DK174247B1 - New substd. borate(s) - useful as intermediates for 8-alkoxy-quinoline carboxylic acid medicaments - Google Patents

Abstract

(6,7-substd.-8-alkoxy-1- cyclopropyl-1,4-dihydro-4-oxo -3- quinolinecarboxylic acid -03, 04) bis (acyloxy-o) borates of formula (I) and their salts and hydrates are new. In (I), X = halogen, R = 2-6C aliphatic acyloxy opt. substd. by halogen or 7-11C aromatic acyloxy, R1 = lower alkyl, R2 = H, halogen, NH2 or NO2, Z = halogen cpd (II), azelidino, pyrrolidino, 3-hydroxypyrrolidino, piperidino, morpholino, or thiomorpholino, n = 1 or 2, R3 = H, lower alkyl, acyl, alkoxycarbonyl or aralkyl, R4, R5 = H, opt. substd. lower alkyl, cycloalkyl or phenyl, K = 0, 1 or 2, L = 0,1 or 2, m = 0 or 1, R6 = H, halogen, lower alkyl or PH, R7 = H or opt. substd. lower alkyl, R8 = H, lower alkyl, acyl, alkoxycarbonyl or aralkyl.

Description

DK 174247 B1

The present invention relates to novel (6,7-substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-03-04) bis (acyloxy-O) borates, salts thereof, hydrates thereof and processes for their preparation. The compounds are important intermediates in the preparation of antibacterial quinoline carboxylic acids with an alkoxy group at the 8-position thereof.

Quinolone carboxylic acid derivatives having an 8-position alkoxy group have been previously prepared by one of the following two methods.

10 (1) (disclosed in Japanese Patent Kokai Sho No. 62-252772) Y 0 R3 o X X ° ° ° ° 15 z '

YES} A

R 'R' (2) (disclosed in Japanese Patent Kokai Sho No. 63-198664) 20? ... ΰ F, coOR10 o '·' ”^

_ y HDF, x Y H

k. '

R

// 0¾ \ .0 30 X Χ ^ Ι ^ γ ^ γ - <: Ο01! Y> .addition R 'i

R1 I R

V R J

2 DK 174247 B1 In the first of these methods (1), there is an electron-donating alkoxy group in the 8-position of the starting compounds. This causes the 7-position activity to be reduced and only the desired 8-alkoxyquinolone carboxylic acid derivatives can be obtained with a very low yield under mild reaction conditions. Making the reaction conditions stronger, the alkoxy group at the 8-position will undergo an alkylation and become a hydroxyl group, and thus the desired product cannot be obtained in a high purity.

The second method (2) is carried out via a boron fluoride organometallic compound, the desired product being formed in a large yield. However, fluorinated boric acid is so expensive that the preparation also becomes expensive and further, it is difficult to prepare the product using ordinary equipment because hydrogen fluoric acid is formed as a side product during the preparation of the intermediate product.

In these circumstances, the inventors of the present invention, after rigorous research into methods for preparing quinolone carboxylic acids with an alkoxy group at the 8-position, have found that the problem can be solved by using (6,7-substituted-8-decoxy) -1-cyclopropyl-1,4-dihydra-4-oxo-3-quinolinecarboxylic acid-03-04) bis (acyloxy-O) borates, salts thereof and hydrates thereof represented as the intermediates.

In other words, the organometallic compounds of the present invention are useful for industrial preparation because not only do they not form hydrofluoric acid as a side product, which corrodes the reaction equipment and other during its synthesis, but also because the desired product can be obtained with a high yield, and with high purity by using these organometallic compounds.

Furthermore, it is also a significant advantage that the product can be manufactured at a substantially lower cost than by the known methods.

The compounds of the invention are characterized by having the general formula (I).

(1 * 10 where X represents a halogen atom, R represents an aliphatic acyloxy group of 2-6 carbon atoms optionally substituted by a halogen atom or an aromatic acyloxy group of 7-11 carbon represents, R 1 represents a lower alkyl group, R 2 represents a hydrogen atom, a halogen atom, an amino group or a nitro group, Z represents a halogen atom, a group of formula 20./- -N N-R 'R' where n is 1 or 2, R 3 represents a hydrogen atom, a lower alkyl group or an aralkyl group, R 4 and R 5 each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group or a phenyl group, or Z represents a group of the formula 5 x € ^ rxf_ · ./r7

5 - N> - (C II a) V -N

where k is 0, 1 or 2, S is 0, 1 or 2, m is 0 or 1, R 6 represents a hydrogen atom, a halogen atom, a lower alkyl group or a hydroxyl group, R 7 represents a hydrogen atom or a lower represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group, or Z represents an azetidine group, a pyrrolidine group, a 3-hydroxypyrrolidine group, a piperidine group, a morphorene group or a thiomorphore group, and compound of general formula (I).

The organometallic compound of the invention can be prepared as indicated by the following reaction process.

Γ? R R

CO ° R '^ B \ * «' VV xx, xii»,: co 0 r Å R (IV)

R R K J

30 X J

Z 'II / B \ ...................: _____> r1 6 o

(V) A ", - A

wherein X 'represents a halogen atom, R9 represents a hydrogen atom or a lower alkyl group, X, R, and R 2 are mentioned above and Z' is one of Z in which a halogen atom is not represented.

A compound of the general formula wherein Z is halogen can be prepared by reacting the compound of the general formula II with triacyloxyborate derivative of the general formula III in the presence of a solvent. The triacyloxyborate derivative of general formula III may be used in quantities of 1-50 equivalents, preferably 5 equivalents, for the compound of general formula II.

As the reaction solvent, an organic acid is e.g. Acetic acid, propionic acid or trifluoroacetic acid useful. At this point, the reaction temperature is in the range of 20-200 eC, preferably in the range of 20 ° C to the boiling point of the solvent used. The triacyloxyborate derivative of the general formula III can be prepared by reacting boric acid in an organic acid, e.g. acetate acid, propanoic acid or trifluoroacetic acid or an organic acid anhydride, e.g. acetate anhydride, propionate anhydride or trifluoroacetate anhydride in the presence of zinc chloride.

20

The boric acid used is used in amounts of 1.1 to 2 equivalents, preferably 1.5 equivalents to the compound of general formula II. In this compound, the triacyloxyborate derivative obtained, without further isolation, can be used to react with the compound of general formula II.

25

A compound of general formula I wherein Z is other than halogen can be prepared by condensing with a cyclic amino compound represented by general formula IV, which is general formula I, wherein Z is halogen Formula V.

30 ΖΉ (V) where Z 'represents a compound of the form 6

/ TRJ

- N N-R1 R '10 wherein R3, R4 and R5 have the meanings specified in claim 1 or 71 denotes a compound of formula v R * 15 - / R7

y ~~ CCII3) „-N

wherein x, l, m, R6, R7 and R8 have the meanings specified in claim 1 or Z 'represents an azetidine group, a pyrrolidine group, a 3-hydroxypyrrolidine group, a piperidine group, a morphore group or a thiamorphore group.

The reaction of the compound of general formula I; wherein Z is halogen with a cyclic amino compound represented by the general formula IV, may be carried out without a solvent or in the presence of a polar solvent such as water, alcohol, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoramide (HMPA), pyridine , picoline and so on.

The reaction temperature is preferably selected between room temperature and 200 ° C, preferably between room temperature and 100 ° C.

DK 174247 B1 7

In particular, it is preferred to react the compound of general formula I wherein Z is halogen with 1-5 times as many moles of cyclic amine compound represented by general formula IV, in 2-10 times the volume of the above solvent, at a temperature between room temperature to 50 ° C for 1-5 50 hours. At this point, it is also preferred to add triethylamine, diazabicyclobase, potassium carbonate or the like.

In the following and with reference to the Examples, the invention is further described.

EXAMPLE 1

To a mixture of 67.5 g of boric acid (0.925 mol) and 1.24 g of zinc chloride was added 300 ml of acetate anhydride, which was then stirred for 1.5 hours at 110 ° C.

15

To this reaction mixture was added 400 ml of crystallized acetate acid and then allowed to stir for 1 hour at the same temperature.

After cooling, 200 g (0.619 mol) of ethyl 1-cyclopropyl-6,7-difluoro-1,4-8-20 methoxy-oxo-3-quinoline carboxylate was added to the mixture at a temperature between 50-60 ° C and then 200 ml of crystallized acetate acid was added. added, which was then allowed to react for 5 hours.

The reaction mixture was then distilled under reduced pressure. The 25 oily distillation residue was poured into 8 liter bottles of ice water. The resulting precipitate was collected by filtration and redissolved in 3 liters of water, then filtered again. Then it was dried to give 249 g of (1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxa-3-quinolinecarboxylic acid-03.04) bis (acetate-O) - borate as a light orange-yellow powder.

30

Mp 113-117 ° C.

Values by Elemental Analysis (%) (as C18H16BF2NOe% H2O) 8 DK 174247 B1

Calculated value C, 50.56; H, 3.89; N, 3.28 Observed value C, 50.32; H, 3.71; N, 3.33 δ NMR spectra (CDClf. Δ) 1.13-1.60 (4H, m.) 1.92 (6H, 5, -OCOCH 3) 4.2 (3H, d, J = 2 Hz, 4.33 - 4.73 (1H, m.) 7.97 - 8.28 (1H, dd, J = 8 Hz, 10 Hz, 5-H) 9.24 (1H, s, 2 -H) EXAMPLE 2

To 12.13 g (29.1 mmol) of (1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxa-3-quinophinecarboxylic acid-03.04) bis (acetate) O) -borate was added a mixture of 4.38 g (43.7 mmol) of 2-methylpiperazine, 8.2 ml of triethylamine and 30 ml of acetonitrile, which was then allowed to stir overnight at room temperature.

The distillation residue after distilling off the solvent was redissolved in 40 ml of ethyl acetate. Then it was washed with water and dried over sodium sulfate anhydride. It was concentrated and dried up under reduced pressure resulting in 12.9 g of [1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methoxy-1,4-dihydro-4 -oxo-3-quinoline carboxylic acid-03.04] -bis- (acetate-O) -borate (purity 91.0%).

Melting point 126-129 ° C.

Values of Elemental Analysis (%) (as C23H27BFN3O8 -% H2O Calculated value C, 53.45; H, 5.56; N, 8.13 * 9 DK 174247 B1

Observed value C, 53.36; H, 5.46; N, 7.93 NMR spectra (CDCl 3, δ) δ 0.84 -1.47 (7H, m.) 2.04 (6H, s, -OCOCH 3) 2.47 (1H, = N - H) 82-3.66 (7H, m,) 3.80 (3H, s, -OCH 3) 4.10-4.35 (1H, m,) 7.93 (1H, d, J = 12 Hz, 5 Hz) 9.12 (1H, s, 2-H) EXAMPLE 3 2.0 g (1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid) 03, O4) bis (acetate-O) borate, 1.4 g of ds-3-t-butoxycarbonylamino-4-methylpyrrolidine, 6 ml of acetonitrile and 1.6 g of triethylamine were mixed and allowed to stir at room temperature for 24 hours. hours.

20

After dissolving in ethyl acetate, wash with water.

After drying over sodium sulfate anhydride, it was concentrated and dried to give 2.8 g of [7-cis-3-t-butoxycarbonylamino-4-methyl-1-25 pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-methoxy -1,4-dihydro-4-oxo-3-quinoline carboxylic acid-03,04] bis (acetate-O) -borate (purity 98.2%).

Melting point 146-148 ° C.

30 Values of Elemental Analysis (%) (as C28H35EFN3O10. 1 -3/4 H2O)

Calculated value C, 52.97; H, 6.11; N, 6.62 Observed value C, 53.01; H, 5.73; N, 6.57 B1 [1-Cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid-03.04] -bis- (acetate-O) -borate (purity 91.0%) and [7-5 cis-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-methoxy -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-03.04] -bis- (acetaM)) -borate (purity 98.2%), prepared in the two examples mentioned above, can be converted to 8- alkoxyquinolone carboxylic acid, which is industrially useful in the following process.

EXAMPLE 4 (Reference Example 1)

To 14.2 g of [1-cycloprapyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-03.04] bis - (Acetate-O) Borate (Purity 91.0%) (29.1 mmol) was added a mixture of 50 ml of triethylamine (0.36 mol), 264 ml of ethanol and 66 ml of water, which was then refluxed under stirring for 6 hours.

After the reaction solution was cooled, undissolved material was filtered off and the filtrate was concentrated and dried to give a yellow oily material.

This material was redissolved under heat in 240 ml of ethanol and then cooled. The resulting precipitate was collected by filtration to give 9.1 g of 1-cyclopropyl7- (3-methyl-1-piperazinyl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (83 , 4%).

EXAMPLE 5 (Reference Example 2) 2.8 g of [7-cis-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4 -oxo-3-quinoline carboxylic acid-03 04] bis (acetate-30 O) -borate (purity 98.2%) was dissolved in dichloromethane and 40 ml of trifluoroacetate was added dropwise thereto under water cooling.

11 DK 174247 B1

After stirring at room temperature for 30 minutes, it was concentrated. Then, 40 ml of water was added to the precipitate and neutralized with sodium hydroxide in aqueous solution, then extracted with ethyl acetate.

After the organic layer was washed with saturated brine, it was dried over sodium sulfate anhydride, then concentrated and dried.

The dried product was redissolved under heat by adding 10 ml of ethanol. After being cooled, the resulting precipitate was collected by filtration followed by drying to give 1.0 g of 7-cis-3-amino-4-methyl-1-pyrrolidinyl-1-cycloprapyl-6-fluoro-8-methoxy -1,4-dihydro-4-oxo-3-quinoline carboxylic acid (57.4%).

Melting point 214-215 ° C.

15

Claims (8)

A process for the preparation of compounds of the general formula (I) wherein Z is a halogen atom and X, R, R1 and R2 have the meanings set forth in claim 1, characterized in that a compound of the general formula is allowed. Formula (II) R 'o 30 x τχτ (II> χ - YES R1 ^ DK 174247 B1 wherein X' and X each represent a halogen atom, R9 represents a hydrogen atom or a lower alkyl group and R1 and R2 1 means react with a triacyloxyborate derivative of the general formula (III) B (R) 3 (III) wherein R is as defined in claim 1. A process for the preparation of compounds of general formula 10 (I) wherein Z is a halogen atom and X, R, R 1 and R 2 have the meanings set forth in claim 1, characterized in that boric acid is reacted in an organic acid. or organic acid anhydride in the presence of zinc chloride to give a triacyloxyborate derivative and without isolating the derivative it reacts with a compound of general formula (II) R3 OXCO OR 'y' (id 20. XN · S SΔ R. ^ where X, X1, R, R \ R2 and R9 have the meanings set forth in claims 1 and 2. 25 A process for preparing a compound of general formula (I) wherein X, R, R1 and R2 have the meanings set forth in claim 1 and Z have the meanings set forth in claim 1 other than a halogen atom, characterized in that: leaves a compound of the general formula (IV) corresponding to the general formula (I) wherein Z is a halogen atom 5. ·· B \ R 'O o (IV), n SA R 1, where X, X 1, R, R 1 and R 2 have the meanings previously stated, condense with a cyclic amino group of general formula (V) ΖΉ where Z 'represents a group of formula 20 / R "-N NR>" Ή -f - '* " R 'wherein R3, R4, R5 and n have the meanings set forth in claim 1 or Z' represents a group of formula 30 / W / R 5 -N V- (CII,) vN X c Xm \ R8 wherein k, i, m, R6, R7 and R8 have the meanings set forth in claim 1 or Z 'represents an acetide group, a pyrrolidine group, a 3-hydroxypyrralidine group, a piperidine group, a morphorene group or a thiomorphine group.