxide solution. The resulting precipitate is collected by filtration and added to concentrated hydrochloric acid (60 mp). The mixture is heated to lOO-l IO C for 1 hour. Thereafter, water (100 mp) is added to the reaction mixture and the resulting crystals are collected by filtration, washed with water and dried. By recrystallization from methanol, 7.1 g (82.5%) of 9- (1-piperazinyl) -8-5slore-2-methyl-1, 2-dihydro-6-oxopyrpropane (3,2,1-ij) xi are obtained. - nalin-5-carboxylic acid, pale yellow rhombic crystals, so pl. 258-260 S.
Calculated,%: C 58.70; H 3.22, N 12.08.
jN30jCl
Found,%: C 58.63 H 5.15, N 12.15.
Example 8. In a manner similar to that described in Example 7, the compounds listed in Table 2 were obtained. 4, from the corresponding source
14282016
products in the table. 4 each compound was combined by the combination of the values of the radicals R, Rj and X in the formula (16), 5 and also indicated by pl. and the output of the compound in Stage b.
Cun
15 Example 9. Phosphorus oxychloride (4ljA g, 0, .27 mol) and diethyl (4-formyl-1-piper, azinyl) -6-chloro-1,2,3,4-tetrahydro-1-quinaldinyl aminomethylene malonate ( 12.5 g. O, 027 mol), obtained in Example 15A, heated at 140-150 ° C for 3 hours. After completion of the reaction, the reaction mixture was poured into ice-water (200 g), the mixture was adjusted to pH 6- 7 aqueous 10 N solution
25 sodium hydroxide. The precipitates that formed are collected by filtration and added with concentrated hydrochloric acid (60 ml). The mixture is heated to 100-1 for PM. After
30% of this, water (100 ml) is added to the reaction mixture, the crystals that have formed are collected by filtration, washed with water and dried. Recrystallization from methanol gives 8.5 g
35 (79%) of 8- (4-formyl-1-piperazinyl) -9-chloro-5-methyl 1-6,7-dihydro-1 oxo-1H, 5H-benzo (1) quinolizin-2-carboxylic acid. White rhombic crystals, so pl. 262-265 seconds
40 Calculated,%: C 58.54; H 5.17; N 10.78.
CigH oNjOiCl
Found,%: C 58.44; H 5.25; N 10.71.
45 Example 10. P-chloride phosphorus (7.0 g, 0.034 mol) and 1ccc isopropylidene (4-mi-1-piperisins I) -5-fluoro-2-methylindolinsh11 aminomethylenemalonate (13.5 g, 0.03 mol)
50 obtained in example 5a, heated at within 0.5 h with stirring. After cooling, water (60 ml) is added to the mixture, the resulting solution is neutralized with 20%
55 aqueous solution of sodium hydroxide, followed by extraction with chloroform (200 mp) twice. The chloroform layer is dried over anhydrous magnesium powder and concentrated to dryness.
To the crystals thus obtained. In this way, methanol (AO ml) and activated carbon (0.5 g) are added and the mixture is heated to form a solution. After removing the activated carbon by filtration and cooling, the crystals that formed were collected to give 9.2 g (82.5%) of 9- (4-methyl-1-piperazinyl) -8-fluoro-2-mets-1,2 -dihydro-6-oxopyrrolo (3,2,1-ij) quinoline-5-carboxylic acid. White rhombic crystals, so pl. 242- 244 sec.
C, 62.59; H
5.84;
Calculated N 12,17.
C jHjpN OjF
Found,%: C 62.50, H 5.87, N 12.11.
PRI me R
diethylene glycol dimethyl ether at 100 ° C for 3 hours. After cooling, chlorofor (200 mp) is extracted twice. After dehydration and drying over anhydrous sulfate, the chloroform layer is not concentrated to dryness, and the crystals thus obtained are added
10 methanol (40 mp) and activated
coal (0.5 g) and the mixture is heated. By removing the activated carbon and the resultant mixture and cooling the developed crystals collect fi
15 rovacia and get 10.1 g (83.8%) of 8- (4-metsh1-1-piperazinyl) -; 9-fluoro-5 methyl-6,7-dihydro-1-oxo-1H, 5H-ben ( ij) quinolizin-2-carboxylic acid White horn ical crista ply, m.p.
25
N
with stirring, for 6 hours at
11. Concentrated 20 26.2-263 s. sulfuric acid (70.6 g, 0.72 mol) Calculated,%: C 63.49; H 6.17,
and cyclic isopropylidenyl-H-15-N 11.69.
(4-metsh1-1-piperazinyl) -6-fluoro-1,2,3,
4-tetrahydro-1-quinaldinyl aminomethylenemalonate (14.0 g 0.075 mol) prepared in Example 1a, the scientific research institute is heated in
After cooling, water (60 mp) is added to the mixture to form a solution, which is then neutralized with an aqueous 20% sodium hydroxide solution and extracted twice with chloroform (200 mp). After dehydrating and drying over magnesium sulfate anhydrous, the chloroform layer is concentrated to a dry residue. To the crystals thus obtained
thirty
Found,%: C 63.44, H 6.27, 11.63.
Example TK. Diethyl-K-5- (4 formyl-1-pipera zinyl) -6-chl or-1,2,3 tetrahydro-1-quinaldine 1 amino-neme lenmalonat (12.5 g, 0.027 moy), prepared in the example For, heated in 50 MP of diphenyl ether at 140 for 6 hours. After completion of the reaction, the solvent is removed under reduced pressure. To residue at
35 bavlo 60 kp concentrated hydrochloric acid. The mixture is heated for 1 hour. After this, water (100 mp) is added to the reaction mixture, methanol (40 ml) and activated carbon (0.5 g) are added and the mixture is heated. After removing the activated carbon from the resulting solution and cooling the resulting crystals, it is collected by filtration, and 9.86 g (81.5%) of 8- (4-methyl-1-piperazinyl) -9-fluoro-5-methyl-6.7 is obtained -dihydro-1-oxo-1H, 5H-benzo (ij) quinolisin-2-caparboxylic acid. White rhombic crystals, so pl. 262-263 0.
Calculated,%: C, 63.49; H 6.17, N11.69.
C-tqHiiNjOaF
Found,%: C 63.40; H 6.23; N 11.59.
Example 12. Cyclic isopropylideneIL-N 5- (4-methyl-1-piperazinyl) -6-fluorop-1, 2,3,4-tetrahydro-1-quinaldinyl aminomethylenemalonate (14.0 t 0.075 mol ), obtained in example 1a, with stirring, heated in 50 ml
diethylene glycol dimethyl ether at 100 ° C for 3 hours. After cooling, extract twice with chloroform (200 mp). After dehydrating and drying over anhydrous magnesium sulphate, the chloroform layer is concentrated to a dry residue. To the crystals thus obtained, add
methanol (40 mp) and activated
coal (0.5 g) and the mixture is heated. After removing the activated carbon from the resultant mixture and cooling the resulting crystals, they are collected by filtration and 10.1 g (83.8%) of 8- (4-metsh1-1-piperazinyl) -; 9-fluoro-5-methyl-6,7- dihydro-1-oxo-1H, 5H-benzo (ij) quinolizin-2-carboxylic acid. White horn riches crista-ply, so pl.
26.2-263 s. Calculated,%: C, 63.49; H 6.17,
five
N
0
Found,%: C 63.44, H 6.27, 11.63.
Example TK. Diethyl-K-5- (4-formyl-1-pipera zinyl) -6-chl or-1,2,3, A-tetrahydro-1-quinaldine1 aminomethylenemalonate (12.5 g, 0.027 washes) obtained in example The mixture is heated to 50 MP of diphenyl ether at 140 for 6 hours. After the completion of the reaction, the solvent is removed under reduced pressure. 60 kp of concentrated chloro are added to the residue at 5 ° C. hydrofluoric acid. The mixture is heated at 1 hour. After that, water (100 mp) is added to the reaction mixture, the resulting crystals are collected by filtration, washed with water and dried. By recrystallization from methanol, 8.87 g (82.3%) of 8- (4-formyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo5 1I, 5H-benzo (1 a) quinolizin-2-carboxylic acid. White rhombic crystals, so pl. 262-265 C.
Calculated,%: C 58.54; H 5.17; N 10.78 ..
,%: C 58.45, H 5.26; N 10.72.
Example 14. Cyclic isopropylidenyl-N-A- (A-methyl-1-pipera
5 zinyl) -5-fluoro-2-methylinzolish1LJabWHo-methylenemalonate (13.5 g, 0.03 mol) obtained in Example 5a is heated in 50 ml of tetralin with stirring for 1 hour. After
the rake pieces 1 and the solvent are removed at. reduced pressure. The residue obtained is chromatographed on a silica gel column. Methanol (40 ml) and activated charcoal (0.5 g) are added to the crystals thus obtained, and the mixture is heated to form a solution. After removing the excitable carbon by filtration and cooling the resulting crystals, it is collected and 9.8 g of 9- (4-methyl 1-piperazinyl) -8-fluoro-2-methyl-1,2-dihydro-6-oxopyrrolo (3,2,1 -ij) xinoLin
5-carboxylic acid. White rhombus recrystallization from methanol 242-244 0. C, 62.59; H 5.84,
Kie crystals, t
Calculated,% N 12,17.
C.iH oN-jOjF
Naideyo,%: C 62.49, H 5.86; N 12.10.
Example 15: Phosphorus trichloride (37 g, 0.27 mol) and diztil- (4-formsh1-1-piperazinyl) -6-chloro1, 2,3,4-tetrahydro-1-quinaldinyl1-25 N 12.12. nomethylenemalonate (12.5 g, 0.027 mol).
6.9 g (80.0%) of 9- (1-piperazinyl) -8-chloro-2-methyl-1,2-dihydro-6-oco-pyrrolo (3,2,1-ij) xinalin-5 -carboxylic acid. Pale yellow rhombic crystals, so pl. 258-260 s.
Calculated,%: C 58.70; H 5.22; N 12.08.
C H iNjOjCl
Found,%: C 58.60; H 5.12;
The example obtained in Example 3 is heated at 4 hours. After completion of the reaction, the reaction mixture is drunk in ice water (200 g) and the mixture is adjusted to pH 6-7 with aqueous 10N. sodium hydroxide solution. The precipitate formed is collected by filtration and added to aqueous 1N sodium hydroxide solution (60 ml). The mixture is left overnight at room temperature. After that, the reaction mixture is adjusted to pH 3-4 with concentrated chloride.
the reaction mixture is poured into ice water (200 g) and the mixture is adjusted to pH 6-7 with aqueous 10 n. sodium hydroxide solution. The resulting precipitate was collected by filtration and added to an aqueous 10% solution of p-toluenesulfonic acid (60 ml). In a sealed vessel, the reaction is carried out in a mixture for .0.5 hours at. Thereafter, water (100 ml) is added to the reaction mixture, the resulting crystals are collected by filtration, washed with water and dried, PeN 12,12.
6.9 g (80.0%) of 9- (1-piperazinyl) -8-chloro-2-methyl-1,2-dihydro-6-oco-pyrrolo (3,2,1-ij) xinalin-5 -carboxylic acid. Pale yellow rhombic crystals, so pl. 258-260 s.
Calculated,%: C 58.70; H 5.22; N 12.08.
C H iNjOjCl
Found,%: C 58.60; H 5.12;
P r and m Lenmalonat
0
ep 17. Diethyl ethoxymethyl- (6.0 g, 0.028 mol) was added to 5- (4-methyl-1-piperazinyl) -6-fluoro-1,2,3,4-tetrahydroquinaldine (6.6 g, 0.025 mol ) and the mixture is heated at 160 ° C. for 30 minutes. Thereafter, polyphosphoric acid (48 g), obtained from five to 5 phosphorus oxides (24 g, 0.12 mol) and phosphoric acid (24 g, 0.24 mol), is added and the resulting mixture is heated at 150 ° C for 1 h. After completion of the reaction, the reaction mixture is set off.
native acid formed in ice water (150 l), collected by filtration, the washed precipitate is collected by filtration,
water and dry. Recrystallization is carried out with water and dried. 8.8 g (81.6%) of crystals thus obtained are obtained by adding methanol (8-formsh1-1-piperazinyl) -9-chloro-5-liter aqueous 19% sodium hydroxide solution ( 70 ml) and the mixture is reacted at 100-1 for 1 hour. After cooling, the reaction mixture is acidified with concentrated hydrochloric acid to form crystals.
methyl 6,7, -dihydro-1-oxo-1H, 5H-benzo (ij) quinolizin-2-carboxylic acid. White rhombic crystals, so pl. 262-265 C.
Calculated,%: C 58.54; H 5.17; 10.7.
N
acid. The crystals are collected by filtration, washed with water, recrystallized from methanol, and 7.7 g (85%) of 8- (4-m 9-ethyl-1-piperazinyl) -9-fluoro-5-methyl- | 6, 7-dihydr-1-oxo-1H, 55 5H-benzo (1) quinolizin-2-carboxylic acid. White rhombic crystals, so pl. 262-263 S.
C..Cl
Found,%: C 58.48; H 5.25; N 10.6.
Example 16. Thionyl chloride (57 g, 0.48 mol) and diethyl 4- (1-piperazinyl) -5-chloro-2-methylindolinyl aminomethylenemalonate (10.0 g, 0.024 mol) obtained in Example 7a, heated at 140 150 C for 1 h.
sodium (70 ml) and the mixture was reacted at 100-1 for 1 hour. After cooling, the reaction mixture was acidified with concentrated hydrochloric acid to form crystals.
acid. The crystals are collected by filtration, washed with water, recrystallized from methanol, and 7.7 g (85%) of 8- (4-m 9-ethyl-1-piperazinyl) -9-fluoro-5-methyl- | 6, 7-dihydr-1-oxo-1H, 5H-benzo (1) quinolizin-2-carboxylic acid. White rhombic crystals, so pl. 262-263 S.
Calculated,%: C, 63.49; H 6.17; N 11.69.
n
CigHj N OjF
Found, Z: C 63.34; H 6.21; N 11.63.
Example 18 Diethyl ethoxymethyl lenmalonate (6.0 g, 0.028 mol) was added to 4- (4-methyl-1-piperazinyl) -5-fluoro-2-methyl-1 dinoline (6.2 g, 0.025 mol) and the mixture was heated at for 30 minutes Thereafter
polyphosphoric acid (48 g), obtained from th phosphorus thioxide (24 g, 0.12 mol) and phosphoric acid (24 g, 0.24 mol), is added, and the resulting mixture is heated at 150 ° C for 1 hour. the reaction mixture is drunk in ice water (150 g), the precipitate formed is collected by filtration, washed with water and dried. The crystals thus obtained were added to an aqueous 10% solution of sodium hydroxide (70 ml) and the reaction was carried out in a mixture of SO-PO C for 1 hour. After cooling, the reaction mixture was acidified to form crystals of concentrated hydrochloric acid. The crystals are collected by filtration, washed with water, recrystallized from methanol, and 7.2 g (85%) of 9- (4-methyl-1-piperazinyl) -8-fluoro-2-methyl-1,2-dihydro-6- oxo-pyrrolo (3,2, t-ij) choline-5-carboxylic acid. White rhombic crystals, so pl. 242-244 0.
Calculated,%: C 62.59, H 5.84, N 12.17.
C.jH oNjOjF
Found,%: C 62.46; H 5.89; N 12.24.
Example 19. Phosphorus trichloride (37 g, 0.27 mol) and diethyl ND (4-formyl-1-piperazinyl) -6-chloro-1,2,3 4-tetrahydro-1-quinyl aminyl amine-methyl manone (12.5 g, 0.027 mol), obtained in Example 3, is heated at 125 ° C for 4 hours. After completion of the reaction, the reaction mixture is poured into ice-water (200 g) and the mixture is adjusted to pH 6-7 with an aqueous solution of 10 N. hydroxide on three . The resulting precipitates are collected by filtration and added to a 1N aqueous solution of sodium hydroxide, (60 ml). The mixture is heated for 1 hour in a sealed tube. After this, the reaction mixture is adjusted to pH 3-4 with concentrated hydrochloric acid, and the crystals formed are collected.
820112
The filtration is washed and dried. Recrystallization from methanol gives 9.0 g (83.4%) of 8- (4-forms: -1-pipa-f-razinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H , 5H-benzo (1z) quinolizin-2-carboxylic acid. White rhombic crystals, so pl. 262-265 ° C.
Calculated,%: C 58.54; H 5.17; 10 N 10.7.
C gHrjoNjO C
Found,%: C 58.45; H 5.26;
N 10.6.
Example 20 Diethyl ethoxymethyl 15 lenmalonate (6.0 g, 0.028 mol) was added to 5- (4-methyl-1-piperazinyl) -6-fluoro-1,2,3,4-tetrahydroquinaldine (6.6 g, 0.025 mol) and the mixture is heated at 30 minutes. Then
20 polyphosphoric acid (19.8 g) obtained from phosphoric pentoxide (9.9 g, 0.05 mol) and phosphoric acid (9.9 g 0.1 mol) are added thereto, and the mixture is heated at 150 ° C.
25–1 h. After completion of the reaction, the reaction mixture is poured into ice-water (150 g), and the precipitates that have formed are collected by filtration, washed with water and dried. To crystals
30 obtained in this way, a 19% aqueous solution of sodium hydroxide (70 ml) is added and the mixture is allowed to react at 100-110 seconds for 1 hour. After cooling, the reaction mixture
35 is acidified with concentrated hydrochloric acid to form crystals. The crystals are collected by filtration, washed with water and recrystallized from methanol, 7.6 g are obtained.
40 (83.9%) 8- (4-methyl-1-piperazis1p) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H benzo (1z) quinolizin-2-carboxylic acid . White rhombic crystals, so pl. 262-263 S.
C 63.49; H 6.17;
45
N
Calculated,%; 11.69. .N2 "ZOZR Found,%: C 63.33, H 6.20,
,
N
11.62.
50 Example 21. Diethyl ethoxymethylene malonate (6.0 g, 0.028 mol) was added to 4- (4-methyl-1-piperazinsh1) -5-fluoro-2-methylindoline (6.2 g, –0.025 mol) and the mixture is heated at
55 160 s for 30 min. Then polyphosphoric acid (49.6 g) obtained from phosphoric anhydride (24.8 g, 0.124 mol) and phosphoric distilot (24.8 g, 0.248 mol) is added, and 1314 is obtained.
The mixture was heated at 1 h in a flow. After the reaction was completed, the reaction mixture was poured into ice-water (150 g), and the precipitates that had formed were collected by filtration, washed with water and dried. A 10% aqueous solution of sodium hydroxide (70 ml) was added to the crystals thus obtained, and the mixture was allowed to react at 100-1 for 1 hour. After cooling, the reaction mixture was acidified with concentrated hydrochloric acid to form crystals. The crystals are collected by filtration, washed with water, and recaptured from methanol to give 7.3 g (86%) of 9- (4-methyl-1-piperazinyl) -8-fluoro-2-m8til-1,2-dihydro-6 -oxopyrrolo (3, 2,1.-13) quinoline-5-carboxylic acid. White rhombic crystals, T.Sh1. 242-244 0.
C, 62.59; H 5.84,
N
Calculated% 12,17.
Found,%: C 62.47, H 5,
87V
N
12.23.
Thus, the proposed method allows to increase the yield of the target product from 36% (according to the prototype) to 71-85% and improve the quality of the target product.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining benzoheterocyclic compounds of general formula I
ABOUT
soon
Ba-K) JL (CH2) / - B
de RI - hydrogen or alkyl group Cl-Cd j
Rj is hydrogen, an alkyl group. which may be substituted by a halogen or hydroxy group, or a lower alkanoyl group, which may be substituted by halogen; X is hydrogen or halogen-, n is an integer. Number, 1 or 2, with
provided that, R does not mean Cf substituted alkyl group by halogen.
one
14
characterized in that, in order to increase the yield and quality of the target product, a benzoheterocyclic compound of general formula II
“2
where R, Rj, X and
Kb
n have the indicated meanings — group of general formula
I
sn
° x
Ri Kd
or a group of general r-mules.
(COOR5) 2
where Rj, R4 and R.; - each means a lower alkyl group,
subjected to cyclization by heating it in a solvent such as diethylene glycol dimethyl ether, diphosphate or tetralin, with 100 or without solvent at 100, but in the presence of 1–20 mol of an acidic substance, such as
phosphorus oxychloride, phosphorus p-chloride, phosphorus trichloride, thionylchloride, concentrated sulfuric acid or phosphoric acid, and polyphosphoric acid is used in
an amount of 3-8 times (by weight) greater than the amount of the compound of general formula II, and when Rg means a residue of general formula (COOR5) 2
where R5 has the specified value
the resulting compound is subjected to hydrolysis at a temperature from room temperature to in the presence of a catalyst such as a base, mineral
or organic acid. Priority on pr to and m
December 18, 1980 with item 2;
25.09.81g with n 1.
and 3 n and g
g g
with
gCN
.gp
"I
with
cope
, five
Yu
so
l
about
hp
Z
V
e GE
about
ABOUT
eat
00
1L vO
CM vO
s
d
w and
1P
-with
fsl
"Ъ
cm
cm sch 00 about
00 FROM - g CS
f, "h" h 00 (
with
vD
1L
f 00
vO
about
 WITH
sh
about
Ti
Yu
Och
00
sh
about
Suche
sj- “Och Yu
YU
WITH
v)
ABOUT
%
Sh
Ti
cho
(Y,
1L
-
SU
Yu
cm vO
vO vO
 CM
cm
VO
0
41-chO
“- CHO SO ..
g "co - o
About vO. “VO -
P
t
d
"N
about
C4
to
e and
ABOUT
rtl
g
Yes
"H
and

C4
ft I "(
about
and
cf h g
S
SB
S. and
(14
P
about
P
oh oh c
W OK
sh
and
year
00
00
cm
PTS
00
sT
00
cho
cm
About VC
CM
oh oh
with
/to
GO
Och cm
cm 0 cm
cm g cm
g, cm
ABOUT
ci
TO
oh oh
go
flH
PTS
U PTS
V
PTS
t
PTS
“F V O
I'm about
"
X
and
sa
k, g
w GS
and
00
PTS
cm
go
g 1 s
 S x h
R,
R.
T.rai. c
HX
N.
Smov NS1 ZOO S (304-306 ROME)
Stand HC1 300 C
SI. H
GB9-273 HC1 (pasi; c ".)
Sya
And С1 258-260 СН, СН, С1 273-276 О CCPj Г
I CCHCJg
CCHj F
about . CH, SNGs
CH,
CH.
CH,
25 "-2E2 (raal" |)
263-266 (raelozh.)
272-275 (decomposed)
238-242 - (decomposed)
TaOl qa}
Output, X
orkul
X-ray analysis, X, calculated (found)
5.5 С „Н„ Н, 0, Р-НС1
3. ,, HCl
.5с „н н, о, -ссг
2.5 СдН „Н, 0, сг. C ,, H, jN, 0, Cl
2.6.C ,,, 0, F
I
, 2C ,, H ,, N, 0, C1, F "
3.5C ,, H ,, N,
2 ,,, N, 0, CIF
C T H 55,514,93
(55.47 4.98
57.23 (57.12 58.37 (58.26 58.70 458.62 59.75) (59.67 53.40 (53.47 51.59 (51.51 61.12 (61.03 55 , 95- (55.87
5.10
5.19
5.47
5,4t
5.22
5.14.
5.57
5.62
4.01
4.12
4,10
4.15
5.40
 .
4.70
N
11.43
11.37)
12.52
12.46)
12.01
12.13)
12.08
12,14)
11.61
11.54)
9.83
9.76)
9.50
9.57)
11.26
11.13)
10.30
4.8110.24)
Table 4
3
outside
C8, 1G, .2 "
(unallocated)
si
I
 OCHClg
263-266 (raeloh.)
CH, ICH, P 272-275 5 (pasno ..)
™ "1Sn, C1 l, t, H2Cl (pasnom.)
ten
ICH, CF.CH. F 287-289
01
32 Continued
C ,, fl ,, N, 0, 404.0
{53,484,13
. 51,594,10
(51,534,13
C ,, H ,, N, 04F, 61,125.40
. (6t, 045.48
C ,, H ,, N, 5S, 954, U
(55,854.80
CrtH ,, N50, F, -HCl 49.60 3.93
(49.66 3 (83
C ,, HnN, OjF46,645,68
(67, 74
tab. four
5t, in 1chip- H
9.83
9.78).
9.50
9.59)
11.26
11.12)
10.30
10.23)
9,644, 70)
12.46
g, stars)

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

BE793524A|1971-12-30|1973-06-29|Riker Laboratories Inc|BENZOQUINOLIZINE-CARBOXYLIC ACIDS AND THEIR DERIVATIVES|

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DE2953974C2|1978-04-12|1992-06-25|Otsuka Pharmaceutical Co., Ltd., Tokio/Tokyo, Jp|NO156828C|1980-11-10|1987-12-02|Otsuka Pharma Co Ltd|ANALOGY PROCEDURE FOR THE PREPARATION OF ANTIBACTERYLY EFFECTIVE BENZOHETEROCYCLIC COMPOUNDS.|

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US4472406A|1982-11-12|1984-09-18|Riker Laboratories, Inc.|Antimicrobial 6,7-dihydro-8--5-methyl-1-oxo-1H,5H-benzo [ij]quinolizine-2-carboxylic acids and derivatives|

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JPH0321031B2|1983-01-26|1991-03-20|Otsuka Pharma Co Ltd|

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JPH0412268B2|1983-02-22|1992-03-04|Kyorin Seiyaku Kk|

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EP0185429A1|1984-12-21|1986-06-25|Duphar International Research B.V|New bicyclic heteroaryl piperazines|

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AT81975T|1984-12-21|1992-11-15|Duphar Int Res|MEDICINAL PRODUCTS WITH PSYCHOTROPER EFFECT.|

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CA1253154A|1985-05-24|1989-04-25|Atsushi Takagi|Benzo¬ij|quinolizine-2-carboxylic acidderivatives|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP55179949A|JPS57102887A|1980-12-18|1980-12-18|Preparation of benzoquinolizine-2-carboxylic acid derivative|

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JP15245181A|JPS5855484A|1981-09-25|1981-09-25|Preparation of pyrroloquinoline-5-carboxylic acid derivative|

---