DE1793144A1 - Phenylsalicylic acid compounds and processes for their preparation - Google Patents

Description

DR.-ING, WALTER ABITZ DR. DIETER MORF

Patent attorneys

1793H4

8 Munich 27, Pienzenauerstraße 28 Telephone 483225 and 480415 Telegrams: Chemindus Munich

August 8, 1968 11,495

JIEROK ft CO., IUC.

126 East Lincoln Avenue, Rahway, N.J. 07065, V · St · A.

Phenylsalioyl Acid Compounds and Processes for their production

The invention relates to a new process for the production of certain compounds * It relates in particular to processes for the preparation of 5- (4-fluorophenyl ) salicylic acid and its Q ~ acetyl derivatives of the general formula (I):

-COOH

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where A is either hydrogen or acetyl. means. The invention also relates to the new intermediate product «. It also relates to processes for the preparation of intermediates which are used in the preparation of the compounds of the formula I. These compounds are anti-inflammatory agents, they are effective to prevent or reduce edema and granuloma formation, and they also have useful antipyretic and analgesic activity.

The invention is based on the discovery that compounds of the formula I can be prepared by a series of reactions as described in the following equation:

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11 495

OBs

II

ÖBa

III

-COOH

IV

II)

COOH

where Bs is an alkyl radical such as benzoyl ».

Invention device is a 4-acylozy "biplienyl-Ve3i ^ indungt
4-bed £ oylo3tybiplienyl of the formula II in a 4-AoyXoacybiplienyl-f4 ^f fluorBUlfonylbiplienyl compound, such as 4 ~ benzoylo3y-4-fluor · »
Bulfonylbiphenyl of the formula III by Utasetssimg with a Verl) itidting, which is capable of a Fluoreulfonylrest eitr grouting

1 * Ό§8-86 / 1 9 18

1733144

to ask, converted. Suitable acids are fluoreulfonic acid or chlorine acidic acid-liumiluorid. The reaction is carried out at temperatures between the freezing point of the reaction mixture and the Iliiekf lues temperature. The most suitable reaction rates are obtained between 0 and 100 ° The product is separated from the reaction product by mixing with a solvent such as methylene chloride, benzene or jithesy, and the extract is then washed with water and dried the product is then isolated «

But one can also use the 4-acylo3cyclplienyl compound (e.g. weia © 4-Benaioyloxybiphetiyl) sulfonate or chlorosulfonate and into the sulfonated derivative (e.g. 4-Beus5oylQxj ~ 4- '~ fluorosulfonylbiphenyl) by reaction with a fluorinating agent, like phosphorus pentafluoride, phosphorus oxyfluoride »potassium fluoride or hydrogen fluoride. Preferably one introduces the metal sulfonate produced by the fluorination.

The compound of the formula III is converted into the corresponding fluorine compound (for example ^ -Benzoyloxy-4 ^l -fluorobipheiiyl), as represented by the formula XV. The reaction is carried out by reacting with a compound which is able to

to convert into a FluorreeU, bewörksteiligt under development in. Transition metal coils are

H) * 8-8 6/19 18 ^ ₁ BAD ORIGINAL

11 495

All catalysts are effective, typical suitable catalysts are

yhodiTimfluorid »Tris-itriphenylphosphin) -, iüetrakis-itriphenylpliogphinj-ruthoniiundicliloria,

Bis- {triplienylpliosphinl-i'iitlieYiiiiiacarTsoiiylcliloriä, cobalt carbonyl, Platinum and palladium catalysts. Sufficient response speeds been "at temperatures ranging from 25" to 400 ° 0 achieved. The reaction product is obtained by crystallization obtained and then filtered or by precipitation with £ a liquid such as petroleum ether, hexene or water, and then Filter.

The compound of the formula IV is then converted into a compound of the formula V, next to k- (4-fluorophenyl) phenol the free hydroxy derivative by solvolysis. ¹¹ SoIvolyse, "which means in addition to the various Reskt-ion obtained as-'■" hydrolysis "' which, bezeiclinet in aqueous reaction M takes place medium such reactions carried out in an acidic medium, which are ^ orgenoiamen under substantially anhydrous conditions" solvolysis may be acidic, neutral, "held oäer basic conditions., under neutral conditions, the Ausgangsmaterlal with water and, if desired, mixed with a solvent and the Mifjöhung is allowed to stand, Ms is the Hydrolys © has taken place. In most cases, ea is desirable to ' Reaction agemioch to temperatures in the range τοη 100 to 250 ° 0 zu-erhitiseu and aie. ÜmsefeiSUEg in an autoclave to increase

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if the IToluinen of the water is in excess over that of the starting material is. If a solvent is used, v / asasermisclibare protonic solvents preferred. Such solvents are, for example, lower alkanols, such as methyl and Ethyl alcohol, and benzyl alcohol.

The acyl group (preferably the benzoyl group) can be removed by acid hydrolysis by forming a mixture of the starting material in an aqueous acid. The reaction conditions can vary within a wide range, but a 10- to 50% acidic solution is preferably used and the reaction is carried out at temperatures between room temperature and reflux temperature for a period of about 1 to 24 hours. The reaction mixture can optionally contain a solvent which is inert under the reaction conditions and this solvent can be miscible or immiscible, the latter being preferred. Among the preferred solvents are miscible protic solvent such as benzyl alcohol and ffiedrigalkanole _f-miscible organic acids,

Suitable acids for the hydrolysis are inorganic or organic Acids, preferably strong acids such as hydrogen chloride, acid, sulfuric acid and p-toluenesulfonic acid ©, however, the choice is yours the acid is not critical »

Instead of an acid hydrolysis, a basic hydrolysis can also be used

10 9 8 * 86/1918 bad original

be applied. For the "basic" hydrolysis, a Ί-Ο to 30% storage solution is preferably used and the reaction is carried out between room temperature and reflux temperature over a period of 1 to 4 hours. The Healctionsmiaclmng temi either a nichtjnischbareo oöor ciu mlsclibares I »öaungs ~ rsiltte * L _f which is inert under the Eeaktiotisbedingringen, © nt 3mlten - * - Preferred solvents are low and Allcanole ■ Benay-laallcohol.- Geoignete basic" connections applied ™

wörfiGw köiinon, are Uatriuaimetlioxid mit Kaliumbutoxicl «the strong inorganic bases such as Hatrimäiydroxid, Kaliitsöiydroxid and Oalciumoxid _y However, the content of the respective basic S-ubstans is not critical

The 4- {4 ^ 1uorplienyl} -phenol obtained is then converted into 5 "- (4-Plu (5rphenyl} -galicyl3 acid (compound Ia, that is the compound in formula ΐγ in which A means hydrogen). This can be made by a carboxylation, ζ, .Br by M

carbon dioxide is allowed to react with 4-C4 ^ fluorophenyl) -phenol in Segenwart © ines basic catalyst. Matriufloiyäroxidy Kaliuraliydroxidi potassium carbonate or Katriumcarbotmt can be used as catalysts. The Oarboxylierungsreaktion feann at a temperature -between "the GefrierpuiLfct and the temperature at _f \ Felcher undesired decomposition of the reactants or product dos" occur can be made. The best reaction rate is achieved with a temperature in the range of 100 to 250 ° C.

. - γ -.
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In the last stage, 5 ™ C4 ~ fluorophene & yl) «salicylic acid is treated with an acetylating agent to form the desired product. puts. The acetylating agents which can be used in the process of the invention include testing and solicitation of the formula

KtiX * p * ~ W "** Jt *

where X is the anion of an acid HX ". Typical anions I are Ghlorld, Bromid, Joöid, Pluorid, /...?.id _f Pheno3ey _r 2,4-binitrophenoxy, Hionylmeron.ptο _P p-Hitropheiiy3.mercapto, IiaidaEolyl _f Alkoxy (a * B. Metlioxy * Bropoxy oderButoxy), Hydroxylj Oarlioöiimidoxyl, <r _r e -unsaturatedGn Alfeanozy (ss · B. Tlnyloxjr, Allyloxy oder Isopropenyloxy}, oliplietisöiieo Äcylomoxy, Almatoyoxlosphi, alfophyloxy oxy, like Acstaoxy or propionoxy MallsylphoepkatOt Bialfeylarseno> sulfonoxy (si. B. -OSO «-), Oyano * alfcoxy and hardened AiainoniuiBsalze, like Pyrrolinium ·

Prevented as an aeotylating agent ketene and the compounds _t in detien X ciloride (acetylochloride), Broaid (acetyl bromide), acetoxy (acetic anhydride) and isopropenyloxy clsopropenyl acetate) mean “MJ.t the preventive acetyelating agents (4 * takes place with the formation of acetic anhydride) ^! luorp! ionyl) -ao @ tylßali0ylsiure smäasig quickly. Bio acetylation reaction can be carried out in the presence of acidic or basic catalysts, which accelerate the acetylation, or in aliwesaiiliait of a catalyst. Typical catalysts are Baserite such as Sri «-

10 9 | 8_6 / 1918 bad orig.nal

1793 HA

11 495.

ethylamine and pyridine and acidic substances such as bohulfuric acid and Phosphoric acid, boron trifluoride, boron trifluoride / mercury oxide, p-Toluenesulfonic acid, trifluoroacetic acid, sodium acetate, latriuafornate or ion exchange resins. Prevented catalysts on * Pyridine, sulfuric acid and boron trifluoride.

The ttaaeteutig is Ainet vorsugaweise in the presence of which is not aoetyliert quickly vorgenoeaen · Such IOE # - "uagemittel are beiapielsweiee pyridine, leneol, toluene, OiaatfejX-formamide, acetone, carbon tetrachloride _t Okloroform. Methyle «- chloride, acidic amhydride and bfeifeture. .

The exercise is carried out at temperature · »iwieohen de« Oefrierpankt vaA Torgenniwt the point at which undesired dissolution of the chemical substances or the reaction products take place. Urine works preventively in the temperature range τοη about 0 ° to about 80 ° C

The proportions of the acetylating agent are not critical, because the product is obtained regardless of which of the reactants is present in excess. If an excess of the acetylating agent is used, the anhydride of the compound becomes the Formula II and acetic acid. If you want to avoid the formation of the anhydride, you have to make sure that during No excess acetylation agent is present in the reaction is. If, however, some anhydride is formed, whether anachliea-

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be hydrolyzed, for example with aqueous acid with the formation of 5- (4-Plucrphenyl) -mcetyletlioylBäiire. The reaction is preferably carried out with a quantity of Aoetyilerungsmittel in the range of 10 to about 000 TO # ·, especially about 100 i "to about $ 00%, in excess of the stoichiometric amount.

The reaction product is isolated, obtained and purified »aoh The usual methods, such as filtering, Yaeuhen, Yerdemfen. Drying and ttakristslliaiereiu

The following examples should be given

Example ι

4 "-Ben80yloxT-'4 * -fluora ^ O fonylb iphenyl

Sin Hol (274.3 g) 4-BenBoylozybiphenyl is used in 2 Hours to 3 moles (300.2 g) of fluorosulfonic acid at 70 ° C sug Added. After the addition is complete, it is heated to 70 ° C. for a further 3 hours heated. The reaction mixture is cooled and poured into Eisvaener poured. The quenched mixture is extracted with three one liter portions of methylene chloride. The extract is made with Yasser washed and dried over sodium sulfate. When slowly diluting with 3 liters of petroleum ether, 4-Benzoyloacy-4-fluorosulfonylphenyl precipitates out »

- 10 -

'109886 / 19-18-' bad original.

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Other 4-acyloxy compounds can be produced in the same way if one uses other biphenyl-Ausgsngs- ■ ver-M-Naungeh in Example 1 used.

A hol (324> 3 ß) ■ 4-Benzoyloxy-4 ^l -fluorsul "foTiyU> iilienyI is at 230 ° C with 3 g (0.00526 mol) t» is - ('3! Ripti6tiyXp! Ioephiii) ^ r] iodiT] mfluoride heated .., - 'until the development of sulfur dioxide onii & rt- .. The residue is recrystallized from ethanol, whereby 4-

with a Schmelapunlct τοη 139 tis

163 ° C.

maii other 4-aoylo: xy ~ output connections at deiü toi * -. at.ehGnd _: en TcrfsBren so one obtains the corresponding 4 ~ acyloxy-

B e i ^ _p i e 1 3

4- {4 "-Fluoi" T) hetiYl} -phenol

Six g (0.02.06 mol) of crude 4-bensoyloxy-4'-fluorobiphenyl are dissolved in 100 ml of 50% aqueous ithanola. To this are added 4 g (0.10 hol) of sodium hydroxide and the mixture is heated for 5% under RUolcflues The hot solution is cooled and fil-

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The Piltrß-Fe is acidified to pH 2.0 with hydrochloric acid. The precipitated roll of 4 ~ C 4-fluoroperb.enyl) -phenol is filtered, washed with water and dried. Men receives 3.7 g with a Schmelabbereich tone 145 "to 155 ° 0" The crude phenol is about Silica gel by Oiiroaiatograpliie. cleaned*

If one uses in example 3 sudöre 4 * -cyloxy-output extension> J.Tif? Uiigen., ao gets siati des equal © Επα product *

100 g of 4 ~ (4-Flti.orpbeTi2rl} «- pheTlol are mixed with 300 g of anhydrous lium carbon & t finely watered; The mixture is in an autoldave under a pressure of 49 to 56 AtU. (700." to 8QO psig) of dry® carbon dioxide Heated for 6 hours to 235 Ms 245 ° G. The mixture is cooled uitä in 1.5 l of water on dried potash 5 - (4 - fluorophenyl) salicylate is filtered 5 liters of water are slurried, the mixture is filtered and the Piltrst acidified with concentrated hydrochloric acid, resulting in 5- (4-fluoropuenyl) - salia. Tile yield is 92 g, the Sehmel sputjkt

iat 202 to 204 ° C

- 12

10 9 8 8 6/1918 m> ORiGiNAu

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B © i 9 ρ 1 e I 5. ■ ■ ■

To 1 g of _ (- 4,3. Hilliffiol) 5- (4-i'luorop3ieayl) "- salicylic acid and 2 g (21.2 millimoles) Escalate at 25 ° C with stirring Given 40 microliters of concentrated sulfuric acid. You let them Temperature rise to 32 ° G and keep it at this temperature 5 minutes. 20 microliters of water slowly become the reaction odor added, allowing the temperature to rise to 40 ° C. The mixture obtained is at 40 ° C for 5 minutes touched. 0-acetyl-5- (4-fluorophenyl) salicylic acid crystallizes from the reaction mixture and is filtered off from it · The filtered product is washed with 10 ml vase and stored at 60 ° .0. Dried to weight constancy. The yield of 130 bis 145 ° G melting product is 1.16 g.

1 g of the 0-acetyl-5- (4- * fluorophenyl) -saiicylic acid thus prepared is dissolved in 80 ml of hot carbon tetrachloride and cooled to 70 ° C. 50 g of decolorizing charcoal are added and the product is stirred under reflux for 15 minutes. The charcoal is separated by filtering the solution and the filter cake is washed with 2 ml of light carbon dioxide. The combined fiI - tread® and 'W &see' are concentrated in vacuo to 50 ml. - 'The obtained slurry is split up un-fcer Ettekflusa and cooled with 20 per stand to 25 ° G, feeli 2 places at 2 ° Q wlM the

filtered, exerts Piikar-

- ^; i3 - ■ ■ BATHROOM

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spawn obtained and with 2 ml of carbon tetrachloride and then with 5 ml of hexane and finally in vacuo at 60 ° C Ms dried to constant weight. The yield of the so obtained Product is 0.75 g.

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BATH ORIGINAL

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Claims (1)

495 8 "August 1968 P a t e η t a η s ν τ u c h e 1 «Process for the production of 4- (4-5 ^l luophenyl) phenol _f characterized in that one 4-bensoyloxybiphenyl with a. Compound which provides a fluorosulfonyl radical with the formation of 4-benzoyloxy-4'-fluorosulfonylbiphetiyl ₅ that the fluorosulfonyl radical of 4-benzoyloacy ^ '- fluorosulfonylbiphenyl is converted into a fluorine radical with formation of 4-BGnZOyIoXy ^ ¹ -fluorobiphen and that the 4-BGnsoyloxy-4 · fluorobiphenyl is hydrolyzed to form 4- (4-fluorophenyl) phenol. 2. Process for the preparation of 5- (4-fluorophenyl) salicylic acid, characterized in that 4-benzoyloxybiphenyl is reacted with a compound which provides a fluorosulfonyl radical to form ^ -Bettzoyloacy ^ '- fluorosulfonylbiphenyl, that one reacts Fluorsulfonylrest AEEA 4-BenEoyl- (| ^oxy-4'-f fluorsulfonylbiphenyls in a Fluorreat to form 4-BenBoyloxy-4 -fluorbiphenyl converts that nan hydrolyzed to give 4- (4 ~ fluorophenyl) -phenol and evaporated to yield 5 - (4-fluorophenyl) salicylic acid 4- (4-fluorophenyl 5. A process for the preparation of 0-acotyl-5- (4-fluoroplienyl) salicylic acid, denBeichnet that 4-benzoyloxy- "biphenyl with a compound that has a fluorosulfonyl radical 10988671918 179-3 U4 ism * provides'converts' with formation of 4-benzoyio:% y ~ 4 ⁱ "" fluorosulfottylMpiienyl _f that men öen fluorosulfcrayl radical of 4-benzoylo3qr-> 4 ^f -fluorsulfonyl "biphetiylB - with formation of 4-benzoyloxy-4 ' -fluoi »" bipIien3rl in one. Fluoro uiiiwanäelt UNAE that 5 ~ (4-fluorophenyl) »salicylic acid clay 0- * Acet3rl-5 ^i-C4 ~ fluorpli © nyl) to form - salicylsfe'.ure hyärolysiert _T car" boxyliert UNAE ßcetylißrt. 4 «YerMtidUBg der wherein Bs is a benzoyl radical. ~ 16 109886/1918 SAD ORIGINAL 5. Compound of the formula OBz wherein Bz daretellt a Benzoylreat · 6. Compound of Formula OZ wherein Z represents an acyl group. 7. Compound of Formula , - 17 109886/1918 1793UA 495 wherein Z represents an aoyl reet . β. Process »tr production of 4- (4-pluophenyl) -phenol, characterized in that 4-pfcenylphenol, in which the hydroxyl group is protected by an acyl group, reacts with a fluorosulfuyl radical to form 4-acyloxy-4'-fluorosulfonylbiphenyl, that the fluorosulfonyl residue of the A- acyloxy-4 ^l -fluorobulfonylbiplienyl is converted into a fluorine residue and the acyl residue is removed by solvolysis before or after the XJm wandlimg with formation of 4- (4-pluophenyl) -phenol. 9. A process for the preparation of 4- (4-fluorophenyl) -phenol, characterized in that 4-acyloxybiphenyl is reacted with a compound which is capable of releasing a fluorosulfonyl residue to form 4-acyloxy-4 * -fluorosulfonylbiphenyl that the fluorosulfonyl radical of 4-acyloxy-4- ^! - * Fluorsulfonylbiphenyls converted into a Fiuorrest and before or after the conversion the glycyl radical with formation of Fluoropkenyl) -p] ionol removed. - 19 - 109886/1918