NO901894L - PROCEDURE FOR THE PREPARATION OF SUBSTITUTED BIFENYL CARBOXYL ACIDS AND NEW INTERMEDIATES. - Google Patents

Description

The invention relates to substituted biphenylcarboxylic acids of formula I

where R<1> means hydrogen or methoxy, as well as methods for their preparation. The substituted biphenylcarboxylic acids of formula I can be transferred by cyclization to the corresponding 2,7-difluoro-fluorenone of formula IX

From these, they can be prepared in a single reaction step 2,7-difluoro-spiro[9H-fluorene-9,4'-imidazolidine]-2', 5'-dione (also designated AL 1576, HOE 843 and Imirestat), respectively 2,7-difluoro-4-methoxy-spiro-[9H-fluorene-9,4'-imidazolidine]-2,5'-dione, which can be used as a drug for the treatment of diabetic tendon injuries (cf. US- PS No. 4,438,272).

2,7-difluorofluorenone, which can easily be prepared from 4,4<*->difluorobiphenyl-2-carboxylic acid, can be prepared according to current technology in a 9-step synthesis from fluorine, and more specifically by nitration in the 2-position, reduction to amine, diazotization and Schiemann reaction to 2-fluorofluorenone, then nitration in the 7-position and continuation with known reaction sequences to 2,7-difluorofluorene as well as subsequent oxidation to 2,7-difluoro-9-fluorenone IX with sodium dichromate (cf. e.g. Chem. Ind. 1961, 179, J. Med.

Chem. 8, 491 (1965), Isr. J. Chem. 1.1 (1963) and Chem. Pray. 112, 3490 (1979)).

These preparation methods consist of several steps and the overall yield is currently 1056 due to the necessary isomer separation at the nitrogen compound step.

A method described in US-PS No. 4,438,272 for the production of 2,7-difluoro-9-fluorenone starts from 2,7-diaminofluorene, which is converted by treatment with fluoroboric acid to the corresponding salt of the fluoroboric acid. The subsequent diazotization leads to the bis-diazonium salt, which releases 2,7-difluorofluorene when heated in xylol. The oxidation to 2,7-difluoro-9-fluorenone takes place with KMnO4i pyridine.

The 2,7-diaminofluorene as starting material in this synthesis is indeed produced by nitration of fluorine to 2,7-dinitro-fluorene and difficult subsequent reduction and in unsatisfactory yield, as isomer mixtures are formed during nitration which must be separated and that 2,7-diaminofluorene is very sensitive to light and oxidation. The overall yield based on the fluorine is also in this method only at approx. 10%.

A particularly serious disadvantage of the known syntheses of fluorenone with formula IX lies mainly in the fact that amino and nitrofluorene derivatives have carcinogenic properties (cf. J. Nat. Cancer Inst. 10, 1201 (1950), Cancer. Res. 22, 1002

(1962), Brit. J. Cancer 4, 235 (1950), Brit. J. Exptl. Path. 25, 1 (1944) and Progressus Med. 3, 79 (1940)).

Production of 2,7-difluoro-4-methoxy-9-fluorenones takes place via 4 h.h.v. 5 further reaction steps from 2,7-difluoro-9-fluorenone.

The task of the present invention is to provide an economical and on a large scale practicable process of 2,7-difluoro-9-fluorenone of formula IX, which avoids the disadvantages that occur in production according to current technology. This means that the overall yield is high, the product is of higher purity and carcinogenic intermediates do not appear in any known way.

According to the invention, this task is solved by making new biphenylcarboxylic acids of formula I available, which are transferred in a simple way by cyclization to the corresponding flurenone, whereby this is obtained in high yield. In the preparation of biphenylcarboxylic acids of formula I according to the invention as well as their further processing to fluorenone IX, the aforementioned disadvantages do not occur.

The invention thus relates to biphenylcarboxylic acids of formula I and a process for their preparation.

The method for producing substituted biphenylcarboxylic acids of formula I is characterized by the fact that

a) reacts a 2-methoxybenzoic acid of formula II

OCH3

(EpC02H II

F

or a reactive derivative of this acid with an ethanolamine of formula III

R2R3

I I

H2N -C-C-OH III

R2R3

where R<2> and R<3> represent hydrogen or (C1-C3)-alkyl, preferably methyl, whereby each R<2> and R<3> does not simultaneously represent alkyl, to an amide of the general formula IV

where R<2> and R<3> have the indicated meaning as in formula III, the amide of formula IV is then cyclized to a dihydro-oxazole of formula V where R<2> and R<3> have the same meaning as indicated in formula III, then dihydrooxazole formula V is reacted with an organometallic reagent of formula VI where R<*> has the indicated meaning which in formula I and M means lithium or Zn-Hal or preferably Mg-Hal and Hal means chlorine, bromine or iodine, to a biphenyl derivative of the general formula VII where R<1> has the indicated meaning as in formula I and R<2> and R<3> have the meaning as indicated in formula III, that the biphenyl derivative of formula VII was obtained possibly after transfer to corresponding alkylated compound of formula VIII where R<1> has the indicated meaning as in formula I and R<2> and R<3> have the indicated meaning as in formula III, R<4> means (C1-C3)-alkyl, preferably methyl, and X" means chloride, bromide, iodide, methyl sulfate or ethyl sulfate, is hydrolyzed to the carboxylic acid of formula I

where R<*> has the meaning as indicated in formula I.

Biphenylcarboxylic acids of formula I can then be directly cyclized in ways known per se, over the corresponding acid chloride or amide of substituted fluorenone of formula

IX.

The method according to the invention has the advantage that it starts from correspondingly substituted starting material and in a targeted way leads to pure biphenylcarboxylic acids of formula I where the position of the substituents is determined through the synthesis. Time-consuming and loss-making isomer separation is not necessary and the overall yield (about 65$) is significantly higher than with the known method (about 105^). According to the method according to the invention, e.g. only two isolated intermediate steps are passed through for the synthesis of 4,4'-difluorobiphenyl-2-carboxylic acid by starting from 5-fluoro-2-methoxybenzoic acid (compounds V and VII).

4,4'-difluorobiphenylcarboxylic acids of formula I occur according to the method of the invention in a much purer form. This also applies to the fluorenone that can be produced from it.

It is particularly important that the known carcinogenic nitro and aminofluorene derivatives must not be run through.

The process for producing benzamide IV according to the invention from benzoic acid II is carried out with amino alcohol III in a manner known per se, e.g. reaction is carried out with a (C 1 - C 2 )-alkyl ester of II with the amino alcohol III by heating the components in the presence or absence of a solvent. The amide of formula IV can also be transferred by reaction with acid II with an acid chloride, such as chloroformate or toluene sulphochloride, in the presence of a base such as e.g. triethylamine, in a suitable anhydride, and then react with an amine of formula III to give the amide IV. In a preferred embodiment of the method according to the invention, the acid II is e.g. transferred with PCI5 under preferably thionyl chloride to the corresponding acid chloride, which in fixed quantitative yields with an amine III gives the corresponding amide IV.

Cyclization of amides with formula IV to the dihydrooxazole V can be carried out in ways known per se with water-binding agents, such as concentrated sulfuric acid, polyphosphoric acid or phosphorus pentoxide. Cyclization with thionyl chloride preferably takes place in a suitable inert solvent such as e.g. diethyl ether, methylene chloride or toluene. They can be carried out at temperatures between -10 and 50°C, preferably at 0 to 30°C. From the hydrochloride that then forms, the free dihydrooxazole derivative V is prepared with bases such as e.g. baking soda.

In a particularly preferred embodiment of the method according to the invention, dihydrooxazole V is prepared from benzoic acid II, without isolating the amide of formula IV. In simplicity, benzoic acid II is heated with a small excess of thionyl chloride in the absence or presence of an inert solvent such as methylene chloride or toluene and the solution with the resulting acid chloride is added dropwise to amino alcohol III. As amino alcohol also acts as an acid acceptor, a double molar amount is used. An alternative to this is the use of one mole of amino alcohol III and one mole of an inert base such as triethylamine. Upon subsequent addition of the molar amount of thionyl chloride in the reaction mixture, the ring closure to dihydrooxazole V takes place. After alkali adjustment of the reaction mixture with caustic soda and evaporation of the organic phase, dihydrooxazole V is obtained in the next quantitative yield. The product can be purified by distillation.

Surprisingly, the reaction of dihydrooxazole V with an organometallic reagent VI proceeds uniformly with substitution of the methoxy group, whereby the biphenyl derivative of formula VII is obtained. Notable side reactions in nucleophilic substitution, e.g. a fluorine atom in compound V or VII does not appear. Ether can be used as a solvent for this reaction, such as diethyl ether, methyl-t-butyl ether or dibutyl ether, tetrahydrofuran is preferred. With magnesium or organic zinc compounds the reaction takes place at temperatures between 0°C and the boiling point temperature of the solvent, with 4-fluorophenyllithium the reaction is allowed to take place between -60°C and room temperature. The organometallic reagents VI are used in excess to achieve a satisfactory yield, and more specifically 1.2 to 3.0 mol, preferably 2-3 mol per mol dihydrooxazole V. The reaction can take place in the presence or absence of a catalytic amount of palladium compound such as e.g. Pd(PPh3)4-

Preferably, formation of biphenyl derivative VII takes place from dihydrooxazole V and Grignard reagent VI (M = Mg Br). Thus, the Grignard reagent can be given to dihydrooxazole or dihydrooxazole V to the Grignard reagent.

In a particularly preferred embodiment of the method according to the invention, e.g. in the preparation of 4,4'-difluorobiphenyl-2-carboxylic acid magnesium with the total amount of THF added and Vitride is added (NaAlH2(0CH2CH20CH3)270# in toluene), until hydrogen evolution is complete. In the boiling THF, 4-bromofluorobenzene is then allowed to run, whereby the Grignard reaction proceeds rapidly. After completion of formation of the Grignard reagent, dihydro-oxazole V is added with or preferably without solvent. After a shorter time (approximately 10 minutes), the reaction is finished. It is hydrolysed with water or saturated ammonium chloride solution and adjusted with hydrochloric acid to pH 4-7, in order to achieve a good phase separation. The product can be purified by crystallization and/or distillation.

The saponification of dihydro-1,3-oxazole VII to biphenylcarboxylic acid I takes place through hydrolysis with aqueous acids, e.g. by heating with hydrochloric acid, sulfuric acid or methanesulfonic acid.

In a preferred variant of the method according to the invention, the compounds of general formula VII are reacted with alkylating agents such as e.g. (C 1 -C 4 )-alkyl halides, methanesulfonic acid (C 1 -C 3 )alkyl esters, toluenesulfonic acid (C 1 -C 3 )alkyl esters or di(C 1 -C 3 )alkyl sulfates to compounds of the general formula VIII. Particularly preferred as alkylating agents are dimethyl sulphate, methyl iodide, methyl bromide and methyl chloride in solvents such as toluene, acetone, 2-butanone or lower molecular weight alcohols. The alkylation reaction can be carried out in the presence or preferably in the absence of a base such as caustic soda, potassium carbonate or triethylamine, possibly also in the presence of phase transfer catalysts such as tetra-butylammonium sulphate. The resulting dihydro-1,3-oxazolium salt VIII is then hydrolysed to biphenylcarboxylic acid I. This can take place by heating with an aqueous alkali hydroxide solution, such as caustic soda or caustic soda, preferably an opening reaction, without isolating the salt VIII.

Ring closure of carboxylic acid I to fluorenone IX takes place in a manner known per se, e.g. with water-releasing agents such as e.g. in polyphosphoric acid at temperatures between approx. 80-120°C.

The compounds with the formulas V, VII and VIII are new and produce valuable intermediates for e.g. production of biphenylcarboxylic acids with formula I. The invention thus also relates to these intermediate products and the methods for their production.

Example 1

4. 4'-difluorobiphenyl-2-carboxylic acid

1) 5-fluoro-2-methoxybenzoic acid-2-(1-hydroxy-2-methyl)propyl-amide (IV)

23.0 g (0.135 mol) of 5-fluoro-2-methoxybenzoic acid are dissolved in 50 ml of methylene chloride. At room temperature, 17.6 ml (0.2 mol) thionyl chloride and 2 drops of DMF are added and heated slowly

for cooking. After completion of the reaction (thin-layer control after addition of methanol to a sample of the reaction mixture) it is evaporated in vacuum and the thionyl chloride residue is removed in vacuum after twice the addition of further methylene chloride. The residue (28.7 g) is dissolved in 100 ml methylene chloride and the solution obtained at 0-5°C is added dropwise to a solution of 24.06 g (0.27 mol) 2-amino-2-methyl-1-propanol in 50 ml methylene chloride. The mixture is stirred for 1 hour without ice cooling and washed twice, each time with 100 ml of water, then with 50 ml of diluted BC1, dried over anhydrous sodium sulphate and evaporated under vacuum. The crystallized residue (30.5 g, 93.556 of theory) is sufficiently pure for further reaction.

Temp. 97 - 98"C (from isopropanol).

1-H-NMR: S = 4.8 ppm (t, 1H), 3.95 ppm (s, 3H), 3.65 ppm

(d, 2H), 1.4 ppm (s, 6H)

2 ) 2-( 5-fluoro- 2- orethoxvf envl )- 4 . 4- d ime tvi- 4 . 5-dihydro-l. 3-oxazole (V) a) To 14.4 ml (0.17 mol) of thionyl chloride, 20 g (0.083 mol) of 5-fluoro-2-methoxy-benzoic acid are added at 20-250 C portionwise 2-(1-Hydroxy-2-methyl)-propylamide, which requires cooling with ice water from time to time. It is stirred for one hour at room temperature, then 100 ml of ether is added twice, stirred and then the ether phase is decanted away. The semi-crystalline residue is taken up in 100 ml of methylene chloride. The solution is added dropwise under ice-cooling at approximately 15° C to 150 ml of semi-concentrated caustic soda. At the end of the dropwise addition, the pH value of the aqueous phase must be above 10. The aqueous phase is separated and once more extracted with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. You get 18.7 g of an oil which little by little crystallizes. After distillation, the product melts at 35 - 36°C. Boiling point ø 98"C.

Yield: Raw product 93 -10056, after distillation 85 - 9556.

<*>H-HMR: S - 6.6-7.6 ppm (m, 3H), 4.05 ppm (s, 2H), 3.8 ppm (s, 3H), 1.35 ppm (s, 6H).

b) (Instillation reaction)

230 g of 5-fluoro-2-methoxybenzoic acid are dissolved in 100 ml

methylene chloride and 1 ml DMF. To this is added 108 ml of thionyl chloride. It is heated under reflux until the formation of acid chloride is excluded (approximately 1 hour). A solution of 293.5 ml of 2-amino-2-methyl-1-propanol in 200 ml of methylene chloride is then added to the clear reaction solution at ICC. After the addition has been completed, it is stirred for 30 minutes at room temperature, and then 98 ml of thionyl chloride is added dropwise at 20°C. It is stirred for 15 minutes and approximately 250 ml of concentrated caustic soda is added drop by drop until a pH value of >10 is achieved. The organic phase is washed once with dilute caustic soda, dried over sodium sulfate and distilled in vacuo.

Yield 276 g (92 .956).

3) 2-(4.4'-difluorobiphenyl-2-yl)-4.4-dimethyl-4.5-dihydro-1.3-oxazole VII

1.18 kg of magnesium shavings are added to 25 1 THF and heated to 50-60°C. Vitride solution in toluene (7056) is added until hydrogen evolution has ended (approximately 150 ml). The mixture is heated while cooling and, with vigorous stirring, 500 g of 4-bromofluorobenzene is added. The exothermic reaction starts almost immediately. 7.99 kg of 4-bromofluorobenzene is further added, while the mixture is still boiled on reflux. After the addition has been completed, it is heated further for 1 hour. Then 3.6 kg of 2-(5-fluoro-2-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole 15 1 dried THF at room temperature are added and heated further for 15 minutes. The mixture is cooled to 10°C. At 10-2 CC, 20 1 of saturated ammonium chloride solution is added with good cooling and adjusted with approximately 3.5 1 of concentrated hydrochloric acid to a pH value of 6. The precipitated salt was dissolved with water and

the phases separated. The organic phase is washed with 9 1 of saturated sodium chloride solution, stirred with 200 g of activated charcoal, dried with sodium sulfate and sucked away. After evaporation of the solvent and drying in vacuum, 4.5 kg of a yellow, crystalline product was obtained, which is sufficiently pure for further processing (9756 after GC analysis, yield 94.256). It can be purified by crystallization from isopropanol or diisopropyl ether and distillation of the original liquor with a thin-layer evaporator.

Boiling point 126 - 130"C (0.1 mm)

Freezing point 83 - 84°C

<1->H-NMR: S - 6.4-7.5 ppm (m, 7H), 3.85 ppm (s, 2H), 1.28

ppm (s, 6H)

4. a) 2-( 4 . 4 ' - difluoroblphenvl- 2- vl)- 3. 4. 4- tri imetvi- 4. 5- dihydro- 1. 3- oxazolium- riodide (VIII. E, R-2- .R-i -

CH3. RAW°H. X - ji^i)

8.6 g of 2-(4,4'-difluorobiphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole are stirred in 60 ml of acetone and 30 ml of methyl iodide for 2 days under cooling back. Evaporate in a vacuum and crystallize the oily residue by adding a little acetone. After suction and washing with a little acetone, 5.8 g of crystals with a freezing point of 179°C were obtained.

<1->H-NMR: 5 - 8.3 - 8.6 (m, IB), 7.1 - 7.6 (m, 6H), 5.25

(s, 2H), 2.85 (s, 3H), 1.6 (s, 6H).

b) 2-( 4 . 4 '- difluorbifenvl- 2- vl )- 3. 4 . 4- trimetvl- 4 , 5- dlhvdro-1. 3- oxazolum- metvlsulphate (VIII. Ri - ° H. R^. R4- - CH3. R3-- H. X ° SO^)

4.3 g of dihydro-oxazole (from 3.) is stirred in 30 ml of toluene and 1.71 ml of dimethylsulphate for two hours under reflux. The salt crystallizes out overnight. One sucks away, washes with a little acetone and gets 5.65 g (92 .656) of the product. It is sufficiently clean for further sales. After recrystallization from isopropanol it melts at 167 - 169°C.

<i>H-NMR: S - 8.05 - 8.35 (m, 1H), 7.0 - 7.6 (m, 6H), 5.05

(s, 2H), 3.7 (s, 3H), 2.75 (s, 3H), 1.5 (s, 6H).

5. 4. 4'- difluorobiphenyl- 2- carboxylic acid ( I)

a) 7.18 g of 2-(4,4*-difluorobiphenyl-2-yl)-4,4*-dimethyl-4,5-dihydro-1,3-oxazole (compound VII) is saponified in

75 ml of dioxane and 80 ml of semi-concentrated hydrochloric acid for 3 days

during recooling. The solvent is removed in vacuo, the residue is taken out in a little semi-concentrated caustic soda, the solution is washed twice with 50 ml of ether each time, clarified with activated charcoal and acidified with dilute hydrochloric acid. One vacuums away and washes with water. Colorless crystals with a freezing point of 117 - 119'C are obtained. After recrystallization from isopropanol/water, the product melts at 124°C. Yield 6156. b) In a solution with 1.6 g of NaOH in 30 ml of water, 4.0 g of 2-(4,4'-difluorobiphenyl-2-yl)-3,4,4-trimethyl-4,5 -dihydro-1,3-oxazolium methyl sulfate (compound VIII) and 30 ml of methanol. After 2 hours at 65°C, the reaction solution is acidified with 2 N HCl and evaporated in vacuo. The residue is recrystallized in isopropanol/EthoO 1:4 and dried.

Yield: 2.25 g (99%) with freezing point 124°C.

c) In an analogous way, carboxylic acid I is extracted from the corresponding iodide VIII (from 4.a)) after recrystallization in

a yield of 92.8%.

d) Instillation reaction:

100 g (0.348 mol) of 2-(4,4'-difluorobiphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (compound VII) is heated in 100 ml of acetone with 40 ml (0.417 mol) of dimethyl sulfate for 1.5 hours under reflux. During the reaction, a colorless precipitate is precipitated. The suspension is then added dropwise to 342 ml (1.54 mol) of 1856 caustic soda and at the same time the acetone is distilled off. At an internal temperature of 90°C, it is then heated while recooling, until the saponification is finished (approximately 1 hour). It is cooled to 20°C, whereby the reaction mixture is separated into two phases. The lower phase is discarded and the upper phase is washed twice with 100 ml of toluene each time and then clarified with activated charcoal. During cooling, it is acidified with concentrated hydrochloric acid, whereby the crystalline, colorless 4,4'-difluorobiphenyl-2-carboxylic acid precipitates out. It is sucked off, washed with water and dried in a vacuum at 30°C.

Yield 70.1 g (86.056).

The carboxylic acid obtained according to example I can be cyclized as follows to 2,7-difluoro-9-fluorenone (IX): 2.34 g of 4,4'-difluorobiphenyl-2-carboxylic acid is added to 35 g of polyphosphoric acid at 40 - 50"C While stirring, heat for 1 hour at 100° C. The yellow suspension is then poured into 150 ml of ice water. The yellow precipitate is sucked off and washed thoroughly with water.

Yield: 2.11 g (9856) of compound IX

Freezing point 208 - 210°C.

Claims (4)

1. Biphenylcarboxylic acid, characterized by formula I where R<1> means hydrogen or methoxy. 2. Process for the production of biphenylcarboxylic acids of formula I, characterized by reacting) a 2-methoxybenzoic acid of formula II or a reactive derivative of this acid with an ethanolamine of formula III where R <2> and R <3> mean hydrogen or (C1 -C3 )-alkyl, However, R <2> and R <3> do not simultaneously mean alkyl, to an amide of general formula IV where R <2> and R <3> have meanings as indicated in formula III, the amide of formula IV is then cyclized to a dihydrooxazole of formula V where R <2> and R <3> have meanings as indicated in formula III, dihydro-oxazole of formula V is then reacted with an organometallic reagent of formula VI where R<1> has the meaning as indicated in formula I and M means lithium, Zn-Hal or Mg-Hal and Hal means chlorine, bromine or iodine, to a biphenyl derivative of general formula VII where R <1> has the indicated meaning as in formula I and R <2> and R <3> have the indicated meaning as in formula III, the obtained phenyl derivative of formula VII is optionally hydrolyzed after transfer to the corresponding alkylated compound of formula VIII where R <1> has the indicated meaning as in formula I and R <2> and R <3> have the indicated meaning as in formula III, R <4> means (Ci -Cs )-alkyl and X" means chloride, bromide, iodide, methyl sulfate or ethyl sulfate, to a carboxylic acid of formula I where R <1> has the indicated meaning as in formula I. 3. Compound characterized by formula V. 4. Compound characterized by formulas VII and VIII.