Title of Invention

"PROCESS FOR PREPARING (-)PYRIDOBENZOXAZINE CARBOXYLIC ACID DERIVATIVES"

Abstract

The present invention provides a process for preparing optically active (-)pyridobenzoxazine carboxylic acid derivative and phatmaceutically acceptable salt thereof by employing a starling material of (+)cthyl 2-(4-chloro-5-fluoro-2-halo-3-nilobenzoyl)-3-nitobcnzoyl)-3-[( 1 -hydroxypropy-2(S)-yl)amino]acrylate. According to the present invention, optically active (-)pyridobenzoxazine carboxylic acid derivative can be manufactured from low-priced 4-chloro-5-fluorobenzoic acid derivative in a simple and economical manner.

Full Text

1A BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a process for preparing an optically active (-) 9-fluoro-3-methyl-7-oxo-2, 3-di hydro-7H-pyrido(l, 2, 3-de] ['. , 4] -benzoxazine-6-carbC'Xylic acid derivative ("pyridobenzoxazir.e car boxy lie acid derivative") represented by the formula (I) or pharmaceutically acceptable sale thereof having an excellent antimicrobial activity. wherein, R1 represents hydrogen atom or lower ,alkyl group having 1 to 5 carton atoms. Description of the Prior Art A variety of optically active pyricobsr.zoxazine carboKylic acid derivatives have been prepared' and used as active ingredients for antibiotic agents, since the compo inds^ are known to possess h Lgher ar.t imicrobial activity and weaker toxicity than optically inactive racemic mixture (see: Drugs of the future, 17 (2) , 559-563(1592)) . 2 In general, optically active (-)pyridobenzoxazine carboxylic acid derivatives have teen prepared in the art by the following two processes: the first one comprises a step of selective hydrolysis of (±)7,8-f iuoro-2, 3-dihydro-3-acetoxymethyl-4:i- [1,4] -benzoxazine by hydrolase; and, the second one comprises a step of optical resolution of (±) 7,8~::luoro-2,3-dihydro-3-acetcxymethyl-4H-[1,4]-benzoxazine by chemical reagent(see: EP 206,283; Korean Pat. No. 60,571). However, those processes have several drawbacks as followings: 1) theoretically 50% of isomers are lost; 2) high-priced reagent for separation is used; and, 3) complicate process of 8 steps are accompanied, which is not suitable for industrial-scale trass production. To sclve the said problems, a process has been developed to prepare (-)isomer by racemizing (+)isomer obtained as a by-product during the said process (iies: Japanese Patent Publication (Hex) 10-357910). Further, processes for preparing optically active pyridobenzoxazine carboxylic acid derivatives are disclosed in U.S.Pat. Nos. 4,777,253 and 5,237,060 and Korean Pat. No. 125,115 as well. These prior arts suggest that optically active (-)pyridobenzoxazine carboxylic acid derivatives using optically active (L)-alaninol can be prepared without Dptical resolution, which is.represented as the following reaction scheme: As shown in the scheme above, a starting material of 4r5-difluorobenzoic acid deri/ative should be employed in the reaction, since f .uorine atom among various halogen atoms is essentiall-.' required for t-.hp 3 last step of substituting proper piperazine for 10-halogen atom. Though this process is improved in a sense that optical- resolution step is not necessary, it has revealed a critical demerit that very expensive 4, 5-difiusrobenzoic acid derivative is required. On the other hand, it has been reported that relatively inexpensive 4-chloro-5-fluorobenzoic acid derivative, whose reactivity is lowered than 4,5-difluorobenzoic acid derivative, leads to substitution reac-ion at 9-f iuor.Lne atom rather than 10-fluorine atom in the last step(see: Chem. Pharm. Bull., 32, 4907-4913(1984)}. Therefore, there are strong reasons for exploring and developing a process for preparing optically active (-)pyridobenzoxazine carboxylic acid derivative by employing a low-priced material in a simple and economical manner. The present inventors su':cessf uly prepared optically active (-)pyridobenzoxazine carboxylic acid derivative, by employing a starting n.aterial of ( + )ethyl 2- (4-chloro-5-f luoro-2-halo-3-nitoben::oyl) -3- [ (1-hydroxypropy-2(S)-yl)amino]acrylate uhich is obtainable from -low-priced 4-chloro-5-fluorobenzoic acid derivative instead of high-priced 4,5-difluorobenzoic acid derivative, and substituting piperazir.e -for chlorine atom. A primary object of the pre sent invention is, therefore, to provide a process for preparing optically active (-)pyridobenzoxazine carboxylic acid derivatives. The other object of the invention is to provide novel compounds which are available ;is intermediates in the coarse of preparing the (-) pyridobenzoxazine carboxylic acid derivatives. 4 DETAILED DESCRIPTION OF THE INVENTION In carrying out the present invention, a low priced compound (V) is employed as a starting material which is obtainable from 4-chloro-5-fluoro-2-halo-3 nitrobenzoic acid derivatives by the known process in the a r t (see: U.S. Pat. No. 5,237,060). As shown in the reaction scheme below, optically active (-) pyridobenzoxazine earboxylic acid derivatives of the invention are prepared by the following steps: (i) reacting a compound (V) with a reactive material (VI) or (VII) in the presence of a base to obtain a compound (TV); ii) converting the compound (IV) to a compound (III) in an organic polar solvent and in the presence of a base; iii) reacting the compound (III) with piperazine or N-mono-substituted-piperazine in an organic polar solvent in the presence of a base to obtain a nove compound (II) by so called one-pot reaction; and, iv) hydrolyzing and cyclizing the compound (II) in an organic solvent in the presence of alkaline metal hydroxide to give the optically active compound (I). 5 Rb-N=C=Y (VII) wherein. X represents a halogen atDm; Z)represents a leaving _grDUp; X represents an oxygen or a sulfur atom; Ra represents -C(=O)-R2 [therein R2 represents an alkyi group having 1 to 5 carbon atoms, phenyl group, substituted phenyl group, alkoxy group having 1 to 5 carbon atoms, cycloalkoxy group having 3 to 5 carbon atoms, phenoxy group, substituted phenoxy group, primary or secoidary arain.e group or alkylthio group havirg 1 to 5 carbon atoms]; Rb represents aikyl group having 1 to 5 carbon atoms, phenyl group or substituted phenyl group; R represents the same as Ra above or Rb-NH-C(=Y) [wherein Rb and Y represent the same above]; and, R1 represents hydrogen atom or alkyl group having 1 to 5 carbon aioms. Specifically, X includes halogen atom such as chlorine atom- and fluorine atora. Z includes halogen atom such as chloride atom and fluorine atom; carboxylate group; and alkoxy group. R2 includes lower alkyl group having 1 to 5 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, sec-butyl- arc up, r.- butyl group, isobutyl group, t-pentyl groip, n-pentyl group, isopeittyl group and r.eopentyl group preferably methyl group and ethyl group; phenyl group; substituted phenyl group such as p-methoxyl phenyl group, 3,5-dimethoxyphenyl group, 3, 5-dimethylplier.yl group, 2,4,6- 6 trimethylphenyl group, p-chlorophenyl group and pfluorophenyl group; alkoxy group having 1 to 5 carbon atoms such as inethoxy group, ethoxy group, n-propoxy group, t-butoxy group, sec-butoxy group, n-butoxy group, isobutoxy group, t-pentoxy group, isopsntoxy group, neopentoxy group and cyclopentoxy group; cycloalkoxy group having 3 to 5 carbon atoms such as cyclopropoxy group, cyclobutoxy group and cyclopentoxy group; phenoxy group; substituted phenoxy group such as p-methoxyphenoxy group, p-chlorophenoxy group and p-fluorophenoxy group; primary or secondary amine group such as methylarnine group, dimethylamine group ethylamine group and diethylamine group; and, alkylthio group having 1 to 5 carbon atoms such as methyl thio group, ethyl thio group, n"propylthiogroup, isopropylthio group, t-butylthio group, sec-butylthio group, n-butylthio group, isohutyifchio group, t-pentylthio group, isopentylthio group and neopentylthio group, Rb includes lower alkyl group having 1 to 5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, sec-butyl group, n-butyl group, isobutyl group, t-penty] group, n-pentyl group, isopentyl group and neopentyl group; phenyl group; and, substituted phenyl group such as p-methoxyphenyl group, 3, 5-dimethoxy phenyl group, 3, 5-dimethylphenyl group 2, 4, 6-trimethylphenyl group, p-chioroplienyl group and p-fluorophenyl group. R1 includes hydrogen atom and lower alkyl group having I to 5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, sec-butyl group, n-butyl group, isobutyl group, t-pentyl group, n-pentyl group, isopentyl group and neopentyl group. The process for preparing optically active (-) pyridobenzoxazine carboxylic acid derivatives is described in more detail. 7 (1) Step 1: Preparation of compound (l'\f) wherein, X and R represent the same above. Starting material(V) of (+)ethyl 2-(4-chloro~5-fiuoro-2-haio-3-nitobenzovX) -3-{ (l-hytroxypropy-2 (S) -y1)amiao] Acrylate which is obtained from 4-chloro-5-fluoro-2-halo-3-nitrobenzoic acid derivative by the conventional process (see: U.S. Pat. No. 5,237,0-6CM is reacted with 1.0-3.0 mole equivalents of reactive material (VI) or (VII) in an organi c solvent in the presence of a base at a temperature cf -40°C to 80 °C to obtain a compound(IV). Ra -z (VI) Rb-N=C'=Y (VII) wherein, Ra Rb. z, and Y represent the same above. The reactive material(VI) includes acyihalide, carboxylic acid anhydride, c.lkylchloroformate, cycloalkylchloroformate, alkylcarbonate, cycloalkylcarbonate/ phenylchlorofornate, substituted phenylcaloroformate; and, the reactive material(VIn includes isocyanate and isothiocyanats. The base includes metal carbonate, metal bicarboiate, metal alkoxide, 1, 8-diasabicyclo [ S . 4 . 0] -7- 9 undeceae(DBU) , 1, 4-ciiazabicyclo[2. 2. ] octane (DABCO) , 1,5- diaza.oicyclo[4. 3. 0] -5-nonene (DBN), pyridine, dimet.iylaminopyridine and trimethylan.ine, where potassium carbonate and sodium carbonate are preferably employed as the metal carbonate; potassium bicarbonate and sodium bicarbonate, as the metal bicarbsnate; and, sodium methoxide and sodium ethoxide, as the metal alkoxide. (2) Sr.ep 2: Preparation of compound (III) wherein, X and R represent the same above, The compound (IV) obtained in Sts;p 1 is converted to a compound(III) in the presence of an organic polar solvent and 2.0-5.0 mole equivalents of base at a temperature of range of 18°C to 150 3C depending on the solvent and the base. The organic polar solvent includes DMF(-N,N'- dimethylformamide) ,. DMSO (cimethylsul foxide) , dioxane, acetonUrile, tetrahydrof uran and acetone. The base includes metal carbonate, metal bicarbonate, metal alkoxide, DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (:., 4 -diazabicyclo [2.2.2) octane, DBN (1, 5- diazab: cyclo[4.3.0]non-5-ene), pyridine, dimethylaminopyridine and trimethylanine, where the metal carboncite, the metal bicarbonate and the metal alkoxide are the: same above. (3) Step 3: Preparation of compound(II) 9 wherein, X and R1 represent the sane above. The compound{III) is reacted with 1.0-3.0 mole equivalents of piperazine or N'-mono-substituted-piperazine to obtain a novel conpound(II), in the presence of an organic polar solvent and 2.0-5.0 mole equivalents of a base at a temperature range of 18°C to 120cC. In the carrying out the said reaction, the compound (III) may be employed in a purified stare or non-pur if.Led state and, the organic so Lvent includes DMF, DMSO, dioxane, acetonitrile, tetrahydrofuran and acetone, and the base includes metal carbonate, metal bicarbonate, metal alkoxide, D3U, DABCO, DBN, pyridine, dimethylaminopyridine and trimethylairune, where the metal carbonate, the metal bicarbonate and the metal alkoxide are the.same above. The piperazine or N-mono-substj tuted-pi'perazine is represented by the following formula(VIII) wherein, R1 represents the same above, The substituted-pdperazine includes N-methypLperazine, N-ethylpiperazine, N-a-propylpiperazine, N-isop.:opylpiperazine, N-t-butylpierazine, N-sec-butylpj.perazine, N-n-butylpipe razine, N- iO isobutylpiperazine, N-t-pentylpiperazine, N-n-pentylpiperazine, N- isopentylpiperazine and N -neopentylpiperazine. (4) Step 4: Preparation of (-) Pyridobenzoxazine carboxylic acid derivative (I) The compound (II) is converted to a compound (1) by hydrolysis and cyclization of compound (II) via one or two steps. In carrying out the said reaction via one step, the compound (1) is obtained by refluxing the compound (II) in the presence of 3.0 ~ 6.0 mole equivalents of alkaline metal hydroxide and an organic solvent with heating. The alkaline metal hydroxide includes potassium hydroxide and sodium hydroxide, and the organic solvent includes alcohol, tetrahydrofuran and a mixed solvent of one of the said solvent and water. In the case of employing the mixed solvent of alcohol and water, mixing ratio may be 100:0 to 25:75(v/v). while in the case of the mixed solvent of tetrahydrofuran and water, mixing ratio of tetrahydrofuran and water, it may be 100:0 to 25:75(v/v). In the carrying -out the said reaction via two steps, as shown in following reaction scheme, the compound (II) was hydrolyzed to give an intermediate compound (II-I), which is in turn, converted to the compound (I) by hydrolysis and cyclization of compound (II-I) in a purified or non-purified state. In addition, the compound (II) was hydrolyzed to form an intermediate compound (11-2), which is in turn, converted to the compound (!) by cyclization of compound (II-2) in a purified or non-purified state. 11 wherein, R and Rj represent the same above; and, M represents metal atom such as potassium and sodium. The compound (II) is reacted with 1.0-2.0 mole equivalents of metal carbonate in a mixed solvent of alcohol and water to give an intermediate compound (II-l), where the mixing ratio of alcohol and water in the mixed solvent may be 100:0 to 25:75(v/v), and the metal carbonate includes potassium carbonate and sodium carbonate. Further, the compound (II) is reacted with 2.0-4.0 mole equivalents of alkaline metal hydroxide in alcohol to give an intermediate compound (II-2), where the alkaline metal hydroxide includes potassium hydroxide and sodium hydroxide. The compound (I) is obtained by refluxing the, intermediate compound (II-l) or (0-2) in the presence of 1.0-3.0 mole equivalents of alkaline metal hydroxide and an organic solvent, where the alkaline metal hydroxide includes potassium hydroxide and sodium hydroxide, and the organic solvent includes alcohol, tetrahydrofuran and a mixed solvent of one of the said solvent and water. In the case of employing the mixed solvent of alcohol and water, mixing ratio of alcohol and water may be 100:0 to 25:75(v/v), while in the case of the mixed solvent of tetrahydrofuran and water, it may be100:0to25:75(v/v). 12 The present invention is further illustrated by the following examples, which should no; be taken to limit the scope of the invention. : ( + ) Ethyl 2- (2, 4 -dichloro-3~nitro-5- fluorobenzoyi)--3- [ (l-acetc-xypropy-2 (S) -yl) amino]acrylate (IV, X=C1, R=COMe) 35.0g(8 5mmol) of (+)ethyl 2-(2,4-dichloro~3-nitro-5-fluorobenzoyl)-3-[(l-hydroxypropy-2(S)-yl) amino] acrylate (V, X=C1) prepared by the conventional process (,sept: U.S.Pat.No. 5,237,060) was dissolved in 150ml of ethylenedichloride, and chilled to a temperature of - NMR(CDC13) 5 (ppm) : 10.99 (q, 1H) , 8, 20 (d, 1H),, 7.17 (d, 1H) , 4.00--4..21(ir# 5H) , 2.11 (s, 3H) , 1.43 (d, 3H) , 1.04 (t, 3H) ( + ) Ethyl 2- (2, 4- dichloro-3-nitro-5- fluorobenzoyl)-3-[(1-ethox ycarboxy-propy-2(S) -yl)amino]acrylate (IV, x=Cl, R=CO2Et) :.7.8g (43.4mmol) of ( + ) ethyl 2-(2, 4-dichloro-3-nitro-!i-f luorobenzoyl) -3- ( (l-hydroxypropy^2 (S) -yl} amino] acrylane (V, X=C1) was dissolved in 60ml of dichloroethane, and chilled to a temperature of 00 C. To the resultant was added 7.9ml of triethylamine, then a 13 solution obtained by dissolving 5. Oml of ethylchloroformate in 20.0ml of e11-yleneciichloride was added for 10 minutes at 0* C with stirring for 3hours. Finally, to the solution was 50ml of vater poured at room temperature to separate an organic layer, washed with 0.IN HC1 solution(50ml), IN NaHCO3 solution(50ml), and NaCl solution (50ml), subsequently cried over anhydrous MgSO4, then evaporated under a reduced pressure to obtain 20.93g?(100%, E/Z -3/1 of the titled compound. NMR(CX13) 8 (ppm) : ll.OKd, 1H) , 8.23(d, 1H) , 7.16(d, 1H) , 4.00-4.29(m, 7H) , 1.50(d, 3H) , l-33(t, 3H) , 1.06(t, 3H) (-) Ethyl N- (l~acetoxy-propy-2 (S) -yl) -6-fluoro- 7-chloro~8-nitro-4-quinolone-3-carboxylate (III, X~C1, R=COMe> 70mg(0.I5mmol) of (+)ethyl 2-(2,4-dichloro-3-nitro-5-fluorobenzoyl)-3-[(l-acetoxypropy-2(S)-yl)amino] acryl.ate (IV, X=C1, R=COMe) was dissolved in 2ml of acetonitrile. To the resultant was added 80mg cf K2CO3, then refluxed for 4hours with heatir g- After cooling to room temperature, the ( solvent was evaporated under a reduced pressure and treated with 5ml, of 'acetic acid ethylsster and' 5ml of water to ob:aih organic layer, dried over anhydrous MgSO4 and then evaporated under a reduced pressure to give 60mg(96%) of the. titled compound NMR(CQC13> S (ppm): 8.6l(s, 1H), 8.46(d, 1H) , 4.45(m, 3H) 4.31 3K) , 1-64 (d, 3K) , 1.43 U, 3H) (-)Ethyl N- (l-acetoxy-propy-2(5)-yl)-6-fluoro- 7- (N-methylpiperazir.yl) -3 -nitro-4-quinolone-3-carboxylate(II, R=C0Me, Ki=Me) 14 60mg{0.14mmol) of NMR(CDC13) 6 (ppm) : 8.53(s, 1H) , 8.31 {d, 1H), 4.51(m, 1.4), ' 4.39(q, 2H), 4.28(dd, 1H) , 4.12(dd, 1H), 3.24(dd, 2H), 3.13(dd, 2K), 2.48{ds, AH) , 2.33(s, 3H) , 1.94(s, 3H), 1.58(d, 3H), 1.40{t, 3K) (-) Ethyl N- (l-acetoxy-propy-2 (S) -yl) -6-fluoro- 7- (N-methylpiperazinyl) -8-nitro-4- quinoione-3-carboxylate{11, R=COKe, Ri=Me) 54.5g (G.I2mol) of { + )ethyl 2-(2,4-dichloro-3-nitro-5-fluorobenzoyl)-3-[£l-acetoxypropy-2(S)-yl)amino] acrylate (IVr X=Cl, R=COMe) was dissolved in 360ml of acetonitrile To the resultant was added 41. 6g of K2CO3, then "refluxed for 8 hours with heating. "After the starting material disappeared from TLC, 14.7ml of- N-methylpiperazine was added to the solution slowly for 10 minutes, further refluxed for 30 minutes with heating and cooled to room temperature. Then, inorganic salt was removed by filtration and evaporated under a reduced pressure, and created with 250ml cf acetic acid ethyl ester and 250ml of water to fractionate an organic layer. The organic layer was dried over anhydrous MgSO4, evaporated under a reduced pressure to give 52g(90%) of 15 the titled compound- The compound was further purified by dissolving in 150ml of ethylacetate/hexane(1/2, v/v) with heating and leaving to stand at room temperature, finally to give 32g{56%} of the pure titled compound. NMR(CDCl3) (ppm): 8.53{s, 1H) , 8.31(d, 1H), 4.51(m, 1H) , 4.39(q, 2H) , 4.2 3(dd, 1H) , 4.12(dd, 1H) , 3.2 4 {dd, 2H) , 3.13{dc, 2H>, 2.48(ds, 4H>, 2.33(s, 3H ), 1.94(s, 3K), 1-58(d, 3H), l,40(t, 3H) Exemple. 6: {-) Ethyl N- (l-ethoxycarbc>:y-propy-2 (S) -yl) -6-fluoro-7-(H-methylpiperazinyl)-8-nitro-4-quinolone*3-carboxylare[11 R=CO2Et, R;=Me) 20.93g{45,3mmol) of (+)ethyl 2-(2,4-dichioro-3-nitro-5-fluorobenzoyl)-3-[(l-ethoxycarboxy-propy-2(S)-y1)aminojacrylateCIV, X=C1, R=BCO2Et) was dissolved in 130ml of acetonitrile. To the result; rt was added 12.0g of K?COjf and refluxed for 8 hours with heating. Then, 5. 3ml of N-rnetnylpiperazine was further added, refluxed for 30 minutes- with heating and cooled to room temperature. After the solvent was conplecely evaporated under a reduced pressure; dissolved in -ethylaceiate, washed with NaCl solution, dried- over .anhydrous MgSO",_ and further evaporated under a reduce-i pressure to give I2.7g(57%) of the .titled compound. NMR(CDCl3) 5 (ppm) : 8.56£s, 1H), e .29{d, IK) , 4 . 55 Cm, 1H) , 4.39(0, 2H) , 4.36 Ida, 1H) , A ,23{ddr 1HJ, 4.11{q, 2H), 3.24{ds, 2H) , 3.ie{ds, 2H3, 2.4 9 ids, 4H- , 2.34(s, 3H) , 1.69(d, 3H;; :,40(,t, 3H), 1.21 Fy-^u 7- (-) 9-fluoro-3 (3) -methyl-10- N-.T.etr.yl-l-piperazinyl) -?-oxo-2, 3-dihyc.ro-"?"-pyrido 16 [1,2,3-de] [1,4 ]benzoxazins-6-carboxylic acid (I, R1=Me) 3.2g of (+}ethyl N-(l-acetcxy-propy-2(S)-yl)-6-fluoro-7-(N-methylpiperazinyl)-8-nitio-4-quinolone-3-carboxylate(II, R=COMe, R1=Me) was cissolved in 48ml of ethanol. To the resultant was added 2.25g of potassium hydroxide, refluxed for 2 hours with heating. Then, the solvent was evaporated under a reduced pressure, and 6.7ml of 3M ACOK solution was added to obtain a pale yellow precipitate, and added 10ml of THE while stirring. Then, the resultant solid was filtered, washed with water/THF(l/l, v/v) followed by drying to give 1.36g(57%) of the titled compound. NMR(CDCl3) 6 (ppm) : 14.99(s, 1H> , 8.62(s, IK), 7.74(d, 1H) , 4.49(dd, 2H) , 4.:5{dd/ IK) , 3.4 3(m, 4H), 2.60(d, 4H), 2.39(3, 3H}, 1.63(d, 3H) Example 8: (-)Ethyl N- (l-hydroxy-propy-2 (S) -yl) -6-f luoro-7-N-methylpiperazinyl)-8-iitro-4-quinolone-3-carboxylate(H-l, R=H) 1.38g (lOmmol) of K2CO3 .was dissolved in 10ml of water, and added 2,39g (5mmol) of (-ethyl "N- (1-acetoxy-"propy-2(SJ-yl)-S-flUoro-7-N-methylpiperazinyl)-S-nitro-4-quinolone-3-carboxylate{II, R=COMe, R1=Me) . 7-. 5ml of metha nol was added and stirred for 1.5 hours at room temperature. To the precipitate thus obtained was added 10ml of water, and subsequently filtered and washed with water. Then, the resultant solid was dried to give 2.1g(96%) of the titled compound. NMR(CDClj) 5 (ppm) : 8.72(s, 1H) , 7.74 {d, 1H) , 4.46(m, 1H) , 4.37(q, 2H), 4.19(m, 1H), 3.92(m, 1H), 3.75 (m, 2H) , 3.25(d:;, 2H) , 3. 14 (ds, 2H) , 17 2.52(ds, 4H) , 2.37(s, 3H) , 1 - 64(d, 3H) , 1.40(t, 3H) Example 9: (-)Potassium N- (1-hydroxy-propy-2(S)-yl)-6-f luoro-7-N-methylpiperazi;:yl) -8-nitro-4-quinolone-3-carboxylate {II -2, R=H) 0.935g (15mmol) of KOH was dissolved in 18ml of 95% ethanol, added 2.39g(Smmol) of (-)ethyl N-(1-acetoxy-propy-2 (S) -yl) -6-f luoro-7-N-methyl-piperazinyl) -8-nitro-4-quinolone-3-carboxylate{n, R=COMe, Ri=Me), and stirred for 2. hours at room temperature. Then, the precipitate thus obtained was filtered, washec with 10ml of 95% ethanol and the 'resultant solid was dried to give 2.07c (93%) of the titled compound. NMR(D2O) 6 tppm): 8.45 1H) , 3.67 (d, 2H) , 3.21 (ds, 2H) , 3.07{dsr 2K), 3.14(05, 2H), 2.46{ds, 4H), 2.18(3, 3H), 1.42{t, 3H) Example 10: (-) 9-f luoro-3 (S) -methyl -10- (N-methyl-piperazinyl)-7-oxo-2, 3 - iihydro-7K-pyrido[l,2, 3-de] [1,4]be izoxa2ine-6-carboxylic acid (I, R1=Me) 5. lg (11. 42mmol) of (-)potassium -N- (_i-hydroxy-propy-2 (S) --yl) -6-f ludro-7-N-methylpiperazitLyl) -S-nitro-4-quinolone-3-carboxylate (II-l, R=H) was dissolved in 34ml of nethanol. To the solution vas added 1.07g of potassium hydroxide, then refluxed for 2.5 hours with heating. The solvent was evaporated under a reduced pressure, then 5.7ml of 3M AcOH solution. was subsequently added to give a pale yellow precipitate, and added 10ml of THF while stirring. Then, the resultant - solid was filtered, washed with wate::/THF(l/l, v/v) and followed by drying to give 18 3.0g (73%) of the titled compound. NMR{CDClj) 6 (ppm) : 14.99(s, 1H) , 8.62 (s, 1H> , 7.74 (d, 1H) , 4.4 9(dd, 2H} , 4.35(dd, 1H) , 3.43 Cm, 4H) , 2.6G(d, -IH) , 2.39(s, 3HJ , 1.63(d, 3H) Example 11 (-)9-fXuoro-3(S)-methyl-10-(N-methyl-1 piperazinyl)-7-OXO-2,3-c ihydro-7H-pyrido[1,2,3-de] [1,4]ber zoxazxne-6-carboxylic acid(I, Ri=Me) 5.0g of (-)ethyl N-(1-hydrocy-propy-2(S)-yl) -6~ f luorc'-7-N-methylpiperazinyl) -8-nitro -4-quinolone-3-carbox ylate (II-l, R=H) was reacted in the same manner as in Example 10 to give about 3.0g{'f3%) of the titled compound. NMRtCDCl,) 5. (ppm) : 14.99(s, 1H) , 8.62.S, 1H) , 7.74(d, 1HJ , 4.4 9(dd, 2H) , 4.:t5(dd, 1H) , 3.43 (m, 4H), 2.60(dr 4H), 2.39(s, 3H) , 1.63rd, 3H) As clearly illustrated and demcnstrated above, the present invention provides a novel process for preparing optically active (-)pyridobenzoxazire carboxylic acid derivatives or pharmaceutically"acceptable salt thereofs. According to the -present invention, optically active (-) pyrido'Denzoxazine carboxylic acid cerivatives can be manufactured from the low-priced A-chloro-5-fluoro-2-halo-3-nitrobenzoic acid in a simple and economical manner. 19 WE CLAIM: 1. A process for preparing optically active (-) pyridobenzoxazine carboxylic, acid derivative (I), which comprises the steps of: i) reacting a compound of formula (V) with a reactive material of formula (VI) or (VII) in the presence of a base to obtain a compound of formula (IV); ii) converting the compound (IV) obtained in step i) in an organic polar solvent in the presence of a base to obtain a compound of formula (III); iii) reacting the compound (III) obtained in step ii) with piperazine or N-mono-substituted-piperazine in an organic polar solvent in the presence of a base to obtain a compound of formula (II); and, iv) hydrolyzing and cyclizing the compound (II) obtained in said step iii) in an organic solvent in the presence of metal hydroxide (such as potassium hydroxide and sodium hydroxide) to give a compound of formula (I) 20 Ra - Z (VI) Rb-N=OY (VII) wherein, X represents a halogen atom; Z represents a leaving group; Y represents oxygen or a sulfur atom; Ra represents -C (=O)-R2 (wherein R2 represents an alky] group having 1 to 5 carbon atoms, phenyl group, substituted phenyl group, alkoxy group having 1 to 5 carbon atoms, cycloalkoxy group having 3 to 5 carbon atoms, phenoxy group, substituted phenoxy group, primary or secondary amine group or alkylthio group having I to 5 carbon atoms); Rb represents alkyl group having 1 to 5 carbon atoms, phenyl group or substituted phenyl group; R represents the same as Ra above or Rh-NH-C (=Y) [wherein Rb and Y represent the same above]; and, R represents hydrogen atom or alkyl group having 1 to 5 carbon atoms. 2. The process as claimed in claim 1, wherein the base is selected from the group consisting of metalcarbonate, metalbicarbonate, metalalkoxide, DBU (1,8 -diazabicyclo - [5.4.0] undec-7-ene), DABCO (1,4-diazabicyclo [2.2.2] octane, DBN (1,5-diazabicyclo [4.3.0] non-5-ene), pyridine, dimethylaminopyridine, and trimethylamine. 3. The process as claimed in claim 1, wherein the reactive material of formula (VI) is selected from the group consisting of acylhalide, carboxylic anhydride, alkylchlorofonnate, cycioalkylchloroformate, alkylcarbonate, cycloalkylcarbonate, phenylchlorofonnale, and substituted phenylchloroformate. 21 4. The process as claimed in claim 1, wherein the reactive material of formula (VII) is selected from the group consisting of isocyanate and isothiocyanate, 5. The process as claimed in claim 1, wherein the organic polar solvent in said steps ii) and iii) is selected from the group consisting of DMF (N, N' -dimethylformamide), DMSO (dimethylsulfoxide), dioxane, acetonitrile, tetrahydrofaran, and acetone. 6. The process as claimed in claim 1, wherein the organic solvent in the step iv) is selected from the group consisting of alcohol, tetrahydrofuran, and a mixed solvent of one of the said solvent and water. 7. The process as claimed in claim 1, wherein the compound (III) is employed in the step iii) in a purified state or non-purified state. 8. The process as claimed in claim 1, wherein the compound (II) is hydrolyzed to an intermediate compound of formula (II-I), which is subsequently hydrolyzed and cyclized to give the compound (I): 22 wherein, R1 represents the same above. 9. The process as claimed in claim 1, wherein the compound (II) is hydrolyzed to an intermediate compound of formula (II-2), which is subsequently cyclized to give the compound (I): wherein, R1 represents the same above; and, M represents metal. 10. The process as claimed in claim 8, wherein the compound (II-l) is obtained by reacting the compound (II) with metal carbonate in a mixed solvent of alcohol and water. 11. The process as claimed in claim 9, wherein the compound (II-2) is obtained by reacting the compound (II) with alkaline metal hydroxide (such as potassium hydroxide and sodium hydroxide) in alcohol solvent. The present invention provides a process for preparing optically active (-)pyridobenzoxazine carboxylic acid derivative and phatmaceutically acceptable salt thereof by employing a starling material of (+)cthyl 2-(4-chloro-5-fluoro-2-halo-3-nilobenzoyl)-3-nitobcnzoyl)-3-[( 1 -hydroxypropy-2(S)-yl)amino]acrylate. According to the present invention, optically active (-)pyridobenzoxazine carboxylic acid derivative can be manufactured from low-priced 4-chloro-5-fluorobenzoic acid derivative in a simple and economical manner.

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in-pct-2000-00414-kol claims.pdf

in-pct-2000-00414-kol correspondence.pdf

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