DE2031226A1 - New biphenylenecarboxylic acids and their manufacturing processes - Google Patents

Description

ion VVa Or. ^ ⁹ '. _p , p.

June 24, 1997O

Case 13839

MERCK & CO., INC, Railway, New Jersey, -USA

New biphenylenecarsonic acids and their manufacturing processes.,

As part of the development of anti-inflammatory compounds ■ A great many drugs have been created in the past two decades. Most of them were steroids the pregnancy series with an oxygen function in the 11-position. Although these are very effective, they have the disadvantage that they cause many side effects. There is therefore a need on the market for compounds that are equally effective with a much simpler structure and fewer side effects.

Generally speaking, the invention relates to new, substituted ones Biphenylenecarboxylic acid compounds and processes for their preparation. These compounds are very useful as they are anti-inflammatory Have effectiveness and are effective in preventing and inhibiting the formation of edema and granuloma tissue. Except-

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BATH ORIQINAL

Some of them have useful antipyretic, analgesic, diuretic, antifibrinolytic, and hypojlycemic Effectiveness.

The invention relates in particular to substituted biphenylenecarboxylic acids, Esters, amides, anhydrides and, 'non-toxic, pharmaceutically acceptable salts thereof. Even more particularly, the invention relates to compounds of the general formula:

R hydroxy, amino, lower alkoxy (such as methoxy, ithoxy, 3utoxy, Pentoxy, etc.), lower alkylamino (methylamino, propylamino, Pentylamino, etc.), di-lower alkylamino (dimethylamino, Dibutylamino, propylpentylamino, etc ". Di-lower alkylamino-lower alkyl, Di-lower alkylamino lower alkoxy, Hydroxy lower alkoxy (3-hydroxypropoxy, 2-hydroxypropoxy, 4-hydroxybutoxy, etc.), polyhydroxy lower alkoxy (2,3-dihydroxypropoxy, 2,3,4,5,6-pentahydroxyhexyloxy, etc.), lower alkoxy-lower alkoxy (ethoxyethoxy), phenyl-lower alkoxy (benzyloxy, phenethoxy, etc.), Phenoxy, substituted phenoxy (such as medrigalkoxyphenoxy, Di-lower alkylaminophenoxy, lower alkanoylaminophenoxyj Oarboxyphenoxy, carbo-lower alkoxyphenoxy, etc.), hydrazino, Can mean morpholino, piperidino, pyrrolidino or hydroxy-lower alkylamino;

Hydrogen, acyl (preferably Medfigacyl, such as Forrcyl,

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Acetyl, propionyl, butyryl, etc.) »alkyl (preferably lower alkyl, _% such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.) or alkoxycartonyl (preferably lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycar- bon ' yl, etc.) can mean;

IU hydrogen, halogen (such as chlorine, bromine, fluorine or iodine, • preferably fluorine or chlorine), Haiοalkyl (preferably • halo-lower alkyl, such as chloromethyl, bromomethyl, trifluoromethyl, etc.), alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl) or alkoxy (preferably medrigalkoxy, such as methoxy, ethoxy, isopropoxy or butoxy) and

X hydrogen, alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), Hydroxy, alkoxy (preferably lower alkoxy such as methoxy, ithoxy, isopropoxy or butoxy, etc.), acyloxy (such as benzoyloxy, acetoxy or propionoxy), halogen (such as chlorine, bromine, fluorine or iodine, preferably fluorine or Chlorine), haloalkyl (preferably halo-lower alkyl, such as Chloromethyl, bromomethyl, trifluoromethyl, etc.), nitro, Amino, alkylamino (preferably low alkylamino, such as methylamino, propylamino, pentylamino, etc.), di-lower alkylamino (preferably dimethylamino, diethylamino, Propylpentylamino, etc.), acylamino (preferably lower acylamino, such as formylamino, acetylamino, propionylamino, Butyrylamino, etc.), mercapto, alkyl mercapto (preferably lower alkyl mercapto, such as methyl mercapto, Ethyl mercapto, etc.), alkylsulfinyl (preferably low, drigalkylsulfinyl, such as methylsulfinyl, ethylsulfinyl, Butylsulfinyl, -etc.), Alkylsulfonyl (preferably lower alkyl sulfonyl, such as methylsulfonyl, ethylsulfonyl, Butylsulfonyl, etc.), sulfonamido, sulfonylamido, alkyl

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103 · S "■ JJ Jl

13839 ■ "· .- .. ■

aminoalkyl (preferably lower alkyl, such as methylaminomethyl, ltliylamittoiiietliyl, etc.)> hydroxyalkyl (preferably hydroxy lower alkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.), alkoxyalkyl (preferably lower alkoxy-lower alkyl, such as methoxyme-. thyl, Ithoxyethyl, Ithoxyethyl, "Ithoxyethyl etc.) j ■ · · mercaptoalkyl (preferably meroaptonloweralkyl, such as marcaptomethyl, mercaptoethyl, etc.)? , etc), carboamyl, aryl (such as phenyl, iDolyl, salicyl), 'aralkyl (such as benzyl)., aryloxy or arylalkoxy, provided the ORp group is always in the ortho position to the -ö «R« $ 2? uppe »
0

Representative Yer "bonds of the present invention are §

3-Hydroxybiphenylen-2-cartonic acid ₉

7-chloro-3-Hydroxybiphenyls ~ 2 ° = carboxylic acid _i, 7-5 ¹ luor-Hydroxybiphenyls 3 ~ 2-ca.r'bonsäurep 7-methoxy-3-Hydroxybiphenyls-2-carboxylic acid 7-trifluoromethyl ~ _s 3 ~ hydro3ry'blphenylen-2-carboxylic acid ₉ 7-amino- _{3-hydroxybiphenylene-2-carboxylic acid 9} 7-dimethylamino-3-hydrox3rbiphenylene-2'-carboxylic acid ₀ 6-methylthio-3-hydroxybiphenylene-2-carboxylic acid < ₎ 6 -Methylsulfinyl-3-hydroxybiphenylene-2-carboxylic acid,

3,6-dihydroxybiphenylene-2-carboxylic acid

and the corresponding anhydrides ^ esters _} amides and salts derived therefrom. .

It was found that the yerbinctogens described above

■ · · - ■ * v , have anti-inflammatory efficacy «and" are effective for the prevention and inhibition of edema and gramoma tissue "". In addition, "" iuige. Has a © Tjrauottbare from them. anti-

- - -. --- 4 .--: "-.049882 / 2241 -

■ t tic

r i * I ι et (C.

X ₃₈₃₉ S. 2031226!

pyretic, analgesic, diuretic, antifibrinolytic and hypoglycemic effectiveness. They become purely for these purposes administered either in tablet or capsule form, the ■ optimal dosage of. the severity of the illness of the ■ to be treated Patient depends. The optimal amount that used also depends on the connection used. Oral dosages are used to control the disease states the preferred compound in the range of 50 mg to 10 g per Day, depending on the activity of the specific compound and the sensitivity of the patient's response.

The acidic compounds of the present invention can be prepared by the garboxylation of the appropriately substituted hydroxybiphenylene. This can be achieved by heating the appropriately substituted biphenylene under pressure with carbon dioxide gas. The product can then be isolated from the reaction mixture by known methods. The temperature at which the Carboxylierungsreäktion can take place, is in the range of 50 to 3OQ ⁰ C. The reaction can also examples. Held printing from atmospheric pressure to high pressure, but preferably at 200 ⁰ C .and about 112 kg / cm pressure (I6oo psi).

These acid compounds can also be obtained by oxidation of the known 2-iOrmyl-3-hydroxybiphenylene compounds by means of rings the appropriately substituted biphenylene compound or , by other known processes, such as by Pries's ester rearrangement, via the Grignard compound or via the Ii- ' thium compound, etc. are produced,

The compounds of the present invention in which R is such a group is that an ester is the end compound (i.e. R is alkoxy) are used according to esterification procedures using an esterifying agent containing the appropriate R group. For example, the carboxylic acid compounds of the present invention can be mixed with the appropriate Lower alkanol (preferably methanol) in the presence

. 009882/2241

INSPECTED

13839. - ^203-226

-a strong acid such as hydrochloric acid. Sulfuric acid, p -tpluenesulfoleic acid and the like are reacted to to produce the desired R-compound «The reaction can take place at room temperature for a longer period of time or at elevated temperatures «'

The compounds of the present invention in which R is a group such that an amide is the end compound (ie. R is amino) can be prepared by any suitable amidation reaction. For example, the carboxylic acid compound (preferably the methyl or ethyl ester) can be prepared with Ammonia, ammonium hydroxide or an amide compound are reacted at a suitable temperature (room temperature to reflux temperature). If it is desired, the amino group, one so-leads preferably the reaction with ammonia in a bomb at temperatures above 100 ⁰ C, to produce the desired R- (amino) compound "If the intention is an amide compound which is derived from an amino acid, as preferably follows the following sequence of reactions. The finished carboxylic acid compound is reacted with isobutyl chlorocarbonate to form the mixed anhydride. This connection in turn is made with; converted to the desired amino acid ester and then hydrolyzed to form the desired amide «

The salts of the final acid compounds of the present Invention! can by any known exchange method getting produced. For example, the carboxylic acid compound can be mixed with an inorganic base such as sodium hydroxide Potassium hydroxide, ammonium hydroxide, barium hydroxide and the like. ■■ ' same to be implemented. The anhydride of the present. Invention can be made by known methods.

The following examples are intended to illustrate the invention without to restrict them however.

001.882 / 2241

INSPECTED

13839,.

B is ν i el .1 * "

Production of l ~ hydroxybiphenylene-2-carboxylic acid

An intimately ground mixture of 1-hydroxybiphenylene (1.0 g) and anhydrous potassium carbonate (3.0 g) is at 20O ⁰ G) in a carbon dioxide atmosphere at a pressure of 105 to 141 kg / cm ² (1500 to 2000 psi) for 10 hours long carboxylated. The reaction mixture is added to water (100 cm) and washed with ether. The aqueous solution is filtered and acidified with 2.5N hydrochloric acid. The 1-hydroxybi- ■ '. Phenylene-2-carboxylic acid »Pp = 200.5 ⁰ C is isolated and dried

Alternatively, the lithium salt of the starting phenol can be prepared from one equivalent of idthium hydroxide and this salt carboxylated and worked up as described above to obtain the acid. .

If 2-hydroxybiphenylene is used instead of 1-hydroxybiphenylene in used in the above reaction, the corresponding carboxylic acid is obtained .. _ ·.

Example 2 -

Production of l-aoetoxybiOhenylene-2-carboxylic acid

To a mixture of 1-hydroxybiphenylene-2-carboxylic acid Acetic anhydride is added (0.008 M) in water-containing liquid (3 ml) (5.6 ml) and heat the resulting mixture for 1.5 hours long in the steam bath. During this time the mixture is kept free of moisture. After cooling down, give the mixture with stirring to 100 ml of water, 'one extracted the aqueous system with ether, washes the ether layers with In hydrochloric acid and water and trooknet over anhydrous Magnesium sulfate. When the filtered ether- ■ '' l-acetoxybiphenylene-2-carboxylic acid is obtained as a solution. Will

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ORlGlMALiNSPECTEO

Propionic anhydride or butyric anhydride distribute νότα acetic anhydride used in the oMgen case, then get mar, the corresponding acyloxy compounds _o

B e PJleJL3

Production of 3-methoxybiphenyllene -2-carbonic acid

To 2-acetyl »3 - methoxybiphenylen (O I ₉ g) in dioxane (6 ml) are added at 60 ⁰ C a solution of sodium hypochlorite (5 ml HPO from ₉ 0.5 g of sodium hydroxide and 0.35 g of Cl ₂ contains) and heats ■ the resulting mixture on the steam bath for one hour.

Another portion of hypochlorite solution is added and. he P hit the mixture for another 0.5 hour. The mixture it is concentrated under reduced pressure, water (15 ml) is added to the residue, the mixture is filtered, acidified and isolates the product, the 3-methoxybiphenylene ~ 2-carboxylic acid "

B is ρ ie 1 4

Manufacture of methyl 3- (2- carboxybiphenylenyl) carbonate

To a mixture of 3-hydroxybiphenylene-2-carboxylic acid (0.001 M), dimethylaniline (0.002 M) and benzene (2 ml) is added methyl chlorocarbonate (0.0011 M) over the course of one hour with constant shaking and cooling. As soon as the odor of the chlorocarbonate has disappeared or remains very weak, hydrochloric acid (in 10 ml) is added and the mixture is filtered. The funnel is filled with CHCl ,. washed out and the washing liquid is added to the benzene part, the organic layer is dried, filtered and the solvent is removed, giving methyl 3- (2- = carboxybiphenylenyl) carbonate. ₀ '.

B e i s ρ i e 1 5

Production "of 2 ~ ^{Hydrqxybiphenylen-3-carbonsäuremeth.ylef:} Ter

Add 3 ™ hydroxybiphenylene-2-carboxylic acid (0.01 M) to one

- 8th -

ORIQINAU

13839

Solution of anhydrous methanol (25 ml), the 200 mg anhydrous Contains hydrogen chloride. The resulting mixture is heated under gentle reflux for 3 hours, the solvent removed in vacuo, the residue between chloroform and dilute sodium bicarbonate solution and the layers are separated. The chloroform layer is dried over anhydrous sodium sulfate, filtered and evaporated, leaving 2-hydroxybiphenylene-3-carboxylic acid methyl ester remains behind. Instead of anhydrous hydrochloric acid, sulfuric acid, phosphoric acid, or any other strong acid can be used.

Will ethanol instead of methanol in the above reaction used, the corresponding ethyl ester is obtained.

Example 6 '■

Production of 3-hydroxybiphenylene-2-carboxylic acid-N, E ~ diethylaminoethyl ester __ ^ _____-_________________

To a mixture of 3-hydroxybiphenylene-2-carboxylic acid (0.001 M) and Ν, Ν-diethylethanolamine (0.001 M) in anhydrous tetrahydrofuran (10 ml) is a solution of Dicyclohexylcarbodiimide (0.001 M) in a minimum of the same solvent. The mixture is sealed and shaken well and left to stand overnight with intermittent shaking. The precipitated dicyclohexylurea is removed by filtration, the tetrahydrofuran is removed in vacuo, the residue between ether and hydrogen chloride acid distributed, the layers are separated, the aqueous layer is washed once with fresh ether, neutralized with saturated bicarbonate solution, extracted with chloroform, the chloroform solution dried, filtered, concentrated in vacuo and the residue evacuated with a high vacuum pump to remove traces of diethylamlnoätha-'tiol to remove, with 3-hydroxybiphenylene-2-carboxylic acid-Ν, Ν-diethylaminoethyl ester remains behind

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BATH ORIGINAL

B e -I ₁₁ S ₁₁ TD ₁₁₁ J el 7

of g-hydroxybiphenylene-2-carboxamide

Thionyl chloride (O ₅ 0011 M) Place! In benzene gradually to 3 ~ Hydroxybip \ henylen-> 2-carboxylic acid (O ₅₀₀₁ M) ϊώ benzene ⁽¹ IO ml) and boiling the resulting mixture was readily refluxed, "until the reaction The cooled solution is then gradually added to a vigorously stirred, ice-cold concentrated ammonium hydroxide solution (25 ml), the mixture is allowed to warm to room temperature, the benzene layer is removed under a stream of nitrogen and the precipitated 3-hydroxybiphenylene-2 ~ carboxamide is isolated and dried »

Are aqueous methyl = ·, dimethyl, ethyl or diethyl amines or piperidine, morpholine or diethylaminoethylamine are used instead of ammonia in the above reaction, one obtains the correspondingly substituted amides »

Is 3-Hydroxybiphenyls-2 = carbonsäuremethylester in methanolic or v / ässerigem ammonia overnight heated, the result is' turn 3 ™ Hydroxymethylbiphenylen = 2 = carboxamide _t>

B_e_ i g_Jg_i, si 8

Production of sodium 3-h "ydroxybiT3h.enylene-» 2-carboxylate

To a solution of sodium hydroxide (0.001 M) in water (15 ml) is added 3 = hydroxybiphenylene = 2 = carboxylic acid (O ₉ OOl M) in ethanol, the mixture is stirred and gently heated for 2 hours, the solvents are dissolved in a valcaum removed on a rotary evaporator, whereby sodium = 3-hydroxyb.iphenylene-2 = carboxylate is obtained »

If potassium hydroxide is used instead of sodium hydroxide in the above Example used, you get the corresponding Ealium-

- 10

ORIGINAL INSPECTED

13839
Example 9

Preparation of the diethylaminoethanol salt of 3-Hydroxybiphe nylen-2-carboxylic acid . . _________ "___>,

Add Ν, ϊί-diethylethanolamine (O ₁ OOl M) in 5 ml of ether with stirring to a solution of 3-hydroxy-2-biphenylenecar "bon acid in ether, the resulting mixture is stirred for one hour, · the salt isolated or the ether removed in vacuo to give the 'diethylaminoethanol salt of 3 »-hydroxy'biphenylene-2-carboxylic acid.

Are piperidine, morpholine, triethylamine, N-methylpiperidine, E-methylmorpholine, tributylamine or other organic amines used instead of diethylethanolamine in the above example, in this way the corresponding salts are obtained.

Example 10 A ■ '■ ■

Preparation of 2-hydroxy-3-methoxybiphenylene

To 2-acetyl-3-methoxybiphenylene (0.001 M) in warm glacial acetic acid (4 ml) is gradually added 40 % peracetic acid (2.5 ml) and the mixture is stirred over power at room temperature. Then water is added, the mixture is extracted with ether, the ether solution is dried, concentrated and the residue is chromatographed on a silica gel column using an ether / petroleum ether system ( ^vol / vol 0 to 10 # ether) as the eluent to remove 2 Acetoxy-3-methoxybiphenylene. .

De_ · Ester is made by gently heating its watery metianolic Solution and hydrolyzed by 'sodium bicarbonate solution. The methanol is removed in vacuo, the organic material taken up in ether, dried, the ether removed in vacuo and 2-hydroxy-3-methoxybiphenylene is obtained.

Are 2-acetyl-3-methylbiphenylene and 2-acetyl- ;, jjilorbip'he · -

" ^{1: L} ■ -""009882/2241

BAlD LOCATION (SlMAi

nylene (from Example 11) instead of the 3 ~ methoxy compound im The example used above gives you the corresponding 3-methyl- and 3-chloro-2-hydroxybiphenyleneo

Example 10 B

Manufacture of 2-hydroxy-3- methoxybiphenylene-1-carbo-: i5 acid

If 2-hydroxy-3-methoxybiphenylene, 2 = hydroxy-3-ynethylbiphe nylene or 2-chloro-3-hydroxybiphenylene instead of hydroxydiphenyls!] used in Example 1, one obtains accordingly 2-hydroxy-3- = methoxybiphenylene-1-carboxylic acid, 2-Hydroxy »3-methylbiphenylene = l» carboxylic acid and 2 = hydroxy-3-chlorobiphenylene-l-carboxylic acid "

Example HA

of 2- acetoxy ~ 3 ~ trifluoromethylbiphenylene

A shaking vessel lined with stainless steel is charged with 3-acetoxybiphenylene-2-carboxylic acid (0 ₉ 002 M) under a nitrogen atmosphere, the system is cooled to dry ice temperatures and sulfur tetrafluoride (approximately OpOL M) is condensed into the tube in "the mixture is enteric heated at 100 ⁰ C for 8 hours, cooled, depressurized, the surückbleibende material is taken up in ether, filtered, and concentrated to άβΏ residue and ehromatographiert at one-Sililcagel-IColonne to give an ether / -Betroläther -System (^ ^ol / lol 0 to 10 fo ether) used as eluent = medium, and you get 2-acetoxy-3- = trifluoromethyl-

If this material is left with an aqueous methanol = · solution with sodium dioa, rboBat slightly reflux and extra, Μ · 32? 'Ϋ́ ίπη, Ώ anselilieieiiä. the mixture with ether is preserved

ORIGINAL INSPECTED

Example 11 B

Production of 2-hydroxy-3-trifluoromethylbiphenylene-1-carboric acid . ; ;

2-Hydroxy-3-trifluoromethyrbiphenylene (0.001 M) is used as in Example 1 carboxylated. The residue from the reaction is slowly added to excess ice-cold 2.5N hydrochloric acid, the precipitate is isolated, partitioned between ether and aqueous sodium bicarbonate solution, the aqueous Layer is filtered off and acidified, the 2-hydroxy-3-trifluoromethylbiphenylene-1-carboxylic acid isolated and dried.

Example 12 A

Production of 2-acetyl ~ 5,6-dimethoxybiphenylene

Becomes 2,7-dimethoxybiphenylene (0.002 M) with acetyl chloride (0.002 M) reacted under the conditions of Example .11 and the mixture worked up in the same way, one obtains 2-acetyl-3,6-dimethoxybiphenylene.

B e i s ρ i e 1 12 B

Production of 5 <6-Diinethoxybiphenylen-2-Carboxylic acid

If the product from Example 12 A is treated with hypochlorite solution as in Treated Example 3, 3,6-dimethoxybiphenylene-2-carboxylic acid is obtained. ■:

Example 12 0

Production of 3,6-dihydroxybiphenylene ~ 2-carboxylic acid .

A mixture of 3,6-dimethoxybiphenylene-2-carboxylic acid (0.001 M) in CH ₂ Cl ₂ (10 ml) is added to boron tribromide (0.001 M) in the same solvent at the same temperature at dry ice temperatures Warm the mixture to room temperature. One carefully adds water, then A'ther and

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separates, the organic layer, dries and concentrates. Recrystallization from benzene / petroleum ether gives 3,6-dihydroxybiphenylene-2-carboxylic acid.

Example 13

Production of 2-Hydrox y-6 - ath.ylbiph.e nvlen

- "^^ * ™ - ^ - ' Mi.t ilii 11 ii ιιι i» iiι aBii iiiiii iiiiiiιιιιι in

A mixture of 6-acetyl-2-hydroxybiphenylene (I ₉ O g) (via bicarbonate hydrolysis of the acetoxy compound), potassium hydroxide (2 g) and 64% hydrasine hydrate (1 ml) in diethylene glycol (10 ml) is gently refluxed for 1 hour cooked, the water and hydrazine boiling from _s the remaining mixture 3 hours, held at about 180 ⁰ G long, to the mixture is cooled, water is added in excess, performs a steam distillation, the vessel residue acidified with 2 ₉ 5 N hydrochloric acid on and extracted with ether. The ether extracts are dried, concentrated - and the residues are chromatographed on a silica gel column, whereby a. Ether / petroleum ether system ( ^Vol / Yol 0 to 10 $> ether) used as eluent, 2-hydroxy-6-ethylbiphenylene is obtained «

Example 14

Production of 2- hydroxy-6- meth "oxybiphenylene

If 2-acetyl-6-methoxybiphenylene is used instead of the -3-methoxy isomer of Example 10 A is used and hydrolyzed in the same way, 2-hydroxy-6-methoxybiphenylene "

Example 15

Production of 6-acetyl-2-hydroxybiphenylene

A mixture of ^ -acetyl-ö-methoxybiphenylene (0 _s 2 .g) and pyridine hydrochloride (5 g) is placed under a nitrogen atmosphere in an oil bath of 230 ⁰ G and left in it for 5 minutes.

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M / 13339

sen, immediately removed from the bath, cooled and ex--. ' traced. The Ätherex; extracts are washed with water, dried and chromatographed on a silica gel column, using an ether / petroleum ether system as eluent (/ VoI O to 60 io ether) to give 6-acetyl Hydroxybiphenyls 2-obtained. .

Example 16 A -

Production of 6-acetyl-2-nitrobiphenylene

A mixture of 2-nitrobiphenylene (0.4 g), acetyl chloride (0.3 g) and aluminum chloride (1 g.) In nitrobenzene (50 ml) is stirred for 60 hours at room temperature. Hydrochloric acid (2.5N) is added, the nitrobenzene is removed by steam distillation and the remaining particulate matter is isolated, dried and chromatographed on a silica gel column using an ether / petroleum ether system ( ^voj - / Vo1 0 to 10 io ether) as Eluent to give 6-acetyl-2-nitrobiphenylene.

If 2-chlorobiphenylene is used instead of 2-methylbiphenylene in the above Example used, you get the corresponding one 2-acetyl ~ 3-chlorobiphenylene.

• Example 16 B '

Production of 2-hydroxy-6- nitrobiphenylene

If 6-acetyl-2-nitrobiphenylene from Example 16 A aas wave of 3-methoxy ~ 2-acetylbiphenylene used in Example 10 A, 2-hydroxy-6-nitrobiphenylene is obtained in this way.

■ Eg 1 17 A

¹ "'". . Ii ι mill ■■ «.-. ■ "

Preparation of 2-Benzoyl-6-chlorobipheny leB

A mixture of 2-Benzoylbiphenyletj O) ₉ To ü) j JodmoBoelilorid (lg) and acetic acid (30 ml) is hot luiolrfeem

BAD ORIOINAL

Heated for 6 hours, cooled, water in excess and sodium hydrogen sulfite are added and the mixture is extracted with ether. The ether mixture is washed with aqueous sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, filtered and the contents of the ether solution are chromatographed on a silica gel column, using an ether / petroleum ether system ( ^Yol / vol 0 to 20 % ether) used as eluent _{9 to} obtain 2-benzoyl-6-chlorobiphenylene.

Example 17 B -. Iphenylen · _ Preparation of 6 ~ ~ 2 ~ Ghlor hydroxyb

If 2-benzoyl ~ 6- = chlorobiphenylene instead of 3-methoxy-2-acetylbiphenylene Used in Example 10 A, 6-chlorine = is obtained 2-hydroxybiphenylene.

Example 18 A.

Production of 6 ° Metho xyJbiphenylen - 2-carboxylic acid

If 2 = acetyl = -6- = meth03 [ybiphenylene is used instead of 2 = acetyl ~ 3-meth · = osy] jij) henylene in Example 5 , 6 = methoxy- = is obtained

B eis -ο .1 e 1

18 B -

6 ° aostosgybiphenylene ° 2 ° carboxylic acid

I2Ö, 6 "= MetliOsylDipheYiylen-2-carbonsäure instead of 3 _S 6-Dimeth

acid used in Example 12 0 and the g acetylated as in Example 2 _s so

ι S

5NSPEGTED

B e i s ρ, i e 1 18 O

Production of 2-acetoxy-6-trifluoromethylbix) henylene

Will use 6-acetoxybiphenylene-2-carboxylic acid instead of the 3-isomer , used in Example 11 A, 2-acetoxy-6-trifluorme.thylbiphenylen is obtained, which is then hydrolyzed to the corresponding 2-hydroxy compound, as in the same. Example is shown. . .

Example 19 A

Preparation of 2-aoetyl-6-methoxyiphen: ylene

2-Acetyl-6-hydroxybiphenylene (0.001 M) in 2N sodium hydroxide solution (5 ml) is treated with dimethyl sulfate in small portions until the thin-layer chromatogram shows no remaining phenol. The mixture is neutralized with dilute sulfuric acid, extracted with ether, then washed and dried (magnesium sulfate) and the extracts are chromatographed on silica gel, using an ether / petroleum ether system ( ^vol / vol 0 to 15 & ether ) used as eluant -and one obtains ^ -acetylro-methoxybiphenylene. · '. ·

Example 19 B ^:

Preparation: of the oxime of 2-aoetal ~ 6-methoxybiphenylene

A mixture of S-acetyl-δ-methoxybiphenylene (lg), hydroxylamine hydrochloride (1 g) and pyridine (6 ml) is heated on a steam bath for 4 hours under a nitrogen atmosphere. The cooled mixture is added to ice water (100 ml) with stirring, the mixture is stirred until the mixture has reached room temperature, filtered, the residue is taken up in excess chloroform, washed, dried, concentrated and the 0xim _f which is obtained as it is is used in Example 30,.

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009882 / 22AV

BAD ORJQj _NAL

Be i a ρ ie 1 19 Q

Manufacture of _._ 2 ~ ^ jnijLO ~ 6-me thoxyhiphenyl en

Mau. Adds the Qxim from Example 19 B (0.9 g) to polyphosphoric acid (30 g) and keeps the mixture on the steam bath for 30 minutes, with the exclusion of puity. After cooling, the viacous mixture is added to water, the aqueous mixture is extracted with ither / ethyl acetate (IsI) _9, washed and dried, and the organic layer is concentrated to dryness. Chromatography of the residue on a silica gel column using an ether / petroleum ether system (% / volume 10 to 100 <fo ether) as the eluent leads "to 2-acetamido-6-methoxybiphenylene ₀

Heat the above amide in water (50 ml) / more concentrated Hydrochloric acid (50 ml) / ethanol, (10 cm) under light Reflux on the steam bath and then extract the

titral material with chloroform ₉ so one obtains 2-amino-6-aietlioxybiph'enylen when neutralizing the aqueous "rope light with dumb latriumhydrosydlösung".

3_e_i spie 1 ^ 193Ρ

Hsrgtellungwg 2 ~ Met hoxy-6 henylen -phenylbip

A mixture of 2-amino = "6 = methoxybiphenjlen (O OOl ₅ M) ₉ 'l-Amyliaitrit (0.0012 M) and benzene (10 ml) is slowly erhitatjbis ice © violent" Eeaktion using _s' then is -2 hours laiag! © lelit @ ® Ethiol flow boiled »One removes the solvent and over @ Qhüsaig © s Beagsns in a vacuum othromatographed on a silica gel ~ lQl © TO @ s, whereby ma ^ © in ether / -. '. P © ts? Olätlier "=" Syst © 5! B © 1s llmienangsmittil used and preserved

18 -

BATH ORIGINAL

Example 19 E.

Production of 2-hydroxy-6-phenylbiphenylene

If 2-methoxy-6-phenylbiphenylene is used instead of 2-J oxybiphenylene in Example 15, 2-hydroxy-6-phenylbiphenylene is obtained. * ■

Example 1 20 A

Production of 2-Ch.lor - 6-meroaptobiphen.ylen

Small amounts of sodium hydride (0.006 M of a 50% mineral oil dispersion) are added to a cold solution of g-chloro-δ-hydroxybiphenylene (0.006 M) in 4.5 ml of dimethylformamide ⁰ O cooled and dimethylthiocarbamoyl chloride (0.008 M) added all at once. After the initial reaction has subsided, the mixture is slowly ^{heated to 80 °} C., the cooled mixture is poured into 20 ml of potassium hydroxide (1 %) solution. The aqueous mixture is saturated with sodium chloride and extracted with benzene, the benzene is mixed well with water Gewä- * see, dried over magnesium sulfate, filtered and concentrated in .Vakimm, whereby the crude Ihiσcarbamat is obtained.

The thiocarbamate is then heated under a nitrogen atmosphere for 20 minutes at 25O ⁰ C, 'the crude migrated connection is cooled in methanol, made to that an excess of 10% -Natriiamhydroxydlösiuig (.entlüftet) errsliält and the resulting mixture is tmtes? Stickstoffatniöephäre heated until the Dtensehxehtolarömatogme no zuriiGlsgefolisfee = nes S-biphenylenyl-thiocarbeiaat more aageigt _s MaB MISiIt dl © Mi «= · - research, acidified with 2.5N Chlorwasserst off acid at ₉ sztraMer-t with benzene, dry the Bengolextrakt® ₉ filtered unchecked . Chromatography of the material obtained from the minor oil solution on a silica gel EoloBne mates Te ^ wGadiiEg allies Ither / Petroläther-Systsms ( ^iw "/ Yol O tie" 40 fS ltlier) as an eluent leads to 2-Όίΐ1θ3? ~ Β-® © ϊοε .ρΐοο1ρ1ι © Ώ3Γΐβϊ = ''

'τη ii y Ό "j" j L · (I ώ (L -j S

BATH

Example 20B

Manufacture of 2 "01llpr76" met hJl · tMp_ ^ b ipheΏyleΏ

If 2-chloro-6-mereaptobiphenylene is used instead of 2-acetyl-6 = .hydroxybiphenylene in Example 19A and the deaerated sodium hydroxide solution ₉ is used to prevent extensive disulfide formation, 2-Clalor-6-methylyl- thiobiphenylene.

Example 20 G

'Production of 2-0yano ~ 6 --- methyl thiobiphenylene

Deaerate a mixture of 2-chloro-6-methylthiobiphenylen (0.002 M), copper cyanide X = (0.003 M) and N-methylpyrrolidone, ■ covered with a Stiokstoffatmosphäre and slowly heated -to 180 ° C for 3 hours keeps _s "at this temperature, let cool ^ distributed between benzene and 7% hydrochloric acid ₉ containing iron-III = chloride (O ₉ 004 M), separates the benzene layer, dried, concentrated and chromatographed the residue of a silica gel = Column using an ether / petroleum ether system ( ^Vo Vvol 0 to 40 fo ether) as eluent and receives 2 ~ cyano = 6 = methylthiobiphenyleno '

IiBB-Mischirog from the above Gyan ο connection (O ₉ OOl M) ₉ . Vinegar = sweet (5 ml) vcää. 20% oleilorwasearic acid (5 ml) is heated on siii'ää Dam'ofbafi 8 stimdea long, the cooled mixture v; isd tofä'a good old Ithsr ^ tsshiert ₉ di @ _ Itherschioht is ab-

ung © arteahed ₉ the was · = utid 'dl © S-Me

BATH ORIGINAL

Example 20 -E

Production of 5-hydroxy-6-methylthiobiphenylene - 2 - carboxylic acid

An aqueous solution of copper (II) sulfate (0.001 M) is added with stirring to a solution of sodium hydroxide (0.002 M) and 6-methyltMo "bipheuyl-n-2-carbolic acid (0.001 M) in water (5 ml). the salt formed is after one hour, collected, washed with water and dried. the rearrangement is performed by -suspendiert the salt in dry nitrobenzene (4 ml), the mixture in an oil bath at 23O ⁰ C single \ emerged that The mixture is refluxed under a nitrogen atmosphere and stirred for 30 minutes. After cooling, an excess of ether is added, the mixture is filtered, the residue is digested in concentrated ammonium hydroxide solution, filtered, the filtrate is acidified, extracted with ither and combined the ether extracts with the original ether filtrate. The ether solution is washed with dilute hydrochloric acid and water and then extracted with sodium carbonate solution. Acidification gives a mixture of the starting acid and the 3-hydroxy -6-methylthiobiphenylene-2-carboxylic acid, which is purified by chromatography of its methyl ester or by extraction with ferric chloride solution.

Example 20 F,. Production of 3-hydroxy->6-mercayto'bi-Dfieay leTi-27 carbQnsäiire

If S-hydroxy-o-methylthiiobiphanylene-S-carboxylic acid is used instead of 3,6-di-ethoxybiphenylene-2-approx. used and the resulting material? ä ~ axQh Oliroraato of Methylesters (made naofc ei '*' ^{T <1} f ear s to B, game 5) to give receives mail Ji "" _It xijb 7-v'v ^ oriAp- 'Nylen-carboneäure 2. ; ■ '.' ■ ·.

- 21. -

00988271141

BAD ORfGiNAL

B'eisDJ el 21 '

Preparation of 3-hydroxy-6-methylsulphylbiplienylylene "-2-carbon"

acid _. _

To a cold Lösimg of 3-hydroxy-6-metliyltliio "biph.enyle'n-2-carboxylic acid ₍₉ OOl O M) in methanol / acetone is added a solution of Natriummetaperjjodat (O OOl ₉ M) in a minimum of V / ater \ xnä TiüiTt the mixture at or below tree temperature until the 'precipitate the Natriumjoäats is completed. the iodate is durGÜi- filtration removed the solvents are removed in vacuo and the residue is dissolved in chloroform and aufgeuoniieii Ä'ther, WSM "combines the organic solvent and concentrates "The concentration is achieved by chromatography of the methyl ester or recrystallization of the acid _s whereby 3-hydroxy = 6-ethylsjulfiny-lbiphen3rlen = 2- = carboxylic acid is obtained"

F or board 22

3 = ^ droxy-6 = methylsulfouyl "biplieTiylen-2-carbQii" -

is Boisjälsl 21 awai Equivalent Hatriumme tap er iodat

Etgixng carried out at 50 to 6O ⁰ G IIathjlsulfonylbiphynylen- = 2 = carboxylic acid

mä ^ iE ¹ O, Äi © Uasetgixng at 50 to 6O ⁰ G carried out ■ “so

1 related © t ₀ . -ic · δ "οΐ © τθ;? © Θ ^ © Ώα. siAiti ^ BidSitdB Ssilejiaäures ₀

sauteli © ₉ s © erhlit © ε® fii ©

BAD ORtQINAL

B e i s p. i e 1 24

Production of 3 »6-'diacetoxybiphenylene-2-carboxylic acid

Used 3,6-dihydroxybiphenylene-2-carboxylic acid (0.008 M) instead of 1-hydroxybiphenylene-2-carboxylic acid used in Example 2 and another equivalent of both pyridine and Added acetic anhydride, 3,6-diacetoxybiphenylene-2-carboxylic acid is obtained.

Example 25 ,

Production of 7-0yano-3-hydroxybiphenylene-2-carboxylic acid

If you use 7-chloro-3-hydroxybiphenylene-2-carboxylic acid instead of 2-chloro- "6-methylthiobiphenylene in Example 20 C, so he ■ one holds 7-cyano-3-hydroxybiphenylene-2-carboxylic acid "

At s ό ie 1 26 \

Production of 5-hydroxy-2 ₁ 6-biphenylenedicarboxylic acid

Will use 7-cyano-3-hydroxybiphenylene-2-carboxylic acid instead of 2-cyano-6-methylthiobiphenylene used in Example 20D, "see above 3-hydroxy-2,7-biphenylenedicarboxylic acid is obtained.

Example 27 Preparation of 5-hydroxy-2, y-ai

If 3-Hydroxybiphenylen-2,7-dicarbollsä ^^ re instead of tob 3-Hydro-dro xybiphenylen-2-carboxylic acid in Example 5 -used, so ®2? Mlt one 3-hydroxy-2,7-dioarbomethoxybiphenylene. ■

Example 28

Preparation of 6 ~ benzyloxy- 5-i:> ydro ::; A mixture of 3 »6-3) iliydi'v ^c 'T;' bipjic _J '

(.0.001 K), anhydrous EeII'iuicjÄl "

. ί

BATH ORIGINAL

(5 ml) is stirred under the protection of a calcium chloride drying tube for 0.5 hours at room temperature. Benzyl chloride (0.002 M) is then added and the mixture is refluxed for 4 hours. A solution of potassium hydroxide (0.004 M) in water (5 ml) is added and the mixture is heated
On the steam bath for 1 hour, cool, filtered and acidified. The isolated 6-benzyloxy ~ 3-hydroxybiphenylene-2-carboxylic acid is purified by recrystallization or chromatography of its methyl ester.

. Example 29

Preparation of 6-benzyl-2-methoxy-phenylenes

If 6-benzoyl-2-methoxybiphenylene is used instead of 6-acetyl-2-hydroxybiphenylene in Example 13, the result is
6-benzyl-2-methoxybiphenylene.

If 6-benzyl-2-methoxybiphenylene is heated with pyridine hydrochloride according to the procedure of Example 15, 6-benzyl-2-hydroxybiphenylene is obtained.

Example 30A

. Production of 6-acetyl-3-meth.yrbiph.enyl en-2-carbon acid emethyl ester "^""^""""^^.""""^,".",""^.", ^ "^.

"If 2-acetyl-3-methylbiphenylene is treated with sodium hypochlorite as in Example 3, the acid formed is esterified as in Example 5 and the methyl 3-methylbiphenylene-2-carboxylate obtained is acetylated as in Example 16A
ö-Acetyl ^ -methylbiphenylen ^ -carboxylic acid methyl ester in the
Chromatography of the resulting mixture on a silica gel column, using an ether / petroleum ether system (/ VoI 0 to 50 # ether) as the eluent.

009882 / 22A1

BATH ORIGINAL

13839

Example 3OB Preparation of 2-aoetyl-7-methylbiphenylene

A mixture of ö-acetyl ^ -methylbiphenylen ^ -carbOnsäureme- " ethyl ester (0.005 M), potassium hydroxide (0.0055 M) in a minimum of water and 1,2-dimethoxyethane is stirred and several

Slightly heated for hours, the mixture is diluted with water, extracted twice with ether, separates the layers, filtered the aqueous layer and acidified, whereby one 6-Ethyl-3-methylbiphenylene-2-carboxylic acid is obtained.

The above acid is used in refluxing quinoline with a trace of the copper (II) salt of the acid heated (produced from the salt of the acid and copper (IIe) sulfate in aqueous solution), the quinoline is removed in vacuo, the residue is taken up in ether and washed with sodium carbonate solution ι water and In hydrochloric acid, dry over magnesium sulfate, filtered and concentrated to a residue. Chromatography on a silica gel column using an ether / petroleum ether system (/ VoI 0 to 40 $ Ither) as the eluent leads to 2-acetyl-7-methylbiphenylene.

B e i s ρ i e 1 30 C

Production of 2-acetozy-7-methylbiphenylene

If 2-acetyl-6-methylbiph "enylene is used instead of 2-acetyl-3-meth-, oxybiphenylene is used in Example 10A and the hydrolysis is omitted, 2-acetoxy-7-methylbiphenylene is obtained.

Example 30 D ■. '■' .: '

Production of 2-acetoxy-7-bromomethylbiphenylene

♦.

A mixture of 2-acetoxy-7-methylbiphenylene (0.005 M), ' N-bromosuccinimide (0.005 M), carbon tetrachloride (50 ml) and Dibenzoyl peroxide (a trace) becomes lightly on for 2 hours Refluxed, the succinimide removed by filtering off,

- 25 - 009882/2241

BATH ORIGINAL

the Piltrat concentrated in vacuo to obtain crude 2-acetoxy-7-brommethylbiphenylen, the _t as it is, E 30 is used in Example.

Example 3OE

Production of 2- hydroxy- 7-methoxymethylbiphenylene

The above bromomethyl compound (0.001 M) is gradually under Stir. Added to a solution of sodium methylate (0.002 M) in methanol (10 ml). After the addition, the mixture becomes a Boiled gently under reflux for one hour, adding 30 ml v / ater add 2N hydrochloric acid until mixture is slightly acidic, the aqueous mixture is extracted well with Ither and the ether-soluble material is chromatographed on a Silica gel column, where 2 = hydroxy-7-methoxy-methylbiphe ~ nylen receives ».

Potassium methyl mercaptide is used instead of sodium methylate , the analogous 7-methylthiomethyl compound is obtained.

Example 31

Production of 2-gluoro- 6-hydroxybiphenylene

If 2-hydroxy-6-methoxybiphenylene is reacted with sulfur tetrafluoride under the conditions of Example 13, 2-fluorine-6-methoxybiphenylene _{0 is obtained}

If this compound is demethylated by the process of Example 15, 2-fluorine-6-hydroxybiphenylene is obtained.

Example 32

Manufacture; _i of biphenylenecarboxylic acids

If 6-benzyl-2-hydroxybiphenylene, 7-methpxymethyl-2-hydrox ^ biphenylene, 7-methylthiomethyl- = 2-hydroxybiphenylene and S-FI ., Or

-26- 009882/2241

BATH ORIGINAL

game 1 used, the corresponding biphenylenecarboxylic acids are obtained. '■

Be is ρ ie 1 33 A

Production of 7-amino-3-hydroxybiphenylene-2-carboxylic acid

A mixture of 3-hydroxy-7-nitrobiphenylene-2-carboxylic acid (0.003 M), ethanol (15 ml), concentrated hydrochloric acid (30 ml) and tin (II) chloride (7.5 g) is refluxed for one hour boiled, neutralized with sodium bicarbonate solution, concentrated to dryness in vacuo and the dry residue is extracted in a Soxhlett extractor with chloroform. Evaporation of the chloroform solution gives crude 7-amino-3-hydroxybiphenylene-2-carboxylic acid, which is purified by chromatography of the methyl ester, prepared according to the method of Example 5, using a silica gel column and a methanol / methylene chloride system ( ^Vol / Vol 0 to 20 io methanol) as. Eluent used.

Example 33 B. .

Preparation of 7-acetamido-3-a-cetoxybiphenylene-2-carboxylic acid

Becomes 7-amino-3-hydroxybiphenylene-2-carboxylic acid with acetic anhydride and pyridine reacted as in Example 24, 7-acetamido-3-acetoxybiphenylene-2-carboxylic acid is obtained. · ■ -. "■

Example 34

Production of ^ -dimethylamino ^ -hydroxybiphenylene ^ -carbon acid _{methyl ester;} ' .

A mixture of 7-amino-3-hydroxybiphenylene-2-carboxylic acid methyl ester (0.001 M) and dimethyl sulfate (0.002 M) is placed in an oil bath at 60 ^° C., slowly ^{heated to 135 °} C., held there for 5 hours, cooled, with stirring added to dilute hydrochloric acid, the mixture is filtered and neutralized with sodium bicarbonate solution and extracted well with chloroform

" ²⁷ " 009882/2241

. and, chromatographed the contents of the chloroform solution on a Silica gel column using a methanol / methylene chloride system (/ VoI $ 0 to $ 20. Methanol) as eluent.-and receives 7-I) imethylamino-3-hydroxybiphenylene-2-carboxylic acid methyl ester.

Example 55 A

Production of 2-hydroxy-7-hydroxy methyl bi-phenylene

A " ¹ mixture of 2-acetoxy-7-bromomethylbiphenylene (0.001 M) ₉ silver acetate (0.0011 M) and acetic acid (3 ml) is gently heated for 3 hours, filtered, the filtrate is added to dilute sodium hydroxide solution ( Excess), the mixture is heated, filtered, acidified, the mixture is extracted well with ether and the ether solution is chromatographed on a silica gel column using an ether / petroleum ether system (0 to 50 % ether by volume) as the eluent, whereby 2 -hydroxy-7- receives hydroxymethylbiphenylen. ¹ If the B rommethylverbindung in an aqueous Uatriumhydroxydlösung heated and purified as above, one obtains directly the hydroxymethyl compound.

Used potassium thiol acetate instead of silver acetate in the above Reaction used, 2-hydroxy-7-mercaptomethylbiphenylene is obtained.

Example 35 B

Preparation of 3-hydr _oxy-l 6-hydroxymethylbiphenylen-2-carboxylic acid and B-hydroxy ^ ^ -carboxylic acid -mercaptomethylbiphenylen

Of 2-hydroxy-7-hydroxymethylbi ^<phenyls "and 2-hydroxy-7-mercaptomethylbiphenylen instead of 2-Hydroxybiphenyls in Example 1, one obtains the corresponding carboxylic acids. '. *

- 28 - 009882/2241

• · «· t r ■

Example 56 A '■ ·

Preparation of 2-dimethylaminomethyl-7-hydroxybiphenylene

2-Acetoxy-7-bromomethylbiphenylene (0.002'M) is heated in methanolic Dimethylamine, removes the solvents in vacuo, the residue is taken up in 2.5ώ hydrochloric acid, filtered » acidifies and isolates the 2-dimethylaminomethyl-7-hydroxybiphenylene formed.

If ammonia is used instead of the dimethylamine in the If the above reaction is used, the corresponding 6-aminomethyl-2-hydroxybiphenylene is obtained. ■

Example 56 B.

Production of ö-dimethylaminomethyl ^ -hydroxybiphenylen ^ - carboxylic acid and 6 ~ aminomethyl-3-hydroxybiphenylene-2-carboxylic acid

Become ^ -Dimethylaminomethyl ^ -hydroxybiphenylene and '2-aminomethyl-7-hydroxybiphenylene used instead of 2-hydroxybiphenylene in Example 1, the corresponding carboxylic acids are obtained . ■■■■ · ■

Example 57

Production of 6-carbamyl ~ 5-hydroxybiphenylene-2-carboxylic acid

One heats a mixture of ^ -
carboxylic acid (0.002 M) and polyphosphoric acid (5 ml) for 2 hours on a steam bath, »cools, adds them to ice water, extracts the aqueous mixture well with chloroform, dries the ChloroforiBSChicht and removes the solvent in vacuo, whereby 7-Qarbamyl -2-hydroxybiphenylene-3-carboxylic acid is obtained.

Be is ρ ie 1 58 A , '·

Production of 2-methoxy-6 _< -phenoxybiphen.vlen

A mixture of the potassium salt of 2-hydroxy-6-jöethoxybi- ·

.- 29 - 009882/2241

* "■ '■■" · ■■ ■' .. ■■ ·

/ ^; , ORlGlNAtINSPECTEO

13839

phenylene (0.005 M), bromobenzene (0.006 M) and copper bronze

• · (0.01 g] is ^{heated for 5 hours at 210 °} C. The mixture

is cooled, extracted well with Ither and chloroform and the organic extracts are chromatographed on a silica gel column • in which (0 / VoI to 50% ether) used an ether / petroleum ether system as the eluant gives 2-methoxy-6 -phenoxy "biphenylet."

• Example 38 B

Production of 2-hydroxy-6-ph.enoxybi-phen.ylen

Becomes 2-methoxy-6-phenoxybiphenylene with pyridine hydrochloride P heated as in Example 15, 2-hydroxy-6-phenoxybiphenylene is obtained.

Example 39 A

Manufacture of 2 _T 3-dimethoxy- 6-hydroxybi-phe'aylene ■

If 2,3-dimethoxybiphenylene is acetylated as in Example 16A and the 2,3-dimethoxy-6 = aetylbiphenylene formed is oxidized as in Example 101, 2 _{s of} 3-dimethoxy-6-hydroxybiphenylene are obtained. · ^;

Example 39 B.

Production of 6,7-dimethoxy-3-hydroxybiphenylene ~ 2-carboxylic acid and 7-phenoxy-3-hydroxybiphenylene-2 »carbo-acid

Are 2,3-dimethoxy-6-hydroxybiphenylene and 2-hydroxy-6-phenoxybiphenylene carboxylated using the procedure of Example 1, the corresponding o-hydroxycarboxylic acids are obtained.

809882/2241

ORIGINAL INSPECTED

Claims (1)

June 24, 1970 Case 13839 MERCK & CO., INC.
Rahway, New Jersey, USA P A ϊ E N T A N S P R Ü C HE Compounds of the general formula: (1-4) in the . R hydroxy, amino, lower alkoxy, lower alkylamino, di-lower. alkylamino, di-lower alkylamino-lower alkyl, di-lower alkylamino-lower alkoxy, Hydroxy lower alkoxy, polyhydroxy lower alkoxy, lower alkoxy lower alkoxy, phenyl, lower alkoxy oxy, phenoxy, substituted phenoxy, hydrazino, morpholino, piperidino, pyrrolidino and hydroxy-lower alkylamino means; Rp is hydrogen, acyl, lower alkyl and alkoxycarbonyl; R, hydrogen, halogen, halo-lower alkyl, lower alkyl, cyclo-lower alkyl and alkoxy means and X is hydrogen, lower alkyl, hydroxy, lower alkoxy, acyloxy, - 31 - 009882/2241 ORIGINAL INSPECTED 13839 Halogen, halo-lower alkyl, nitro, amino, lower alkylamino, Di-lower alkylamino, acylamino, mercapto, lower alkyl mercapto, Lower alkylsulfinyl, Medrigalkylsulfonyl, SuIfοώ-amido, Sulfonylamido, amino lower alkyl, lower alkylamino lower alkyl, Hydroxy lower alkyl, alkoxy lower alkyl ,. Mercapton lower alkyl, Lower alkyl mercapto lower alkyl, cyano, carboxy, carboalkoxy, orarbamoyl, aryl, aralkyl, aryloxy and Aralkoxy means, ■,. provided the ORp-G group is always in the o-position to the -C-R group is located. O Compounds of the general formula: in the X is hydrogen, medrigalkoxy, halogen, halo-lower alkyl or is di-lower alkylamino; R is hydroxy or amino; Rp is hydrogen or _{t is} medrigalkanoyl and R is hydrogen or lower alkyl and their pharmaceutically acceptable, non-toxic addition salts, provided the ORg group is always in o-Stelluttg eur -OR-öruppe. - 32 - 009882/22 At ORlGWAi INSPECTED. \ > ■ 13839 3. 4. 5. 6 »7. 8. 9. 7-Clilor-3-liydroxy "bipheiiylen-2-carboxylic acid, 7-fluoro-3-hydroxybiphylene-2-carb "onic acid. 7-methoxy-3-hydroxybiphene-2-carboxylic acid. 7-Trifluorometh.yl-3-hydroxybiphenylTi ~ 2-carbovic acid. 7-Amino-3-hydroxybiph.enylene-2-carboxylic acid. 7-I ⁾ iπletl·lylamiΏO-3-llydroxybiplleΏyleΏ-2-carboΏic acid. 10. 6-Methyltb, io-3-hydroxybip] aenylene-2-carboxylic acid. 11. ^v ö-iietliylsulfinylrJ-liydroxybipheTayleii-S-oarboxylic acid. 12. 6-Methylsulfonyl-3-hydroxybiplienylTi-2-carbonic acid. 13. 3,6-Diliydroxybiplienyl3-2-carboxylic acid. 14. Process for the preparation of compounds of the general a formula: in which R ₂ , Rv and X have the meaning b defined in claim 1 and the OR ₂ group is always in the -o position to the -COOH group, characterized in that · that a compound . '. ,,, .. : ■. - 33 - 009882/2241 13839 the formula: in which X and R, have the meaning given above, with Xohlend.ioxyd is reacted at elevated temperatures and pressures. 15. The method according to claim 14, characterized in that the reaction takes place in the presence of an alkali metal carbonate. 16. The method according to claim 14, characterized in that the reaction at a temperature of 50 to 30O ⁰ C is carried out. 17. Compounds of the general formula; ■ (1-2) 1 in which X is halogen, provided that the hydroxyl group is always in the o-position to the carboxy group. 18. Process for the preparation of compounds of the general Formula: GOOH - 34 - 009882Λ2241 ORlGiNAL INSPECTED 13839 in which X denotes halogen, provided that the hydroxyl group is always in the o-position to the carboxy group, characterized in that a compound of the formula: (1-2) is reacted with carbon dioxide at elevated temperatures and pressures. '.- - 35 - 009882/2241 BAD ORlGMNAL