GB2301354A

GB2301354A - Preparation for intermediates for quinolone antibiotics

Info

Publication number: GB2301354A
Application number: GB9506905A
Authority: GB
Inventors: Otto Meth-Cohn
Original assignee: Resolution Chemicals Ltd
Current assignee: Resolution Chemicals Ltd
Priority date: 1995-04-04
Filing date: 1995-04-04
Publication date: 1996-12-04
Also published as: GB9506905D0

Abstract

Key intermediates in the production of quinolone antibiotics of formula in which R 1 represents a lower alkyl group, a lower aralkyl group, a vinyl or allyl group, a lower hydroxy alkyl group or a lower halogeno-alkyl group, a cyclopropyl group or an aryl group, R 2 represents a substituent displaceable by an amine, and R 3 represents a hydrogen atom or, together R 3 and R 1 represent the group -OCH 2 CH-R 4 , where R 4 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, are obtained by a process comprising the following steps: ```(a) reaction of a compound of the general formula with a malonic acid derivative of the general formula in which R 5 and R 6 each represent a C 1-5 aliphatic group or R 5 and R 6 , together with the nitrogen represent a cyclic amine optionally containing one or more further heteroatoms, and R 7 represents a carboxylic acid ester, amide or nitrile, in the presence of a chlorinating agent capable of promoting a Vilsmeier-Haack reaction to obtain a compound of the general formula and ```(b) hydrolysis of the intermediate of general formula IV under hot aqueous acidic conditions sufficient to form the quinolone and to convert the substituent R 7 into a carboxyl group, to obtain the product of general formula I.

Description

Synthesis of Intermediates for Quinolone Antibiotics This invention relates to the synthesis of a key intermediate for the preparation of quinolone antibiotics such as norfloxacin and ciprofloxacin, in particular the intermediate used as the starting material for the introduction of the 7-piperazinyl substituent.

The quinolone antibiotics, a very important alternative to p-lactams, tetracyclines and aminoglycosides, operate as DNA gyrase inhibitors against all types of Gram-negative bacteria. Typical compounds include norfloxacin, ciprofloxacin and ofloxacin (formulae A, B and C)

In each case the synthesis involves the introduction of the heterocyclic group (usually piperazinyl or 4-methyl-piperazinyl) at the 7-position, by displacement of an appropriate leaving radical, generally a halogen atom such as chlorine or an alkylsulfonyl group (see, for example, US-A-4 146 719, US-A-4 292 317, 4 670 444 and EP-B-0047005).

The main synthesis of this type of intermediate, the Bayer synthesis, is shown in scheme 1

CH2(CO2Etk, Mg(OEtk ii Ho iii HC(OEth,AclO iv

v Base wi piperane Scheme 1 This long and costly synthesis starts with an expensive starting material and thus results in high drug costs.

There is thus a need for a cheaper simpler synthesis of the key intermediate which is, nevertheless, high yielding and regiospecific.

The use of a modified Vilsmeier reaction in the preparation of quinolines is disclosed in Synthesis, 1986, 76-78. In particular, by the interaction of an N-substituted formanilide, phosphoryl chloride and a malonyl ester chloride (to serve as an electrophilic alkene precursor), a 4-chloro-quinolinium-3- carboxylate is produced which is readily transformed into a 4-quinolone by boiling in aqueous acid or by action of a base (scheme 2)

Scheme 2 While this short, high yielding reaction might appear useful for application to the synthesis of quinolone antibiotics, problems arise when the initial anilide is asymmetric. Thus, 3-chloro-4-fluoroaniline is readily converted into 3-chloro-4-fluoro-N-ethylformanilide by the action of triethyl orthoformate and a catalytic amount of sulfuric acid.However, this unsymmetrically substituted formanilide is capable of cyclizing either ortho- or para- to the chloro substituent and on treatment with methyl malonyl chloride and phosphoryl chloride as in the prior art process, the reaction yields equal quantities of the two possible cyclization products. Thus, not only is the yield of the required product no more than about 40%, but it would be necessary to separate it from an equal amount of the unwanted byproduct.

It has now been recognised that appropriate substitution of the malonyl reagent can provide a reaction which yields only the required isomer.

According to the invention there is thus provided a process for the preparation of a compound of the general formula

in which R1 represents a lower alkyl group, a lower aralkyl group, a vinyl or allyl group, a lower hydroxy alkyl group or a lower halogeno-alkyl group, a cyclopropyl group or an aryl group;R represents a substituent displaceable by an amine e. g. a chlorine or bromine atom or alkylsulfonyl group; and R3 represents a hydrogen atom or, together R3 and R1 represent the 4 4 group -OCH2CH-R , where R represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; comprising the following steps: (a) reaction of a compound of the general formula

in which R1, R2 and R3 are as defined for formula I, with a malonic acid derivative of the general formula

in which R5 and R6 each represent an aliphatic group with up to 5 carbon atoms or R5 and R6, together with the nitrogen represent a cyclic amine optionally containing one or more further heteroatoms, and R7 represents a carboxylic acid ester, amide or nitrile, in the presence of a chlorinating agent capable of promoting a Vilsmeier-Haack reaction, e. g. phosphorus oxychloride, to obtain a compound of the general formula

in which R1 R2 R3 and R7 are as defined above, and (b) hydrolysis of the intermediate of general formula IV under hot aqueous acidic conditions sufficient to form the quinolone and to convert the substituent R into a carboxyl group, to obtain the product of general formula I.

It will be seen that the invention lies in the use of a compound of formula III in which the amide group -CONR 5R6 has the effect of inhibiting the cyclization to the position ortho to the substituent R2 and instead facilitates cyclization at the position para to R3. While we do not wish to be bound by theory, it may be proposed that the amide group -CONR5R6 exerts some steric control because of interaction with R2. It is preferred that the amide is cyclic and it is especially preferred that R5 and R6, together with the nitrogen, represent a morpholino group.

The groups R1 and R3 will be chosen depending on the quinolone antibiotic to be prepared from the compound formula I. The prior art patents US-A-4 292 317, US-A-4 670 444 and EP-B-0047005 all disclose a range of such substituents. R1 preferably represents an ethyl group (for norfloxacin), a cyclopropyl group (for ciprofloxacin) or R1 and R3 together preferably represent a -OCH2C (CH3)H- group (for ofloxacin).

The substituent R2 which comprises a leaving radical displaceable by an amine is conventionally a chlorine atom.

The malonic derivative of formula III is preferably a malonic ester amide, where R7 represents a carboxylic acid ester, in particular a lower alkyl ester such as the methyl or ethyl ester.

As indicated above, R5 and R6, together with the intervening nitrogen preferably represent a nitrogen heterocycle which, for reasons of effectiveness and economy is preferably a morpholino group. Thus, a compound of choice is methyl malonyl morpholide.

The chlorinating agent is an inorganic acid chloride, preferably phosphorous oxychloride, but alternatively phosphorus pentachloride, phosgene or thionyl chloride may be used. The reaction is conveniently effected in an excess of the acid chloride (where liquid) as a solvent, or alternatively in the present of an inert solvent or diluent such as a halogenated hydrocarbon, e. g. 1, 2-dichloroethane. The reaction is effected at an elevated temperature, e.g. 80-120-C, and is then quenched by cooling and addition to an excess of ice and water.

The hydrolysis in step (b) can easily be achieved by heating the aqueous system, e. g. at reflux, the product being isolated by filtration of the cooled system.

The compound of the formula II, where R3 represents an hydrogen atom, is conveniently obtained by reaction of the corresponding aniline of formula V

in which R2 is as defined above, R3 is hydrogen and R1 is a lower alcohol group, with a trialkyl orthoformate and a catalytic amount of an acid such as sulfuric acid. For the compound where R1 represents a cyclopropyl group, the aniline of formula V should first be N-cyclopropylated, for example by reaction with 1-chloro-1-ethoxycyclopropane, and the product subsequently formylated, e. g. by reaction with formic acid and acetic anhydride.

For a compound of formula V where R1 and R3 together form an oxyalkylene bridge, the general technique of EP-B-0047005 may be used, followed by N-formylation as described above.

The products of general formula I may be treated as conventional in this art in order to prepare the required quinolone antibiotic, by a reaction to displace the substituent R with the heterocyclic amine of choice, e. g. piperazine, 3-methyl-piperazine, 4-methylpiperazine, 4-ethyl-piperazine etc. using reaction conditions known per se.

The following examples illustrate the invention.

Example 1 Preparation of methyl malonyl morpholide Morpholine (8.OOg), 0.09mop) in anhydrous diethyl ether (40 ml) was stirred at 0 C in an ice bath. Methyl malonyl chloride (5.44g, 0.04mol) in anhydrous diethyl ether (20 ml) was added carefully over a 1/4h period. A vigorous reaction occurred producing a white precipitate of morpholine hydrochloride. When addition was complete the solution was stirred at room temperature for 10 minutes and the white precipitate was removed by filtration. The filtrate was evaporated to give the crude product as a yellow oil.Kugelruhr distillation (185-C, 4.0 mm/Hg) gave a colourless liquid. (5.70g, 76% infra red absorption spectrum [gBr] (may.' cm 1739 (C-O), 1643 (C=O), 1440 (C=O); nuclear magnetic resonance spectrum (CDCl3, 270 MHz) 8 ppm: 6. 35 (6H, m), 3. 71 (3H, s), 3.40 (4H, m).

Example 2 Preparation of 3-chloro-4-fluoro-N-ethyl formanilide In a two necked round bottomed flask fitted with a 15 cm Vigreux column packed with glass helices and provided with heated jacket and magnetic stirrer was placed 3-chloro-4-fluoroaniline (14.5g, 0.1 ml), triethyl orthoformate (22. 2g, 0. 15mol) and conc. sulfuric acid (0. 4g). This was heated to 115-120-C in an oil bath.

Over a one and a half hour period ethanol (approx. 10 ml) was collected. The oil bath temperature was gradually raised to 175'C in a 30 minute period and maintained at this temperature for a further 60 minutes. In this time a small amount of distillate was collected. After allowing to cool somewhat, the Vigreux column was removed and the remaining brown oil was distilled under reduced pressure.After a small forerun (approx. 3 ml) the product was collected (180'C/2mm Hg) as a pale yellow, low melting point solid, (15.2g, 75.68) m.p 34-36 C; (Found: C, 53. 68; H, 4. 56; N, 6. 94%. C9H9NOClF requires C, 53. 61; H, 4. 50; N, 6. 95%). vmax(KBr, cm 2980, 1685, 1505, 1251; EH (acetone d6) 1.21 (3H, superimposed triplets), 8.46 (2H, superimposed quartets), 7. 64 (2H,m), 7.45 (1H, dd) 3. 94 (1H,s).

Example 3 Reaction of 3-chloro-4-fluoro-N-ethylforrnanilide, methyl malonyl morpholide and POC13 in a 1. 1 to 1. 0 molar ratio To a stirred solution of 3-chloro-4-fluoro-N-ethyl formanilide (0. 63g, 3. 12 mmol) in POCl3 (5ml) was added methyl malonyl morpholide (0. 50g, 2. 67 mmol) with POCl3 washings (lml). The resulting solution was stirred in an oil bath at 100-C over a 12 hour period during which the colour changed from pale yellow to brown. After this time the reaction mixture was allowed to cool to room temperature whereupon it was poured onto a solution of ice and water (300 ml) and vigorously stirred. The resulting pale yellow solution was then boiled for one and a half hours and then allowed to cool to room temperature. The product, 7-chloro-1-ethyl-6fluoroquinolin-4-one 3-carboxylic acid, was collected by filtration as a white solid (5. 10g, 70. 8%).

Recrystallised from acetic acid/acetonitrile m.p 279 C, may (KBr, cm1) 3058, 1718, s, 1691, s, 1616, m, 1465; #H (CF3CO2D) 2.05 (3H, t, J 7.29), 5. 18 (2H, q, J 7.29), 8.66 (2H, overlapping d, JF57.8 and F85 9), 9. 69 (1H, s).

Claims

1. A process for the preparation of a compound of the general formula

in which R represents a lower alkyl group, a lower aralkyl group, a vinyl or allyl group, a lower hydroxy alkyl group or a lower halogeno-alkyl group, a cyclopropyl group or an aryl group, R2 represents a substituent displaceable by an amine, and R3 represents a hydrogen atom or, together R3 and R represent the group -OCH2CH-K , where R4 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms comprising the following steps:: (a) reaction of a compound of the general formula

in which R5 and R6 each represent an aliphatic group with up to 5 carbon atoms or R5 and R6, together with the nitrogen represent a cyclic amine optionally containing one or more further heteroatoms, and R7 represents a carboxylic acid ester, amide or nitrile, in the presence of a chlorinating agent capable of promoting a Vilsmeier-Haack reaction to obtain a compound of the general formula

in which K 1, R2 R3 and R7 are as defined above, and (b) hydrolysis of the intermediate of general formula IV under hot aqueous acidic conditions sufficient to form the quinolone and to convert the substituent R7 into a carboxyl group, to obtain the product of general formula I.

2. A process according to Claim 1 in which R2 represents a chlorine or bromine atom or a methanesul fonyl group.

3. A process according to claim 1 or claim 2 in which said chlorinating reagent is phosphorus oxychloride.