FI100531B - Process for the preparation of 8-chloroquinolone derivatives - Google Patents

Description

100531

This invention relates to a process for the preparation of 8-chloroquinolone derivatives which have potent antimicrobial activity and are very safe and promising as synthetic antimicrobial agents.

The 8-chloro-7-substituted-1- (2-fluorocyclopropyl) -4-quinolone derivatives of formula (II) or (III) described below are expected to have use as effective antimicrobial agents as described in EP-A-0 341 493 and JP-A-Hei-2-231,475 (the term JP-A as used herein means "Japanese Patent Application Published Unexamined").

These compounds have been prepared starting from 3-chloro-15β-2,4,5-trifluorobenzoic acid. However, since 3-chloro-2,4,5-trifluorobenzoic acid is relatively difficult to obtain very pure due to the considerable difficulties involved in its synthesis, the method starting from this compound is not considered to be economically advantageous.

It is an object of the present invention to provide a process for the preparation of 8-chloroquinolone derivatives by simple and easy work processes and with very economical efficiency.

As a result of extensive studies, the inventors have provided a method by which an 8-chloroquino- *: ··: ionic derivative can be obtained in a simple and easy manner, with satisfactory yield and purity.

The present invention relates to a process for the preparation of an 8-chloroquinolone derivative of the formula • · · • · «

• · A

• · M

χ ^ γΑγΟΟΟΗ c f111)

... 35 H t; I F

cl K-J

KN / H

2 100531 wherein X represents a halogen atom and R2 represents a cyclic amino group selected from 0i R8 R9 v rX JJn- ** +! IN- RUNHLyN- R '>' * ^ r R14 10 f ^ -nTn- νΦν- Η2Ν ^ * N-% wherein R5, R6, R7, RB, R9, R10, R11, R12, R13, R14 and R15 each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and wherein R14 and R15 may be bonded to each other as a methylene chain , forming a 3- to 6-membered ring.

The invention is characterized in that the quinolone compound of formula (I) is wherein R 2 is the same as R 3 above, and wherein the amino substituent of the cyclic amino group is optionally protected, and wherein X is the same as above, is reacted with a chlorinating agent, and the obtained * ·] * compound of formula (II) • · · • · • «··· _ Χγ ^ γΛ ^ ΟΟΟΗ '35 r-XIF <n>

Cl kr X

hvh 3 100531 wherein X and R2 are as defined above, optionally treated to remove the protecting group.

DETAILED DESCRIPTION OF THE INVENTION Chlorinating agents that can be used in connection with this invention include sulfuryl chloride, sodium hydrochloride, N-chlorosuccinimide, chlorine, and alichloroaccharide ester represented by formula (IV): R 40 Cl (IV) 10 wherein R 4 represents an alkyl group having 1 to 6 carbon atoms, a phenylalkyl group or a chlorophenylalkyl group.

Among the chlorinating agents set forth above, the subchloric acid ester is preferred for the reasons set forth below.

Chlorination of a compound of formula (I) in which R 2 is an amino group in the heterocyclic group tends to involve side reactions which result in a decrease in yield and purity of the product unless the 20 amino group is protected. When compound (I) is used with its amino group protected, two additional steps are required - deprotection and deprotection. In addition to the increase in steps, the addition and removal of a protecting group tends to cause undesirable side reactions, further causing a decrease in yield and purity .... i.

Studies on the economics and simple synthesis of 8-chloroquinolone derivatives have now ... confirmed that such a problem can be solved by using the aliquoric acid ester of formula (IV) as a chlorinating agent. That is, the use of an alichloroacetic acid ester of formula (IV) as a chlorinating agent provides: the possibility of improving the chlorination of a compound of formula (I) having an amino group in its heterocyclic group R 35 to give the chlorinated compound of formula (II) in the highest yields. and very pure regardless of whether the amino group is protected or not.

Alichloroacid esters of formula (IV) include alkyl esters, e.g. propyl esters (e.g. n-propylhy-5 chlorochlorite and isopropyl hypochlorite), butyl esters (e.g. n-butyl hypochlorite, isobutyl hypochlorite, sec-butyl hypochlorite and t-butyl hypochlorite) with butyl hypochlorite being preferred.

These hypochlorites are synthesized in the usual way, i.e. by reacting the alcohol with an aldichloric acid salt or by reacting a mixture of the alcohol and an alkali hydroxide (e.g. sodium hydroxide) with chlorine.

In the case where the substituent R2 is still an amino group as a substituent, this amino group may be protected by a protecting group. Protecting groups that can be used to protect the amino group in R2 include an alkylcarbonyl group, an alkyloxycarbonyl group, a haloalkylcarbonyl group, a haloalkyloxycarbonyl group, a phenylalkyloxycarbonyl group, and a nitro or chlorophenylalkyloxyalkyl group. Specific examples of protecting groups include acetyl, chloroacetyl, 2,2,2-trichloroethyloxycarbonyl, p-nitrobenzyloxycarbonyl, n-yl and p-chlorobenzyloxycarbonyl groups.

«· · ·

In formulas (I), (II) and (III), R2 or R3 pre- ···. The heterocyclic group is a so-called cyclic amino group which is a derivative of a cyclic amine. A cyclic amine is a compound obtained from an alicyclic compound by replacing the carbon atom in the ring with a nitrogen atom. The cyclic amino group R2 is preferably a 4-7 membered ring, and more preferably a 5- or 6-membered ring, and the ring may further have an oxygen atom, a sulfur atom and / or another nitrogen atom. Examples of such a cyclic amino group are oxazolidine, morpholine, thiazolidine, thiomorpholine, imidazolidine, pyrazolidine and piperazine, with pyrrolidine and piperazine being particularly preferred.

As mentioned above, the cyclic amino group 5 may have a substituent (s) such as polar groups (e.g., a substituted or unsubstituted amino group, a substituted or unsubstituted aminoalkyl group, a 5-substituted-2-oxo-1,3-dioxol-4-ylmethyl group, and a hydroxyl group). ); and a straight-chain, side-chain or cyclic alkyl group having 1 to 6 carbon atoms. Of these substituents, the polar group may be attached via an alkyl chain of up to 6 carbon atoms. Suitable substituents for the above-mentioned amino group include an alkyl group, an acyl group and an alkyloxycarbonyl group. Polar groups include primarily an unsubstituted amino group, an aminomethyl group, a 1-aminoethyl group, and a hydroxyl group. The alkyl group substituted as a substituent on the cyclic amino group is primarily methyl, ethyl, propyl, gem-dimethyl and gem-diethyl groups. It is also preferred that such an alkyl substituent form a cyclopropane ring or a cyclobutane ring to form: a spiro ring in combination with a cyclic amino group.

Further, the 4-7 membered cyclic amino group may be cross-linked to the cyclic amino group to form a bicyclic ·; 25 amino groups.

• «i«

Suitable examples of these cyclic amino groups, in particular amino-substituted cyclic amino groups, are given below.

• · 30 7 R8 R9 Λ »·. - r6'n ^:; ; R14 6 100531 wherein R5, R6, R7, R6, R9, R10, R11, R12, R13, R14 and R15 each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and R 14 and R 15 may be joined together to form a methylene chain to provide a 3- or 6-membered ring to form a spirocyclic ring structure.

Specific examples of these nitrogen-containing heterocyclic groups include 3-aminopyrrolidinyl, 3-methylaminopyrrolidinyl, 3-dimethylaminopyrrolidinyl, 3-10 ethylaminopyrrolidinyl, 3-propylaminopyrrolidinyl, 4-propylaminopyrrolidinyl, 3-isopropylaminopyramine, 3-isopropylaminophenyl 2-methylpyrrolidinyl, 4-amino-2,3-dimethylpyrrolidinyl, 3-methylamino-4-methylpyrrolidinyl, 4-methylamino-2-methylpyrrolidinyl, 4-methylamino-2,3-dimethylpyrrolidinyl, 3-dimethylamino ethylpyrrolidinyl, 4-dimethylamino-2-methylpyrrolidinyl, 4-dimethylamino-2,3-dimethylpyrrolidinyl, 3-methylpiperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3,5-dimethylpiperazinyl, 3,4,5- 20 trimethylpiperazinyl, 4-ethyl-3,5-dimethylpiperazinyl, 4-isopropyl-3,5-dimethylpiperazinyl, 3-aminomethylpyrrolidinyl, 3-methylaminomethylpyrrolidinyl, 3- (1-amino) ethylpyrrolidinyl, 3- (1- methylamine-no) ethylpyrrolidinyl 1,3- (1-ethylamino) ethylpyrrolidin-25-dinyl, 3- (1-amino) propylpyrrolidinyl, 3- (1-methyl- [±] (amino) propyl] pyrrolidinyl, 3-aminopyrrolidinyl, 4-amino- 3,3-dimethylpyrrolidinyl, 7-amino-5-azaspiro [2,4] heptan-5-yl, 8-amino-6-azaspiro [3,4] octan-6-yl group, 1,4-diazabicyclo [3,2,1] octan-4-yl, 3,8-diazab-30-cyclo [3,2,1] octan-3-yl, 8-methyl-3,8-diazabicyclo [4] [3, 2,1] -octan-3-yl and 8-ethyl-3,8-diazabicyclo [3.2.1] octan-3-yl groups.

The chlorination of the compound represented by the formula (I) can be carried out usually by dissolving the compound (I) in a solvent and adding the chlorinating agent to the solution by cooling the solution.

7 100531

The solvents used for chlorination are not particularly limited as long as they are capable of dissolving the starting compound and are inactive with respect to the chlorinating agent. Such solvents include halogenated hydrocarbons, e.g., methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane; alkyl carboxylic acids, e.g. acetic acid; and formic acid. In addition, chlorosulfonic acid, alcohols (e.g., methanol, ethanol, and propanol), acetonitrile, N, N-dimethylformamide, and ethyl acetate are also useful. From the point of view of dissolution property and reaction-accelerating effect, formic acid and acetic acid are preferred.

The chlorination of a compound of formula (I) is carried out either in solution or in a suspension of compound (I) in a solvent, preferably in solution. The reaction is carried out at a temperature not exceeding the boiling point of the solvent used, usually under ice-cooling or at room temperature (i.e., between 0 and 30 ° C).

The chlorinating agent is usually used in an amount of 1 to 20 molar equivalents relative to the starting compound (I). When chlorine is used as the chlorinating agent, it can usually be used in excess.

The chlorination reaction of this invention proceeds rapidly, completing in about 5 minutes to about 10 hours, usually about 5 minutes to about 2 hours when frozen on ice.

When the chlorinated compound of formula (II) has a protected amino group in R2, the protecting group may be removed by known methods, such as by catalytic reduction or hydrolysis with an acid or alkali.

The desired 8-chloroquinolone derivative of formula (III) can then be isolated from the reaction mixture by conventional chemical means such as extraction, washing with an extract, separation on a silica gel column by chromatography, recrystallization and reprecipitation.

8 100531 The present invention will now be illustrated in more detail by reference examples and examples, but it is to be understood that they are not to be construed as limiting the present invention. All percentages are by weight unless otherwise indicated.

Reference Example 1 7- (S) -Amino-5-azaspiro [2.4] heptane dihydrochloride A mixture of 6.07 g of 7- (S) -amino-5-benzyl-5-azaspiro [2, 4] heptane, 7.5 ml of concentrated hydrochloric acid and 2.4 g of 5% palladium on carbon catalyst 10 (moisture 50%) in 200 ml of methanol were shaken under a hydrogen pressure for 20 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness in vacuo to give 5.13 g of the title compound as a powder. Melting point 222-238 ° C (dec.) 15 [?] D: -43.27 ° (c = 0.537, H 2 O)

Elemental analysis for C 6 H 12 N 2 .2HCl: Calculated (%): C, 38.93; H 7.62; N 15.13 Found (%): C 38.83; H 7.88; N 14.67 1 H-NMR (D 2 O) δ: 0.9-1.3 (4H, m), 3.25 and 3.72 (1H, d, 20 J = 12.2 Hz (each)), δ , 68 and 3.82 (1H, dd, J = 12.2, 2.9 Hz, each), 4.10 (1H, dd, J = 7.3, 6.4 Hz)

Reference Example 2 7- [7- (S) -Amino-5-azaspiro [2.4] heptan-5-yl] -6-25 fluoro-1 - [(1R, 2S) -2-fluoro-1- cyclopropyl] -1,4-dihydro-4 - [; ··· oxoquinoline-3-carboxylic acid monohydrochloride To 85 ml of acetonitrile was added 4.25 g of 6,7-difluoro-1 - [(1R, 2S) -2-fluoro-1-cyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3.33 g of 7- (S) -amino-5-30 azaspiro [2,4] heptane dihydrochloride and 10, 5 ml of triethylamine and the mixture were heated at reflux for 2.5 hours.

»Ti ί ##> ϊ The precipitate formed after cooling was collected by filtration and suspended in 30 ml of water. To the suspension was added 2.5 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. The crystalline material in the suspension was collected by filtration, washed with water and dried to give 5.81 g of the title compound.

Melting point: 228-233 ° C (decomposed) δ [α] D: -23.93 ° (c = 0.499, 1N NaOH)

Elemental analysis for C19H19N3F2O3. HCl.1 / 2H2O: calculated (%): C 54.22; H 5.03; N 9.98 Found (%): C 53.88; H 5.24; N 9.64 1 H-NMR (NaOD) δ: 0.4 - 0.81.3 (4H, m), 1.4-1.7 (2H, m) δ 2.97 (1H, br s), 3.10 and 3.53 (1H, d, J = 10.3 Hz, each), 3.15-3.3 (2H, m), 3.71 (1H, br s), 5.05 (1H , br, d, J = 64.0 Hz), 6.40 (1H, d, J = 7.3 Hz), 7.51 (1H, d, J = 15.1 Hz), 8.28 (1H , s) Example 17 7 [7- (S) -t-Butoxycarbonylamino-5-azaspiro [2,4] heptan-5-yl] 8-chloro-6-fluoro-1 - [(1R, 2S) - 2-Fluoro-1-cyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

20 Q Q

Fy ^ Y ^ COOH Fs ^ Y ^ yCOOH

c '* F

^ rf) ys)

BoeNH BocNH

In 20 ml of dichloromethane was dissolved 120 mg of 7- (7- (S) -t-butoxycarbonylamino-5-azaspiro [2.4] heptan-5-yl) -6-fluoro-1- [(1R, 2S) -2-Fluoro-1-cyclopropyl] -1,4-di - (hydro-4-oxoquinoline-3-carboxylic acid) was added dropwise over 5 minutes under ice-cooling. ·. * By stirring a solution of 40 mg of sulfuryl chloride in 5 M »ml of dichloromethane After stirring, stirring was continued for a further 10 minutes. The residue was purified through a column packed with 10 g of silica gel using a 9: 1 (v / v) mixture of chloroform and methanol as eluent to give 101 mg of the title compound. . Melting point: 223 - 226 ° C [a] D: -211.15 (c = 0.771, chloroform)

Elemental analysis for C 24 H 26 ClF 2 N 3 O 5: Calculated (%): C 56.53; H 5.14; N 8.24; Found (%): C, 56.67; H 4.95; N 8.14.

The 1 H-NMR spectrum of the product was identical to the reported values.

Example 2 7- (7- (S) -Amino-5-azaspiro [2,4] heptan-5-yl) -8-chloro-6-fluoro-1 - [(1R, 2S) -2-fluoro- 1-Cyclopropyl] -1,4-dihydro-4-oxoline-3-carboxylic acid 20 Wv °° "s ^ yV00" * ^ nXjCJf 1rO, S) C> O C1

BocNH q nh2 2 s I fyVtcoo "\ t: T: * OQ (rX ^ J (s> 'm2 1: .r 30 • ·

To chlorosulfonic acid was added 120 mg of 7- (7- (S) -t-butoxycarbonylamino-5-azaspiro [2,4] heptan-5-yl) -6-fluoro-1 - [(1R, 2S) -2-fluoro-1 -cyclopropyl] -1,4-dihydro-4-oxoline-3-carboxylic acid with stirring under ice-cooling, and then a small amount of iodine was added thereto. Chlorine gas was bubbled into the solution for 10 minutes and the mixture was stirred for one hour. The reaction mixture was poured into ice water. The mixture was made alkaline at 1-norm at a time. aqueous sodium hydroxide solution and then the pH was adjusted to 7 with aqueous citric acid solution. The mixture was extracted with three 50 ml portions of chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was recrystallized from aqueous ethanol to give 45 mg of the title compound.

Melting point: 127.3-135.5 ° C

[α] D: -179 ° (c = 1.12, 1 N NaOH)

Elemental analysis for C 19 H 18 ClF 2 N 3 O 3 .3 / 2 H 2 O Calculated (%): C, 52.24; H 4.85; N 9.61 Found (%): C 52.16; H 4.70; N 9.53 Example 3 7- [7- (S) -Amino-5-azaspiro [2.4] heptan-5-yl] -8-chloro-6-fluoro-1 - [(1R, 2S) - 2-Fluoro-1-cyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 20 0 o ΥτΥ0 '"YrV0 ·" Y λ r YY -

NH, Z_V N », Z-V

In 15 ml of formic acid was dissolved 3.09 g of 7- [7- (S) -amino-5-azaspiro [2.4] heptan-5-yl] -6-fluoro-1- [ (1R, 2S) -2-Fluoro-1-cyclopropyl] -1,4-dihydro-4-oxo-; t-quinoline-3-carboxylic acid hydrochloride and the solution was cooled to within 30 ° C. 5-10 ° C. To the solution was slowly added dropwise at that temperature 1.25 g of t-butyl hypochlorite. After the addition was complete, the reaction mixture was further stirred for 5 minutes, poured into cold water and neutralized with 20% aqueous sodium hydroxide solution. The precipitated crystallization 12 100531 was collected by filtration, washed with water and dried to give 3.02 g of the title compound as pale yellow crystals.

Melting point: 221-226 ° C (decomposed) δ [α] D: -209.7 ° (c = 0.631, 1 N NaOH)

Elemental analysis for C 19 H 1 BClF 2 N 3 O 5 • 3/2 H 2 O: Calculated (%): C 52.24; H 4.85; N 9.61 Found (%): C 52.31; H 4.52; N 9.60

The 1 H-NMR spectrum of the product was identical to the reported values.

Example 4 7- [7- (S) -t-Butoxycarbonylamino-5-azaspiro [2,4] heptan-5-yl] -8-chloro-6-fluoro-1 - [(1R, 2S) -2- fluoro-1-cyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 15 In 5 ml of methylene chloride, 238 mg of 7- [7- (S) t-butoxycarbonylamino-5-azaspiro [2.4] heptan-5-yl] -6-fluoro-1 - [(1R, 2S) -2-fluoro-1-cyclopropyl] -1,4-di - ... ·; hydro-4-oxoquinoline-3-carboxylic acid and was slowly added dropwise with ice-cooling 80 mg of t-butyl hypochlorite. After the addition was complete, the mixture was further stirred at that temperature for 2 hours. The reaction mixture * ... 30 was washed successively with 5% aqueous citric acid solution and water, and the solvent was removed in vacuo to give 217 mg of the title compound as a pale yellow powder.

Melting point: 220-224 ° C 35 [α] D: -208.31 ° (c = 0.693, chloroform) 4 13 100531

Elemental analysis for C 24 H 26 ClF 2 N 3 O 5: Calculated (%): C 56.53; H 5.14; N 8.24 found (%): C 56.21; H 5.04; N 8.31

The 1 H-NMR spectrum of the product was identical to the reported values of 5.

According to the present invention, when the 8-unsubstituted quinolone derivatives are chlorinated, the 8-chloroquinolone derivatives can be obtained in satisfactory yields and in high purity by simple and easy work processes. In particular, when the quinolone derivative starting compound has an amino group as a substituent in its molecule, the use of an alichloroacid ester as a chlorinating agent allows the chlorination of such a compound without protecting the amino group to ensure a satisfactory yield and purity of the product.

Although the invention has been described in detail and with reference to specific examples thereof, it will be apparent to those skilled in the art that various changes and modifications may be made therein without departing from the spirit and scope thereof.

• · • «· • · · • · ··· · · • ·« «« • · · · · · · · · · · · · ·

Claims (4)

A process for the preparation of an 8-chloroquinolone derivative of the formula: wherein X represents a halogen atom and and R 3 represents a cyclic amino group selected from the group R '? " „--O- -» »x- R ** ^ .3 R14 Rl-nT "vJ-n ^ Tn-HjN" * 7 VlV W where R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 each represent a hydrogen atom or an alkyl group having 1-6 * · ** · carbon atoms, and wherein R14 and R15 may be bonded to each other · to a methylene chain, forming a 3- to 6-membered ring, characterized in that: a quinolone compound of formula (I) wherein R 2 is the same as R 3 above, and where an amino substituent on the cyclic amino group is optionally protected -d, and where X represents the same as above, is reacted with a chlorinating agent, and the obtained compound of formula (II) Χγ ^ γ ^ γαοοΗ F (11) 10b JbÄ where X and R2 are defined above, possibly treated for removal of the protecting group. 2. A process according to claim 1, characterized in that the chlorinating agent is selected from sulfuryl chloride and chlorine. 3. A process according to claim 1, characterized in that the chlorinating agent is a subchloric acid ester of formula (IV) R 4 OC 1 (IV) wherein R 4 is an alkyl group of 1-6 carbon atoms. 4. A process according to claim 3, characterized in that R 4 is a t-butyl group. • · • · · · · · · · · · · · · · · · · · · · · ·