DE2162038A1 - Process for the production of synthetic alkanoic acids and their derivatives - Google Patents

Description

WILLIAMH, RORER, INC .. Fort Washington, Pa., USA.

William H '.. Rorer, Inc., Port Washington (Pennsylvania, USA)

1. Additional patent to the main patent t -Nr .. ^{P 2}

(Law no. 6621/71)

^22nd 275.1

Process for the production of synthetic alkanoic acids and their derivatives.

Extensive research has been carried out so far to develop drugs that have powerful anti-inflammatory and analgesic effects at the same time with antipyretic effects ". Above all the field of steroids has been explored, but have been

3.12.71 / B / gl

209839/1254

also developed compounds which are not steroid in character. These are among others Alkanoic acids, which differ from compounds with biphenyl, stilbene, indole, naphthalene and various heterocyclic Derive rings. Although some of these compounds are extremely effective, so have On the other hand, they have shown the disadvantage that various side effects occur, or that they are only for certain diseases are effective.

It has now been found, surprisingly, that in the presence of a hydroxyl group, a halogen atom o ^ he a ^ hiogruppe or a derivative thereof in the α-, β- or 7-position of the side chain Substituted phenylalkanoic acid molecule, pharmacological properties exist in the molecule that are suitable for the Healing and Preventing Inflammatory Conditions suitable.

It was also found that "the invenient Compounds obtainable according to the invention are used for the treatment of inflammation and for the healing of arthritic diseases, which are based on inflammation, suitable.

The α, β or 7-hydroxy, halo and thiophenyl alkanoic acids obtainable according to the invention and their derivatives represent new compounds.

209839/125

The compounds obtainable according to the invention have valuable analgesic and antipyretic properties and are therefore suitable for the treatment of Pain and fever.

It also created an entirely new class of anti-inflammatory, analgesic, and antipyretic pharmaceutical preparations found which contain an oc-, ß- or 7-hydroxy-, -halo- or -thiophenylalkanoic acid or contain a derivative thereof as an active ingredient.

The present invention also relates to a convenient method for synthesizing them Links.

With the new, according to the invention available ' Compounds, plural a phenylalkanoic acid group or contain a derivative thereof to which a hydroxyl group, a halogen atom, a mercapto group or a thio derivative adheres to the oc-, ß- or 7-position the phenyl ring carry further substituents.

The following description is based on the following numbering system:

/> C C C C-

VI 1 ■. » γ ß ο

209839 / 12B4

The compounds obtainable according to the invention can be represented by the following general formula;

(CH) _m -COZ

where R is alkyl, cycloalkyl, cycloalkenyl, aryloxy, arylthio, Arylamino, aroyi, heteryl, aryl or substituted aryl, in which the substituent has the same meaning as 7 has means; Y hydrogen, alkyl, halogen ', nitro, amino, acylamino, mono- and di-lower-alkylamino, Mercapto, acylthio, lower alkylthio, lower alkylsulfinyl ,. Lower alkylsulfonyl, hydroxyl, lower alkoxy, acyloxy, Is halo-lower-alkyl, cyano or acetyl; η Ο to represents 2; m represents 0 to 2; η + m = 0 to 2 is; R, Rg and R represent hydrogen or lower alkyl; X halogen, hydroxy, lower alkoxy, lower acyloxy, aroyloxy, carb-lower alkoxy, carbamyloxy, lower alkylcarbamyloxy, Di-lower-alkylcarbamyloxy, lower alkanesulfonyloxy, Benzenesulfonyloxy, toluenesulfonyloxy, carboxyacyloxy, carboxyaroyloxy, mercapto, lower alkylthio, acylthio, aroylthio, sulfo, sulfino, lower alkyl

209839/1254

sulfinyl, lower alkylsulfonyl, thioacylthio, thiosulfq, thioeyanato, amidinothio, carbamylthio, lower alkyl-.carbamylthio, di-lower-alkylcarbamylthio, lower alkoxythiocarbonylthio, lower alkoxycarbonylthio, di-lower alkylthiocarbamylthio-lower or caroxyaro-lower alkylthiocarbamylthio-lower or caroxyaro-lower alkylthiocarbamylthiothio or caroxyaro-lower alkylthiocarbamylthio-lower or caroxyaro-lower alkylthiocarbamylthio-lower or carboxyaro-lower alkylthiocarbamylthio-lower or caroxyaro-lower-alkylthiocarbamylthio-lower or caroxyaro-lower-alkylthiocarbamylthio-lower or carboxyaro-lower alkylthiocarbamylthio-lower or carboxyaro-lower-alkylthiocarbamylthio-lower or caryl-lower alkylthiocarbamylthio-lower or Z is hydrogen, -OH, lower alkoxy, Ar-lower-alkoxy, -NHp, lower-alkylamino, di-lower-alkylamino, cyclo-lower-alkylamino, -NA (where A is a lower-alkylideriyl or hetero-lower-alkylidenyl radical; -NHOH, -NHNH ₂ or -OM (where M is an alkali metal, alkaline earth or aluminum salt or an ammonium salt), with the proviso that in those cases in which η = ■ 0 and m = 0, the symbol X has a meaning other than a hydroxyl -, lower alkoxy or lower alkylsulfonyl radical or halogen atom; however, in those cases in which R _{ß represents} hydrogen and R represents a cycloalkyl radical, the symbol X can represent a halogen atom or lower alkylsulfonyl; that furthermore, provided η = 0 and m = 1 and R are lower alkyl and R are cycloalkyl, the symbol X is not a hydroxyl group; and finally, provided η = 1 and m = 1 or η = 0 and m - 2 and R _a , R _ß and R are hydrogen, the symbol X represents a group other than the hydroxyl group, provided n R one

209839/1254

Means phenyl radical.

The applies to the R substituents. p-position as preferred position. The o-position is also preferred when R is an arylamino group. ·

The compounds obtainable according to the invention contain at least one asymmetric carbon atom in the alkanoic acid side chain. Therefore let see the above-mentioned compounds of formula I as race ™ get mixed mixtures of the dextrorotatory (+) and levorotatory (-) isomers. Under the present connection Both the right-handed and left-handed isomers, as well as the d £ mixtures, thus fall of that. ■.

The compounds obtainable according to the invention with a particularly good "effect as anti-inflammatory, analgesic and antipyretic agents correspond to the following formulas II to VII.

209839/1254

.-COZ

II

III

C-CH-COZ

IV

I.

—CH- C-COZ

CH-C-CH-COZ

^R ß ^R a

VI

G-CH-CH-COZ

VII

209839/1254

The compounds with preferred properties correspond to the following formulas VIII to X:

X "- C - CCH) _1n - COZ

Rß ^R a

VIII

wherein Alk is an alkyl radical having 3 to 7 carbon atoms means,

CH) _n -C - (CH) _1n -COZ

te R _n

IX

where X represents the numbers 0 to 2,

(CH) ₁₁ -C

209839 / 125A

Those compounds whose properties are even more preferred are those according to the formulas

VIII to X, where Y is a hydrogen atom or a halogen atom, X is the number and R, R _ß and R are hydrogen atoms

mean.

Most preferred compounds are those in which X is in the α or β position.

In the accompanying description:

"Alkyl" means a lower hydrocarbon group An alkyl radical containing 1 to about 7 carbon atoms, this group being a straight-chain or can be branched group; ·

"Alkenyl" means an unsaturated or partially unsaturated hydrocarbon group of 2 to about 7 carbon atoms, which are straight or branched can be;

. "Cycloalkyl" has a hydrocarbon ring up to 7 carbon atoms;

"Cycloalkenyl" means a partially unsaturated hydrocarbon ring of up to about 7 carbon atoms;

"Aryl" any benzenoid or non-benzoid aromatic group, preferably a phenyl group;

209839/125 4

"Acyl" means any organic radical that can be different from an organic acid by eliminating its Hydroxyl group, such as formyl, acetyl, propionyl, 3-carboxy-2-propenoyl ,. Camphoryl, benzoyl or toluoyl, or a heterocyclic group such as pyridinoyl, piperidinoyl, thenoyl, etc .;

"Aroyl" benzoyl, lower alkyl benzoyl, e.g. Toluoyl, or halobenzoyl, such as p-chlorobenzoyl, etc .;

"Alkoxy" means a lower alkoxy group of 1 to about 6 carbon atoms which is straight-chain or can be branched;

"Lower alkylidenyl" means a lower alkylidenyl hydrocarbon group of 2 to about 6 carbon atoms and

"Hetero-lower alkylidenyl" means a lower alkylidenyl hydrocarbon group, having about 2 to 5 carbon atoms which are one or more hetero atoms in the chain such as an oxygen, nitrogen or sulfur atom such as piperidinyl, morpholinyl, etc.

Preferred alkali metals or alkaline earth metals are sodium, potassium, calcium and magnesium.

The term "ammonium salts" refers to the cation which is formed when ammonia or forming an organic amine with the carboxyl group

209839/1254

of ammonium salts of the structure shown in the formula above. Form the ammonium salts with (1) lower alkyl amines, such as methylamine, Diethylamine, triethylamine; (2) hydroxy-lower alkylamines, such as β-hydroxyethylamine; (3) heterocyclic amines such as 2-aminopyridine, piperazine, Piperidine; (4) aralkylamines such as oc-methylbenzylamine, Phenethylamine; (5) cycloalkylamines, e.g. Cyclohexylamine; (6) Alkaloids such as quinine, cinchonidine, cinchonine, ephedrine.

"Heteroyl" or "heterocyclic rings" are those with 5 to 7 atoms, some of which are saturated can be saturated or unsaturated and one or more heteroatoms, such as nitrogen, sulfur and / or oxygen atoms.

Hetery rings are e.g. thienyl, furyl, pyridyl, Pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyranyl, 2H-pyrrolyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, morpholinyl.

The new compounds can be made using the following general methods:

2 0 98 39/1254

Acetic acids (η + m = 0}

By condensing a substituted benzene with an alkyl or aralkyloxalyl chloride in the presence a substituted phenyl glyoxylate is obtained from anhydrous aluminum chloride. This connection can be then react with an Alkylgrxgnard reagent, whereby the α-alkyl-substituted phenylglyxolate is obtained. Man This compound can also be substituted by catalytic hydrogenation with platinum oxide or by means of sodium borohydride Reduce phenyl glycolates. It is preferable to start from a substituted benzene compound, where as product · the corresponding in α-position a-alkylated phenyl glycolate or a di- or polysubstituted phenyl glycolate is obtained.

I.

CICCOOR "

AlCl.

OH

CHCOOR "

^ OQ \ CCOOR "

R _a MgX

IH COOR "

209839/125

Propionic acids (n -fm = 1)

α-position

The Claisen condensation of a substituted Benzaldehyde with an active acid ester (preferably a lower alkyl or benzyl ester) in the presence of a metal alkoxide yields a β-substituted phenyl acrylate. The aldehyde can also be a Perkin reaction by means of acetic anhydride and an acetic acid salt or a Knoevenagel condensation using of malonic acid and ammonia in an amine base, with a substituted, ß-substituted Phenylacrylic acid is obtained. By the addition of chlorine and Bromine on the double bond gives an α, β-dihalo * - propionic acid or an ester. By treating the dihalide with 3 moles of piperidine, a complex compound is obtained which by acid hydrolysis forms a ß-substituted pheny! pyruvic acid or an ester, whereupon the desired lactic acid is obtained from it by hydrogenation in the presence of platinum oxide as a catalyst or the desired ester is obtained. This hydrogenation can also be carried out by selective reduction with sodium borohydride be carried out when catalytic hydrogenation is impossible because of the presence of a sensitive group is.

209839/12 5 4

CH ₂ (COOH) ₂ ZHH ₃ CHO or (CH ₃ COOR ¹ YNaOR

IC ₆ H ₁₁ NH ₂

-CH ₂ -C-COOH (R ") <

or NaBH

OH > -CH-

—CH ₂ -CH-COOHCR ")

CH = CHCOOH (R ")

CIp or Br,

(Br) (Br) Cl Cl

CH-CH-COOH (R ")

where R "denotes a lower alkyl or benzyl radical.

The β-substituted phenylpyruvate can also be reacted with an equivalent of a Grignard reagent, an α-substituted lactic acid ester which can be hydrolyzed to acid.

209839/12

H2-C-CO0R "

OH

-CH ₂ -C-COOR "

OH

> r-CH ₂ -C -COOH

R ¹ α

wherein R 'is lower alkyl.

A substituted benzaldehyde can also be used with hippuric acid in the presence of sodium acetate and acetic anhydride according to the method of Cavalline and Massarani according to Italian patent specification No. 611.973 (1960): [Chem. Abstracts 55 * 19868g] are condensed. This condensation gives a 2-phenyl-5-oxazolone, which is a substituted benzal residue in the 4-position having. This compound gives ß-substituted pheny! Pyruvic acid by basic hydrolysis. These the latter can be reduced to this or in the above-mentioned

209839/1254

- l6 -

treated with a Grignard reagent, whereby the corresponding lactic acid is obtained.

.HO

CH ₉ -NH

¹ I HOCO COC ₆ H ₅

CH = C N

■ I Il

alkali

> -CH ₂ -C-COOH

ß-position

A Reformatsky reaction of a substituted benzaldehyde with an α-haloacetate in the presence of a metallic catalyst, such as zinc powder or magnesium, provides a ß-hydroxypropionic acid ester, which has a phenyl radical in the β-position. This implementation takes place in an anhydrous, non-polar medium, such as e.g. dry benzene, whereby iodine can be added to get the reaction going.

209839/125 4

The reaction can also be carried out using an α-A-alkyl-α-haloacetate, wherein one an a-alkyl-ß-hydroxypropionate, in its ß-Starte a phenyl radical adheres, receives. If the reaction takes place with a substituted phenyl alkyl ketone and an α-haloacetate, so one obtains a ß-alkyl-ß-hydroxypropionate, which has a phenyl radical in the ß-position. The hydrolysis with formation of the acid takes place in a conventional manner.

BrCHCOOR "

HO

Zn

Y ^ß

^ BrCH ₂ COOR "

2 0 9 8 3 9/1254

CHCHCOOR "

alcKOH

^ d

-CHCHCOOH

HCH ₂ COOR "

γ ^Λ *

alcKOH

HCH ₂ COOH

Y ^R ß

The one having a phenyl radical in the ß-position α-Alkyl-ß-hydroxypropionic acid can in an analogous manner can be prepared by using an appropriate substituted alkylmalonyl chloride.

0 R

I! l ^a

Cl-C-CH-

COOR "

AlCl.

H-CH-COOH

alcKOH

-CH-COOR "

H ₂ (Pt)

, or NaBH ^

'H-CH-COQR "R

The ß-alkyl-ß-hydroxypropion-

acids can be derived from the ß-ketopropionic acids and a Prepare alkyl grignard reagent.

20 98 39/125

Butyric acids (n + m = 2)

g position

By Claisen condensation of a substituted benzaldehyde with an active acid ester, preferably a lower alkyl or benzyl ester, in the presence of a metal alkoxide, a β-acrylic acid ester is obtained. The aldehyde can also be a Perkin reaction with acetic anhydride and an acetic acid salt or a Knoevenagel condensation using of malonic acid and ammonia in an amine base to form a substituted β-acrylic acid. The propionic acid is obtained by hydrogenating the double bond in the presence of a heterogeneous catalyst or the corresponding ester. By converting the propionic acid into the acid halide and then through Rosenmund reduction in the presence of a catalyst leads to propionaldehyde. This the latter can in turn be treated with cyanohydrin

2098 3 9 / 125A

, whereby the propionaldehyde cyanohydrin is obtained, which is then hydrolyzed to α-hydroxybutyric acid. The ester or the amide can also be used in the same manner get v / earth.

CH ₂ (COOH) ₂

CH ₃ COQR ¹¹ ■ NaOR "

= CHC00H

CH = CHCOOR ¹¹

CH ₂ CH ₂ COOR "

SOoCl

209839/1254

W ₂ CH ₂ COOH SO ₂ Cl

CH ₂ CH ₂ COCl

H ₂ / Pd-BaS0 ₄

CH2CH2CHO

"NaCM MaHSO,

CH ₂ CH ₂ CHCN.

Η + / Ή ₂ 0

^ ₂ CHgCHCQOH

209839/12 5 4

2162033

The a-alkyl-a-hydroxy-7-phenyl-

Butyric acid can be obtained by reacting a β-substituted phenylpropionic acid ester with an alkyl Grignard reagent to obtain a phenyl-3-butanone substituted in the 1-position, which is obtained by reaction with sodium cyanide in the presence of sodium bisulfite
supplies phenyl-jü-butanoncyanohydrin substituted in the 1-position. The desired one is obtained by hydrolysis
Acid, ester or amide.

₂ CH ₂ C00R " R _a MgI

CH ₂ CH ₂ CR ₀

NaCN NaHSO-

OH

H ₂ CH ₂ C-COOH H ₂ O / HCl

/ - \ f

\ Q) CH ₂ CH ₂ C-CH

The p-alkyl-a-hydroxy-7-phenylbutyric acids
can be obtained according to the information given above for the preparation of the a-hydroxy-7-phenylbutter ^: acid compounds, if an α-alkyl malonic acid is used with anvien-

209839/125

BATH

tion of the Knoevenagel condensation, whereby one oc-alkyl acrylic acid substituted in the ß-position is obtained.

CH (COO H) ₂

NH ₃

^R ~~ rO V-CH ₂ CHCOCl _c SO ₂ CI

KaCN

2CHÖ

CH = C-COOH R ₃

H ₂

CH ₂ CHCOOH Rβ

. GH

CH ₂ CHCHCN

, H ₂ OZHCl ^{v L} GH

¹ * "" ~ / q \ CH ₂ CHCHCOOh

2Ö9S39 / 125A

The 7-alkyl-a-hydroxy-7-phenylbutyric acids can according to the above for the preparation of the α-hydroxy-7-phenylbutyric acids given information can be obtained. A substituted one is used as the starting material Phenyl alkyl ketone, whereupon a Reformatsky reaction is carried out in the presence of zinc with an α-haloacetate. The ß-hydroxy-ß-alkyl-ß-phenylk thus obtained Propionate is then dehydrated with acid at an elevated temperature, a ß-alkyl-ß-phenylacrylic acid receives. This can also be done with the help of a Doebner modification of the Perkin reaction with a Substituted phenyl alkyl ketone and malonic acid happen in the presence of pyridine, one being a ß-alkyl-ßphenylacryläure receives. The latter can be implemented in the way mentioned above, whereby one the desired 7-alkyl-α-hydroxy-7-phenylbutyric acid is obtained.

209839 / 125.4

BATH ORIGINAL

00 HaICHoCOOR "

1 ² ->

R .. 2n

JH '

i,

-CH ₂ COOR "

CH ₂ CCOOH) ₂ acid

HCH ₂ COOH H ₂

SO ₀ CI

= CHC00H

H ₂ ZPd-BaSO ₄

OH

-CHCh ₂ CHCOOh, ^ I ¹ I! "

R ₇

CHCHpCHO

ι L

OH

HCN

OH

-CHCH ₂ CHCM

209839/1254

BATH ORIGINAL

A combination of the above-mentioned reactions leads to di- and trisubstitution in the side chain.

ß-position . ■

Substituted phenylmagnesium bromides are obtained by reacting a substituted bromobenzene under Grignard conditions. Condensing these compounds with 2, 3-Epoxypropylchlorid, one arrives at l-chloro-3-phenylpropan-2-ols. By reacting the chlorohydrin thus obtained with an aqueous potassium cyanide solution, the corresponding 1-cyano-3-phenylpropan-2-olj is obtained, which by hydrolysis and esterification yields a 7-phenylß-hydroxybutyrate. Acid hydrolysis of this ester leads to 7-phenyl-ß-hydroxybutyric acids.

/; ii

MgBr

CH ₂

0 9839 / ί; β

BATH ORIGINAL

H ₂ CHCH ₂ CM

M- ⁷

R ¹¹ OH-H ₂ O HCl

KCN

H ₂ O

H ₂ CHCH ₂ COOR ¹¹

NaOH _N

OH > CHCH

CH ₂ CHCH ₂ Cl

If you want one to be made

α-Alkyl-ß-hydroxy-Y-phen ^ lbutyric acid, then l-methyl-ci ^ -epoxypropyl chloride is used. The corresponding ß-Alkylyerblndung is obtained when methyl 2-2 verivendet as Äusgangsmateriäl _i 3-epoxypropylchlorid while! Connection obtained by using 2,3-Epoxybutylchlorid as starting material the 7-alky.

209839/125 4

HgBr

M ^

<Γθ V-

Y-A

Cl-CH-CH-CF

CH ₂

YA

Cl-CH ₂ -C-CH ₂

Cl-CH ₂ -CH-CH-R ₁

H-C-CH-COOH ^

Μα

Using the corresponding Epoxyalky1 -chlorids one arrives at the corresponding di- or trialkyl-substituted compounds.

7 position

The Friedel-Crafts reaction of a substituted benzene with an alkyl succinyl chloride or succinic anhydride provides a 7-phenyl-7-ketobutyric acid ester or the corresponding acid. By Reduction of the 7-keto group in the presence of a metallic one

2098 39/1254

1162038

Catalyst or in the presence of sodium borohydride, a 7-phenyl-7-hydroxybutyric acid ester is obtained, which can then be converted into the corresponding acid by hydrolysis.

Cl-C-CH ₂ -CH ₂ -COOR "

AlCl.

OH

1-CH ₂ CH ₂ COOH aicKOH

AlCl

-CH ₂ CH ₂ COOR "

H ₂ (Pt) ^ά or

NaBH ₄

OH

-CH-CH ₂ CH ₂ COOR "

C-CH ₉ CHoCOOH

or NaBH ₄

OH H ^ -CH ₂ CH ₂ COOH

2 09839/125 />

The a-alkyl-7-phenyl-7-hydroxybutyric acids or

.the ß-alkyl-7-phenyl-7-hydroxybutyric acids, their phenyl radical is substituted, can be according to analogous V / eise

using the corresponding substituted alkyl succinyl chlorides or succinic anhydrides.

CICCh ₂ CHCOOR "AlCIo

CCHoCHCOOR "

L

FU (Pt) or NaBH.

OH

"ViQ \ CHCh ₂ CHCOOR"

CICCHCh ₉ COOR "

CCHCH ₂ COOR "

H ₂ (Pt) or NaBH ₄

OH

HCHCH ₂ COOR "

209Ö3 9/125

BATH ORIGINAL

The 7-alkyl-7-hydroxybutyric _i which bear a substituent in the 7-position can be prepared from 7-ketobutyric and produce eine'm Alkylgrignardreagenz.

CCH ₂ CH ₂ COOR " - RyNGX \ V / CCH ₂ CH ₂ COOR"

The hydroxyalkanoic acids can also be converted into an aldehyde with the aid of a Rosenmund reaction in itself usually be reduced. The acid halide is formed first according to the above information, whereupon the same thing can be said catalytically reduced in the presence of a palladium catalyst.

209839/1254

BATH ORIGINAL

OH

OH

rv, R _Q R
τ pa

OH

(CH) _n -C- (CH) _m -CH0

RR _ß R _n
γ β α

By reacting a substituted phenylalkanoic acid ester with a nitrogenous base such as ammonia, a lower alkylamine, a lower dialkylamine, a cycloalkylamine with a lower alkyl radical, one containing a nitrogen atom Hetero-compound, such as pyridine, morpholine, piperazine, Hydroxylamine and hydrazine, leads to the corresponding amide, to the corresponding hydroxamic acid or to the corresponding hydrazide.

209839/4254

OH

V '

(CH) _m -C00R "-

R.

where R "denotes a lower alkyl radical.

20983

NH-,. R.

_3 y

NH ₂ R "R

HN (R ") ₂ R

HlTB. _x R

HoNOH R

9/1254

H ₂ NNH ₂

(CH) _n -C- (CH) _1n -CONH ₂

Rß

CH) _n -C- (CH) _1n -CONHR "

_n -C- (CH) _1n

CH) _n C (C ^R

■ (CH) _n -C- (CH) _m -CON '(R ") ₂

^R 3 ^R a

OH

(CH) _n -C- (CH) _1n -CON ^

Y Rv ^R ß ^R o

OH I

^R 8 ^R a

OH I

(CH) _n -C- (CH) _m -COf! HOH

111

Ry Rß Κα

(CH) _n -C- (CH) ₁₁₁ -CONHNH ₂ Rβ R _o

The alkanoic acid esters can be hydrolyzed to form the corresponding acids. By reacting a hydroxyalkanoate or a hydroxyalkanoic acid with an acid chloride X ¹ Cl or an acid anhydride X ¹ OX ¹ in the presence of a tertiary amine such as pyridine, picoline or quinoline, an acyl derivative of the hydroxyalkanoate is formed. Examples of X'Cl and X'OX 'are acetyl chloride, acetic anhydride, propionyl chloride, butyryl chloride, succinic anhydride, maleic anhydride, phthalic anhydride, benzotrichloride, benzoic anhydride, chlorocarbonic acid benzyl ester, benzyl sulfonylamyl chloride, benzyl sulfonyl amyl chloride, benzene sulfonyl chloride, methyl chlorocarbonyl ethyl chloride, benzylcarbulfonyl chloride, benzylcarbulfonyl chloride, butyryl chloride, succinic anhydride, butyryl chloride, butyryl chloride.

209839/1254

alckOH

IH

OH (CH) _n -C- (CH) _m -C00R "

CfH) _n -C- (CH) _1n -COOH

X ¹ Cl

or X ¹ OX ¹

β α

X ¹ Cl

or

X ¹ OX ¹

209839/12

2182038

CH

- (CH) ₀₁ -COOH (R ")

^R Y

It

ClCAr R

(ArC) ₂ O 0

CT COR " R (R ¹¹ OC) ₂ O 0

XCONH ₂ R

Lr

ρ α

where R "is lower
Alkyl radical and ar den
Phenyl or a substituted phenyl radical
mean.

Il

CICNR ¹¹ R " R

C lSO ₂ R " R

ClSO ₉ Ar R.

OCOAr

OCOOR "<CH) _n -C- (CH) _m -COOH (R")

OCONH ₂

- (CH) _n -C- (CH) _1n -COOH (R ") Rp R _a

OCON (R ")

CH) _n -C- (QH) _1n -COOH (R ¹¹ )

20983 9 /) 25A ^Y 0 Ra

OSO ₂ R "

'CH) _n -C- (CH) _1n -COOH (R ") Ry Rg R _a

OSO ₂ Ar CH) _n -C- (CH) _1n -COOH (R ¹ ')

OH

(CH) _n -C- (CH) _1n COOH (R ") Κ ^RR

H-

ClOR "R

(R ¹¹ C) ₂ O
0

OCOR "{CH) _n -C- (CH) _m -C00H (R")

OCOCH ₂ CH ₂ COOh CH) _n -C- (CH) _1n -COOH (R ¹¹ )

OCOCH = CHCOOh ■

CH) _n -C- (CH) _m -C00H (R ")

OCOC ₆ H ₄ COOH P) _n -C- (CH) _n -COOH (R ") - R ^

where R "denotes a lower alkyl radical,

209839/1254

By converting a substituted phenyl • hydroxyalkanoate with a suitable halogenating agent, such as bromine, chlorine, etc., one arrives at the corresponding substituted phenyl haloalkanoates. By hydrolysis with formation of acid and subsequent treatment with a thionyl halide, one arrives at to haloalkanoic acid halides. If such haloalkanoic acid halides are treated with an alcohol, e.g. Methanol ,. Ethanol, etc., one arrives at the corresponding haloalkanoates.

2098 39/12 54

Hal

CH) _n -C- (CH) _m -C00R "

\ ί

Hal

CHL-C- (CH) _1n -COOH

ⁿ U

wherein Hal represents a fluorine, chlorine, bromine or iodine atom. ·

If a substituted hydroxyalkanoate is used with a phosphorus trihalide, a phosphorus pentahalide, a phosphorus oxyhalide, a SUlfury! halide,

209839/1254

a thionyl halide or a Schviefel halide, the corresponding substituted haloalkanoates are obtained.

OH Hal

CH) _n -C- (CH) ₀₁ -COOR ">""Χξ)> - (CH) _n C- (CH) _1n -COOR"

Marg

where R "represents a lower alkyl radical and Hal represents a chlorine, bromine or iodine atom.

By reacting a sulfonate derivative with a metal halide, preferably an alkali metal halide the corresponding halogen compounds are obtained.

OSO ₂ R (Ar) shark

1 MHV R / TTX I.

(f ^H V ^C - ( ^CH V ^COZ

wherein Z is hydrogen, -OH, lower alkoxy, Ar-lower alkoxy,. -NH ₂ , lower alkylamino, di-lower alkylamino, cyclo-lower alkylamino, -NA (where A is a lower alkylidenyl or hetero-lower alkylidenyl radical), -NHOH, -NHNHp or -OM (where M is an alkali metal, alkaline earth metal or aluminum salt or an ammonium salt ), represents.

2098 3 9/125 4

- ill -

The corresponding haloalkanoic acids can be obtained by treating the ester with acetic acid., which contains the corresponding hydrogen halide is heated.

Hal

(CH) -C- (CH) _m -COOR "

HOAc R HHAI

^R ß ^R a

al

^R ß ^R o

where R "represents a lower alkyl radical.

The substituted fluorine compounds can also be prepared from the corresponding iodine, bromine or chlorine compounds are obtained when they are ⁰ to 200 C, but preferably at 80 ⁰ C in acetonitrile, is reacted with potassium fluoride at about 130th

Br -C- (CH) _m —COOR "

ct

CH) _n -C- (CH) ₁₁₁ -COOR "

^R ß Ra

209839/12

The acid addition salts can be prepared by the action of an equivalent amount of a suitable base to form the substituted haloalkanoic acid. Suitable bases are, for example, alkali metal alcoholates, such as e.g. sodium methylate, etc., also alkali metal and alkaline earth metal hydroxides and the corresponding carbonates, Bicarbonates, etc., such as sodium hydroxide, potassium

ψ hydroxyd, calcium hydroxide, potassium carbonate, sodium bicarbonate, magnesium bicarbonate etc. You can also use the. Prepare aluminum salts of the new compounds by treating the corresponding sodium salt with a suitable aluminum complex, such as, for example, aluminum hydroxychloride hexahydrate, etc. The ammonium salts can be obtained by reaction with the corresponding amines, such as methylamine, diethylamine, β-hydroxyethylamine, piperazine, piperidine, α-methylbenzylamine, cyclohexylamine, triethylamine, phenylethylamine, etc.

Shark. _k shark

(CH) _n -C- (CH) _m -COOH -> \ ©) (CH) _n -C- (CH) _n IC ⁰ ^

OS)> () _n ( T * r ^R ß ^R

The implementation of a substituted haloalkanoic acid ester with a nitrogenous base such as e.g. ammonia, a lower alkylamine, a di-lower-

209839/1254

alkylamine, cyclo-lower alkylamine, with one nitrogen atom containing heterocyclic compound, such as piperidine, morpholine or piperazine, provides the corresponding Amide. The alkanoic acid ester gives the corresponding hydroxamic acid with hydroxylamine, while with hydrazine the corresponding hydrazide is formed.

Quay

:-( CH) _n , -COOR "- ^R o

Shark

(CH) _n -

:-( CH) _m -coz

where Z is -NH, lower alkylamino, di-lower alkylamino, cyclo-lower alkylamino, -NB (where B is a lower alkyl- ~ .denyl or hetero-lower alkylidenyl radical), -NHOH or -IxFHNH ₂ .

209839/1254

where R "represents a lower alkyl radical.

NH-:

NH ₂ R "R

HN (R ") _? R

H ₂ NOH

200839/1254

i ₂ NNH ₂

. Hal (CH) _n -O- (CH) _{111 -CGNH 2}

Shark

(CH) _n -C- (CH) ₀₁ -CONHR ¹¹

Hal

R _R R

R ο

Shark

_n C- (CH) J _n

^R ß ^R a

Shark

(CH) _n -G- (CH) ₁₁₁ -CONHNH ₂

The haloalkanoamides, the alkanohydroxamic acids and the alkanohydrazides can be selected from the corresponding Hydroxyalkanoamides with thionyl halides obtained by the method of I. A. Smith, Chem. Reports 71B: 634 (1938) will.

(CH) _n -C- (CH) _1n -COMH ₂

Rg R _a SO ₂ HaI R

Shark

(CH) _n -C- (CH) ₁₁₁ -CONH ₂

Rß «\»

OH

(CH) -C- (CH) -CONHR "• - m ₍

SO ₂ HaI R

r "ι t

'2

Shark

(CH) _n -C- (CH) ₁₁₁ -CONHR "

^! Πι ι ι »/ mn

^R a

OH I

^R. _Y h κ

SO ₂ HaI R

Shark

(PH) _n -C- (CH) _1n -CMB

OH

(CH) _n -C- (CH) _m -CONHOH

1 1 I.

^ Y ^R ß ^R a

SO ₂ HaT R

Shark

:-( CH) _m -CONH OH

ß "α

(CH) _n -C- (CH) _1n -CONHNH ₂ Rr R "

SO ₂ shark

Shark

(CH) _n -C- (CH) _1n -CONHNH ₂

^R ß ^R a

OH I

I i (CH ₂ ) _n SO ₂ HaI R (CH) _n -C- (CH) ₀₁ -CONv - j?

ß ^R O

R «

The substituted haloalkanoic acids and their Derivatives, such as their salts, amides or esters, can be prepared with various nucleophilic reagents, which replace the halogen group, implement. For example, an alkali hydrosulfide, an alkali thioalkanoate, can be used Alkali thiobenzoate, an alkali lower alkyl xanthate, thiourea, an alkali thiocyanate, an alkali thiosulfate, an alkali-lower alkyl mercaptide, an alkali sulfite or a Alkali sulfinate with chlorine, bromine or iodine alkanoic acid implement, giving the corresponding derivative of mercaptoalkanoic acid. This can also be done with sulfonate compounds

happen. ·

SH

-L

MSH

Hal (OSO ₂ R ₁ ) CjH) _h -C- (CH) _m -COOH

\ ^R ß ^R a

wherein R- ^ is an alkyl or Means aryl radical.

M SR " R

R "

'- (CH) _1n -COOH

M SCOR "ν R

SCOR "

(CH) _n -O- (CH) -COOH

_1n

MSCOAr

209839/1254

COAr

(CH) _n -C- (CH) _m -COOH R Rß R_

I!

MSCR ". R

Shark (QSO ₂ R ₁ )

[MSC-N R

MSO ₂ M

2098

IHSCNH ₂ R

SCR "

(? 0 _n -C- (CH) _m -C00H

RR ₀ R

CN

(CHL-C- (CH) _1n -COOH

--ψ

SO ₂ M

SO ₃ M

(CH) -b- (CH) _m -C00H

RR ₀ R

SSOqM

(CH) _n -C- (CH) _m -C00H

R _ft R ρ α

SCNH ₂ (CH) _n -I (CH) _1n -COOH

RR ₀ R

SCOR ¹¹ CAr)

CH) _n -C- (CH) _1n -CQOH

«Γ ^R ß ^R a

The mercaptoalkanoic acids can then with a chlorocarbonic acid alkyl ester with a lower alkyl radical, a Alkali isocyanate in the presence of hydrogen chloride, a lower alkyl carbamyl chloride or a di-lower alkyl carbamyl chloride reacted or converted into the metal salt, which with a carbamyl chloride to form the corresponding Mercaptoalkanoic acid derivatives will react. The mercaptoalkanoic acid can also be mixed with succinic anhydride, ™ maleic anhydride or phthalic anhydride are converted, whereby the corresponding derivatives arise.

209839/1254

- • 49 -

Cl COOR " _Ν R

KOCN R

HCT

SH (Na)

(CH) _n -CMCHVCO ^

k. R « κ

ClCONHR '^ R

ClCONR ¹¹ OR

> K > ο

SCOOR "

209839/125 A

(CH) _n -C- (CH) ₁₁₁ -COOH R L

SCONH ₂ (CH) _n -C- (QH) _1n -COOH (M)

SCONHR "

(CH) _n -C- (CH) ₁₇₁ -COOH (M)

^R a

SC0N (R ") ₂ (CH) _n -C- (CH) _m -C00H (M)

H ^R.

^R a

SCOCHoCHoCOOH

i-,

(CH) _n -C- (CH) _1n -COOH

SCOCH = CHCOOh

^R a

SCOC ₆ H ₄ COOH K.

^R a

The lower alkyl mercaptoalkanoic acids can also be oxidized ^ to lower alkyl sulfinyl and lower alkyl sulfonyl derivatives.

HoO

SR "

(CH) _n -C- (CH) _m -COOH-

HoO

2 ^U 2

SOR "

11

where R "denotes a lower alkyl radical.

The various
Mercaptoalkanoates, mercaptoalkanoamides and mercaptoalkanoic acid salts from the corresponding haloalkanoates,
Haloalkanoamides or haloalkanoic acid salts are obtained.

209839/1254

MSH ^ R I >

SH

HSR R

HaT (OSO ₂ R ₁ ) CH) _n -C- (CH) _1n -COZ-

Ry

( h ^R

HSCOR "R

(CH) _n -

- (CH) _1n -COZ \ _R Ra

SR "

CH) _n -Cr (CH) _1n -COZ

R _Y R _ß Ra

SCOR "CH) _n -C- (CH) _1n -COZ

Ry h ^R a

SCOAr

K ^R ß ^R a

SCR "

HSCN ^ R

<3 ^K a

CN

CH) _n -C- (| H) _m -C0Z

Ry Rß ^R a

wherein R _{1 is} an alkyl or aryl radical,

20983971254

MSOoM

HaI (OSO ₂ R ₁ )

(CH) _n -C- (CH) _1n -COZ-IMSO ^ R Rfi R.

SO ₃ M

^R a

MSSO ₃ --ψ

NH

W.
HSCNH ₂

VJV

MSCOR "(Ar) R SSO ₃ M

y '^ ioU

g Ra

NH

Ii

SCNH ₂

L ι

Il

SCOR "(Ar)

wherein M is an alkali metal; R " _{on the leather A}

rest, Ar is a phenyl or tolyl radical or aryl radical.

and R _{1 is} an alkyl

209839/1284

The implementation of a substituted haloalkanoic acid derivative with an alkali metal cyanide leads to the corresponding substituted cyanoalkanoic acid derivative.

Shark

KCN

CH) _n -C- (CH) _1n -COOR ¹¹ j

ß Ra

η " ; ν CH) :-( cH)
I. "γ

The corresponding acids, acid salts, esters and amides of the aforementioned cyanoalkanoic acids can according to using the methods described above ^ or the halogen atom can be replaced by the cyano group in the desired acid salt, ester or amide.

Substituted aminoalkanoic acids and their acid derivatives are made from substituted ketoalkanoic acids Reaction with ammonia or a lower alkylamine and hydrogen over a Raney nickel or platinum catalyst obtain.

209839/1254

(CH) _m -COQH

NH ₃

CH) _n CH- (CH) _1n -COOH

H) _n -C- (CH) _m -C00H

β R α

H (V

- (CH) _n -CH- (CH) _1n -COOH

R.

Substituted aminoalkanoic acids can also be obtained by using a substituted ketoalkanoic acid oxime hydrogenated over a platinum catalyst. The oxime is derived from the substituted ketoalkanoic acid with Obtained hydroxylamine.

NH ₂ OH R

-OH

<CH) "- C- (CH) _m -COOH

Ry Kg R (J.

H ₉ (Pt)

NH2 CH) _n - | - (CH) _{| n} -COCH

209839/1254

The treatment of aminoalkanoic acids or their derivatives with an alkyl halide leads to the corresponding Acylaminoalkanoic acids or to the corresponding derivatives.

NHAc R— —- ~ ji _ / - ^ \

NH,

IMI

R Rr F

-C- (CH) _1n -COOR "R_

Suitable end products with different substances Y can, using suitable reactions, thanks to which one group is converted into another, can be obtained. So you can, for example, the hydroxyalkanoates alkylate, halogenate or nitrate, with the desired in the aryl or heterocyclic rings Can achieve substitutions. -

Γ.

J) _n -C- (CH) ₁₁₁ -COOR "

Nu, Hal Alk

2098 39/1254

: - (CH) _1n -COOR "

OH

CH) _n -C-

An aminophenyl hydroxyalkanoate can also be diazotized to the diazonium fluoroborate, which is then added can thermally decompose with the formation of fluorophenyl hydroxyalkanoates.

OH

NH,

ENT

OH

(CH) _n -C- (CH) ₀₁ -COOR "

N ₂ BF ₄

OH

CH) _n -C- (CH) ^ COOR "

RR ₀ R γ 0- ο

The aminophenyl hydroxyalkanoates can also diazotized and heated in an aqueous medium to form hydroxyphenyl compounds. One can they also in an alcohol to form alkoxyphenyl compounds heat. The hydroxyl group can also react with lower alkyl halides or sulfates to form Alkoxy • groups are alkylated. You can also use lower acyl chlorides or anhydrides to acyloxy compounds in Acylate the presence of tertiary amines such as pyridine.

20983 9/125 4

NH,

(CH) -C- (CH) _m -C00R "
^RR

OH

^R B ^R <*

ΗΝ02 H ₂ O

OH

or

R ¹¹ CI T R ¹¹ COCl pyridine

v /

OR "(COR")

^R _Y ^R 3 ^R a

Nitrophenyl hydroxyalkanoates can be used hydrogenate corresponding amines.

NO ₂ ^Ύ

- (CHL-COOR "

H ₂ ^ R

OH

NH,

Aminophenyl hydroxyalkanoates can then be mono- or dialkylated with lower alkyl halides or sulfates or acylated with lower acyl chlorides or anhydrides. the.

09 8 39/1254

OH

_n c (c

R "X R

NH,

R ¹¹ COCl (R ¹¹ CO) ₂ O

OH (CH) _n -C- (p) _m -COOR ^H

NHCOR "

OH

(CH) _n -C- (CH) _1n -COOR "R .. Rß Κα

NHR "

R ¹¹ X

OH (CH) _n -C- (CH) _1n -COOR ¹¹

NO"),

^R S ^R «

Aminophenyl hydroxyalkanoates can be diazotized, whereupon a Sandmeyer reaction can be connected can to introduce a halogen atom.

OH

I ENT2

(CH) -C- (CH) -COOR "

NH,

I I

'm

HNO ₂ CuCl

CuBr

ENT ₂

CuJ Br

OH

CH) _n

(CH) _n -C- (CH) ₀₁ -COOR "

OH

Cl

OH

209839/1254

But you can also diazotized and heated in an aqueous potassium iodide solution, the iodophenyl hydroxyalkanoates receives.

OH

CH) _n -C- (CH) -COOR " ^{1 n} ι ι m

ENT ₂ R

CH

^R B ^R «

KJ

OH CH) "- C- (CH) _m -CCOR"

"LL

You can also diazotize further and add cuprocyanide, giving cyanophenyl hydroxyalkanoates.

OH

CH) _n -C- (CH) _1n -COOR "

R Rß R γ α

OH CH) _n -C-CCH) _1n -COOR-

The aminophenyl hydroxyalkanoates can also be diazotized and then reacted with potassium ethyl xantliogenate and then hydrolyzed, whereby mercaptophenyl-hydroxyalkanoic acids are obtained, which one to Can esterify mereaptoalkanoates. These in turn can be alkylated to lower alkylthio compounds. One can also oxidize with the formation of lower alkylsulphinyl and lower alkylsulphonyl groups or to give acylthio compounds acylate.

209839/1254

- 6ο -

NH,

SOR "

OH

(CM) _n -A- (CH) -COOR ¹ ' ^{1 η} ϊ I ^m )

CM) _n ^η

H ₂ O ₂

I ^R

J 1

Rr R

1) ENT ₂
KSCSOCpH _B
Z) NaOH

OH

SH

(χι

NaOH R ¹¹ X

SR

or

OH

(CH) _n -UCH) _1n -COOR "

SO ₂ R "

SCOR "

(CH) _n -C- (CH) _1n -COOR "Κγ Rβ ^R a

A halogen compound in which the halogen atom is a chlorine, bromine or iodine atom can also be mixed with cuprocyanide in quinoline at about 150. ⁰ C converted, whereby a cyano compound is obtained.

209839/125

- 6i -

Hal

OH (CH) _n -C- (CH) ₀₁ -COOR ¹¹

CuCN

_s

'm

K-, Ro R

ι Ρα

ß ^R a

Can also be reacted with Trifluormethyljödid and copper powder at about I50 ⁰ C in dimethylformamide to give a Trrifluormethylglycolat or -iactat obtained [see FIG. Tetrahedron Letters ' Kj ₃ 4095- (1959) 1

Shark

OH

ί CF ₃ J

CH) "- C- (CH) _m -COOR"

• η

R _a

Cu

OH

CF,

(CH) _n -C- (CH) ^ - COOR "Rß Ra

Halogenglycolate or Lactate can also be reacted with Cupromethansulfinat in quinoline at about I50 ⁰ C, wherein one or lactate receives a Methylsulfonylglycolat.

Shark

OH j

CH) _n -C- (CH) m-COOR "

CuSO ₂ CH ₃ R

OH (CH) -C- (CH) _1n -COOR "

Rß \

209839/1254

If R represents a substituted aryl radical, then can be nitrated, halogenated and alkylated according to the above information, one group in another Group can convict.

In those cases in which R is a phenyl radical
the following reaction can be carried out, for example:

OH I CH) _n -Cr (CH) _1n -COOR ¹¹ -?

Rr R.

CH) _n -C- (CH) _1n -COOR "

Rp

- (CH) _1n -COOR "FL

OH

:-( CH) m-C00R "

209839/1254

CF ₃ J

CU

OH

CH) _n -C- (CH) ni-C00R ^{: 1}

CF

CuCN

OH

CH) nC- (CH) _m -C00R "

^R a

CuSO ₂ CH ₃

SO ₂ CH ₃

K ₁

209839 / 12Si

2 WZO 38

NH ₂ Y

HBF /

ENT ₂

OH

ENT ₂ R ¹¹ OH

ENT

CuBr

ENT

2 ν

GuCN

ENT 'KSdOC ₂ H ₅

2) NaOH

209839/1254

OH

RS R

OH I

CH) _n -C- (CH) ₁₁₁ -COOR ¹¹ CH) _n -C- (CH) _m -COOR ^(I.

^R a

OH

(CH) nC- (CH) _m -COCR "

Marg

OH ■. -CH) _n -C- (CH) _1n -COOR "

R ^R e ^R a

IH

CH) _n -C- (CH) _1n -CPOR "

RS R _a

Those obtainable according to the present invention Products are in the form of racemates, namely in the form of racemic mixtures of right-handed and left-handed Isomers obtained because at least one of the carbon atoms is asymmetric. If the α-, β- and / or 7-carbon is an alkyl group, then are two or three asymmetric carbon atoms present ^ and the product can be in the form of a mixture of these dia ^ · stereomers exist in syn and anti configurations. These diastereomers can. Through fractional crystallization be separated. Each diastereomer can be divided into the right-handed and the left-handed optical Cleave the isomer in a conventional manner.

One method of resolution that can be used is that of the racemic compound with an optically active compound by salt formation, ester formation or amide formation to form two diastereomeric products combined. If the acids present are added to an optically active base, thus two diastereomeric salts are produced which have different properties and different solubility properties have, which is why they can be separated by fractional crystallization. After the salts have been completely separated from one another by repeated recrystallization, the base becomes acidic

0 9 8 3 9/1254

Split off hydrolysis, giving the pure d- or ε-acids. The alkanoic acid is preferably reacted in alcoholic or acetone solution with an equivalent amount of the optically active primary / secondary or tertiary amine, such as cinchonidine, cinchonine, quinine, ephedrine, α-methylbenzylamine, sec _e- butylamine, secv-amylamine, etc. The diastereomeric amine salts obtained in this way are fractionated by. tes crystallization separately, whereupon each optically active salt is hydrolyzed with dilute mineral acid in order to obtain the dextro or levo form of that alkanoic acid. Each optical isomer can then be reacted with X'-Cl or XOX ¹ , the corresponding optically active, alcoholic derivative being obtained. On the other hand, an alkanoic acid ester can be reacted with an optically active primary or secondary amine, such as ephedrine, a-methylbenzylamine, sec-butylamine, etc., in order to obtain a mixture of diastereomeric alkanoates which can be separated by fractional crystallization. Each optically active amide can be hydrolyzed to the corresponding optically active acid with a mineral acid.

On the other hand, you can an alkanoate with an optically active alcohol, such as. C-menthol or d-borneol or £ -a -methylbenzyl alcohol. Implements, whereby one

209839/1254

-67-2152038

Mixture of diastereomeric alkanoic acid esters obtains ^ the can be separated by fractional crystallization. Every optically active ester can be treated with a mineral acid ' or with an alkali to the corresponding optically active Hydrolyze acid »The optically active acids can also obtained from the a-methylbenzyl esters by hydrogenolysis in the presence of palladium. In this way you can use the α-, β- or 7-oxy, halogen, thio, cyano or produce amino isomers.

It was found that the invention. mass "available compounds valuable anti-inflammatory Exert effects in mammals and for the treatment of pain accompanied by fever and are effective under similar conditions. The inventive

■ from

according to available compounds can be used in diseases /?

Use in mammals and humans, provided symptoms inflammation accompanied by fever and pain appear. Examples are yheumati-, see diseases such as rheumatoid arthritis, osteoarthritis and other degenerative joint diseases,

• soft tissue

also rheumatic diseases such as tendinitis, § Muscular rheumatism, such as seiatics, pain and inflammation in dental operations and the like human and veterinary disease states, which the use of anti-inflammatory anal

209839/1254

* ORIGINAL BATHROOM

require getic and / or pyretic means.

For these purposes, the erfindungsgernäss available compounds are usually administered orally, topically, parenterally or rectally. Oral are such Compounds preferably in the form of tablets, capsules, Suspensions or syrups administered. The optimal dosage of course depends on the type of compound and on the nature and severity of the disease being treated. Of course you will see the state of the Take into account patients, such as their state of health, age, weight, etc. Oral dosages the preferred compounds when administered to humans and animals are normally from about 0.5 to 100 mg per kg of body weight per day. The preferred range is 0.5 to 15 mg / kg. -

The active substances are preferably administered in the form of pharmaceutical preparations which can contain one or more other substances. For example, such preparations can contain sweeteners, taste-correcting agents, coloring agents, preservatives, etc. The active alkanoic acids and their derivatives can be .as such or in. Mixture with agents against gastric acidification, such as sodium bicarbonate, magnesium carbonate, magnesium hydroxide, aluminum hydroxide, magnesium silicate and the like. _; and in connection with non-toxic,

r . -2098 39 / 12S4

Administer pharmaceutically acceptable additives. Such additives are, for example, inert diluents, such as calcium carbonate, lactose etc., granulating and loosening agents such as magnesium stearate, Talc, etc., binders such as starch, gelatin, etc., suspending agents such as methyl cellulose, vegetable oils, etc., dispersants such as lecithin, etc., thickeners such as e.g. Beeswax, hard paraffin, etc., emulsifiers such as naturally occurring gums, etc., as well as not irritating excipients such as cocoa butter and polyethylene glycols. ·.

Experiments on animals have shown that the alkanoic acids obtainable according to the invention and whose derivatives exert reactions that are likely to equal anti-inflammatory effects in humans. One of these tests is the so-called carrageenan paw edema test, which shows that the available according to the invention Compounds obtained by injection of an anti-inflammatory agent such as carrageenan into the Can prevent edema formation caused by tissue from paws of rats. This test method is better known Art. For comparison. you can test with agents such as aspirin, phenylbutazone, cortisone, hydrocortisone and prednisolone. Compared with these

2 0 9 8 3.9 / 1 2 5 4 BAD ORIGINAL

The alkanoic acids obtainable according to the invention and their derivatives are excellent anti-inflammatory compounds Middle.

The Randall-Selitto test method is suitable for measuring the pain threshold. The anaigetic effect can be detected "in inflamed rat paws, with the pain response being measured.

The antipyretic effect is through subcutaneous Injection determined in rats with yeast-induced fever. It is done by measuring the rectal temperature the determination of the effect of the test compounds.

It is shown that the invention available alkanoic acids and their derivatives have an extremely valuable analgesic and antipyretic effect exercise.

Other tests have shown that the invention available compounds are good anaigetics, in rats polyarthritis and in guinea pigs able to cure ultraviolet erythema.

The invention is illustrated by the following examples explained.

0Q839 / -U64 '-

BATH ORIGINAL

2182038

Example 1 ■

Ethyl 2'-chloro-4-biphenylyl glyoxylate

57 g (0.33 mol) of 2-chlorobiphenyl and 50.5 g (0.37 mol) of oxalyl chloride ethyl ester are dissolved in 200 cm of dry 1,1,2,2-tetrachloroethane. Then added to the reaction mixture under stirring within 2 hours with 52 g (0.39 mol) of anhydrous aluminum chloride During the addition the temperature of the mixture at l6 to l8 is held ⁰ C. The mixture is then stirred for an additional hour and then left to stand overnight. The solution is then slowly stirred into 1500 cm of ice-cold salt solution. After standing, two layers form. The aqueous layer is extracted with 500 cm "* of ether and the ether extract is combined with the organic layer, which is dissolved in 1,500 cm of ether. Then the layers are separated. The ether solution is added 10 times with 100 cm"

mixture
tions of a saturated sodium chloride solution and 10 ^ iger hydrochloric acid solution (mixing ratio 1: 1) and washed 5 times with 100 en * water each time. The ethereal solution is then dried over anhydrous magnesium sulfate for one hour and filtered. The solvents are removed by distillation under reduced pressure and the residue is distilled to give ethyl 2 ¹ -chloro-4-biphenylyl glyoxylate.

209 8 3 9/1254

A) If the oxalyl chloride ethyl ester is replaced in the above example the compounds in Table I below lead to the corresponding products according to table II.

Table I.

Oxalyl chloride methyl ester oxalyl chloride propyl ester oxalyl chloride isopropyl ester Oxalyl chloride benzyl ester succinyl chloride ethyl ester tx-methyl succinyl chloride ethyl ester ß-methyl succinyl chloride ethyl ester

ajß-Dimethylsuccinylchloride ethyl ester

Table II

Methyl 2'-chloro-4-biphenylyl glyoxylate w propyl 2'-chloro-4-biphenylyl glyoxylate

Isopropyl S'-chloro-A-biphenylyl glyoxylate tert-butyl 2'-chloro-4-'biphenylyl glyoxylate Benzyl 2 ^l -chloro-4-biphenylyl glyoxylate ethyl 7-keto.-7- (2'-chloro-4 -biphenylyl) -butyrate ethyl-a-methyl-7-keto-7- (2'-chloro-4-biphenylyl) -butyrate ethyl-ß-methyl-7-keto-7- (2'-chloro-4-biphenylyl ) -butyrate ethyl-a, ß-dimethyl-7-keto-7- (2'-chloro-4-biphenylyl) butyrate

209839/1254

B) If the 2-chlorobiphenyl is replaced in the above example through the compounds of Table III below, one arrives at the corresponding products according to table IV.

Table III 2-nitrobiphenyl 2-bromobiphenyl 2-methylbiphenyl 4-nitrobiphenyl 4-chlorobiphenyl 4-bromobiphenyl 4-methylbiphenyl toluene ■ 'isopropylbenzene tert.-butylbenzene cyclohexylbenzene cyclohexylbenzene 2-phenylbenzylbenzene-benzene-cyclohexylbenzene

2 0 9 iJ 3 9 / i? h Λ

3-phenylfuran 2-phenylpyr.idine 4-phenylpyridine 2-phenylpyrasine 2-phenylpyrimidine 3-phenylpyridazine 2-phenyltriazine 2-phenylimidazole. ■ __ ■ 1-phenylpyrazole "3-phenyl-2H-pyran 4-phenyl-2-imidazoline 2-phenylimidazolidine 1-phenylpyrazolide-2-phenylpyrrolidine 2-phenylpiperidine 4-phenylpiperidine 1-phenylpiperazine 2-phenylpiperazine 3-phenylmorpholine 4-phenylmorpholine

Table IV

Ethyl 2'-nitro-4-biphenylyl glyoxylate Ethyl 2'-bromine - ^ - biphenylyl glyoxylate Ethyl 2'-fflethyl-4-biphenylyl glyoxylate

20383 <) / 125-4

BATH ORIGINAL

Aethyl-4 ^f -nitro-4-biphenyIylglyoxylat Aethyl-4'-chloro-4-biphenylylglyoxylate Ethyl-4'-bromo ^ -biphenylylglyoxylat Ethyl-4'-methyl-4-biphenyly "lglyQxylat Aethyl-p-tolylglyoxylat Aethyl-p-tolylglyoxylat isopropylphenylglyoxylate, ethyl p-tert-butylphenylglyoxylate, ethyl p-cyclopentylphenylglyoxylate, ethyl p-cyclohexylphenylglyoxylate, ethyl p-cycloheptylphenylglyoxylate, ethyl p-cycloheptylphenylglyoxylate, ethyl p-cyclohex-1-phenylglyoxylate-phenoxy-phenyl-phenyl-phenyl-p-cyclohexyl-1-enylphenylglyoxyl-phenoxyl-phenyl-phenyl-phenyl-phenoxyl-phenyl-phenyl-p-cyclohexyl-1-enylglyoxyl-phenoxyl-phenyl-phenyl-phenyl-p-cyclohexyl-1-enylglyoxyl-phenoxyl-phenyl-phenyl-p-cyclohexyl-1-enylglyoxyl-phenoxyl-1-enylglyoxyl-phenoxyl-phenylglyoxyl-phenoxy-1-cyclopentylphenylglyoxylate-ethyl-p-cyclopentylphenylglyoxylate Ethyl p-phenylaminophenyl glyoxylate, ethyl p-benzoylphenyl glyoxylate; ethyl p- (2-thienyl) phenyl glyoxylate, ethyl p- (3-furyl) phenylglyoxylate, ethyl p- (2-pyridyl) phen3 ' ^r lglyoxylate, ethyl - (4-pyridyl) -phenylglyoxylate ethyl-p- (2-pyrazinyl) -phenylglyoxylate ethyl-p ~ (2-pyrimidinyl} -phenylglyoxylate ethyl-p- (3-pyridazinyl) -phenylglyoxylate ethyl-p- (2-triazinyl) -phenyl glyoxylate, ethyl p- (2-imidazolyl) -phenyl glyoxylate

20983 9/125 A

Ethyl p- (l-pyrazolyl) phenyl glyoxylate Ethyl p- (2-imidazolin-4-yl) phenyl glyoxylate Ethyl p- (2-imidazolidinyl) phenyl glyoxylate Ethyl p (l-pyrazolidinyl) phenyl glyoxylate Ethyl p- (2-pyrrolidinyl) phenyl glyoxylate Ethyl p (2-piperidinyl) phenyl glyoxylate Ethyl p- (4-piperidinyl) ~ phenyl glyoxylate Ethyl p- (1-piperazinyl) phenyl glyoxylate Ethyl p- (2-piperazinyl) phenyl glyoxylate Ethyl p (3-morpholinyl) phenyl glyoxylate Ethyl p- (4 ~ morpholinyl) phenyl glyoxylate

C) If in the above example the 2-chlorobiphenyl is replaced by the compounds of Table III and the oxalyl chloride methyl ester is replaced by the compounds of Table II, one arrives at the corresponding Links.

Example 2

4- (2'-chlorophenyl) cinnamic acid

21.6 g (0.1 mole) 4- (2'-chlorophenyl) benzaldehyde are on the steam bath with 13.2 g of malonic acid and 95 cm ^ pyridine, containing 5 drops of piperidine, heated. The mixture is then heated for 4 hours

heated until the evolution of carbon dioxide ceased 20983 9/125 4

Has. The cooled mixture is then poured into a mixture of 110 cubic centimeters of concentrated hydrochloric acid and 500 cubic centimeters of ice water. The precipitated solid material is filtered off, washed with cold water and then resuspended in 200 ater CRRR cold V /, filtered / ater and washed with cold V · dried at 4o C ^0. The residue is then recrystallized from ethanol, whereby one
4- (2 * -Chlorophenyl) -cinnamic acid is obtained.

A) If in the above example the malonic acid is replaced by methylmalonic acid or ethylmalonic acid, the following compounds are obtained;
α-methyl-4- (2'-chlorophenyl) cinnamic acid

α-ethyl-4- (2'-chlorophenyl) cinnamic acid.

B) Replacing 4- (2'-chlorophenyl) benzaldehyde in the above example the compounds in Table I below lead to the corresponding compounds Table II below.

Table I.

4- (4'-chlorophenyl) benzaldehyde.

4- (2'-nitrophenyl) benzaldehyde ■

4- (4'-nitrophenyl) benzaldehyde
4- (2-methylphenyl ^t) benzaldehyde

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4- (4'-methylphenyl) benzaldehyde 4- (2'-Bromophenyl-benzaldehyde 4- (4'-Bromophenyl) -benzaldehyde 2-chloro-4-biphenylcarboxaldehyde 2-nitro-4-biphenylcarboxaldehyde 2-methyl-4-biphenylcarboxaldehyde 2-bromo-4-biphenylcarboxaldehyde 4-tolualdehyde

4-isopropylbenzaldehyde 4-tert-butylbenzaldehyde ^ -Cyclopentylbenzaldehyde 4-Cyclohexylbenzaldehyde 4-cycloheptylbenzaldehyde 4-cyclohex-1-enylbenzaldehyde 4-phenoxybenzaldehyde 4-phenylthiobenzaldehyde 4-anillobenzaldehyde 4-benzoylbenzaldehyde 4- (2-thienyl) benzaldehyde 4- (3-furyl) benzaldehyde 4- (2-pyridyl) -benzaldehyde 4- (4-pyridyl) -benzaldehyde 4- (2-pyrazinyl) -benzaldehyde 4- (2-pyrimidinyl) benzaldehyde 4- (3-pyridazinyl) benzaldehyde

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4 ~ (2-triazinyl) ~ benzaldehyde 4- (3-Isoxazolyl) -benzaldehyde 4- (3-IsOthiazolyl) -benzaldehyde 4- (2H-pyrrol ~ 3-yl) -benzaldehyde 4- (2-imidazoIyI) -benzaldehyde 4- (l-pyrazolyl) -benzaldehyde 4- (2H-pyran-2-yl) -benzaldehyde 4- (l-pyrrolyl) -benzaldehyde, 4- (2-imidazolin-4-yl) -benzaldehyde 4- (2-imidazolidinyl) -benzaldehyde 4- (1-pyrazolidinyl) benzaldehyde 4- (2-pyrrolidinyl) benzaldehyde 4- (2-pyrrolin-3-yl) -benzaldehyde 4- (2-piperidinyl) -benzaidehyde 4- (4-piperidinyl) benzaldehyde 4- (1-piperazinyl) benzaldehyde 4- (2-piperazinyl) benzaldehyde 4- (3-morpholinyl) benzaldehyde 4- (4-morpholinyl) benzaldehyde;

Table II

4- (4 ¹ -chlorophenyl) -cinnamic acid 4- (2'-nitrophenyl) -cinnamic acid 4- (4'-nitrophenyl) -cinnamic acid 4- (2'-methylphenyl) -cinnamic acid

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4 - "(4'-methyl phenyl) cinnamic acid 4- (2'-bromophenyl) cinnamic acid 4- (4'-Bromophenyl) cinnamic acid 4- (2-chlorophenyl) cinnamic acid 4- (2-nitrophenyl) cinnamic acid 4- (2-methylphenyl) cinnamic acid 4- (2-bromophenyl) cinnamic acid 4-methylcinnamic acid

* 4-xsopropylcinnamic acid

4-tert-butylcinnamic acid 4-cyclopentylcinnamic acid 4-cycloheptyl cinnamic acid · 4-cyclohexyl cinnamic acid 4-cyclohex-i-enylcinnamic acid 4-phenoxycinnamic acid 4-phenylthiocinnamic acid 4-anilinocinnamic acid

If 2-anilinocinnamic acid

4-Benzoylcinnamic acid 4- (2-thienyl) cinnamic acid 4- (3-puryl) cinnamic acid 4- (2-pyridyl) cinnamic acid 4- (4-pyridyl) cinnamic acid 4- (2-pyrazinyl) cinnamic acid 4 - '(2-pyrimidinyl) cinnamic acid

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4- (3-pyridazinyl) cinnamic acid 4- (2-triazinyl) cinnamic acid

4- (3-isoxazolyl) cinnamic acid '

4- (3-Isothiazolyl) cinnamic acid 4- (2H-pyrrol-3-yl) cinnamic acid 4- (2-imidazolyl) cinnamic acid

4- (1-pyrazolyl) cinnamic acid

4- (2H-pyran-2-yl) cinnamic acid 4- (1-pyrrolyl) cinnamic acid

4- (2-Imidazolin-4-yl) cinnamic acid ~

4- (2-imidazolidinyl) cinnamic acid '

4- (1-pyrazolidinyl) cinnamic acid 4- (2-pyrrolidinyl) cinnamic acid 4- (2-pyrrolin-3-yl) cinnamic acid 4- (2-piperidinyl) cinnamic acid 4- (4-piperidinyl) cinnamic acid 4- (1-piperazinyl) cinnamic acid 4- (2-piperazinyl) cinnamic acid 4- (3-morpholinyl) cinnamic acid 4- (4-morpholinyl) cinnamic acid

C) Replacing 4- (2'-chlorophenyl) benzaldehyde in the above example by the compounds of Table I and if, on the other hand, the malonic acid is replaced by the compounds according to paragraph A), then one arrives at the corresponding

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related products.

Example 3

β- (2'-chloro-4-biphenylyl) propionic acid

A suspension of 100 g of p- (2-chlorophenyl) cinnamic acid in 1 liter of 95% ethanol is hydrogenated at atmospheric pressure using 1 g of a platinum oxide catalyst. The uptake of hydrogen ceases when approximately 9 to 10 liters of hydrogen have been used up . The catalyst is then filtered off and the solution is evaporated to dryness, ^{β- (2?} -Chloro-4-biphenylyl) propionic acid being obtained.

A) Replaces p- (2-chlorophenyl) cinnamic acid by the cinnamic acid compounds of Table II, Example 2, and dividing C), Example 2, one arrives at the corresponding Propionic acids.

Example 4

β- (2'-chloro-4-biphenylyl) propionyl chloride

26 g of β- (2'-chloro-4-biphenylyl) propionic acid are treated ^{with 18 g of thionyl chloride at 0 to 5 ° C.} After 10 minutes the temperature is increased for 30 minutes at 60 ⁰ C, after which the residue is distilled at 0.0-5 mm Hg. In this way, β ~ (2'-chloro-4-biphenylyl) propionyl chloride is obtained.

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A) If you replace the above implementation

ß- (2'-chloro-4-biphenylyl) propionic acid by the propionic acids mentioned in Example 3, one arrives at the corresponding propionyl chlorides.

Example 5

β- (2'-chloro-4-biphenyIyI) propionaldehyde

28 g of ß- (2'-chloro-4-biphenylyl) propionyl chloride in 500 cnr of ethylene glycol dimethyl ether are treated dropwise with a solution of 25.5 g of lithium tri-tert-butoxyaluminum hydride in 500 cnP of diethylene glycol dimethyl ether, the reaction temperature being treated with dry ice holds at -70 ^{0 C.} When the addition is complete, the mixture is allowed to cool to room temperature, diluted with ether and washed with water, dilute hydrochloric acid and brine. The solvent is then dried over sodium sulfate, evaporated in vacuo and the residue is distilled, ^{β- (2 1} -chloro-M-biphenylyl) propionaldehyde being obtained.

A) If, in the above reaction, the ß- (2 ¹ -chloro-4-biphenylyl) propionyl chloride is replaced by the propionyl chloride according to Example 4, the corresponding propionaldehyde is obtained.

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Example 6

4- (2'-Chl or-4-biphenylyl) -butan-2-one

A solution of 28 g of β- (2'-chloro-4-blphenylyl) -propionyl anhydrous in 1 liter of ether is cooled to -70 ⁰ C. > 4 cm3 are added dropwise to this solution

'a 3 ^m ° l ren ^a solution of Methylmagnesiumbrömid in ether. The reaction mixture is stirred thoroughly. After the addition of the Grignard reagent has ended after about one hour, the mixture is allowed to cool to room temperature and is decomposed by carefully adding about 500 cirr of a saturated ammonium chloride. The ether phase is washed with brine, dried over sodium sulfate, evaporated in vacuo and the residue is distilled to give 4- (2'-chloro-4-biphenylyl) butan-2-one.

A) If in the above reaction the) ß- (2'-chloro-4-biphenylyl) propionyl chloride is replaced by the Propionyl chloride according to Example 4, this leads to the appropriate connection.

Example 7 q, β-Dibromo-β- (2'-chloro-4-bi- pennylyl) propionic acid

A mixture of 35 g (0.13 mol) of β- (2'-chloro-4-biphenylyl) cinnamic acid with 280 carbon tetrachloride • is gently heated to the boil. This hot sus-

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7> 1 cnr (0.13 mol) bromine diluted with 15 cnr carbon tetrachloride is then added dropwise with stirring over the course of 50 minutes. The bath temperature is kept at approximately 80 ^° C. and then heated further for 1 1/2 hours with stirring. The mixture is then cooled to room temperature and filtered, α, ß-dibromo-ß- (2'-chloro-4 ~ biphenyIyI ^ propionic ■. -.

acid receives.

A.) If the ß ~ (2 ^f -chloro-4-biphenylyl) cinnamic acid in the above example is replaced by the cinnamic acids or by ester compounds from Example 2, corresponding products are obtained.

Example 8

ß- (2 '-Chlor-3-biphenyIyI ^ pyruvic acid

A mixture of α, β-dibromo-β- (2'-chloro-4-biphenylyl) propionic acid with 3 moles of piperidine is prepared by the method according to Henri Moureu, Paul Chovin and Michel Garein in Compt. Rendu 221 , pages 410-2 (1945), a tripiperidyl adduct being obtained which, when heated under reflux, with 2N sulfuric acid.

which supplies ß- (2 * -chloro-4-bipheny Iy! ^ pyruvic acid. A) If one replaces the α, β-di-

2 0 9 8 3 9/125 4

bromo-ß- (2'-chloro-4-biphenyl; /!) ··· propionic acid through the propionic acids or esters according to Example Y ₃ this leads to the corresponding products.

Example 9

ß-Hydroxy-ß- (2'-chlor -4-biphe nylyl) -propionic acid ethyl ester

A mixture of 23.6 g (0.1 mol) of 2'-chloro-4-biphenylyl methyl ketone, 20 g of ethyl bromoacetate and 8 g of zinc is placed in 75 cm of benzene. The reaction mixture is heated to reflux and stirred vigorously for one hour. Then the mixture is cooled and diluted with sulfuric acid. The organic layer is separated, dried over calcium chloride and distilled to give the ethyl β-hydroxy-β- (2'-chloro-4-biphenylyl) propionate.

A) In the above reaction, the 2'-chloro-4-biphenylyl methyl ketone is replaced by the ketones of Table I below, you get to the corresponding products according to Table II below.

Table I.

2'-Bromo-4-biphenylyl methyl ketone
2'-nitro-4-biphenylyl methyl ketone
4'-chloro-4-biphenylyl methyl ketone
2-chloro-4-biphenylyl methyl ketone

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Table II ■

ß-Hydroxy-ß- (2 '-brorn-4-biphenylyl) -butyric acid ethyl ester' ß-Hydroxy-ß- (2 '-nitro-4-biphenylyl) -butyric acid ethyl ester.r ß-Hydroxy-ß- (4 ¹ -chlor -4-biphenylyl) -butyric acid ethyl ester ß-Hydroxy-ß- (2-chloro-4-biphenylyl) -butyric acid ethyl ester

Example 10

ß-methyl-ß- (2'-chloro ~ 4-biphenylyl) -zlmtsäureäthyleste r

To 31 g of ß-hydroxy-ß- (3-chloro-4-cyclohexylphenyl) propionic acid ethyl ester in 8o cnP benzene add 6 cm ^ Phosphorus oxychloride is added and the mixture is heated during 30 minutes to boiling point. The mixture is then cooled, -Washed twice with water, over calcium chloride dried and distilled, whereby the ß-methyl-ß- (2'-chloro-4-biphenylyl) cinnamon acid ethyl ester receives.

A) If in the above process the α, ß-dibromo-ß- (2'-chloro ~ 4-biphenylyl) propionic acid is replaced by the propionic acids according to Example 9 1 Table II, one arrives at the products, which are in the see Table I below.

Table I.

ß-Methyl-ß- (2 * -bromo-4-biphenyIyI) -cinnamic acid ethyl ester 3-Methyl-ß- (2 ¹ -nitro-4-biphenyIyI) -cinnamic acid ethyl ester

209839/1254

ß-Methyl-ß ~ (4'-chloro-4-biphenylyl) -cinnamic acid ethyl ester ß-Methyl-ß- (2-chloro-4 ~ biphenylyl) -cinnamic acid ethyl ester

Example 11

p- (2-ChI or phenyl) -phenylmagnesium bromide

54 g of 4-bromo-2'-chlorobiphenyl in 70 cm- ⁵ ether are added in portions to 4.8 g of purified magnesium turnings. After the first 5 cm of the solution has been added, an iodine crystal and 3 drops of ethyl iodide are added to start the reaction. As the conversion increases, the remainder of the solution is added as quickly as possible without quenching the reaction. When the addition is complete, the mixture is refluxed with stirring until only a trace of metal remains. It can then be assumed that the formation of the Grignard reagent is complete.

Example 12

1-chloro-3- (2'-chloro-4-biphenylyl) -2-propanol

The information according to the Example 11 conservation "tene Grignard solution is cooled in an ice bath to 0 ⁰ C, and this solution dropwise with stirring with a solution of 18.0 g of freshly distilled epichlorohydrin in 100 cnr ether at such a rate offset that the temperature does not rise to more than 5 ⁰ C.

209 8 3 9/1254

After the addition is complete, the reaction mixture 7zin ™ is tempered door left to cool, whereupon you start with an excess saturated ammonium chloride solution added. The ethereal phase is separated off, washed with brine and dried and the solvent is evaporated, the crude product being 1-chloro-3- (2'-chloro-4-biphenylyl) -2-propanol obtained, which can be reacted directly or distilled under very low pressure, where you can 1-chloro-3- (2'-chloro-4-bophenylyl) -2-propanol is obtained.

A) If the epichlorohydrin is replaced in the above example by 2-chloro-3,4-epoxybutane, 1-chloro-2-methyl-2,3-epoxypropane or 1-chloro-2,3-epoxybutane, the following compounds are obtained: 2-chloro-4- (2'-chloro-4-biphenylyl) -3-butanol 1-chloro-2-methyl-3- (2'-chloro-4-biphenylyl) -2-propanol l ~ chloro-3-methyl-3- (2'-chloro-4-biphenylyl) -2-propanol.

B) Replacing the 2'-chloro-4-biphenylylmagnesium bromide in the above process by using the Grignard agents according to Table I below, the corresponding ones are obtained Products according to the following table II.

Table I.
4'-chloro-4-biphenylyl magnesium bromide

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S'-Nitro- ^ biphenylylmagnesium ^{bromide 4 l} -nitro-4-biphenylylraagnesium bromide 2'-methyl-4-biphenylylmagnesium bromide 4'-methyl-4-biphenylylmagnesium bromide 4'-bromo-4-biphenylylbromide 2-bromo-4-biphenylylbromid 2-bromo-4-biphenylylbromid 2-bromo-4-biphenylybromide 4 ~ biphenylylmagnesium bromide 2-methyl-4-biphenylylmagnesium bromide 4-tolylmagnesium bromide
4-Isoprqpylphenylmagnesiumbromid 4-CyclopentylphenylmagnesiumbrOmid 4-CyGlohexylphenylmagnesiumbromid Cycloheptylphenylmagnesiumbromid 4-4-cyclohex-l-enylphenylmagnesiurabromid 4-Phenoxyphenylmagnesiumbroniid Phenylthiophenylmagnesiumbromid 4-4- (2-thienyl) -phenylmagnesiumbromid 4- (3-furyl) -phenylmagnesium.bromid 4- (2- Pyrazinyl) -phenylmagnesium bromide 4- (3-pyridazinyl) -phenylmagnesium bromide 4- (3-isoxazolyl) -phenylmagnesium bromide 4- (3-isothiazolyl) -phenylmagnesium bromide 4- (2-imidazolyl) -phenomylmagnesium-pyryzolylesi-phenomylmagnesium-pyrazolyl-4- (l- - (2H-Pyran-2-yl) -phenylmagnesium bromide

209339/1254

4- (2-imidazolin-4-yl) phenylmagnesium bromide 4- (2-Imidazolidinyl) -phenylmagnesium bromide 4- (1-pyrazolidinyl) -phenylmagnesium bromide 4_ (4-morpholinyl) phenyl magnesium bromide

table II

l-chloro-3- (4'-chloro-4-biphenylyl) -2-propanol l-chloro-3- (2 ^l -nitro-4-biphenylyl) -2-propanol l-chloro-3- (4 ^l - nitro-4-biphenylyl) -2-propanol l-chloro-3- (2'-methyl-4-biphenylyl) -2-propanol l-chloro-3- (4 ^{t-methyl-4-biphenylyl)} -2-propanol '1-chloro-3- (2'-bromo-4-biphenyIyI) -2-propanol. l-chloro-3- (4 * -bromo-4-biphenyIyI) -2-propanol l-chloro-3- (2-chloro-4-biphenyIyI) -2-propanol l-chloro-3- (2-nitro- 4-biphenylyl) -2-propanol l-chloro-3- (2-methyl-4-biphenylyl) -2-propanol l-chloro-3- (2-bromo-4-biphenylyl) -2-propanol l-chlorine- 3- (4-tolyl) -2-propanol 1-chloro-3- (4-35opropylphenyl) -2-propanol 1-chloro-3- (4-tert-butylphenyl) -2-propanol 1-chloro-3 - (4-cyclopentylphenyl) -2-propanol 1-chloro-3- (4-cycloheptylphenyl) -2-propanol 1-chloro-3- (4-cyclohexylphenyl) -2-propanol 1-chloro-3- (4-cyclohex -l-enylphenyl) -2-propanol 1-chloro-3- (4-phenoxyphenyl) -2-propanol

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.l-chloro-3- (4-phenylthiophenyl) -2-propanol 1-chloro-3- [4- (2-thienyl) phenyl] -2-propanol 1-chloro-3- [4- (3-furyl) phenyl] -2-propanol 1-chloro-3- [4- (2-pyrazinyl) -phenylI-2-propanol 1-chloro-3- [4- (3-pyridazinyl) phenyl] -2-propanol 1-chloro-3-C4- (3-isoxazolyl) phenyl] -2-propanol 1-chloro-3- [4- (3-isothiazolyl) phenyl] -2-propanol 1-chloro-3- [4- (2-imidazolyl) -phenyl] -2-propanol 1-chloro-3- [4- (1-pyrazolyl) -phenyl] -2-propane 1 1-chloro-3- [4- (2H-pyran-2-yl) -phenyl] -2-propanol 1-chloro-3- [4- (2-imidazolin-4-yl) -phenyl] -2-propanol 1-chloro-3- [4- (2-imidazolidinyl) -phenyl] -2-propanol 1-chloro-3- [4- (1-pyrazolidinyl) phenyl] -2-propanol

C) If you proceed according to the above information under Using a Grignard reagent according to Table I and an epoxy compound according to Part A), this leads to to the corresponding products.

Example 13

β-Hydroxy-7- (2'-chloro-4-biphenylyl) -butyronitrile

The crude l-chloro-3- (2'-chloro-4-biphenylyl) -2-propanol, that is obtained according to ^ Example 12 is shown in 100 g of dimethyl sulfoxide dissolved and powdered with 20 g Treated sodium cyanide. After stirring at room

20 9839/1254

temperature for 24 hours, the mixture is ^{heated to 60 0} C for 4 hours, then poured into water and extracted with ether. The ether extracts are washed thoroughly with water, with sodium bicarbonate solution and with brine and dried over sodium sulfate. Evaporation of the solvent and distillation of the residue at 0.01 to 0.5 mm Hg give β-hydroxy-Ύ- (2'-chloro-4-biphenyIyI) butyronitrile.

A) In the reaction just mentioned, if the l-chloro-3- (2'-chloro-4-biphenylyl) -2-propanol is replaced by 2-chloro-4- (2 ^l -chloro-4-biphenyiyl) -3- butanol, l-chloro-2-methyl-3- (2'-chloro-4-biphenylyl) -2-propanol or l-chloro-3-methyl-3- (2'-chloro-4-biphenylyl) -2- propanol, the following compounds are obtained: α-methyl-β-hydroxy-7- (2'-chloro-4-biphenylyl) butyronitrile _; ß-methyl-ß-hydroxy-7- (2'-chloro-4-biphenylyl) -butyronitrile or

β-Hydroxy-7-methyl-7- (2'-chloro-4-biphenylyl) -butyronitrile.

B) If the propanol and butanol compounds are used according to Example 12 in the above process, the corresponding butyronitrile compounds are obtained.

209839/125 4

Example l4

α-Hydroxy-7- (2'-chloro-4-biphenylyl) butyronitrile

10 g SS (2'-chloro-4 - biphenylyl) propionaldehyde be treated with aqueous saturated sodium bisulfite solution in 50 car 80 cnr absolute ethanol. The addition complex compound is filtered off, then successively washed with v / ater, ethanol and ether and washed * dry material to 4o CIik ^ Dimethy sulfoxide was added. It is then treated with an excess of powdered sodium cyanide. The amount of sodium cyanide is about 5 g. After 3 hours the mixture is poured into water, whereupon the extracts are washed with brine, dried over sodium sulphate and, after adding a trace of sulfuric acid, evaporated to dryness. In this way one obtains oc-hydroxy-7- (2'-chloro-4-biphenylyl) -butyronitrll,

A) By replacing in the above method the SS (2'-chloro-4-biphenylyl) propionaldehyde to the invention by the Propionaldehyde or ketones Examples 5 and 6 _y we arrive at the corresponding products.

Example 15

q-Hydroxy-Ύ- (2'-chloro-4-biphenylyl) butyric acid

A mixture of 10 g of crude α-hydroxy-7- (2'-

209839/1254

chloro-4-biphenyIyI) -butyronitri'l, obtained according to the information from Example 14, with 250 cm.sup.3 acetic acid and 150 cm.sup conc. Hydrochloric acid is stirred on the steam bath for 4 hours, cooled, with 500 cmr Diluted water -and extracted with benzene. The benzene extract is washed with brine and dried with sodium sulfate and then evaporated to dryness. The residue is dissolved in ether and the organic phase extracted three times with sodium bicarbonate. After acidifying the bicarbonate extracts, a precipitate is obtained, consisting of biphenylylbutyric acid, which is dissolved in ether, washed with brine and evaporated freed from solvent. This is how you get the α-Hydroxy-7- (2'-chloro-4-biphenyIyI) butyric acid.

A) If, in the above process, the α-hydroxy-7- (2'-chloro-4-biphenylyI) -butyronitrile is replaced by the nitriles according to Examples 13 and 14, the corresponding carboxylic acid products are obtained. A list of such compounds is given below. a-Hydroxy-7- (4 ^f -chloro-4-biphenylyl) -butyric acid a-Hydroxy-7- (2'-nitro-4-biphynylyl) -butyric acid a-Hydroxy-7- (4 ^f -nitro-4- biphenyIyI) butyric acid a-Hydroxy-7- (2 ¹ -methyl-4-biphenylyl) butyric acid

2Q9839 / 1254

α-Hydroxy-7- (^ '-methyl-4-b'iphenylyl) -butyric acid α-Hydroxy-7- (2'-bromo-4-biphenyIyI) butyric acid α-Hydroxy-7- (4 '- bromo-4-bipheny IyI) «- butyric acid α-Hydroxy-7- (2-chloro-4-biphenylyl) -butyric acid α-Hydroxy-7- (2-nitro-4-biphenylyl) butyric acid a-Hydroxy-7- (2-methyl-4-biphenylyl) butyric acid α-Hydroxy-7- (2-bromo-4-biphenyIyI) -butyric acid α-Hydroxy-7- (4-tolyl) -butyric acid α-Hydroxy-7- (4 * isopropylphenyl) butyric acid α-Hydroxy-7- (4-tert-butylphenyl) -butyric acid. α-Hydroxy-7- (4-cyclopentylphenyl) -butyric acid α-Hydroxy-7- (4-cycloheptylphenyl) butyric acid α-Hydroxy-r7- (4-cyclohexyl phenyl) butyric acid α-Hydroxy-7- (4-cyclohex-1-enylphenyl) butyric acid α-Hydroxy-7- (4-phenoxyphenyl) butyric acid α-Hydroxy-7- (4-phenylthiophenyl) butyric acid α-Hydroxy-7- (4-anilinophenyl) -butyric acid. α-Hydroxy-7- (2-anilinephenyl) -butyric acid a-Hydroxy-7- (4-benzoylphenyl) butyric acid ' α-Hydroxy-7- [4- (2-thienyl) phenyl! butyric acid α-Hydroxy-7- [4- (3-furyl) phenyl! butyric acid α-Hydroxy-7- [4- (2-pyridyl) -phenyl] -butyric acid. α-Hydroxy-7- [4- (4-pyridyl) -phenyl] -butyric acid α-Hydroxy-7- [4- (2-pyrazinyl) phenyl! butyric acid α-Hydroxy-7- [4- (2-pyrimidinyl) phenyl! butyric acid

9/1254

a-Hydroxy-Ύ- [4- (3-pyridazinyl) -phenyl! -butyric acid a-Hydroxy-Ύ- [4- (2-triazinyl) -phenyl! -butyric acid a-Hydroxy-Ύ- [4- (3- isoxazolyl) -phenyl! -butyric acid a-hydroxy-Ύ- [4- (3-isothiazolyl) -phenyl! -butyric acid a-hydroxy-7- [4- {2H-pyrrol-3-yl) -phenyl! -butyric acid a -Hydroxy-Ύ- [4- (2-imidazolyl) -phenyl! -Butyric acid a-Hydroxy-7- [4- (1-pyrazolyl) -phenyl! -Butyric acid a-hydroxy-7- [4- (2H-pyran -2-yl) -phenyl! -Butyric acid α-hydroxy-7- [4- (l-pyrrolyl) -phenyl! -Butyric acid a-hydroxy-Ύ- [4- (2-imidazolin-4 ~ yl) -phenyl! -butyric acid a-hydroxy-Ύ- [4- (2-imidazolidinyl) -phenyl! -butyric acid a-hydroxy-Ύ- [4- (l-pyrazolidinyl) -phenyl! -butyric acid a-hydroxy-Ύ- [4- ( 2-pyrrolidinyl) -phenyl! -Butyric acid a-hydroxy-Ύ- [4- (2-pyrrolin-3-yl) -phenyl! -Butyric acid a-hydroxy-Ύ- [4- (2-piperidinyl) -phenyl! - butyric acid a-Hydroxy-Ύ- [4- (4-piperidinyl) -phenyl! -butyric acid a-Hydroxy-Ύ- [4- (l-piperazinyl) -phenyl! -butyric acid a-hydroxy-Ύ- [4- (2 -piperazinyl) -phenyl! -butyric acid a-hydroxy-Ύ- [4- (3-morpholinyl) -phenyl! -butyric acid a-hydroxy-Ύ- [4- (4-morpho linyl) -phenyl! -butyric acid α-hydroxy-α-methyl-Ύ- ( β'-chloro-4-biphenyIyI) -butyric acid. . '"

α-Hydroxy-α-methyl-Ύ- (2'-nitro-4-biphenylyl) butyric acid α-Hydroxy-α-methyl-Ύ- (2'-bromo-4-biphenylyl) -butyric acid α-Hydroxy-α-methyl-Ύ- (4'-nitro-4-biphenyIyI) butyric acid

20983 97 1254

a-Hydroxy-a-methyl-7- (4'-chloro-4-biphenylyl) ~ butyric acid a ~ Hydroxy-a-methyl-7- (4'-bromo-4-biphenylyl) -butyric acid a-Hydroxy-a- methyl-7- (2'-chloro ^ -biphenylyl ^ butyric acid a-hydroxy-a-methyl-7- (2-nitro-4-biphenylyl) -butyric acid a-hydroxy-a-methyl-7- (2-bromo- 4-biphenylyl) butyric acid a-hydroxy-a-methyl-7- (4-isopropylphenyl) -butyric acid a-hydroxy-a-methyl-7- (4-cyclohexylphenyl) -butyric acid a-hydroxy-a-methyl-7- [4- (1-pyrrolyl) -phenyl] -butyric acid α-hydroxy-β-methyl-7- (2'-chloro-4-biphenyIyI) -butyric acid α-hydroxy-β-methyl-7- (2'-nitro -4-biphenyIyI) -butyric acid a-hydroxy-ß-methyl-7- (2'-bromo-4-biphenyIyI) .- butyric acid a-hydroxy-ß-methyl-7- (4'-nitro-4-biphenyIyI) -butyric acid a-hydroxy-ß-methyl-7- (4'-chloro-4-biphenyIyI) -butyric acid a-hydroxy-ß-methyl-7- (4 ¹ -bromo-4-biphenyIyI) -butyric acid a-hydroxy- β-methyl-7- (2-chloro-4-biphenyIyI) -butyric acid α-hydroxy-β-methyl-7- (2-nitro-4-biphenylyl) -butyric acid α-hydroxy-β-methyl-7- (2 -bromo-4-biphenyIyI) -butyric acid α-hydroxy-β-methyl-7- (4-isopropylphenyl) -b Butyric acid α-hydroxy-β-methyl-7- (4-cyclohexylphenyl) -butyric acid α-hydroxy-β-methyl-7- [4- (1-pyrrolyl) -phenyl] -butyric acid α-hydroxy-7-methyl-7 - (2'-Chloro-4-biphenylyl) -butyric acid a-Hydroxy-7-methyl-7- (2'-nitro-4-biphenylyl) -butyric acid a-Hydroxy-7-methyl-7- (2'-bromo -4-biphenylyl) butyric acid a-hydroxy-7-methyl-7- (4'-nitro-4-biphenyIyI) butyric acid a-hydroxy-7-methyl-7- (4'-chloro-4-biphenylyl) - butyric acid

209839/1254

a * Hydroxy-7-methyl-7- (4'-bromo-4-biphenyIyI); - butyric acid ct-hydroxy ^ -methyl ^ - (2-chloro-4-biphenyIyI) -butyric acid a-hydroxy-7- methyl-7- (2-nitro-4-biphenylyl) -butyric acid a-Hydroxy-7-methyl-7- (2-bromo-4-biphenylyl) -butyric acid a-Hydroxy-7-methyl-7- (4-isopropylphenyl ) -butyric acid ■ a-hydroxy-7-methyl-7- (4-cyclohexylphenyl) -butyric acid a-hydroxy-7-methyl-7- [4- (l-pyrrolyl) -phenyl! -butyric acid ß-hydroxy-7- (2 ^! -Chlor-4-biphenyIyI) -butyric acid ß-Hydroxy-7- (4'-chloro-4-biphenyIyI) -butyric acid ß-hydroxy-7- (2'-nitro-4-biphenylyl) -butyric acid ß- Hydroxy-7- (4'-nitro-4-biphenylyl) -butyric acid β-hydroxy-7- (2'-methyl- ^ i-biphenyIyI) -butyric acid β-hydroxy-7- (4'-methyl-4-biphenyIyI ) -butyric acid ß-hydroxy-7- (2-bromo-4-biphenylyl) -butyric acid ß-hydroxy-7- (4 ^! -bromo-4-biphenyIyI) -butyric acid ß-hydroxy-7- (2-chloro-4 -bipheny IyI) -butyric acid ß-hydroxy-7- (2-nitro-4-biphenylyl) -butyric acid ß-hydroxy-7- (2-methyl-4-biphenylyl) -butyric acid ß-hydroxy-7- (2-bromo -4-biphenyIyI) -butyric acid ß-hydroxy-7- (4-tolyl) -butte ß-Hydroxy-7- (4-isopropylphenyl) butyric acid ß-Hydroxy-7- (4-tert-butylphenyl) butyric acid ß-hydroxy-7- (4-cyclopentylphenyl) butyric acid ß-hydroxy-7- ( 4-cycloheptylphenyl) -butyric acid ß-Hydrox3 ^r -7- (4-cyclohexylphenyl) -butyric acid

209839/125 4

ß-Hydroxy-7 - (4-cyelohex-l ~ enylphenyl) butyric acid ■ ß-Hydroxy-7- (4-phenoxyphenyl) -butyric acid ß-Hydroxy-7- (4-phenylthiophenyl) -butyric acid ß-Hydroxy-7- (4-anilinophenyl) butyric acid ß-Hydroxy-7- (2-anilinophenyl ^ butyric acid β-Hydroxy-7- (4-benzoylphenyl) -butyric acid β-Hydroxy-7- [4- (2-thienyl) -phenyl-butyric acid ^ β-Hydroxy-7- [4- (3-furyl) phenyl] butyric acid

β-Hydroxy-7- [4- (2-pyridyl) phenyl! butyric acid β-Hydroxy-7- [4- (4-pyridyl) phenyl] butyric acid β-Hydroxy-7- [4- (2-pyrazinyl) -phenyl] -butyric acid β-Hydroxy-7- [4- (2-pyrimidinyl) -phenyl] -butyric acid β-Hydroxy-7- [4- (3-pyridazinyl) phenyl / butyric acid. β-Hydroxy-7- [4- (2-triazinyl) phenyl] butyric acid β-Hydroxy-7- [4- (3-isoxazolyl) phenyl] butyric acid. β-Hydroxy-7- [4- (3-isothiazolyl) phenyl] butyric acid β-Hydroxy-7- [4- (2H-pyrrol-3-yl) -phenyl] -butyric acid β-Hydroxy-7- [4- (2-imidazoIyI) -phenyl] -butyric acid β-Hydroxy-7- [4- (1-pyrazolyl) phenyl] butyric acid β-Hydroxy-7- £ 4- (2H-pyran-2-yl) -phenyl! -butyric acid β-Hydroxy-7- [4- (1-pyrrolyl) -phenyl! -butyric acid β-Hydroxy-7- [4- (1-pyrrolyl) -phenyl! -butyric acid β-Hydroxy-7- [4- (2-imidazolidin-4-yl) -phenyl! -butyric acid β-Hydroxy-7- [4- (2-imidazolidinyl) -phenyl! -butyric acid β-Hydroxy-7- [4- (1-pyrazolidinyl) -phenyl! -butyric acid β-Hydroxy-7- [4- (2-pyrrolidinyl) phenyl] butyric acid

209839/1254

ß-Hydroxy-7- [4- (2-pyrrolin-r3-yl) '- phenyl] -butyric acid .ß-Hydroxy-7- [4- (2-piperidinyl) -phenyl! -butyric acid ß-hydroxy-7- [4- (4-piperidinyl) -phenyl! -Butyric acid ß-hydroxy-7- [4- (l-piperazinyl) -phenyl! -Butyric acid ß-hydroxy-7- [4- (2-piperazinyl) -phenyl! - butyric acid ß-hydroxy-7- [4- (3-morpholinyl) -phenyl! -butyric acid ß-hydroxy-7- [4- (4-morpholinyl) -phenyl! -butyric acid α-methyl-ß-hydroxy-7- ( 2'-chloro-4-biphenylyl) butyric acid α-methyl-β-hydroxy-7- (2'-nitro-4-biphenylyl) butyric acid α-methyl-β-hydroxy-7- (2'-bromo-4 -biphenylyl) -butyric acid. α-methyl-ß-hydroxy-7- (4'-nitro-4-biphenyIyI) -butyric acid a-methyl-ß-hydroxy-7- (4'-chloro-4-biphenylyl) -butyric acid α-methyl-ß- hydroxy-7- (4 ¹ -bromo-4-biphenylyl) -butyric acid α-methyl-ß-hydroxy-7- (2-chloro-4-biphenylyl) -butyric acid α-methyl-ß-hydroxy-7- (2- nitro-4-biphenylyl) butyric acid a-methyl-ß-hydroxy-7- (2-bromo-4-biphenylyl) butyric acid a-methyl-ß-hydroxy-7- (4-isopropy! phenyl) butyric acid a- Methyl-ß-hydroxy-7- (4-cyclohexy! Phenyl-butyric acid a-methyl-ß-hydroxy-7- [4- (1-pyrrolyl) -phenyl! -Butyric acid

ß-methyl-ß-hydroxy-7- (2'-chloro-4-biphenyIyI) -butyric acid ß-methyl-ß-hydroxy-7- (2'-nitro-4-biphenylyl) -butyric acid ß-methyl-ß- hydroxy-7- (2'-bromo-4-biphenylyl) -butyric acid ß-methyl-ß-hydroxy-7- (4'-nitro-4-biphenylyl) -butyric acid ß-methyl-ß-hydroxy-7- (4 ^1- chloro-4-biphenyIyI) butyric acid

209839/1254

, ß-methyl-ß-hydroxy-7- (4 '~ bromo-4-biphenylyl) -butyric acid ß-methyl-ß-hydroxy-7- (2-chloro-4-biphenylyl) -butyric acid ß-methyl-ß- hydroxy-7- (2 <-nitro-4-biphenylyl) -butyric acid ß-methyl-ß-hydroxy-7- (2-bromo-4-biphenylyl) -butyric acid ^N

rf. - ■

ß-methyl-ß-hydroxy-7- (4-isopropylphenyl) butyric acid ß-Methyl-ß-hydroxy-7- (4-cyclohexylphenyl) -butyric acid ß-methyl-ß-hydroxy-7- [4- (l-pyrrolyl) -phenylj-butyric acid β-Hydroxy-7-methyl-7- (2'-chloro-4-biphenylyl) -butyric acid β-Hydroxy-7-methyl-7- (2'-nitro-4-biphenylyl) -butyric acid β-Hydroxy-7-methyl-7- (2'-bromo-4-biphenylyl) butyric acid β-Hydroxy-7-methyl-7- (4'-nitro-4-biphenylyl) -butyric acid β-Hydroxy-7-methyl-7 -. (4'-chloro-4-bipheny IyI) -butyric acid β-Hydroxy-7-methyl-7- (4'-bromo-4-biphenylyl) butyric acid β-Hydroxy-7-methyl-7- (2-chloro-4-biphenyIyI) butyric acid β-Hydroxy-7-methyl-7- (2-nitro-4-biphenyIyI) butyric acid β-Hydroxy-7-methyl-7- (2-bromo-4-biphenyIyI) butyric acid β-Hydroxy-7-methyl-7- (4-isopropylphenyl) butyric acid β-Hydroxy-7-methyl-7- (4-cyclohexylphenyl) butyric acid β-Hydroxy-7-methyl-7- [4- (1-pyrrolyl) phenyl] butyric acid

Example l6

2-phenyl-4- (2'-chloro-4-biphenylal) -5-oxazolone

A mixture of 13 g (0.06 mol) of 4- (2'-chlorophenyl) benzaldehyde, 10 g (0.06 mol) Hippur ^ acid and 9.6 g (0.06 mol) of sodium acetate in 200 cnr ⁵ Acetic acid-

209839/1254

anhydride heated to 100 ⁰ C with stirring for 4 hours. The reaction mixture is then cooled to room temperature and made to crystallize out. The product is filtered off, washed with water / water and recrystallized from benzene, 2-phenyl-4- (2 ^! -Chloro-4-biphenylal) -5-oxazolone being obtained.

A) Replacing 4- (2'-chlorophenyl) benzaldehyde in the above example the aldehydes according to Example 2 lead to corresponding products.

Example 17

ß- (2 * -Chlor-4-biphenylyl ^ pyruvic acid

A mixture of 19.6 g (0.055 mol) of 2-phenyl-4- (2'-chloro-4-biphenylal) -5-oxazolone with 500 cnr of a 10% sodium hydroxide solution is refluxed in a nitrogen atmosphere for 15 minutes . The hot reaction mixture is filtered. The cold filtrate is then slowly mixed with 200 cnr of a βη-hydrochloric acid solution while stirring. The solid material is then collected by filtration and stored at room temperature
Air dried. The crude product is dissolved in 210 cnr glacial acetic acid and then heated to the boil for 10 minutes. The acidic mixture is then stirred until room temperature is reached, whereupon one drips

209839/1254

stir in 105 cnr water. The solid material will collected by filtration, washed with water and dried at room temperature, the ß- (2'- ■ Chlorine-4-biphenylyl ^ pyruvic acid is obtained.

A) If the oxazolones mentioned in Example 16 are used in the above process instead of the 2-phenyl- W 4- (2'-chloro-4-biphenylal) -5-oxazolone, a corresponding product is obtained.

Example 18

ß- (2 ^! -Chlor-4-biphenylyl) -pyruvic acid ethyl ester

By reaction of .beta. (2'-chloro-4-biphenylyl) pyruvate was obtained with absolute ethanol containing a small amount of anhydrous hydrochloric acid, yields the ß (2'-chloro-4-biphenylyl) -brenztraubensäureäthyl- w ester.

q-Methyl-ß- (2 * -chlor-4-biphenylyl) -lactic acid ethyl ester A solution of methyl magnesium iodide is prepared from 6.7 g (0.047 mol) of methyl iodide, 1.24 g (0.051 gram atom) of magnesium shavings and 40 cm ^ of anhydrous ether . This solution is added within one hour to a solution of 0.05 mol of ß- (2'-chloro-4-biphenylyl) -pyruvic acid ethyl ester. The addition takes place with vigorous stirring at 0 to 5 ^° C. Then is

2098 39/12 54

the mixture to room temperature within 10 hours let warm up. It is then poured into an ice-cold solution of 0.2 molar sulfuric acid. the ethereal layer is separated off with aqueous sulfuric acid extracted, dried over magnesium sulfate, filtered and evaporated, whereby the α-methyl-ß- ' (2'-chloro-4-biphenyIyI) lactic acid ethyl ester is obtained.

A) If in the above example the ß- (2'-chloro-4-biphenyIyI ^ pyruvic acid is replaced by the ketoalkanoic acids or esters obtained in Examples 1, 8 and 17, this is how you get to the. corresponding products. A list of such products can be found below Table I.

Table I.

Aethyl-a-methyl-4'-chloro-4-biphenylyl glycolate Aethyl-a-methyl-2'-nitro-4-biphenylyl glycolate Aethyl-a-methyl-4 ¹ -nitro-4-biphenylyl glycolate Aethyl-a-methyl-2 ' -methyl-4-biphenyIylglycolate ethyl-a-methyl-4'-methyl-4-biphenylyl glycolate ethyl-a-methyl-2'-bromo-4-biphenyIylglycolat ethyl-a-methyl-4'-bromo-4-biphenylylglycolate ethyl- α-methyl-β- (2'-chloro-4-biphenylyl) -lactate, ethyl-α-methyl-β- (4'-chloro-4-biphenylyl) -lactate

209839/1254

Ethyl-a-methyl-ß- (2'-nitro-4-biphenylyl) -lactate Ethyl-a-methyl-ß- (4'-nitro-4-biphenylyl) -lactate Ethyl-a-methyl-ß- (2 '-methyl-4-biphenyIyI) -lactate ethyl-a-methyl-ß - ^' - methyl ^ -biphenylylJ-lactate ethyl-ß-methyl-ß-hydroxy-ß- (4 ^f -chlor-4-bipheny IyI) -propionate

Ethyl-ß-methyl-ß-hydroxy-ß- (2'-chloro-4-biphenylyl) propionate . ■

Ethyl-ß-methyl-ß-hydroxy-ß- (2'-nitro-4-biphenylyl) propionate Ethyl-ß-methyl-ß-hydroxy-ß- (4'-nitro-4-biphenylyl) propionate, ethyl ß-methyl-ß-hydroxy-ß- (2'-methyl-4-biphenylyl) propionate

Ethyl-ß-methyl-ß-hydroxy-ß- (4 * -methyl-4-biphenyIyI) propionate

Ethyl 7-methyl-7-hydroxy-7- (4'-chloro-4-biphenylyl) butyrate ethyl 7-methyl-7-hydroxy-7- (2'-chloro-4-biphenylyl) butyrate ethyl 7-methyl-7-hydroxy-7- (2 ^l -nitro-4-biphenylyl) butyrate, ethyl 7-methyl-7-hydroxy-7- (4'-nitro-4-biphenylyl) butyrate, ethyl 7- methyl 7-hydroxy-7- (2'-methyl-4-biphenylyl) butyrate, ethyl 7-methyl-7-hydroxy-7- (4'-methyl-4-biphenylyl) butyrate

Ethyl-a-methyl-p-isopropylphenyl glycolate '

Ethyl a-methyl-p-tert-butylphenyl glycolate Ethyl a-methyl-p-cyclohexylphenyl glycolate Ethyl a-methyl-p-cyclohex-1-enylphenyl glycolate Ethyl a-methyl-p-phenoxyphenyl glycolate Ethyl-a-methyl-p- (phenylthio) -phenylglycolate

209839/1254

Ethyl-a-methyl-p-phenylaminophenyl glycolate ethyl-a-methyl-p- (2-thienyl) -phenyl glycolate ethyl-a-methyl-p- (3-furyl) -phenylglycolate ethyl-a-methyl-p- (2- pyridyl) phenyl glycolate, ethyl a-methyl p- {H- pyridyl) phenyl glycolate, ethyl a-methylr-p- (1-pyrrollyl) phenyl glycolate, ethyl a-methyl p- (1-piperazinyl) phenyl glycolate, ethyl -a-methyl-p- (3-njorpholinyl) -phenylglycolate ethyl-a-methyl-ß- (p-isopropylphenyl) -lactate ethyl-a-methyl-ß- (p-tert-butylphenyl) lactate ethyl-a -methyl-ß- (p-cyclohexylphenyl ) - lactate ethyl-a-methyl-ß- (p-cyclohex-1-enylphenyl) -lactate ethyl-a-methyl-ß- (p-phenoxyphenyl) -lactate ethyl-a- methyl-ß- (p-phenylthiophenyl) -lactate ethyl-a-methyl-ß- (p-phenylaminophenyl) -lactate ethyl-a-methyl-ß- [ρ- (2-thienyl) -phenyl] -lactate ethyl-a -methyl-ß- [ρ- (3-furyl) -phenyl] -lactate ethyl-a-methyl-ß- [ρ- (2-pyridyl) -phenyl-lactate ethyl-a-methyl-ß- [ρ- ( 4-pyridyl) -phenyl] -lactate ethyl-a-methyl-ß- [ρ- (1-pyrrolyl) -phenyl] -lactate ethyl-a-methyl-ß- [p- (l-piperazihyl) -phenyl] - lactate ethy la-methyl-ß- [ρ- (3-morpholinyl) -phenyl] -lactate ethyl-a-methyl-ß-hsydroxy-ß- (p-isopropylphenyl) -propionate ethyl-a-methyl-ß-hydroxy-ß- (p-tert-butylphenyl) propionate ethyl-a-raethyl-P-liydroxy-p- (p-cyclohexylphenyl) propionate ethyl-a-methyl-ß-liydiroxy-p- (p-cyclohex-l-enylphenyl) -propiona · Aethyl-a-raethyl-P-iiydroxy-p- (p-phenoxyphenyl) -propionate 209839 / 125A

- io8 -

Ethyl-a-methyl-ß-hydroxy-ß- (p-phenylthiophenyl) propionate Ethyl-a-methyl-ß-hydroxy-ß- (p-phenylaminophenyl) propionate Ethyl α-methyl-β-hydroxy-β- [p- (2-thienyl) phenyl J-propionate

Ethyl a-methyl-ß-hydroxy-ß- [p- (3-furyl) phenyl] propionate Ethyl α-methyl-β-hydroxy-β- [p- (2-pyridyl) phenyl] propionate Ethyl α-methyl-β-hydroxy-β- [p- (4-pyridyl) phenyl] propionate Ethyl a-methyl-ß-hydroxy-ß- [p- (l-pyrrolyl) -phenyl] -propionate ethyl-a-methyl-ß-hydroxy-ß- [p- (l-piperazinyl) -phenyl] -propionate

Ethyl α-methyl-β-hydroxy-β- [p- (3-morpholinyl) phenyl] propionate

Ethyl 7-methyl-7-hydroxy-7- (p-isopropylphenyl) butyrate, ethyl 7-methyl-7-hydroxy-7- (p-tert-butylphenyl) butyrate Ethyl 7-methyl-7-hydroxy-7- (p-cyclohexylphenyl) butyrate Ethyl 7-methyl-7-hydroxy-7- (p-cyclohex-1-enylphenyl) butyrate Ethyl 7-methyl-7-hydroxy-7- (p-phenoxyphenyl) butyrate Ethyl 7-methyl-7-hydroxy-7- (p-phenylthiophenyl) butyrate Ethyl 7-methyl-7-hydroxy-7 ~ (p-phenylaminophenyl) butyrate Ethyl 7-methyl-7-hydroxy-7- [p- (2-thienyl) phenyl] butyrate Ethyl 7-methyl-7-hydroxy-7- [p- (3-furyl) phenyl] butyrate Ethyl 7-methyl-7-hydroxy-7- [p- (2-pyridyl) phenyl] butyrate Ethyl 7-methyl-7-hydroxy-7- [p- (4-pyridyl) phenyl] butyrate Ethyl 7-methyl-7-hydroxy-7- [p- (1-pyrrolyl) phenyl] butyrate Ethyl 7-methyl-7-hydroxy-7- [p- (1-piperaainyl) phenyl] butyrate

Ethyl-7-methyl-7-hydroxy-7- [p- (3-morpholinyl) -phenylj-

butyrate 209839/1254

Ethyl α, β-dimethyl-β-hydroxy-β- (2'-chloro-4-biphe ny Iy 1) propionate

Ethyl α, 7-dimethyl-7-hydroxy-7- (2'-chloro-4-biphenylyl) butyrate

Aethyl-ß ^ -dimethyl ^ -hydroxy ^ -Ca'-chloro - ^ - biphenylyli-butyrate ethyl-a, ß-dimethyl-7-hydroxy-7- (2'-chloro-4-biphenylyl) -butyrate ethyl-a , β _i 7-trimethyl-7-hydroxy-7- (2'-chloro-4-biphenylyl) butyrate

B) Used as Grignard reagent, ethyl magnesium iodide, propyl magnesium iodide or butyl magnesium iodide is used to get to the corresponding products. '·

Example 19

ß- (2'-chloro-4-biphenylyl) lactic acid

To a suspension of 8.64 g (0.031 mol) of β- (2'-chloro-4-biphenyIyI) -pyruvic acid in 300 cnK 90% ethanol is given to 1 cnP. 0.1 mclare ferrous sulfate solution and then add 0.5g of a platinum oxide catalyst. The mixture is hydrogenated for 3 1/2 hours shaken. The catalyst is then filtered off. Then the dark yellow filtrate is under distilled under reduced pressure, whereby the "ß- (2'-chloro-4-biphenylyl) -lactic acid receives.

209839/1254

A) If in the above process the β- (2'-chloro-4-biphenyIyI ^ pyruvic acid is replaced by the Ketoalkanoic acids obtained in Examples 1, 8 and 17 or esters, this leads to the corresponding products. A list of such products can be found in the table below.

Table I.

4'-chloro-4-biphenylyl glycolic acid 4'-methyl-4-biphenylyl glycolic acid 4 ^! -Nitro-4-biphenylyl glycolic acid 4'-Bromo-4-biphenylyl glycolic acid. ■ 2'-chloro-4-biphenylyl glycolic acid, 2'-bromo-4-biphenylyl glycolic acid, 2'-nitro-4-biphenylyl glycolic acid

2'-methyl-4-biphenylyl glycolic acid ß- (4'-chloro-4-biphenylyl) lactic acid

f ß- (4'-methyl-4-biphenylyl) lactic acid

ß- (4'-Nitro-4-biphenylyl) ^{-lactic acid ß- (4 t} -bromo-4-biphenylyl) -lactic acid ß- (2'-bromo-4-biphenylyl) -lactic acid 'ß- (2'-nitro -4-biphenylyl) -lactic acid ß- (2'-methyl-4-biphenylyl) -lactic acid ß-hydroxy-ß- (4'-chloro-4-biphenyIyI) -propionic acid ß-hydroxy-ß- (4'-methyl -4-biphenylyl) propionic acid

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- Ill -

ß-hydroxy-ß (4'-nitro-4-biphenylyl) propionic acid .beta.-hydroxy-.beta. (2 ^J chloro ~ 4-biphenylyl) propionic acid .beta.-hydroxy-.beta. (2'-methyl-4- biphenyIyI) propionic acid ß-hydroxy-ß- (2'-nitro-4-biphenylyl) propionic acid 7-hydroxy-7- (4'-chloro-4-biphenylyl) -butyric acid 7-hydroxy-7- (4 ¹ - nitro-4-biphenylyl) -butyric acid 7-hydroxy-7- (4'-methyl-4-biphenyIyI) -butyric acid 7-hydroxy-'Y- (2 '- chloro-4-biphenylyl) -butyric acid 7-hydroxy- 7- (2 * -nitro-4-biphenylyl) -butyric acid. 7-Hydroxy-7- (2'-methyl-4-biphenyIyI) -butyric acid cc-methyl-ß-hydroxy-ß- (2 ¹ -chloro-4-biphenylyl) propionic acid a-methyl-ß-hydroxy-7- (2'-chloro-4-biphenylyl) butyric acid ß-methyl-7-hydroxy-7- (2'-chloro-4-biphenylyl) butyric acid a, ß-dimethyl-7-hydroxy-7- (2 ^t - chloro-4-biphenylyl) butyric acid p-isopropylpheny! glycolic acid
p-tert-butylphenyl glycolic acid p-cyclohexylphenyl glycolic acid
p-Cyclohex-1-enylpheny! glycolic acid p-Phenoxypheny! glycolic acid
p-phenylthiophenyl glycolic acid
p-phenylaminophenyl glycolic acid p- (2-thienyl) -phenylglycolic acid

p- (3 ~ furyl) -pheny! glycolic acid ■ _t - ■

p- (2-pyridyl) -phenylglycolic acid p- (4-pyridyl) -pheny! glycolic acid '

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2162G38

ρ- (l-pyrrolyl) -pheny! glycolic acid ρ- (1-piperazinyl) -pheny! glycolic acid p- (3-morpholinyl) phenylglycolic acid ß- (p-isopropylphenyl) -lactic acid ß- (p-tert-butylphenyl) -lactic acid ß- (p-Cyclohexylphenyl) -lactic acid ß ~ (p-Cyclohex-l-enylphenyl) -lactic acid ß- (p-Phenylthiophenyl) -lactic acid "ß- (p-Phenylaminophenyl) -lactic acid

ß- [p- (2-Thlenyl) -phenyl3-lactic acid ß- Ep- (3-Fur ^> yl) -Phe ⁿ yl] -lactic acid ß- [p- (2-pyridyl) -phenyl] -lactic acid ß- [p- (4-Pyridyl) -phenyl] -lactic acid ß -. [p- (1-Pyrrolyl) -phenyl] -lactic acid ß-Cp- (l-piperazinyl) -phenyl] -lactic acid ß- [p- (3rd -Morpholinyl) -phenyl] -lactic acid ß-hydroxy-ß- (p-isopropylphenyl) -propionic acid ß-hydroxy-ß- (p-tert-butylphenyl) propionic acid ß-hydroxy-ß- (p-cyclohexylphenyl) propionic acid ß-Hydroxy-ß- (p-cyclohex-1-enylphenyI) -propionic acid ß-Hydroxy-ß- (p-phenoxyphenyl) -propionic acid ß-hydroxy-ß- (p-phenylthiophenyl) -propionic acid ß-hydroxy-ß- ( p-phenylaminophenyl) propionic acid ß-hydroxy-ß- [p- (2-thienyl) -phenyl] -propionic acid ß-hydroxy-ß- [p- (3-furyl) -phenyl] -propionic acid

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ß-Hydroxy-ß- [ρ- (2-pyridyl) -phenyl! -propionic acid ß-Hydroxy-ß- [ρ- (4-pyridyl) -phenyl! -propionic acid β-hydroxy-β- [p- (l-pyrrolyl) phenyl] propionic acid ß-Hydroxy-ß- [p- (1-piperazinyl) -phenyl-propionic acid ß-Hydroxy-ß- [p- (3-morpholinyl) -phenyl! -propionic acid 7-Hydroxy-7- (p-isopropylphenyl) -butyric acid 7 ~ Hydroxy-7- (p-tert-butylphenyl) -butyric acid 7-hydroxy-7- (p-cyclohexylphehyl) butyric acid. 7-hydroxy-7- (p-cyclohex-1-enylphenyl) butyric acid 7 ~ · Hydroxy-7- (p-phenoxyphenyl ^ butyric acid 7-hydroxy-7- (p-phenylthiophenyl) butyric acid 7-hydroxy-7- (p-phenylaminophenyl) butyric acid 7-Hydroxy-7- [p- (2-thienyl) phenyl] butyric acid 7-Hydroxy-7 ~ [p- (3-furyl) phenyl! Butyric acid 7-hydroxy-7- [p- (2-pyridyl) phenyl! Butyric acid 7-hydroxy-7- [p- (4-pyridyl) phenyl! Butyric acid 7-Hydroxy-7- [p- (1-pyrrolyl) -phenyl! -Butyric acid 7-Hydroxy-7- [p- (1-piperazinyl) -phenyl-3-butyric acid. 7-Hydroxy-7- [p- (3-morpholnyl) -phenyl! -Butyric acid

Example 20

3-chloro-4-biphenylyl glyoxylic acid ethyl ester

96.6 g (0.38 mol) ethyl-p-biphenylylglyoxylat and 6.1 g (0.048 mol) of iodine are dissolved in 100 CRRR ⁵ carbon tetrachloride. This solution is then followed by a

2098.39 / 125 4

Solution of 4o.4 g (0.57 mol) of chlorine, dissolved in 365 cnr. ⁵ carbon tetrahydrofuran, added within 2 hours. The temperature of the reaction mixture is kept at 0 ^° C. during the addition. The mixture is then stirred for --- "3 hours and left to stand for 15 hours, allowing the mixture to gradually warm to room temperature. The solvent is then removed by distillation under reduced pressure. The residue is fractionally distilled, whereby ethyl 3-chloro-4-biphenylyl glyoxylate is obtained.

A) Replacing the chlorine in the above example bromine gives ethyl 3-bromo-4-biphenylyl glyoxylate.

B) The other compounds mentioned above can be chlorinated and brominated in a similar manner.

Example 21 Ethyl - ^ - nitro-4-biphenylyl glyoxylate

ΐβ, 7 g (0.066 mol) of ethyl p-biphenylyl glyoxylate are added to 18 cnr ice-cold concentrated sulfuric acid and stirred for 5 minutes while cooling. Then add 2.5 οηκ conc. nitric acid (specific gravity 1.51), whereby the temperature

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door stops if necessary by cooling with V / ater at 30 to 4o C ^0. After all the nitric acid has been added, the mixture is stirred for 1½ minutes and then in. Poured water. The mixture is then made alkaline with sodium hydroxide and then extracted with ether. The ethereal extract is washed, dried over sodium sulfate and evaporated, and the residue is fractionally distilled to give ethyl 3-nitro-4-biphenylyl glyoxylate.

B) In a similar way you can according to the invention nitrate available compounds.

Example 22 Ethyl β- (2 ¹ -nitro-4-biphenylyl) lactate

A sodium borohydride solution (1.142 g, 0.302 mol in 13 cnr V / water, containing 1 drop of 10N sodium hydroxide solution) is poured into a solution of 1.8.4 g (0.059 mol) of ethyl-β- (2'-nitro-4 -biphenylyl) pyruvate, 50 cnr methanol and 5 cnr water were added dropwise while cooling with an ice water mixer. The solution is then partially neutralized by means of 15 cm ^{5 of} a solution containing 0.04 l mol of acetic acid and urea each. The pH value after the addition is close to the neutral value. Beer up is the pH value by adding

209839/1254

2.8 cnr 18N sulfuric acid acidified. Then will the product extracted with ether, twice with each 25 cm of a saturated sodium bisulfite solution and then dried over anhydrous sodium sulfite for 2 hours. Then first the desiccant and then the solvent is removed, the ethyl β- (2'-nitro-4-biphenylyl) lactate being obtained.

A) If you work according to the above information using the nitro compounds obtainable according to the invention, this is how you get to the corresponding connections.

Example 23

Ethyl-ß- (2'-trifluoromethyl-4-biphenyIyI) -lactate , a solution of 0.01 mol of ethyl-ß- (2'-bromo-4-

biphenylyl) lactate in 50 cmrP dimethylformamide is added. Add 0.15 mole of trifluoromethyl iodide and 0.02 g of copper powder. Then the reaction mixture is in a ^zugeschmol: shaken Zenen tube for 5 hours at l4o ° C,.. cooled and then filtered and concentrated in vacuo. Then the residue is mixed with 200 cups of water and then extracted with ether. The ether extract is dried, evaporated to dryness and distilled, whereby the ethyl β- (2'-trifluoromethyl-4-biphenylyl) lactate is obtained.

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A) Corresponding trifluoromethyl compounds can be prepared in a similar manner.

Example 24

Ethyl-ß- (2 * -am ino-4- biphenyIyI) -lactate

15.7 g (0.05 mol) of ethyl β- (2'-nitrq-4-biphenylyl) lactate in 100 cnK of methanol, containing 0.05 mol of citric acid and 1.5 g of 5% palladium-on-carbon , are with hydrogen at a pressure of 2 atm. and shaken at 27 ^° C. until 3 mol of hydrogen have been absorbed. Then the mixture is filtered,

the catalyst

/ washed with methanol and the piltrate concentrated in vacuo, whereby the ethyl-ß- (2'-amino-4-biphenylyl) lactate in the form of the citrate salt.

A) According to the invention, other amino compounds can be prepared in a similar manner.

Example 25 Ethyl β- (2 ^> -methylamino-4-biphenylyl) lactate

To a solution of 0.01 mol of ethyl β- (2'-amino-4-biphenylyi) -actate 0.1 mol of methyl iodide is added in 100 cnr of pyridine. Then the reaction mixture Stirred overnight at room temperature, filtered and concentrated. The residue is distilled, whereby the ethyl-ß- (2'-methylamino-4-biphenylyl) -

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lactate.

A) Use 0.01 mol acetyl chloride instead of methyl iodide when working according to the above

man

Example, this is how / sum ethyl-ß- (2'-acetylamino-4-biphenylyl) lactate.

B) According to the invention, methylamino and acetylamino compounds can be prepared in a similar manner.

Example 26

Ethyl β- (2'-dimethylamino - ^ - biphenyI yI) lactate

A solution of 0.005 mol of ethyl β- (2'-nitro-4-biphenylyl) lactate and 1.6 cnP of 37% formaldehyde in 50 cnP of methanol is made up of 5% palladium with hydrogen in the presence of 0.5 g Coal existing catalyst at a pressure of about 3 at and a temperature of 27 ⁰ C so long shaken until 5 mol of hydrogen have been absorbed. The catalyst is then filtered off and the piltrate is evaporated in vacuo. The residue is then distilled to give ethyl β- (2'-dimethylamino-4-biphenylyl) lactate. ■ ·

A) In a similar manner, according to the invention prepare the dimethylamino compounds.

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Example 2?

Benzyl-β- (2'-cyano-4-biphenylyl) -lactate '

To 30.8 g (0.1 mole) of benzyl β- (2'-amino-4-blphenylyl) -laetat in 35 cur 28 $ strength hydrochloric acid and 100 to keep cirr crushed ice to maintain the temperature at 0 ⁰ C, a solution of 7 * 1 g (0.102 mol) of sodium nitrite in 20 cnA of water is added. The reaction mixture is then neutralized using sodium carbonate. This diazonium mixture is added to a cuprocyanide solution (prepared from 31> 5 g of copper sulfate and 16.2 g of sodium cyanide in 75 cm ^{−3 of} water). 250 cc of toluene are then added and the mixture is stirred for 30 minutes. It will then take another 2 hours

to 50 ⁰ C
gradual warming / touched. It is then cooled and the toluene is separated off, whereupon the product is dried over sodium sulfate and evaporated to dryness. In this way, benzyl β- (2'-cyano-4-biphenylyi) lactate is obtained.

A) According to the invention, corresponding cyano compounds can be obtained in a similar manner.

Example 28 Ethyl β- (2'-fluoro-4-biphenylyl) lactate

To 46.2 g (0.15 mol) of ethyl-ß- (2'-amino-4-bi-

2 0 9 8 3 9/1 25 A

phenylyl) lactate is added at ⁰ ° C. 44 cnP (1.5 mol) of conc. Hydrochloric acid added. The reaction mixture is then kept at 0 ^° C. and the diazonium salt is prepared with the aid of 23.2 g (0.32 mol) of 95% sodium nitrite in 80 cirr of water. A solution of 10.4 g (0.17 mol) of boric acid dissolved in 22 g (0.66 mol) of 60% hydrofluoric acid is quickly added to this mixture. The reaction mixture is then stirred for 30 minutes and filtered, then washed three times with 25 cm of water each time, then twice with 25 cm of methanol each time and finally with 25 cm of ether. The filter cake obtained is then treated in vacuo. The treated cake is then placed in a still and heated to cause spontaneous decomposition. After the decomposition has taken place, the residue is fractionally distilled, the ethyl β- (2'-fluoro-4-biphenylyl) lactate being obtained.

A) According to the invention, other fluorine compounds can be prepared in a similar manner,

Example 29

ß- (2 * -Hydroxy-4-biphenylyl) -lactic acid ■

To 4.5 g of an ethyl-ß- (2'-amino-4-biphenylyl) ~ lactate suspension in 125 cm ^ 80 hydrochloric acid, cooled

20 9839/1254

to ⁰ ° C., a solution of 1.2 g is added dropwise. Add sodium nitrite in 15 cnr water. After about 10 minutes, 200 cnP of 50% hydrochloric acid are added in portions and the mixture is stirred for 15 hours. The reaction mixture is then poured onto ice water and extracted with chloroform, the extract is dried over sodium sulfate and concentrated in vacuo. The residue is allowed to crystallize out, whereby β - (2 '"- hydroxy-4-biphenylyI ^ lactic acid is obtained.

The ethyl ester of this compound is obtained if one with absolute ethanol containing something anhydrous hydrochloric acid, · converts.

A) In a similar way, one can

get to the corresponding hydroxyl compounds.

ι ·

Example 3 °

Aethyl ^ - ^ '- methoxy- ^ biphenylyl ^ lactate . . '

In a suspension of 0.01 mol of sodium hydride

-z. ";.'- - · '" ■ "■" ■ .. · · ■■ "> in 25 CNH dry dimethylformamide, cooled to 0 ⁰ C, is added dropwise a solution of 0.01 mol _v ethyl-.beta. - (2'-hydroxy-4-biphenylyl) lactate is stirred into 10 cm ^ dimethylformamide. Then the reaction mixture is stirred for 15 minutes and then 0.015 mol of methyl iodide is added dropwise. Then the '

209839/1254 '' - -

Mixture stirred overnight at room temperature. then 200 citk water is added and the resulting mixture is extracted thoroughly with ether. The ethereal The extract is washed with water over sodium sulfate

■ abde stilli ert, dried, evaporated to dryness and the residue / whereby one obtains the ethyl-β-r (2'-methoxy-4 ~ biphenylyl) lactate.

A) If the benzyl ester and 0.01 mol of acetyl chloride are used instead of methyl iodide, the benzyl β * (2 ^r -acetyloxy-4-biphenylyl) lactate is obtained.

B) In a similar way. Way can be according to the invention the corresponding methoxy and acetyloxy compounds produce.

Example 31 . _.,

To 13.5 g (0.044 mol) of an ethyl-β- (2'-amino-r 4-biphenylyl) -laetatsus.pension in 225 cm- ^ 40 ^ iger bromine _T ; hydrochloric acid are added dropwise under cooling auf.0 ⁰ C a solution of 2.34 g of sodium nitrite in 30.cm <. Add water. Then the mixture with a solution of 20 g of cuprobromide in 350 om? 40% hydrobromic acid was added in portions and the mixture was stirred for 15 hours. The reaction mixture is then poured onto ice water, extracted with chloroform, dried over Na-

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2102038

Trium sulfate dried and concentrated in vacuo. The residue is then allowed to crystallize out, giving β- (2'-bromo-4-biphenyIyI) lactic acid.

The ethyl ester of this product is made by reaction with absolute ethanol, containing little anhydrous Hydrochloric acid.

A) In a similar way, according to the invention. also get to other bromine compounds.

Example 32

ß- (2'-iodo-4-biphenylyl) lactic acid

To 0.05 mol of ethyl-ß-CS'-amino - ^ - biphenylyl) lactate, dissolved in a mixture of 50 g of ice water and 0.06 mol of conc. Sulfuric acid, a solution of 0.05 mol of 95% sodium nitrite in 8 cnP of water is added ^{at 0 6 C.} The mixture is stirred for a further 30 minutes and then 1.5 cm3 of conc. Sulfuric acid. This solution is poured into an ice-cold solution of 0.06 mol of potassium iodide in 10 cm ^ V / water. Then added to the reaction mixture with stirring with 0.075 g of copper bronze and the solution warmed slowly to the water-bath to about 8o ⁰ C, and the course of 2 hours, After cooling to room temperature the reaction mixture is extracted three times with 15 cm of chloroform. Of the

209839/1254

The extract is then diluted with thiosulfate solution and then washed with water over sodium sulfate dried and evaporated in vacuo. The residue is made to crystallize out, using β- (2'-iodo-4-biphenylyl) lactic acid receives.

The corresponding ethyl ester is made slightly anhydrous by reaction with absolute ethanol Hydrochloric acid.

A) According to the invention, other iodine compounds can be prepared in similar catfish.

Example 33 '

β- (2'-mercapto-4-biphenylyl) lactic acid

To 18.8 g of ethyl β- (2'-amino-4-biphenylyl) lactate in 11.1 cnr -conc. Hydrochloric acid and 20 g of ice are added to 4.1 g of sodium nitrite in 2 cm ^ of water. This mixture is stirred for 10 minutes and then gradually added to an ice-cold solution of 10.3 g of potassium ethyl xarithogenate in 14 cm.sup.3 v / water. The reaction mixture is gradually heated in 45 minutes at 50 ⁰ C and then stirred for a further 45'Minuten. The mixture is then cooled, extracted with ether and the extract is then washed with water, then with dilute sodium hydroxide and finally again with water,

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_Ί 2182038

dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in 35 cm * boiling ethanol, and 13 g of potassium hydroxide are gradually added to the solution. The reaction mixture is refluxed for one hour and then in vacuo Evaporated to dryness. Then the residue is in water dissolved and extracted with ether. The alkaline phase is acidified with βη-sulfuric acid and then with Aether extracted. The ether extract is washed with water, dried over sodium sulfate and dried to dryness evaporated, whereby ß- (2'-mercapto-4-biphenylyl) -lactic acid receives.

The ethyl ester of this compound is obtained by mixing with absolute ethanol containing some anhydrous hydrochloric acid.

A) According to the invention, other mercapto compounds can be prepared in a similar manner.

^yi '' ■ Example 34

Ethyl β- (2'-methylthio-4-biphenylyl) lactate

To 3.85 g of ethyl β- (2 ^l -mercapto-4-biphenylyl) lactate in 40 cm ^ of water containing 0.65 g of sodium hydroxide, 2 cnr of dimethyl sulfate are added with stirring. Then the reaction mixture is gradually warmed to ⁰ C and currency 4o

209839/1254

Stirred for 2 hours. The mixture is cooled and extracted with ether, the extract washed with water, dried and evaporated in vacuo and the residue is distilled =, using ethyl β- (2'-methylthio-4-phenylyl) lactate receives. -

A) Treating the bericyl ester of ß- (2'- ■ methylthio-4-biphenylyl) lactate with 3O ^ hydrogen peroxide, the product obtained in this way is benzyl β- (2'-methylsulfinyl-4-biphenylyl) lactate or benzyl β- (2'-methylsulfonyl-4-biphenylyl) lactate.

the benzyl ester and other

B) If you use "" /

If an equimolar amount of acetyl chloride is substituted for dimethyl sulfate, then benzyl β- (2'-acetylthio-4-biphenylyl) acetate is obtained.

C) In a similar way, other methylthio-, methylsulfinyl-, methylsulfonyl- and acetylthiov.erbindurigen can be produced with the present process. _κ ■ ;

Example 35 '

ß - (- 2'-chloro-4-biphenylyl) -lactic acid ■ '■'

To a solution of 0.144 mol of ethyl-ß- (2'-

209839/125

chloro-4-biphenylyl) lactate, dissolved in 220 cmrr isopropanol, add 3 & S (0 * 7 mol) potassium hydroxide. The mixture is then heated at reflux temperature in a nitrogen atmosphere. Then the solution is in vacuo too a viscous oil, which is concentrated in 500 cm Water dissolves and filtered. The Filtr.at is acidified with 10 ^ iger hydrochloric acid and the precipitate is taken up in ether, The ethereal layer is dried and filtered, and the filtrate is concentrated to dryness. By recrystallization the residue from a mixture of benzene and cyclohexane in a mixing ratio of 1: 1 is obtained ß- (2'-chloro-4-biphenyIy1) -lactic acid,

A) In a similar way, according to the invention convert other esters into the corresponding acids.

Example 36

A solution of 0.01 mol of benzyl-ß- (2'-cyano-4-biphenylyl) lactate, dissolved in 100 cm of acetic acid, 0.01 mol of hydrogen chloride is added and the mixture is poured over a 5 $ palladium-on-charcoal catalyst for so long with hydrogen shaken until 0.01 mole of hydrogen has been absorbed. The catalyst is then filtered off and the solution evaporated to dryness. Through crystallization

209839/1254

left to simmer, β- (2 '~ cyano-4-biphenylyl) ~ is obtained lactic acid.

A) In a similar way, from the benzyl ester of the various cyano, acetylamino, acetylthio, Acetyloxy, methyl sulfynyl or methyl sulfonyl compounds produce the corresponding acids.

Example 37
(i-ß- (2'-chloro ~ 4-biphenylyl) -lactic acid

A boiling solution of 26.9 g (0.10 mol) d6-ß- (2'-Οι1ογ-4- biphenylyl) lactic acid in 500 cc absolute ethanol was added. The solution is then stirred for a short time and then allowed to cool to room temperature overnight. The precipitate is collected and washed twice with 25 cnr ethanol each time and air-dried. Recrystallization from isopropanol gives white needle-shaped crystals. This material is hydrolyzed with 200 citk 1,2N hydrochloric acid. The white solid product is collected, washed three times / ater washed with 50 cnr V and dried overnight at 55 ⁰ C. Recrystallization from a mixture of benzene and cyclohexane in a mixing ratio of 3: 2 gives β- (2'-chloro-4-biphenylyl) lactic acids.

20.9839 / 1254

A) By modifying the above cleavage method and by replacing the d8-β- (2 '~ chloro-4-biphenylyl) lactic acid with an equimolar amount of another of the do- alkanoic acids obtainable according to the invention, the corresponding ^ isomers are obtained,

Example 58

d ^ ß- (2 ^! -Chlor-4-biphenylyl) -lactic acid

The combined ethanol and isopropanol filtrates from Example 37 are evaporated to dryness. Then this material is stirred with 1 liter of boiling acetone. The material that has not gone into solution is filtered off. The filtrate is evaporated to dryness and hydrolyzed with 100 ml of 1.2N hydrochloric acid. The precipitate is collected, washed three times with 25 CRRR and- water at 55 ⁰ C dried. Recrystallization from a mixture of benzene and cyclohexane in a mixing ratio of 3: 2 gives d-ß- (2'-chloro-4-biphenylyl) lactic acid o

A) By modifying the above Spaltungsverfahrensund by using an equimolar amount of another of the invention obtainable according to d £ -Älkansäuren instead of the DSS-SS ^(r 2-chloro-4 ~ biphenylyl) -lactic acid passes one to the corresponding d-isomers.

209839/1254

Example 59

β- (2'-chloro-4-biphenylyl) lactic acid (sodium salt)

A solution of 12.4 g of sodium bicarbonate in 135 cnP of water is stirred dropwise into a solution of 44.1 g (0.164 mol) of β- (2 ^t -chloro-4-biphenylyl) lactic acid in 150 cnP of methanol. The solvent is then removed in vacuo and the residue is dried by repeated distillation with anhydrous ethanol. The crystalline residue is triturated with 100 cnP of ether, collected and washed with ether. The residue is dried in a vacuum desiccator, β- (2'-chloro-4-biphenylyl) lactic acid (sodium salt) being obtained.

A) If in the above procedure the sodium bicarbonate is replaced by an equimolar amount of sodium hydroxide, Potassium hydroxide, calcium hydroxide, potassium carbonate or

. Magnesium bicarbonate, this leads to the corresponding, the salts. ■ ·

B) If those obtainable according to the invention are used acidic compounds in the above reaction, the corresponding salts are obtained.

20 98 3 9 / 12S4

Example 4o

ρ, (2 ^! -Chlor-4-biphenylyl) -lactic acid ('diethylammonium salt)

0.11 mol of anhydrous diethylamine is added dropwise then stirred in a solution of .beta. (2'-CtLlor-4-.biphenylyl) -milchs'äure (0.10 mol) in 100 cm ^ η-hexane at 0 ⁰ G.
The precipitated diethylammonium salt is collected on a filter, washed with n-hexane and dried in a vacuum desiccator, the -β- {2'-chloro-4-biphenylyl) -lactic acid in the form of the diethylammonium salt
receives.

A) If you replace that in the above implementation
Diethylamine with an equimolar amount of the compounds listed below gives the corresponding salts:.

Dimethylamine
ß-hydroxyethylamine
Piperazine
Piperidine

α-methylbenzylamine
Cyclohexylamine
Triethylamine

Phenylethylamine

B) If the accruing according to the invention is used

209839/1254

the acidic compounds in this reaction, one arrives at the corresponding salts.

Example 4l

N-isopropyl-β- (2'-chloro-4-biphenylyl) lactamide

30.4 g (0.1 mol) of ethyl-.beta. (2'-chloro-4-biphenylyl) lactate are stirred with 20 crcr isopropylamine at about 35 ⁰ C overnight, after which the temperature during 28 hours · Reflux temperature increased. The reaction mixture is then evaporated in vacuo and the residue is distilled, N-isopropyl-β- (2'-chloro-4-biphenylyI) lactamide being obtained.

A) Isopropylamine is replaced in the above process an equimolar amount of the following compounds leads to the corresponding products.

Diethylamine
Ethylmethylamine
tert-butylamine
Cyclopropylamine
Isothiazolidine

Piperidine '

Morpholine
N-methylpiperazine
N-methyl homopiperazine

2 09839/125 4

* By replacing in the above reaction, the isopropylamine by ammonia, methylamine or dimethylamine and the reaction is carried in a bomb at 150 ⁰ C., is obtained .beta. (2 ^l -chloro-4-biphenylyl) -lactamid, N-methyl -ß- (2 ¹ -chloro-4-biphenylyl) -lactamide or N, N-dimethyl-ß- (2 ¹ -chlor-4-biphenylyl) -lacfcamid.

B) If the acidic compounds obtained according to the invention are used in the above reaction, then the result is obtained one to the corresponding amides.

Example 42 Ethyl-q-chloro-β- (2'-chloro-4-biphenyIyI) lactate

227 g (0.747 mol) of ethyl β- (2'-chloro-4-biphenylyl) lactate are stirred with 106.67 g (0.895 mol) of thionyl chloride at room temperature for 24 hours and then heated under reflux for 6 hours. The cold reaction mixture is then stirred into 1125 cnr ice-cold water. Then the mixture is extracted with 800 cnr of ether. The ethereal solution is mixed with 450 cnP of cold saturated sodium

trium hydrogen carbonate solution and then twice with each Washed 250 ccm in cold water. The essential solution is dried over anhydrous sodium sulfate and fil-

• triert. The solvent is removed in vacuo, where ■ the ethyl-a-chloro-ß- (2'-chloro-4-biphenyIyI) lactate ■■ · receives. ■

f _{: i} , _r . _v ._ 209839/125 4

A) In the above procedure, the "ethyl p- (2'-chloro-4-biphenylyl) lactate is replaced by the hydroxyalkanoates according to Examples 18 to 36, the corresponding chloroalkanoates are obtained. An enumeration of the Products obtained in this way can be found in the following table I.

Table I.

EthyVctj 2'-d1chlor-4-biphenylyl acetate
Ethyl-a, 4'-dichloro-4-biphenylyl acetate
Ethyl a ^ -dichloro-4-biphenylyl acetate
A ethyl-α-chloro-2 '-nitro-4-biphenylyl acetate
Ethyl-archlor-4'-nitro-4-biphenylyl acetate
A ethyl -α-chloro-2-methro-4-biphenylyl acetate
A ethyl-α-chloro-ß- (4-chloro-4-biphenylyl) propionate Ethyl-a-chloro-ß- (2-chloro-4-biphenylyl) propionate Aethyl-a-chloro-ß- (4 ^l - nitrc-4-biphenylyl) propionate. :

Ethyl-a-chloro-0- (2'-nitro-4-biphenylyl) propionate Ethyl-a-chloro-ß- (2-nitro-4-bipheny1yl) propionate EthyUß-chloro-ß- (4 '-chlor - 4-biphenylyl) propion.at A ethyl-B-chloro - ß- (4 ^l -; nitro-4-biphenylyl) propionate ethyl 2-chloro-ß- (2'-chloro-4-biphenylyl) propionate ethyl-ß -chlor · -β- (2'-m "tro-4-biphenylyl) propionate

Aethyl β-chloro-2- (2-chloro-4-biphynylyl) propionate · ■ ' Ethyl β-chloro - & - (2-nitro-4-biphcnylyl) propionate ''■■■' ^[ : ■ ethyl -Y-chloro ~ Y- (4'-chloro-4-biphenylyl) butyrate

^ .2098 39/1254

■ ■■ ■ - 135 - "

Ethyk-chloro-Y- (4 ^I -nitro-4-b-iphenylyl) -butyrate Ethyl-Y-chloro-Y-iZ'-chloT-A-biphenylyDbutyrat Ethyl-Y-chloro-γ- (2 '-nUro ^ -bi phenyl yl> butyrate ethyl-Y-chloro-rY-CZ-chloro-A-biphenylyl> butyrate ethyl-Y-chloro-Y- (2-nitro-4-biphenylyl) -butyrate ethyl-o-chloro-Y - (4 ^l -chlor-4-b1pher _i ylylH) utyrate A ethyl-a-chloro-Y- (4'-nitro-4-bi phcnylyl> butyrate. Ethyl ~ a-chloro ^ Y- (2 ¹ - chloro-4-biphenylyl> butyrate ethyl-a-chloro-Y- (2 ^l -nitro-4-biphenylyl) butyrate A _e thyl-a-chloro ^ Y- (2-chloro-4-biphenylyl) ethyl butyrate a-chloro-Y- '(2-nitro-4-biphenylyl) -butyrate ethyl - «- chloro-a-methyT-v ^ (2'-cino'r-4-b1phenylylH) utyrate ethyl a-chloro-e- _me ethyl-Y- (2'-chloro -4-biphenylyl> butyrate ethyl-a-chloro-γ-methy! -γ- (Z'-chi or -4-biphenylyl H> utyrate ethyl-a-methyl-ß-chloro ^ Y- (2'-chloro-4-biphenylynbutyrate ethyl-ß-chloro-ß-niethyl-Y- (2 ^I- chloro-4-biphenylyl> butyrate ethyl-ß-chloro- _Y . _R1 ethyl-Y- (2 '-chloro-4-biphenylyl> butyrate A ethyl-α-methyl-a, 2'-dichi or -4-biphenylyl acetate ethyl-a-methyl-a, 2-dichloro-4-bipheny lylacetat ethyl-a-methyl-a ^ '- dichlor ^ -biphenylylacetat _A ethyVa-chlor-a-methyl -B- (4'-chior -4-biphenylyl> propionate AethyVa-chlor-a-methyl-ß- (2' -chlor ^ 4-bi _P henylyl> propionate ethyl-a-chloro-a-rr, ethyl-S- (2-chloro-4-biphenylyl> propioP.at ethyl-ß-chloro ^ ß-ir _i ethyl-6- (4 ^I -chlor-4-biphenylyl> propionate Ethyi> -ß-chloro _r -e-methyl-ß- (2 ^I -chlor-4-biphenylyl) -p.opionate

209839/1254 _{ßAD 0RlQiNAL}

2182038

A ethyl-ß-chiqr-ß-methyl-ß- (2-chloro-4rbiph Aethyl-Y-chloro-Yrmnethyl-Y- (4 ^! -Chlorr-4-bipiienylylH: utyrst A ethyl-γ-chloro-Y- mQthy] -Y- {2'-GhloF-4-biphany] y1) i! utyrate • A ethyl-Y-clilor-y-methyl-Y- (2-chloro • -4-biphenylyl 5 ^ utyrate ^r Ethy1-c ! _> S-dimethyl-3-chloro-'3- (2 ^l -chlO {: - 4-biphsny] yl) -propiQnai. Ethyl-ajY-dimethyl-Y-chlpr-v- {2'-chloro-4- biphsnylyl) butyrate

Aetbyl'α, ß-Gl ^ ■ nletl ^ y ^ -γ-ch ^ or -, γ- {2 ^l -ch] or --- 4-b ^ ^> p ^ ιeny ^ yl} butyrate Aethy1 ~ a, ß, a-triniethy1-Y-chlpr-Y- (2 ^l -Ghlpr-4-bipheny'ly1i! bLjtyrat Aetliyl -a-methyl-ß-chl or- ß- {2 '-chi or -4-bi phenylyl } butyrot ethyl-cx-methyl-γ-chlpr-γ- (2'-chloro-4-biprieny / lyl) -butyrate Aet; hy1-ß-methyl-Y-chloro-γ- (2'-chloro-4rbi phenylyl ) -butyrate ethyl'ct-chloro-p-iscpropyl phenyl acstat aetjiyl-o-ch] or-p-tr PMty] phenyl acetate ethyl-a-chloro-p-cyclplipxylphenylacetai: ethyl-a-chi or-p-cyc] phe ^ -1-, enyl phenyl acgtat

-cxrGh] pr-rp-f4rpyridyl ^ -phenyl acetate

BATH ORIGINAL

A ethyl-oct-chloro-p- (3-morpholynyl} -phenyl acetate Ethyl-α-chloro-β- (p-i ^ ropylphenyT) propionate A ethyl α-chloro-β- (p-t-butylphenyl propionate Ethyl-α-chloro-ß- (p-cyclohexylphenyl) propionate Ethyl-α-chloro-S- (p-cyclohex-T-enylphenyl J-propionate A ethyl α-chloro-3- (p-phenoxyphenyl) propionate Ethyl-a-chloro-B- (p-phenylthiophenyl) i-dropionate EthyUa-chloro-B-ip-benzoylphenyl propionate Ethy! -Α-chloro - ß- (p-phenylaminophenyl) -propionate A ethyl-a-chloro-S- [p- (2-thienyl> phenyl3-propionate Ethyl α-chloro-S- [p- {3-furyl} phenyl] propionate Ethyl-a-clilor-ß-ip-CS-pyridyl) phenyl] propionate A ethyl-a-chloro-ß- [p- (4-pyridyl phenyl} propionate Ethyl-α-chloro-o- [p- (l-pyrrolyT) -phenyl3f) ropionate Ethyl-o-chloro-β- [p-0-Pip6i * a2inyT) -pht: nyl3-proponate Ethyl'α-chloro-S- [p- (3-morpholynyl) phenyl] propionate Ethyl-Y-chloro-Y- (p ~ i ^ ropyl phenyl) -butyrate Ethyl-Y-chloro-γ- (p-t-butyl phenyl) 4Dutyrate Ethyl-γ-chloro-γ- {p-cyclohexyl phenyl) butyrate ' Ethyl-Y-chloro-Y ^ (p-cyclohex-1-enylphenyl H> utyrate Ethyl-Y-chloro -Y- (p-phenoxyphenylH) utyrate ■ Ethyl-Y-chlorine-Y- (p-phenylthiophenyl) butyrate Ethyl-Y-chloro- ^ γ-ίρ-phenyl ami nophenyl) butyrate Ethyl-Y-chloro-γ- [p- (2-thienyl} phenyl] butyrate ' Ethyl-Y-chlorine. -Y- [p- (3-furyl) phenyl} butyrate

209839/1254 BADORtGlNAl.

Ethyl-Y-chloro-Y-Cp-iZ-pyn'dyl-phenyl-butyrate Ethyl-Y-chloro-Y- [p- (4 ^ pyridyT> phenyl] εutyrate Ethyl-Y-chloro-Y- [p- (I-pyrrp1y1 phenyl} butyrate

Ethyl ~ Y-chloro-Y- [p- (3- [norphoHnyl) -phei) yl} i> utyrate _:

AethyWa-chTor - Y- (p-t-butyTphenyT) -butyrate Ethyl-a-chloro-Y-ip-cyclohexylphenyl-bytyrate Ethyl-a-chloro-'Y- (p-phenyTthiophenyl} ijtyrat Ethyl-a-chloro-Y- [p- (2-thieny1 J-phenyl fetyrate Ethyl-a-cHior-Y- [p- (4-pyn'dy1) -phenyl] butylate Ethyl S-eh1or-Y- (p-fäpropy] phenyl) butyrate

Ethyl β-chloro-γ- {p-cyclohexyl phenyl H> utyrate ^;

Aethyl-0-chloro-γ- (p-benzoyi phenyl} butyrate Aethyl-ß-chloro-Y- [p- {3- (nQrpholinyl} -phenyl] ^ utyrate AethyUa-chlor.-a-methyl-Y-ip- cyclohsxyiplicnylJ-butypat Aethyl.a-chloro-ß-methyl-Y-Cp cytlohexylphsnyi uiyl ^ ^ t ν V ^s - _^'.':; _ ethyl a-chloro - Y-methyl * -Y- (p-cyclohexyipiienyl ^ ] Mbüty | at, ethyl-a-methyl-.beta.-chloro-7- (p-cyclQhexylphenyl) -t) utyrat ethyl - ß-chl or - S-rnethy 1ί-γ- (p-cycl ohexyl phenyl} buiyrät. Aethyl-c-chloro "-Y-iethyl-Y - ^ 'p-cycIoriexyiphenyl) -butyr? T; Aethyl-a-chloro-Y-fS-chloro-4-cycl ohexyl phenyl} -butyrät Ethyl-ß-chloro- Y- (3-chloro-4-cyclohexyl-phenyl-butyrate. Ethyl-a-chloro-a-methyl-Y- (3-nitro-4-t-butylphenyl-butyrate 'ethyl-0-chloro-β-diethyl-γ - (3-fluoro-4-cycl ohexyl phenyl) -butyrate ethyl-a-niethyl-ß-dilor -Y- (3-chloro-4-ii "cpropylphenyl) -butyrate ^:

209839/1254

■ "V ■ - 139 r

Aethyl-cx-methyl-a-Ghlqr -ρ-trhutyl phenylapet ^ t

Γ ^ R-cycl Qhexyl phenyl ace || t

■ EthyVct-methyl-a-chlpr -ρ- (1-pyrrolyl phenyl acetal ethyl- α-chloro-α-methyl -ß- (p-propylphenyl} -prppJonat ethyl- "a-chloro ~ a-methyl - $ - ( R-cyclqhex-l-enylphpyl} p.fopionat Aßthyl-α-chl or t - ct-methyl-ß- [p- {2-i: hienyl phenyl 3p rQpiqnat A ethyl- ß-cHl or - S-methyl - Sr (P-tr butyl phenyl) propionate ·. Ethyl-β-chlpr-ßr-riethyl-ß-ip-phenylthiqphenylprqpipnat

A ethyl-γ-Ghlqr-γ-methyl rY- | p-trbutyl phenyl) -butyr§t A.ethyl-γ-chl or -γ-methyl-γ-ίρ-cyGTqhexyl phenyl) t) utyr.at A (Btjwl - ^ chl or-γ-methyl -Y- [p- (3-furyl) fihenyl3tiut ^ rat A ethylrtt _? ß-d.imethyl -ß-chl or -ß- (p-cycl phexyl phenyl | grppipnat

§T ^ 1 _r g, ^ d ^ ftfiy 1 r ^ -ghl 8F =: Yr · (p-cypl Phexyl pheny

he - ^ f p-gy gl

- l4o -

Ethyl-a _J 3-di-chloro-4- (l-pyrrolyl) -phenyl acetate Ethyl-α-chi or - 3-nitro-4- (cyclohex-1-enyl) -phenyl acetate ethyl ~ a-chloro-3- tnflupr - R] ethyl-4-t-butylphenyl acetate ethyl-ct-chloro-S-bromo-A-cyclohexyl phenyl acetate ethyl-chloro-3- (3-fluoro-4-cyclopentylphenyl) propionate ethyl-a-chloi -S- [3-chfor-4- (27thienyl) phenyl] propionate EthyKy-chloro-Y- (3-nitro-4-t-butylphenyl) -butyrate ethyl-Y-chloro -Y- (3-trifluoro ^; p, ethyl-4-cyclohexylphenyl) butyrate ethyl-a, 3-di chi or-a-methyl-4-cyclohexyl phenyl acetate ethyl-a-chloro-a-methyl -S- (3-chloro-4-cyclohexy 1 phenyl) propionate ethyl-ß-chloro-S-methyl-S- [3-nitro-4- (l-piperazinyl> phenyl] propionate ethyl-Y-chloro-r-methyl-Y- (3-bromo- 4-phenoxyphenyl) butyrate, ethyl α-chloro-2-phenylaminophenyl acetate

Aethyl α-chloro-2-phenyl aminophenyl propionate Aethyl a-chloro or -2-phenyl aminophenyl butyrate ' ethyl "ß-chloro-2-phenylaminophenyl butyrate

Aethyl'Y-chloro -2-phenyl aminophenylbutyrate '"

Example 43

If the instructions in Example 42 are followed, but the ^{amides mentioned in Example 41 are used instead of ethyl β- (2 l} -chloro-4-biphenylyl) lactate, the corresponding α-chloropropionamide products are obtained.

209839/1254 'BATH ORIGINAL

If one uses in the above implementation the. dßj d- and ß-propionamides, the corresponding amides are obtained. . -.

: Example 44

α-chloro-ß- (2 * -chlor-4-biphenylyl) -propionic acid

A mixture of 54 g (0.167 mol) of ethyl-α, 2'-dichloro-β- (4-biphenylyl) propionate and 16o cm ^ ¹ glacial acetic acid, containing 40 % 37% hydrochloric acid, is refluxed for 20 hours. The mixture is concentrated under reduced pressure to give a gummy residue. This material is dissolved in 300 cc of n-hexane, washed with a total of 100 cups of ice-cold water, dried over sodium sulfate and filtered. The hexane is then removed, whereupon the α, 2'-dichloro-β- (4-biphenyIyI) propionic acid receives.

A) In a similar way, you can according to the invention convert available esters into the corresponding acids.

Example 45

q-chloro-ß- (2 * -chlor-4-biphenylyl) - * propionic acid (sodium salt) A solution of 12.4 g sodium bicarbonate in 135 cm · water is added dropwise to a solution of 47.1 g (0.164

2 09839/126 4

2Ί62038

Mol) α-chloro-ß- (2'-chloro-4-biphenylyl) propionic acid in 150 cirr iMethanol stirred. The solvent is then removed in vacuo and the residue is dried by repeated distillation with anhydrous ethanol. The crystalline residue is triturated with 100 cnP of ether, collected on a filter and washed with ether. After drying in a vacuum desiccator, the α-chloro-β- (2 ^f -chloro-4-biphenylyl) propionic acid is obtained in the form of the sodium salt.

A) Is used in the above implementation instead of sodium bicarbonate, an equimolar amount of sodium hydroxide , Potassium hydroxide, calcium hydroxide, potassium carbonate or magnesium bicarbonate, the corresponding salts are obtained.

B) If the chloroalkanoic acid compounds obtainable according to the invention are used in the above reaction, this is how one arrives at the corresponding salts.

Example 46

q-chloro-ß- (2'-chloro-4-biphenylyl) propionic acid (diethylammonium salt)

0.11 mol of anhydrous diethylamine is added dropwise to a solution of α-chloro-ß- (2'-chloro-4-biphenylyl) .-

209839/1254

propionic acid (0.10 mol) in 100 cirr η-hexane at 0 ⁰ C stirred. The precipitate is collected on a filter, washed with η-hexane and dried in a vacuum desiccator, giving the α-chloro- {i- (2'-chloro-4-biphenyIyI) propionic acid in the form of the diethylammonium salt.

A) Replaces that in the above reaction system Diethylamine by an equimolar amount of the following Connections, you get the corresponding products: Dimethylamine, {? -Hydroxyethylamine, piperazine, piperidine, α-methylbenzylamine, cyclohexylamine, triethylamine, phenylethylamine.

B) If the chloroalkanoic acid compounds obtainable according to the invention are used in the above reaction, this is how one arrives at the corresponding salts.

Example 47 N »-Isopropyl-a-chloro-P- (2'-chloro-4-biphenyIyI) -propionic acid

A mixture of 5.2 g (-0.016 mol) of ethyl achlor-β- (2'-chloro-4 ^ biphenylyl) propionate and 5 * 5 cm ^ anhydrous isopropylamine is poured over a Linde 4A molecular sieve for 16 hours at room temperature touched. Then the reaction mixture is dissolved in ether.

209839/1264

taken and three times with 15 cm of 10 ^ iger hydrochloric acid each time washed. The ethereal layer is dried over sodium sulfate; filtered and the ether removed. Then it will be the residue triturated with η-hexane and the precipitate collected, N-isopropyl-a-chloro.r-ß-CS'-chloro-4-biphenylyl) -prqpionamide receives.

A) In the above reaction, the isopropylamine is replaced by an equimolar amount as follows amines enumerated, one arrives at the corresponding products;

Diethylamine, ethylmethylamine, tert-butylarain, cyclppropylamine, N-methylhomopiperazine, ispthiazolidine, piperidine, morpholine, N-methylpiperazine.

C) If the above method is used according to the invention available chloroalkanoates, then F one arrives at the corresponding compound.

Example 48 Ethyl-q-bromo-2 ^! -chlor-P- (4-biphenylyl) -propionate

To 15.4 g (0.0476 mole) of ethyl-a'-chloro-SS (4-biphenylyl) -laetat is added slowly with stirring at 40 to 50 ⁰ C. 23 g (0.053 mol) of phosphorus added. Then the mixture is at for 16 hours.

209833/1254

- BAD ORIGINAL

Stirred at room temperature, then diluted with 70 cm of petroleum ether and poured into 125 cm of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to give ethyl-a-bromo-2 ¹ ~ chloro-SS (4-biphenylyl) propionate is obtained. '

'A) In a similar way, you can according to the invention available hydroxyalkanoates or hydroxyalkanepamides Convert into the corresponding bromoalkanoates or bromoalkanoamides. .

Example 49

If, according to the information in Example 44, the If bromoalkanoates obtained according to the invention are hydrolyzed, the corresponding bromoalkanoic acid compounds are obtained.

Example 50

Are the bromoalkanoic acid compounds obtainable according to the invention according to the examples 45 and 46 are implemented, this is how you get there to the corresponding bromoalkanoic acid salts.

BAD ORlGINAL. 209839/1254

Example 5I Ethyl ct-fluoro-ß- (2'-chloro-4-biphenylyl) propionate

121 g (0.33 mol) of ethyl a-bromo-ß- (2 ^f -chloro-4-biphenylyl) propionate are at 130 to 140 ⁰ C with 29 g (0.5 mol) of potassium fluoride in 100 cnP of ethylene glycol during Vigorously stirred for 12 hours. The reaction mixture is then cooled and 400 cnP of water are added. The raw product is then eliminated. The aqueous glycol mixture is extracted with ether, the ether

the residue was then dried, evaporated to dryness and distilled. In this way, ethyl α-fluoro-β- (2'-chloro-4-biphenylyl) propionate is obtained.

A) Using the above procedure using the various bromoalkanoates and bromoalkanoamides obtainable according to the invention, see above one arrives at the corresponding fluoroalkanoates resp. Fluoralkanoamides.

Example 52

Are those available according to example 51 Fluoroalkanoates according to the information given in Example 44 hydrolyzed, the corresponding fluoro, alkanoic acid compounds are obtained.

209839/1254

Example 55

Are the inventions available Fluoroalkanoic acid compounds reacted according to the information in Examples 45 and 46, this leads to the corresponding fluoroalkanoic acid salts.

Example 54 Ethyl q-iodine-ß-Ca * chlorine-4-biphenylyl) proplonate

A mixture of 36.8 g (Ch, 1 mol) of ethyl a-bromo (B- (2 ^! -Chloro-4-biphenylyl) propinate and 150 g of sodium iodide in 1 liter of anhydrous acetone is refluxed for 4 hours The reaction mixture is then evaporated to dryness and extracted with ether, the ether is then washed with water, dried and completely evaporated to give ethyl α-iodo-β- (2'-chloro-4-biphenylyl) propionate.

A) If you work according to the above information The various bromoalkanoates and bromoalkanoamides obtainable according to the invention are used in this way to the corresponding iodine alkanoates or iodine alkanoamides.

Example 55

If the information given in Example 54 available iodine alkanoates according to the method according to

20 9839/125 4

game 44 hydrolyzed, this leads to the corresponding iodoalkanoic acid compounds.

Example 56

V / ground the iodoalkanoic acid compounds according to the Information according to Examples 45 and 46 implemented, so obtained the corresponding iodoalkanoic acid salts.

Example 57

q-Mercapto-ß- (2'-chloro-4-biphenylyl) propionic acid

A mixture of 16.2 g (0.05 mol) of α, 2'-dichloroβ- (4-biphenyIyI) propionic acid and 5 S sodium hydrogen sulfide in 100 errr absolute ethanol is in a nitrogen atmosphere stirred for 15 hours. Then the mixture is acidified with 6N hydrochloric acid. The solvent

is then removed in Va-uum and the residue with de r Ext rakt

Aether extracted, / first with .water and then with washed a saturated sodium chloride solution, dried and evaporated to dryness, whereby the a-mercapto-ß- (2 * -chlor-4-biphenyIyI) -propionic acid holds.

A) Are the according to the invention obtainable Chloroalkanoic acids, chloroalkanoates and chloroalkanoamides used in the above reaction this leads to the

BATH ORIGINAL

corresponding mercaptoalkanoic acids, mercaptoalkanoates or mercaptoalkanoamides.

Example 58 ; g-Methylthio-ß- (2'-chloro-4-biphenylyl) propionic acid

Methy! Mercaptan is dissolved in a solution of 18.4 g Potassium tert-butoxide in 100 cm-3 tert-butanol during Blown in a nitrogen atmosphere for 45 minutes. The reaction mixture is then with 12 g (0.04l mol) of α, 2 '-Dichlor-ß- (4-biphenyIyI) -propionic acid in 60 cnr dry tetrahydrofuran added. Then the mixture heated to boiling for 3 hours under reflux and then for 15 hours at .Room temperature stirred. This is followed by 30 cm Acidified 6N hydrochloric acid. The solvent is removed in vacuo and the residue extracted with ether, washed with water and then with saturated sodium chloride solution, dried and to dryness evaporated, whereby the a-methylthio-ß- (2'-chloro-4-biphenyIyI) propionic acid receives.

A) If the chloroalkanoic acids obtainable according to the invention are used in the above reaction, Chloralkanoates or chloroalkanoamides, this leads to the corresponding methylthioalkanoic acids, methylthioalkanoates and methylthioalkanoamides, respectively.

209839/125 4

15Q -

Example 59

α-Acetylthlo-ß- (2 '- chloro-4-biphenyl.yl) propionic acid

To a solution of 600 ever anhydrous methanol and 21 g (0.317 mol) of potassium hydroxide to 45 cnr * thioacetic acid was dropwise added thereto. 79 g (0.244 mol) of α, 2'-dichloro-β- (4-biphenylyl) propiolic acid are then added to the mixture and the mixture is stirred for a further 15 hours. k The solid product that has formed is filtered off and washed with ethanol. The piltrate is evaporated to dryness and the residue is dissolved in 500 ml of ether and washed several times with water. The ethereal solution is dried and evaporated to dryness, giving α-acetylthio-β- (2'-chloro-4-biphenylyl) propionic acid.

A) The corresponding a-propionylthio-ß- (2 ^! -Chlor ^ -biphenylylj-propion-

make acid compounds. "..

B) If the chloroalkanoic acids, chloroalkanoates, available according to the invention are used in the above reaction and chloroalkanoamides, one arrives at the corresponding acetylthioalkanoic acids, acetylthioalkanoates and acetylthioalkanoamides, respectively.

209839/125

Example 6o

α -Benzoy lthi a- B- (2 '■ - chio r- H - bi phenylyl) propionic aur e To 17.4 criP of an alcoholic 2N potassium hydroxide solution (0.035 mol) are added 4.84 g (0.035 mol) thiobenzoic acid added. This solution is cooled to room temperature and then in small portions with 11.3 g (0.035 mol) a, 2 ^! -Dichlor-P- (4-MphenyIyI) -propionic acid added. The reaction mixture is then stirred for 25 hours at room temperature, whereupon the solvent is removed, the residue is dissolved in ether, filtered and washed with cold water. The ethereal solution is then dried over magnesium sulfate and evaporated to dryness, giving α-benzoylthio-3- (2 * -chloro-4-biphenylyl) propionic acid.

A) If the chloroalkanoic acids obtainable according to the invention are used in the above reaction, Chloralkanoates and chloroalkanoamides, this leads to the corresponding benzoylthioalkanoic acids, benzoylthioalkanoates and benzoylthioalkanoamides, respectively.

Example 6l

Ethyl-a-thioacetylthio-ß- (2'-chloro-4-biphenylyl) propionate

A mixture of 0.2 moles of sodium dithioacetate

209839/125 4

BATH

and 38.9 g (0.12 mol) of ethyl a., 2 ¹ -dichloro-β- (4-biphenylyl) propionate in 300 cmrr of absolute ethanol is stirred for 15 hours at room temperature .. The reaction mixture is then filtered ·, Washed with absolute ethanol and evaporated to dryness in vacuo. The residue is treated with ether, filtered and evaporated to dryness, ethyl a-thioacetylthio-β- ^ '- chloro-4-biphenylyl) propionate being obtained.

A) If the chloroalkanoic acids, chloroalkanoates, obtainable according to the invention are used in the above reaction and chloroalkanoamides, one arrives at the corresponding thioacetylthioalkanoic acids, thioacetylthioalkanoates and thloacetylthioalkanoamides, respectively.

B) If sodium dithioformate is used in the above process instead of sodium dithioacetate, then P is obtained ethyl o.-thioformj'-lthio-β- ^ ¹ -chloro-4-biphenylyl) propionate.

Example 62

g-Thiocyanato-ß- (2'-chloro- ^ biphenylyl) -propionic acid

To a solution of 300 cm ^ anhydrous Ethanol and 0.15 mol of sodium thiocyanate are added to 38.9 g (0.12 mol) α, 2'-dichloro-β- (4-biphenyIyI) propionic acid

0983 9/126 4- -

BATH ORIGINAL

and the mixture is stirred for 15 hours. then

d lagging behind he R

the reaction mixture is filtered and / with absolute
Washed ethanol. The filtrate is then evaporated to dryness, the residue is dissolved in 250 curd of ether and washed several times with water. The ethereal solution is then dried and evaporated to dryness, the ^{α-thiocyanato-β- (2 f} -chloro-4-biphenylyl) propionic acid being obtained.

A) Are in the above Rea.ktion the inventive Chloralkanoic acids, chloroalkanoates and chloroalkanoamides used, this leads to the corresponding thiocyanatoalkanoic acids, Thiocyanatoalkanoates or thiocyanatoalkanoamides. '

Example 63

q-sulfo-ß- (2'-chloro-4-biphenylyl) propionic acid (pinodium salt) . .

32.3 g (0.1 mol) are added to a solution of 250 cnr anhydrous ethanol and 0.12 mol of sodium sulfite
a, 2 ^! -Dichloro-ß- (4-biphenylyl) -propionic acid (sodium salt) added. The reaction mixture is then stirred for 15 hours, then filtered and the residue is worked up with ethanol. The filtrate is evaporated to dryness, the ci-sulfo-2 '-ehlor-ß- (4-biphenylyl) -propion-

BATH ORIGINAL _, 2 0 98 39/1254 "" "" "" ""

acid in the form of the diriatrium salt.

A) If sodium sulfinate is used instead of sodium sulfite in the above process, the α-sulfino-β ~ (2'-chloro-4-biphenyIyI) propionic acid (di-. sodium salt). . - ■

^ B) If one uses in the above reactions the

chloroalkanoic acids according to the invention, chloroalkanoates and Chloralkanoamides, then one arrives at the corresponding Sulfo- and sulfinoalkanoates or alkanoamides.

Example 64

Aethyl * -q-thiosulfo-ß- (2 ^> -chlor-4-biphenylyl) propionate (sodium salt)

A mixture of 7.4 g (0.023 mol) of Ethyi-a, 2 '~ . diehlor-ß- (4-biphenylyl) propionate and 5.7 g sodium thio

sulfate pentahydrate in 75 cm ^ of a water / alcohol mixture . (40:45) '* ■ ■

/ is refluxed for 2 hours. Then a further 0.8 g of sodium thiosulfate pentahydrate are added and refluxed for a further 30 minutes. The reaction mixture is then evaporated to dryness in vacuo, with ethanol an azeotropic distillation subjected and then dried to dryness in a vacuum

13 9/1254

narrowed. The residue is triturated with ether, triturated with titanium and evaporated to dryness. The residue is then triturated with hexane and the gum obtained is dissolved in alcohol and evaporated to dryness in vacuo. In this way the sodium salt of ethyl-thiosulfo-ß- (2 ¹ -chlor - ^ - biphenjrlyl) propionate is obtained.

A) If one uses in the above reaction the chloroalkanoates and chloroalkanoamides according to the invention, this leads to the corresponding thiosulfoalkanoates or thiosulfoalkanoamides. .

Example 65

α-Amidinothlo-β- (2 '~ chloro ^ 4-biohenylyl) propionic acid hydrochloride

15.2 g (0/2 Hoi) thiourea are packed in 15Ο cn? dissolved in absolute ethanol. 35> 5 S (0.11 mol) of α, 2 ¹ -dichloro-R- (k- biphenylyl) propionic acid are then added. The mixture is then stirred for I5 hours at 0 ⁰ C, and then filtered. In this way one obtains the a-Amidinothio-P- (2 ¹ -chlor-4-biphenyIyI) -propionic acid hydrochloride,

A) If the chloroalkanoic acids or esters obtainable according to the invention are used in the above process and amides, one arrives at the corresponding amidino

2 0 9 8 3 9/125 4 BAD ORIGINAL

alkanoic acids, esters or amides.

example 66

g-Aethoxythiocarbamylthio-ß- (2'-chloro-4-biphenyl ) -propionic acid - -

3> 63 g (0.22 mol) of the potassium salt of Aethylxanthogensäure / ground in I50 CRRR of absolute ethanol under stirring dissolved v *. 35> 5 S (0.11 mol) of α, 2'-dichloro-β- (4-biphenylyl) propionic acid is then added to the solution and the mixture is stirred for 15 hours. The collected solid material is isolated and washed with absolute ethanol. Then the solid product is treated with acetone and the insoluble material is filtered off. The filtrate is concentrated to dryness, the α-ethoxythiocarbamylthio-β- (2 ^! -Chloro-4-biphenylyl) propionic acid being obtained.

A) If the chloroalkanoic acids, esters and amides according to the invention are used in the above process, this leads to the corresponding ethylxanthylalkanoic acids, -esters or -amides.

Example 67

a-Etho>: carbonylthio-G ~. (2'-chloro- H- biphenylyl) -prooralic acid ; ■

A solution of 5.2 g (0.02 mol) of α-mercapto

; ^. ^ 09839/1254 BADORJGfNAL

β- (2 * -chloro-4-biphenylyl) -propionic acid in 25 cnr pyridine ■ is cooled in an ice bath. 2.1 enr (0.022 mol) of ethyl chloroformate are then added dropwise to the reaction mixture. Then the mixture is made alkaline with 10 ^ iger sodium bicarbonate solution. The alkaline mixture is then worked up with ether, then acidified with the above hydrochloric acid, washed with ether, dried and filtered. The solvent is removed and the residue is triturated with hexane, the α-ethoxy carbonylthio-β- ^ ^1- chloro-4-biphenylyl) propionic acid being obtained.

A) If one uses the inventive mercaptoalkanoic acids, esters and in the above process -amides, one arrives at the corresponding ethoxycarbonylthioalkanoic acids, -esters or -amides.

Example 68
a-diethylearbamylthio-ß- (2'-chloro - ^ - biphenylylj-propion-

A solution of 5.2 g (0.02 mol) of a-mercapto-

β- (2'-chloro-4-biphenyIyI) propionic acid in 2S cnP pyridine is cooled in an ice bath. Then the resulting mixture is added dropwise with 0.022 mole of dietary carbamyl chloride vurnet '/ t ". This is where the mixture confuses

.- '0! Η j H / VZS h - '■ -' BAD ORIGINAL '

216M38

- 15ο -

Stirred for 2 hours, diluted with ether and filtered. The mixture is then treated with 10 ^ iger liatrium bicarbonate solution made alkaline. The alkaline mixture is washed with ether, with 10 ^ iger hydrochloric acid acidified, extracted with ether, the extract then washed with cold water, dried and concentrated to dryness. Stirring with hexane gives a-diethylcarbamylthio-r> - (2'-chloro-4-biphenylyl) propionic acid.

A) In the above process, diethyl carbamyl chloride is replaced by carbamyl chloride, which is exposed Potassium cyanate and anhydrous hydrogen chloride in anhydrous chloroform obtained in situ, ethyl carbamyl chloride or dimethylcarbamyl chloride, one obtains a-carbamylthio-ß- (2'-chloro-4-biphenylyl) - propionic acid, a-ethylcarbamylthio-ß- (2'-chloro-4-

biphenylyl) propionic acid or ci-dimethylcarbamylthioß- (2'-chloro-4-biphenylyl) propionic acid.

B) Verv / ends in the above process, the inventive Hercaptoalkanoic acids, esters or -amides, one arrives at the corresponding carbamylthioalkanoic acids, -esters or -amides.

? ΙΗ) Β iO f 12 54 - - BAD ORiGtNAL

Example 69

If you proceed as in Example 57, but replace the t) l a thy I carbons t with succinic anhydride, maleic anhydride or phthalic anhydride, a-butyrylthio-ß- (2'-chloro-4-biphenylyl) propionic acid, a-butenoylthio- ß-Cs'-chloro-4-biphenyIyI) propionic acid or ao-carboxybenzyolthio-ß- (2 ^r -chloro-4-biphenylyl) propionic acid obtained.

Example 70

If a-methylthio-ß (2 '~ chloro - ^ - biphenylyl) propionic acid with 30 ^' is treated iS ^e m hydrogen peroxide, is obtained a-methylsulfinyl-ß (2 ^l -chloro-4-biphenylyl) -propioncäure hzvu a-methylsulfonyl-p- (2'-chloro-4-biphenylj ^r l) -propionic acid.

209839/1254

Claims (17)

Claim e - 1, Phenylhaloalkanoic acids substituted as new compounds or their derivatives of the following formula; V ^coz wherein R is alkyl, cycloalkyl, cycloalkenyl, aryloxy, arylthio, acylamino, aroyl, a heterocyclic radical, aryl or substituted aryl, in which the substituent is Y; Υ hydrogen, alkyl, halogen, nitro, amino, acylamino, mono- or di-lower alkylamino, mercapto, acylthio, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, hydroxyl, lower alkoxy, aeyloxy, halo-lower alkyl, cyano. Or acetyl; η = 0 to 2; W = 0 to 2; η + m = 0 to 2; R, R _n and. R is hydrogen or lower alkyl; X halogen, hydroxyl, - lower alkoxy, lower acyloxy, aroyloxy, carbo-lower alkoxy, carbamyloxy, lower alkylcarbamyloxy, di-lower alky 1 carbaniyloxy, lower alkanesulphonyloxy, benzenesulphonyloxy, toluenesulphonyl oxy, carboxyacyloxy, lower alkylsulphyno, aledo, acycloxy, carboxyarethioxy, mercapto, lower alkyl, aledo, arylsulphinyl, aledrokylsulphyno, aledrokylsulphinyl, aledrokylsulphyno, aledrokylsulphyno, aledo, acytylsulphinyl, aledrokylsulfio, aledrokylsulfio, aledo, acyclothio, aedrokylsulfio, aedrokylsulfioxy, a di-lower alkylcarbamyloxy, , Niederalkylsulfonyl, Thioacylthio, Thiosulfo, Thiocyanato, Amidinothio, Carbamylthio, IJiedcralkylcarbamylthlo, Di-Niederalkylcarbarnylthio, IJiederalkoxythiocarbonylthio, j'JiederalkoxycarbonylthJ o, 209S39 / 12B4 BATH Di-lower alkylthiocarbarnylthio, Ar-lower alkoxycarbonylthio, carboxyaroylthio or carboxyacylthio; and Z is hydrogen, -OH, _{lower alkoxy, Ar-lower alkoxy, -NH 2} , lower alkylamino, di-lower alkylamino, cyclo-lower alkylamino, -NA, wherein A is lower alkylidenyl or hetero-nie-. deralkylidenyl denotes -NHOH, -NHNH ₂ or -OH ₃ wherein M denotes an alkali metal, alkaline earth metal, aluminum or ammonium cation; where X is not hydroxyl, lower alkoxy, 'halogen' or lower alkylsulphonyl when η = Ό and m = 0, but X can be halogen or lower alkylsulphonyl when R "is hydrogen and R is cycloalkyl; furthermore, X is not hydrogen when n = 0, m = 1 _y R _{a is} lower alkyl and R is cycloalkyl; and when η = 1 and m = 1 or η = 0 and m = 2 and Π _α , R _ß and R are hydrogen, X is not hydroxyl when R is phenyl. . ? 0 ¹ J; · ' - 162 - 2. Phenylthioalkanoic acid compounds substituted as new compounds the formula: τ4 ·. where R is alkyl, cycloalkyl, cycloalkenyl, aryloxy, arylthio, substituted arylamino, aroyl, a heterocyclic radical, aryl or / tes aryl, in which the substituent is Y; Y is hydrogen, alkyl, halogen, nitro., Amino, acylamino, ..mono- or di-lower alkylamino, mercapto, acylthio, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, hydroxyl, lower alkoxy, acyloxy, halo-lower alkyl, cyano or acetyl; η = 0 to 2; m = 0 to 2; η + τη = O his 2; R, Rn and R “are hydrogen or lower alkyl; X ¹ mercapto, alkylthio, acylthio, aroylthio, SuIfo, SuIfino, lower alkylsulfinyl, lower alkylsulfonyl, Thioacylthio, Thiosulfo, thiocyanato, amidinothio, Carbamylthio, Niederalkylcarbamylthio, Diniederalkylcarbamylthio, Nlederalkoxythiocarbonylthio, Niederalkoxycarbonylthio, di-niedGralkylthiocarbamylthio, Ar-niederalkoxycarbonylthio, Carboxyaroylthio or Carboxyacylthio; Z water 9839/1254 substance, -OH, lower alkoxy, ar-lower alkoxy, -NHp, lower alkylamino, di-lower alkylamino, cyclo-lower alkylamino, -NA, in which A is lower alkylidenyl or hetero-lower alkylidenyl, -NHOH., -NHNH ₂ 'or -OM, in which M is Alkali metal, alkaline earth metal, aluminum or ammonium salt denotes, represent, with the proviso that if η = 0 and m = 0 and X 'represents a lower alkylsulfonyl _{radical, R ß} denotes a hydrogen atom. 3 »Phenylhydroxyaikansäurederivate substituted as new compounds der.FormeIi H\ where R is alkyl, cycloalkyl, cycloalkenyl, aryloxy, arylthio, substituted-arylamino, aroyl, a heterocyclic radical, aryl or / tes aryl, in which the substituent is Y; Y VJhydrogen, alkyl, halogen, nitro, amino, acylamino, mono- or di- lower alkylaniino, mercapto, acylthio ,, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, hydroxyl,. Lower alkoxy, aeyloxy, halo-lower alkyl, cyano or acetyl; η = 0 to '2 .; m = ■ -O- to 2; η + m = - 0 to 2; R, R and R are hydrogen or lower alkyl; X ¹ lower alkoxy, iliederacyloxy, "aroyloxy, carbo-lower alkoxy, BATH ORIGINAL 209839/1254 ί: ■ Carbamyloxy, lower alkylcarbamyloxy, di-lower alkylcarbamyloxy, lower alkanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, carboxyacyloxy or carboxyaroyloxy; Z is hydrogen, -OH, lower alkoxy, Ar-lower alkoxy, -NHp, lower alkylamino, di-lower alkylamino, -NA / where A is lower alkylidenyi or hetero-lower alkylidenyl, -NHOH, -NHNH ₂ or -OM, where M is an alkali metal, alkaline earth metal -, aluminum or ammonium cation; mean, with the proviso that, if η = 0 and m = 0, X does not represent a lower alkoxy radical. 4. Process for the preparation of the new compounds claimed in claim, characterized in that that one is a substituted phenylhydroxyalkanoic acid "ester the formula: ~ -_ OH CH) -C- (CH) _m -COOR " wherein R "represents a lower alkyl radical, with a Halogenating agent which is able to replace the hydroxyl group by a halogen atom, converts and, if desired the halogenated phenylalkanoic acid ester thus obtained converted into a free phenylalkanoic acid which is halogenated or the halogenated phenyl 20S839 / 1254 acid ester with a nitrogen base of the formula Z-H to form a phenylalkanoic acid amide, the is halogenated, amidated. 5. The method according to claim 4, characterized in that that the halogenating agent is a thionyl halide, a sulfuryl halide, a sulfur halide, a phosphorus trihalide, a phosphorus oxyhalide or a phosphorus pentahalide is used. 6. The method according to one of claims 4 and 5. » characterized in that the saponification by means of glacial acetic acid containing a hydrogen halide, the halogen atom is the same halogen as that which is present in the halogenating agent is caused. __-— ~ "" 7. The method according to claim k, characterized in that a sulfonate derivative of a substituted phenylhydroxyalkanoic acid or ester or amide thereof of the formula is used. OSO ₂ R ¹ (CH) _n -G- (CH ^ -COZ ¹ Y ^R ß ^R 209839/1254 BADORIGtMAt wherein R 'is an alkyl, phenyl or substituted phenylr-est represents, with a metal halide capable of replacing the sulfonyloxy group with halogen atoms. 8. The method according to claim 7 *, characterized in that that an alkali metal halide is used as the metal halide. 9 · The method according to any one of claims 4 to 7, characterized in that the substituted Phenylhaloalkanoic acid or its ester in a metal salt, in an ammonium salt or in a salt with a organic amine of this acid is converted. 10. Process for the preparation of the compounds according to. Claim 2, characterized in that one substituted phenylhaloalkanoic acid compound of the formula: _ _. Shark where Hai represents a halogen atom, with a nucleophilic reagent that can replace the halogen atom, such as an alkali hydrogen sulfide,
Alkalithioalkanoatj
Alkali thiobenzoate, ,. 209839/1254 ^ AD ORlG ₁ NAL Alkali lower alkyl xanthate, Thiourea Alkali thiocyanate, Alkali thiosulfates Alkali-lower alkyl mercaptide, Alkali sulfite or Alkali sulfinate; '- converts and if necessary (a) the thus obtained Mercapto compound with a lower alkyl chlorocarbonate ,,; an alkali isocyanate or a di-lower alkyl carbamyl chloride implements; (b) the said mercapto compound is converted into a metal salt and with a carbamyl chloride implements; and (c) oxidizing the lower alkyl mercapto compound so formed. 11. A method for producing the 'compounds according to claim 2, characterized in that one is a sulfonate derivative of a substituted phenylhydroxyalkanoic acid or an ester or amide thereof of the formula: OSO ₂ R ¹ 4- (CHL- ' (CH) _n -I- (CH) _1n -COZ 209839/1254 wherein RV is an alkyl radical, a phenyl radical or a substituted. Represents phenyl radical with a hükieophi; len reagent, which the Sülföhyiöxygrupppe by the desired Thio derivative able to replace, converts. 12. Process for the preparation of the compounds according to claim 3 *, characterized in that one substituted Phehylhydrbxyalkanoat of the formula: CH5 _h -G- (| H) _m -GOZ with an acid halide or anhydride of the formulas X ¹ Hal or X ¹ OX ¹ in the presence of a tertiary amine. ' 13; Method according to Claim 12, characterized j that the acid halide or anhydride is acetyl chloride, acetic anhydride, propionyl chloride, Butyryl chloride> succinic anhydride, liquid acid anhydride Phthalic anhydride, Benzoylchloridi Benzoic anhydride, Benzyl chloroate, ethyl chloroate, Dimethylcarbyl chloride, di butylcarbarnyl chloride, Benzenesulfonyl chloride or methanesulfonyl chloride used. 209839/1254 BATH ORIGINAL l4. As new compounds according to claim 1 β- (p-biphenylyl) -lactic acid
β- (p-Biphenylyl) -β-hydroxypropionic acid β- (2 * -chloro-4-biphenylyl) -β-hydroxypropionic acid α-methyl-α- (3-chloro-4-cyclohexylphenyl) -glycolic acid benzoate. a- (3-Ch.lor-4-cyclohexylphenyl) -a-mercaptoacetic ^{acid a- (3-chloro-J} l - cyclohexylphenyl) -glyoxyl acid-oxime d-chloro-α- (3-chloro-4-cyclohexy! phenyl) acetic acid ethyl-a-chloro-a- (3-chloro-4-cyclohexylphenyl) -acetate a-chloro-a- (3-chloro- ¹ l ^; -cyclohexylphenyl) -acetamide N-isopropyl-a-chloro- α- (3-chloro-4-cyclohexylphenyl) acetamide. ,. ■ Ethyl-a-bromo-a- (3-chloro-4-cyclohexylphenyl) acetate a-methylthio-a- (3-chloro-4-cyclohexylphenyl) acetic acid an-butylmercapto-a- (3-chloro-4-cyclohexylphenyl ) -acetic acid ethyl-a-thiosulfo-a- (3-ChIOr - ^ - CyClOhOXyIPhCnYl) -acetate a-chloro-a- (3, S-dichloro - ^ - cyclohexylphenyl) -acetic acid a-Benzoylthio-a- (3- ChIOr- ² I-CyClOhBXyIPhOnYl) -acetic acid a-Acetylthio-a- (3-chloro-4-cyclohexylphenyl) -acetic acid _a _ (3_Chlor-4-cyclohexylphenyl) -glycolic acid acetate a-ethylxanthyl-a- (3-chloro-4- cyclohexylphenyl) acetic acid ß_ (3_Chlo.r-4-cyclohexylphenyl) -ß-hydroxypropionic acid a- (3-chloro-4-cyclohexylphenyl) -ßlycolic acid ethyl carbonate ß- (3-chloro-4-cyclohexylphenyl) -lactic acid a-Bcnz- oylthio-a-bi phony lylacetic acid a-Methylsulfinyl-a-Cj-chloro - ^ - cycloliexylphenyl) acetic acid a-Acetylthio-a-O-chloro - ^ - cyclohexylphenyl) acetic acid a-chloro-a-biphenyly! acetic acid α-Fluoro-α- (3-chloro - ^ - cyclohexylphenyl) acetamide a-Bromo-7-biphenyIy! butyric acid a-chloro-ß-bipheny3ylpropionic acid α-acetyloxy-ß-biphenyly! propionic acid j | α-Benzoylthio-β-biphenylyl propionic acid α-Hydroxy-p-methyl-ß-biphenyIy! propionic acid Ethyl-a-hydroxy-ß-methyl-ß ~ biphenyly! Propionic acid α-chloro-ß-methyl-ß-biphenyIy! propionic acid 15. Therapeutic agents containing a A compound according to claim 1 or 1 ^. 16. Solid means according to claim 15 in the form of tablets or capsules. 17. Liquid means according to claim 15 il kForm of syrups or suspensions. J / f Dipl.-f _ Intan < 209839/1254