DE1941543A1 - New benzo [b] thiophene-acetic acid compounds - Google Patents

Description

DR.INTG. F. WUBSTJIOFF DIPIi. ING. G. P0LS

DRJB.r.PKGHMANir DR. ING. D. BEnRENS

8 MÜNCHEN8O SCHWEIGERSTHASSE 3 33 06 Sl

PIOUOTFATIHT

1A-36,641

Description of the patent application

PARKE, DAVIS & COMPANY Joseph Campau "Avenue at the River Detroit, Michigan 48232, USA

Concerning New Benzo / S7thiophene Acetic Acid Compounds

The present invention relates to new heterocyclic ones Acid Compounds That Are Suitable As Medicines And Methods For Their Preparation. It affects new ones Benzo £ bjthiophenessig8äure - Compounds by the formula

W-OH-COOH

(D

can be represented, as well as their pharmaceutically suitable ones Salts; where R is a hydrogen atom or a lower alkyl group having no more than 4 carbon atoms and W is one of the following groups;

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a 4-pbenylbenzojVJtbiophen-2 group of the formula

a 7-pbenylbenzo £ b} tbiopben-3 group of the formula

a 7-pbenylberizoCbltbiopben-4 ~ group of the formula

a 2-pbenylbenzoCb3tbiopben-6 group of the formula

00 9813/1893

•. - 3 - ■ · U-36 641 a phenylbenzoOiJthiophene-7 group of the formula

a T-cyclohexylbenzo-thiophene-S group of the formula

or a Y-cyclohexylbenzof / thiophene - ^ - Cr group of the formula

in which one of the groups Hg and E _{3 is} a hydrogen atom and the other is a phenyl group of the formula

R _{4 is} a hydrogen atom or a methyl group and X is a hydrogen or halogen atom or a methyl group.

0 9 8 13/1683

£ AD OFUGlNAL

1A-36,641

According to the invention, benzo / b_7thiophenacetic acid Compounds of the formula I and their salts are prepared by hydrolysis of a compound by the general formula:

W-OH-Y ·· (II)

can be represented in the R ^ and W the above Have meaning and X is a group which can be hydrolyzed to a carboxyl group. Some Examples of groups that can be hydrolyzed to a carboxyl group are the cyano, alkoxycarbonyl, Aryloxycarbonyl, aralkoxycarbonyl, carbamyl, alkyl-substituted carbamyl, trihalomethyl, amidino, alkyl-substituted amidino, haloformyl,

p 0 HH NOH 'HH

-C— ΙΤΙΠΠι ₂ , -C— IiHOH, -C— O-alkyl, -C — ITII ₀ , ~ C— NIIIiIL.,

-C— halogen and the -C (halogen) ^ - group «

The exact nature of the group X which can be hydrolyzed to a carboxyl group is not critical as it will be converted to a carboxyl group during the process. Therefore, the X group may, if desired, in appropriate cases or more ßubctituenten as an I logenaton ⁷ ~, a lower alkyl, lower Alko a: cy-, Titre-, Carbo: RY or Alko :: ycarbonylgruppe contain . In the cases in which the group Y is basic, it can

- K -.

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can also be used in the form of an acid addition salt. The term "group belonging to a carboxyl group can be hydrolyzed ", here stands for substituted as well as unsubstituted groups. Compounds, in which the group Y is the cyano group or an alkoxycarbonyl group are the preferred starting materials for this process as they are readily available and in high yields to carboxyl derivatives can be hydrolyzed.

The hydrolysis can take place under both acidic and alkaline conditions with the help of an acidic or alkaline Hydrolyzing agent can be carried out. Alkaline conditions are preferable and should be used when certain Groups Y, such as the

-0- (halogen) ^ - group are used exclusively. The hydrolysis can be carried out in water or in an aqueous solution of non-reactive, water-miscible, organic Solvents such as an aliphatic alcohol, dioxane, tetrahydrofuran, ethylene glycol, propylene glycol or a lower alkyl ether of ethylene glycol or des Diethylene glycol to which an acid or base has been added to the medium to make acidic or alkaline. Some examples of suitable bases are alkali hydroxides, hydroxides of the Alkaline earths, alkali carbonates, alkali alcoholates and trialkylammonium hydroxides. Some examples of suitable acids are mineral acids, strong organic acids such as p-toluenesulfonic acid and acidic ion exchange resins. Preferred agents are alkali hydroxides, such as sodium hydroxide or Potassium hydroxide. The hydrolyzing agent is normally

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se applied in an important XJberschuij.

The hydrolysis is carried out so that a solution or suspension of the starting material in a solvent, which contains an acid or base, is heated until "until the group X is essentially complete is hydrolyzed. The time and temperature required is different and depends on the species of the specific starting material of the formula II used and of the basic or used

fc acidic agent. In general, the reaction will but at a temperature between 25 and 200 G or 'Performed at the temperature at which the solvent refluxes. Here is the 'Response time 1 to 75 hours v / hen you have one of the preferred basic hydrolyzing agent is used, the Reaction is normally carried out at a temperature between 60 and 125 ° C and is within τ, -those essentially complete than 24 hours. When the hydrolysis is carried out under alkaline conditions, the product in the reaction mixture is in the form of a salt before; it can or it can be isolated in this form

. after treatment with an acid, especially an ax Mineral acid, can be isolated as a free acid. If the hydrolysis is carried out under acidic conditions, if the product is in the reaction mixture as a free acid ■ before and can be isolated directly in this form or it can be done by subsequent treatment with a base isolated in salt form.

The ones required for the procedure described above Starting materials can be prepared in different ways, e.g. different ethyl-7-phenyl-

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1A-36,641

benzo / b_7thiophen-4-acetate by the following reaction sequence getting produced. A substituted benzotrichloride of the formula: ■. ". - '

(III)

is made to react with thiophane in the presence of tin chloride and gives a 2-benzoylthiophene der Eorrnel: ■ ■. .
O

(IV)

The 2-Benzovlthioplienzvfischeriprodukt ^T "; ird anschlie2end nit zinc and -athylbrosiacetat reacted and the resulting iithyl-3-phenyl-5- (2-thieiiyl) acryiat is catalytically hydrogenated and results in a ethyl J-

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■ '■ ". - ■■ - ■ - ■' -.... ■ ■; '■ - 8 -.

- (2 ~ thienyl) propionate of the formula:

G ₂ H ₅ OG-CH ₂

(V)

_f -.J) this

product is then reduced by reaction with lithium-ion aluminum hydride. The reaction product is hydrolyzed and gives a 3-i ³ -henyl-3- (2-thienyl) propan'-1-ol.

- I * örmei:

HO-CH ₂ CH ₂ -CH

(VI)

that with phosphorus tribromide into a 3-phenyl - ^ - (2-thienyl) · PropylbroEiid of the formula:

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iA-36 641

Br-GH ₂ CH ₂ -CH

(VIJ)

is converted. _ "_......

This intermediate bromide product is then dissolved in aqueous Acetone-ethanol with sodium cyanide. brought to reaction and the resulting 4-Phen3rl-4- (2-thienyl) -butyronitrile product the formula:

NC-CH ₂ CH ₂ -CH

(VIII)

It is produced by reaction with aqueous potassium hydroxide hydrolyzes and gives a 4-plienyl-4 ~ (2-thienyl) butyric acid the iOrmel:

- 10 -

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1Δ-36 64-1

HO-G-CH ₂ GH ₂ -CH

X '

(IX)

This butyric acid intermediate is then cyclized by reaction with trifluoroacetic anhydride in trifluoroacetic acid and the 7-thenyl-6, 7-dihydrobenzo / ~ b J- thiophen-4- (5H) -one product of the formula:

(X)

is made with zinc and an ethyl bromoacetate compound Formula:

- 11 -

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IA-36 64-1

- 11 -

I ^{1 II}

Br-OH-O-OOoHc

(XI)

reacted and gives an ethyl-7-phenyl-6,7-

the formula:

(XII)

which is finally dehydrated by reaction with sulfur at about 23O ⁰ C and one of the desired ethyl-7-phenylbenzo / ^^ / thiophene - ^ - acetate starting materials of the formula:.

- 12 -

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1A-36,641

- 12 -

¹ II

CH-C-OC ₂ H ₅

(XIII)

results. In formulas III to XIII, R ^ and X have the meaning given above.

Also as an example, various J- / ~ b_7 ⁱ thiophen-7-acetonitrile starting materials can be prepared by the following reaction sequence. o-Thio cresol is made with a phenacyl bromide of the formula:

C-CH ₂ Br

(XIV)

The 2- / (o-tolyl) thio_7acetophenone product is brought to reaction the ■■ formula: -

r 13 -

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is produced by reaction with phosphorus pentoxide in. phosphorus, acid cyclizes and gives a 3-phenyl-7-methylbenzo. / ~ b 7tliiophene of the formula:

(XVI)

The J-Phenyl ^ naethylbenzo / b_7thiophen-Zvrischeaj> rodukt is then with IT bromosuccinimide in Gegenv / art reacted by benzoyl peroxide in carbon tetrachloride and gives a 3-phenylbenzo / ~ b 7thiophene-7-methyl bromide the formula:

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- 14 -

(χνΐί)

finally, with sodium cyanide in aqueous acetone is reacted and the desired 3-phenylbenzo / ~ b / thiophene-γ-acetonitrile starting material der Formula:

(XVIII)

CH ₂ ClT
results. In the previous formulas XIV to XVIII, Xy is a hydrogen or halogen atom. .

Further, for example, α-alkyl-J-phenylbenzo / B / thiophene-7-acetonitrile starting materials are used prepared for the process described above that a J-phenyl-benzo ^ b 7thiophene-7 ~ acetonitrile of the above Formula XVIII first? with sodium hydride and then with an alkyl halide of the formula:

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■■ • ■ 'W'

1A-36-. 641 - 15 -. ■ "■ ..

• R ₁ -HaI (XIX)

reacts and the desired starting material of the; Formula:. .

(XX)

results, V.ob ^ iT ^ i ^WC1 ^ ^L ^ i ^d ^ ^e ot> ^eri have the meaning given and Hai means a ChloB, bromine or iodine atom.

The preparation of specific examples of the above-described starting materials and others for the method of the invention is needed in detail described later.

The free acid compounds corresponding to the invention, represented by Formula I. above, form with a "variety of inorganic and organic Bases pharmaceutically acceptable carboxylates. Some examples of suitable bases are: sodium hydroxide, Potassium hydroxide, calcium hydroxide, aluminum hydroxide, Sodium carbonate, ivalium bicarbonate, choline, 2-hydroxyethylamine, ammonia and diethylamine. The pre-

, - 16 . 0098 13/1883 "

. <;'■ - ... · 1A-36,641.

Additional salts of this invention are the salts of alkalis and alkaline earths and of ammonia or .a substituted ammonia. The carboxylates and the free acids differ in relation to one another ■ certain physical properties, such as solubility in polar solvents, but on the other hand they are ..... equivalent to the intended use envisaged in the invention. If desired, the invention Compounds in which IL, is a lower alkyl group, can also be obtained in optically active form by an optically inactive free acid by fractional crystallization of one with an optically active base formed salt is broken down into their optical antipodes.

The compounds of this invention are new chemical Compounds useful as medicaments, particularly as anti-inflammatory agents. As such are They're both useful to those associated with inflammation Symptoms to mild, eriij, as well as to the occurrence of inflammation to prevent or suppress. Your anti-inflammatory Activity can be demonstrated and measured quantitatively using an appropriate test is to measure the ability of a connection, the normal Occurrence of erythema in animals exposed to ultraviolet radiation under standardized conditions have been stopped. The test procedure used is described in Archives Internationales de Pharmacodynamie et de Therapy, Volume 116, pages 261-292, 1958. This Test has proven itself such as for known clinically useful agents such as aminopyrine, antipyrine, and aspirin could be shown to be a reliable indicator of the inflammatory / negative activity of a compound has been demonstrated.

00 9813/188 3

1A-36,641

- 17 -

The activities of some representative associations of the present invention as determined by this standard test procedure are in the following compiled. In the table, the activity is given in values for the minimum dose that . is sufficient to stop erythema from occurring. ■■ · ■ '· ■.

Anti-inflammatory activity

Connection · least effective

Dose, mg / kg

4-phenylbenzo / b-7thiophene-2-acetic acid 6.2 acid - - '

7-phenylbenzo / ~ b_7thiOphen-3-vinegar-

acid ". 0.1

7-Phenylbenzo / ~ b_7thiophene-4-acetic acid / '. 0.1

7- (m-tolyl) ben "zo / ~ b_7thiophen-4-acetic 'acid ^. *

, a-methyl-7-phenylbenzo / b-7thiophene-4-acetic acid "Pi ^

2-phenylbenzo / ~ b_7thiOphen-6-vinegar-

acid 12.5

3-phenylbenzo / ~ b 7thiophene-7-vinegar-

acid ~ 0.4

3- (p- ⁱ I'luorophenyl) benzo / ~ b / "bhiophen-7-acetic acid ~ 3 _} 1

a-Butyl-3-plienylbenzo / ~ b_7thiophene-

7-acetic acid ~ 6.2. ■ ".,

4-Phenylbenzo / ~ b ^ thiophene -? - acetic acid . ~ 0.2

2-methyl-7-phenylbenzo / ~ b-7thiophene-4-acetic acid ~ .0.4

7-Cyclohexyroenzo / ~ b 7thiopheix-3-acetic acid . "* ~ .- 3.1 _

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• 1A-36 641.

The invention is further illustrated by the following examples explained.

Example 1 1 .._ ■■ "

To a solution of 6.7 g of 4-phenylbenzo / ~ b_7thiophene-2-acetonitrile in 100 ecm of ethanol and 25 ecm of dioxane: 20 ecm of an aqueous 5 _S 3 & potassium hydroxide solution are added and the resulting mixture is under. Heated to reflux and evaporated under reduced pressure. The residue is treated with a mixture of water and ether and the aqueous layer is separated, washed with ether and washed with dilute saline.

- acid "acidified. The acidic mixture is then extracted with ether and the ether-flues are washed with water until neutral and dried. The dried solution is then evaporated and the black oily pecker obtained is cleaned by using an acid from 120 g of silica gel chromatographed. The column is first eluted with benzene. These eluates are discarded. It is then eluted with a mixture of 10 % ether in benzene and these eluates are combined and evaporated. The residue obtained is dissolved in benzene. The benzene solution is dissolved treated with activated charcoal and, after filtering off, evaporated to dryness and gives 4-Phen3rlbenzo / ~ b_7-thiophene-2-acetic acid

Sp. 140 to 143? ° C after successive recrystallizations from aqueous ethanol, benzene and benzene, eexane.

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- 19 - "·". ■■. ■

Example 2

A solution of 11.7 S potassium hydroxide in 50 ecm V / water becomes a solution of 11.7 g of ethyl-7-phenylbenzo / ~ b_7 ~ thiophene-3-acetate in 100 ecm of ethanol is added and the disfiguring mixture is refluxed for 1 hour .and then evaporated under reduced pressure * The residue is dissolved in water and the aqueous solution is washed with ether and with dilute hydrochloric acid • acidified. The precipitating solid 7-phenyl-benzo / "~ b_7-thiophene-3-acetic acid is isolated and made from benzene

'ifexan recrystallized. '"■'

Mp 137-138 ° C. -. '■ ·. ■

Follow the previous procedure with only minor changes the following benzo / b_7thiophene-acetic acid compounds by basic hydrolysis of the below. given ester compounds:

(k) 2-Methyl-7-phenyl-benzo / ~ b_7thiophen-4-acetic acid, Pp. 134- I32 to ⁰ C after recrystallization from benzene by basic hydrolysis of ethyl 2-methyl-7-phenyl-benzo / ~ ~ b_7 thiophene ^ -acetate.

(Jo) 7-Cyclohexylbenzo / ~ b _i _7thiophene- ^z } -acetic acid by basic hydrolysis of 7-cyclohexylbenzo / b_7thiophene-

Example '3

A solution of 10 g of potassium hydroxide in 25 ecm of water becomes a solution of 8.3 g of ethyl-7-phenylbenzo / ~ b_7-

"- 20 -

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*. . ·. ■ -. · ■ -1A-36 641,

-20- ■

thiophene-4-acetate in 100 ecm of ethanol was added and the resulting mixture was refluxed for 2 hours and then evaporated under reduced pressure. The residue is dissolved in water and the aqueous solution is washed with Ither and acidified with dilute hydrochloric acid. The acidified mixture is extracted with ether and the ethereal solution is washed with water, dried and evaporated. A black solid residue of 7-phenylbenzo / ~ 'b-7thiophene- ⁱ -acetic acid is obtained, which is purified by chromatography over silica gel as described in Example 1 and recrystallized from benzene-hexane. ■ ·. ·, -

Mp 128.5 Ms 129.5 ° C. .; '

To a solution of 2.68 g of 7-Hlenylbenzö / ~ b_7thiophene-4-acetic acid in 10 ecm of hot ethanol 10 ecm of an aqueous 1.0 η I sodium hydroxide solution are added and the resulting solution is evaporated to dryness under reduced pressure and gives sodium-7 -phenylbenzo / ~ b_7thiophene- ^z t'-acetate.

To a warm solution of 2.90. g of sodium 7-phenylbenzo- / ~ b_7thiophene- ^z ^ acetate in 50 ecm of methanol, a solution of 1.4 g of choline chloride in 10 ecm of methanol is added with stirring. The mixture is stirred for 1 hour, filtered in order to remove the insoluble sodium chloride and the filtrate is evaporated to dryness under reduced pressure and yields 7-1 ⁾ henylbenzo / b_7-thiophene-4-acetic acid-crioline salt.

With the help of the only slightly modified preceding

■ '' ■■ ■. - '- "■■■ _ 21 -

0098 137 1883

.. ■ - ■ - 1A-36 641

_ 21 -

The following benzo- / b_7thiophenacetic acid compounds are used obtained by basic hydrolysis of the ester compounds given below:

(a) a-methyl-7-phenyrbenzo / ~ b / thiophenedacetic acid, Mp. 159 j 5 to 161.5 ° C (after recrystallization from aqueous ethanol) from ethyl = -a-methyl-7-phenylbenzo / ~ b_7thiophene-4-acetate.

(b) 7-phenyl-a-propylbenzo / b_ / thiophene-4-acetic acid, mp. 129 to 131 ⁰ C (after. Recrystallization from aqueous ethanol) of ethyl-7-phenyl-a-propylbenzo- / b. / thiophene acetate.

(c) 7- (o-fluorophenyl) benzo / b_ / thiophene-4-acetic acid, Mp. 125 to 126 ° G (after recrystallization from Benzene-hexane) from • ethyl-7- (o-fluorophenyl) benzo / ~ bj7- · thiophene-4-acetate.

(d) 7- (m-Tolyl) benzo / ~ b_7thiophene-4 ~ acetic acid, m.p.

1 ^ -3 to 144-, 5 ⁰ C from ethyl-7- (m-tolyl) -benzo / ~ b_7thiophene-4-acetate. ■.

(e) a-methyl-7- (o-fluorophenyl) benzo / ~ b_7thiophene-4-acetic acid, Mp. 116 to 7.5 ° C. (benzoil-hexane) from ethyl-amethyl-7- (o-fluorophenyl) benzo / b-7thiophene-4-acetate.

(f) a-Ethyl-7- (o-fluorophenyl) benzo / ~ b_7thiophene-4-acetic acid, Mp. 138 »5 to 139» 5 ° G (benzene-hexane) Ethyl-a-ethyl-7- (o-fluorophenyl) benzo / ~ b_7thiophene-4-acetate.

(g) α, 2-Dimethyl-7-phenylbenzo / ~ b_7thiophene-4-acetic acid,

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1A-36,641

Pp 93 to 95 ⁰ C. (aqueous ethanol) from lthyl-a, 2-dimethyl-7-phenylb'enzo / ~ b_7t;. ~ Hiophen 4-acetate.

(h) 7-Cyclohexylbenzo / '~ b-7thiophene-3-acetic acid, m.p. 135 to 136 ⁰ g (.aqueous ethanol) from ethyl-7-cyclohexylbenzo / ~ b_7tMoplien-3-acetate.

Example 4 -

A mixture heated ^ consisting of 2.4 g of 2-phenylbenzo / ~ b 7-thiophen-ö-acetonitrile, 2.6 g of potassium hydroxide and 75 cc of diethylene glycol is 18 h at 130 ⁰ G, then cooled and poured into V / ater . The aqueous solution is acidified with dilute hydrochloric acid. . The acidified mixture is extracted with ethyl acetate and the 'combined ethyl acetate extracts are washed / dried with water and evaporated. Han receives 2-phenylbenzo / "b • 7'bhiophen-6 ~ acetic acid. '

Pp. 225 to 226.5 0 _} after

• ester

B e is ρ ie 1 5 "

A solution of 108 g of aluminum hydroxide in 300 ecm of water is added to a solution of 108 g of 3-phenylbenzo / ~ b 7'bhiophen- * 7-acetonitrile in 2 liters of ethanol and the resulting mixture is refluxed for 18 hours and then lactated evaporated under reduced pressure. The residue is treated with a mixture of water and ■ Ither and the aqueous layer is separated washed with ether _t and acidified with dilute hydrochloric acid.

.:. '■ ·: ■. ■ ■ ■ = "- 23 -

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- 23 -

The acidified mixture is then extracted with ether and the extracts of it are washed with water until neutral and dried. The dried essential solution is evaporated and the oily residue obtained is purified by chromatography on a silica gel column as described for the product of Example 1. The (solid is 3-i ⁾ henylbenzo / b_7thiophene-7-acetic acid obtained from the eluate of 10 % ether in benzene.
Mp. 129-130 ⁰ G.nach recrystallization from benzene.

Using the above procedure, the. the following phenylbenzo / ~ b 7'kkooplien-acetic acid compounds obtained by basic hydrolysis of the nitriles indicated below, with only the mode of operation and the type of Insulation can be changed somewhat:

(a) a-methyl-3-phenylbenzo / ~ b 7thiophen-7 ~ acetic acid, mp. 162 to 164 ⁰ C (after recrystallization from benzene) by hydrolysis of a-methyl-3-phenylbenzo / ~ b_7thiophen-7-acetonitrile. .

(b) a- & thyl-3-phenylbenzo / ~ b_7thiophene-7-acetic acid? Mp 155 to 157.5 ⁰ C (benzene) by 2 1/2 days long refluxing. Of a mixture of 9.0 g ct-ethyl-3-phenylbenzo / b_ / thiophen-7-aaetonitril ecm in 250 g of ethanol and 9jO Potassium hydroxide in 30 ecm of water. .

(c) a-butyl-3-phenylbenzo / ~ b__7 "tb.iophen-7-acetic acid, mp. 94.5 95.5 -Me ⁰ C (benzene-hexane) by hydrolysis of a-butyl-5-phanylbenzo / ~ b_7thiophene-7-acetonitrile.

(d) 3- (p-Pluophenyl) benzo / ~ b_7thiophene-7 ~ acetic acid,

■ - 23 -

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. "■ · 1A-36,641

Ep. 152 to 153.5 ⁰ C (benzene-hexane) by hydrolysis of 3- (p-i'luorphenyl) benzo / ~ b_7tliiophen-7-acetonia? Il

(e). 3- (p-Chlorophenyl) benzo / b-7thiophene-7-acetic acid Ep. 152 to 154 ⁰ C (benzene) by hydrolysis of 3- (p-chlorophenyl) benzO / b-7thiophene-7-acetonitrile.

3- (p-bromophenyl) behzo / "~ b 7thiophene-7- ^ acetic acid, Mp. 1.59 to 162 ° C (benzene) by hydrolysis of 3- (p-bromophenyl) benzo / b-7thiophene-7-acetonitrile.

B e i s.p i e 1 6

Using "a procedure similar to that in the previous Examples are analogous to the following phenylbenzo- / b_7thiophene-acetic acid compounds by hydrolysis of the nitrile compounds given below. like received *

(a) 4; -Phenylbenzo / ~ b_7thiophene-7-acetic acid.

Melting point: 39.5 to 141.5 ° C (benzene-hexane). hydrolysis of 4-phenylbenzo / b-7thiophene-7-acetoniril.

(b) 4 - (in ~ l ⁱ 'luorphenyl) benzo / ~ b_7thiopheii-7-acetic acid, mp 123 to 124.5 ⁰ C by hydrolysis of 4- (m-Pluor-.' phenyl) benzo / ~ ^b_7th: i-ophen-7-acetonitrile.

(C), 4- "■ (ο ο rphenyl -ChI) b enz o / ~~ b_7thiophen-7 - ess i gsäur e, mp 158-161 ° C after chromatography on silica gel and recrystallization from Äthanöl- ^T Jasser by hydrolysis. of 4- (o-chlorophenyl) benzo / '~ b-7thiophene-7-acetonitrile.

(d) 4- (m-Chlorophenyl) benzo / ~ b7thiophene-7-acetic acid

^; ■■■ .-. . "'-25.-

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. 1A-36 641,

- 25 - ■ - ■: '- ■ - ■

Mp. 131.5 to 133 »5 ° C after successive Recrystallization from benzene-hexane and benzene by hydrolysis of 4- (m-chlorophenyl) benzo / ~ b_7thiophene-7-acetoniril.

(e) a-methyl-4-phenyl-benzo / ~ b_7thiophen-7-acetic acid, mp. 132 to 134.5 ⁰ C after two recrystallization from benzene-hexane by hydrolysis of OEC methyl-4-phenyl-benzo / ~ b_7thiophen-7- acetonitrile. ·

(f) a-Ethyl-4-phenylbenzo / ~ b_7thiophene-7-acetic acid, Mp. 15 s to 160 ° C. after chromatography over silica gel and recrystallizing from ethanol-water by hydrolysis of a-ethyl-4-phenylbenzo / ~ b_7thiophene-7-acetonitrile.

(g) a-I'rethyl-7-phenylbenzo / ~ b_7-thiophene-3-acetic acid, Mp. 122 to 1.24 ° C after chromatography over silica gel and recrystallization from water-ethanol by hydrolysis of a-methyl-7-phenylbenzo / b_7thiophene-3-acetonitrile.

Separation of Optical Isomers

A solution of 43.4 g of a-methyl-3-phenylbenzo / b_7thiophene-7-acetic acid (which was prepared according to Example 5 (a)) in 300 ecm warm ethyl acetate is converted into a solution of 18.6 g of 2-a -Phenethylamine in 75 ecm of ethyl acetate is added and the resulting mixture is left to stand for 2 days at room temperature. The crystalline salt that separates out is collected on a filter and the filtrate set aside. The solid salt is then crystallized 4 times from ethyl acetate-methanol. Each crystallization solution is left to stand for a second day at room temperature. The Mutterlau _t s are connected to the first

■. ■■ '.- *' 1A-56 641;

Lind Filtrat'vereinigt this solution "is retained for. Later use. The Saiz obtained after four recrystallisation _5, mp. 154 to 157.5 ⁰ G, is mixed with 5% hydrochloric acid and the acidic mixture is extracted with Ither. The Itiie out Zones are combined with 5 % hydrochloric acid and then washed with water until neutral, -dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The oily residue obtained is recrystallized from a mixture of hexane and benzene and gives the- -a "methyl-3-phenylbenzo / ~ b_7thiophen-7-acetic acid, mp. 102.5 ° ö bis-IO5 / cc ~ 7 ψ + 100 ° 0.02% in chloroform). '··'. * ·

The ethyl acetate-methanol solution previously worked up is evaporated to dryness and the j? Est body obtained is "mixed" with an excess of 5% hydrochloric acid. The acidic mixture is extracted with ither and the extracts are mixed with 5 % hydrochloric acid and then washed with water until neutral, dried and evaporated to dryness. A-methyl-3-phenylbenzo / "b-7thiophene-7-acetic acid is obtained, which is enriched in the left-rotating isomer. This acid (18.9 g) is dissolved in 130 ecm of ethyl acetate. The solution is added to a solution of 8.1 g of da-phenethylamine in 35 ml of ethyl acetate and the mixture is left to stand for 2 days at room temperature. The crystalline salt that separates out is isolated and recrystallized 3 times from ethyl acetate-methanol. The purified salt thus obtained, Fg * ^ 5 & _% 5 to 158 ° C, is then

Treated with 5 % hydrochloric acid and the acidic mixture is treated with pus as above. This gives ^ -a-methyl-J .benzo2 "b_Jthiophene-7-acetic acid, Ip. 103 to 105.5 ° C? -96.5 ° "0.03 % in chloroform).

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- 27 -

ft

Ausreangsmat eri ali en

The different ones used in the previous examples Starting materials and intermediates are manufactured in the following ways:

A. 2-Benzoylthiophenes

(1) 2- (o -]? Luobenzoyl) thiophene

253 g of tin chloride are added dropwise with stirring to a mixture of 81.7 g of thiophene, 154 g of o-fluorobenzoyl chloride and 1 l of benzene, the temperature being kept below 10 ^° C. The resulting mixture is stirred for 1 hour below 10 ° C and 2 hours at room temperature and then decomposed with dilute hydrochloric acid. The organic phase is separated off, washed with water, saturated aqueous sodium bicarbonate solution and again with water until neutral, dried and concentrated. The residue is distilled and gives 2- (o-i'luorobenzoyl) thiophene, bp. 108 to 115 ° G / O, 7 mm Hg.

- (2) 2- (m-Toluyl) thiophene, b.p. 103 to 110 ° C / 0.07 to 0.15 mm Hg ₄ is obtained by the method described above under (1) by reacting m-toluyl chloride with thiophene in Presence of tin chloride obtained. '

■ '(3) 2-Benzoyl-5-methylthiophene, b.p. 135 to 150 ° G / 1.2 up to 1.5 mm Hg is determined by that described in (1) above Method by reaction of benzoyl chloride with 2-ethylthiophene obtained in counterv / kind of tin chloride.

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B. Ethyl-3-phenyl-3- (2-thienyl) acrylates

■. (1) Ethyl 3- (o-fluoroplienyl) -3- (2-thienyl) acrylate

Iodine is added in crystal to a mixture of .104-, 5 .g 2- (o-fluorobenzoyl) thiophene, 101.5 g bromoacetic ester, -4-0 g zinc and 600 ecm benzene and the resulting mixture is 90 min under Heated to reflux. It is then cooled and decomposed with dilute hydrochloric acid. The organic phase is separated off with water, a saturated aqueous solution of . Sodium bicarbonate and washed again with water until neutral, dried and concentrated. The residue is distilled and yields ethyl 3- (o-fluorophenyl) -3- (2-thienyl) acrylate, Ep. 1-4-3 to 145 ° C / 0.7 to 1.1 mm Hg. :

. (2) Ethyl 3- (m-tolyl) -3- (2-thienyl) acrylate, b.p. 120 to 130 ° C / O, 15 to 0.25 mm Hg ₍ is determined by that described under (1) above Method obtained by reaction of 2- (m-toluyl) thiophene with bromoacetic ester in the presence of zinc.

(3) ethyl 3- (5-methyl-2-thienyl) r -3-phenyl acrylate, ICp. 160 to 190 ° C / 1.2 to 1.4- mm Hg ^ vi is given by the above below (1) method described by reaction of 2-benzoyl-5-methylthiophene with bromoacetic ester in the presence of zinc obtain.

0. Ethyl 3-phenyl-3- (2-thienyl) propionate (1) Ethyl-3-phenyl-3- (2-thienyl) propionate

A mixture of 161 g of ethyl 3-phenyl-3- (2-thienyl) acrylate,

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20 ίέ ~

13 g / palladium on charcoal and 1 l of methanol is at 27 ° C

2 with hydrogen at an initial pressure of 3.52 kg / cm (50 lbs./in) until sufficient hydrogen has been absorbed to remove the double bond to reduce. The mixture is then filtered and the I filtrate is distilled. Ethyl 3-phenyl-3- (2-thienyl) propionate is obtained, Zp. 117 to 130 ° C / O, 2 to 0.3 mm Hg.

(2) Ethyl 3- (o-fluorophenyl) -3- (2-thienyl) propionate, b.p. 112 to 115 ° C / 0.1 to 0.2 mm Hg ₍ is determined by the above under (.1) The method described obtained by catalytic hydrogenation of ethyl 3- (o ~ fluorophenyl) -3- (2-thienyl) acrylate.

(3) Ethyl 3- (m-tolyl> -3- (2-thienyl) propionate, bp. 139 "to 160 ° C / 1.5 to 2.0 mm Hg, is indicated by the above below (1) method described by catalytic hydrogenation obtained from ethyl 3- (ia-tolyl) ^ - (2-thienyl) acrylate.

• (4) ethyl 3- (5-methyl-2-thienyl) -3-phenylpropionate, b.p. 115 to 135 ° C / 0.4 to 0.6 mm Hg. Is determined by the above Method described under (1) by catalytic hydrogenation of ethyl 3- (5-diethyl-2-thienyl) -3-phenyl acrylate obtain. '

D. 3-phenyl-3- (2-thienyl) propan-1-ols (1) 3-I ^l -phenyl-3- (2-thi.enyl) propan-1-ol

A solution of 151.9 g of ethyl-3-phenyl-3- (2-thienyl) Propionate in 750 ecm of dry ether becomes a suspension of 22.2 g of lithium aluminum hydride in 450 ecm of dry ether

- 30 '0 0 981371883' ·

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added dropwise and the resulting mixture is -90 min under Heated to reflux. It is then cooled and decomposed by treatment with ethyl acetate and with water. The organic phase is separated off, washed with a saturated aqueous sodium chloride solution and dried. The dried solution is then distilled and gives 3-phenyl-3- (2-thienyl) propan-1-ol, Ep. "119 to 165 ° C / 0.6 to 0.7 mm Hg. '

'(2) 3- (o-Fluorophenyl) -3- (2-thienyl) propan-1-ol, boiling point 91 to 150 ° C / 0.4 to 0.5 mm Hg ₁ is given by the above under " (1) method described by the reaction of ethyl 3- (o-fluorophenyl) -3- (2-thienyl) propionate with lithium aluminum hydride.

(3) 3- (m-Tolyl) -3- (2-thienyl) propan-1-ol, bp 102 up to 140 ° C / 0.30 to 0.35 mm Hg is given by the above below (1) method described by reaction of ethyl 3- (m-tolyl) -3-i2-thienyl) propionate with lithium aluminum hydride obtain.

(4) 3- (5-Methyl-2-thienyl) -3-phenylpropan-1-ol, b.p. 128 to 135 ° C / O, 2 to 0.5 mm Hg ₁ v / ird by the above under (1 ) method described by the reaction of

- ethyl 3- (5-methyl-2-thienyl) -3-phenylpropionate with Obtained lithium aluminum hydride.

E. 3-Phenyl-3- (2-thienyl) propyl-bromide .. "■ ■

3-phenyl-3- (2-thienyl) propyl bromide

A solution of 51 g of phosphorus tribromide in 400 ecm of ither is made to a solution of 111.4 g of 3-phenyl-3- (2-thienyl) propan-1 ~ ol

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in 600 ecm of ether added dropwise, the temperature being kept at 0 to 10 ⁰ C. The resulting mixture is stirred at room temperature overnight. The gummy mass that forms during this time is separated off and discarded. The solution is washed with water, with 5% sodium hydroxide and again with water until neutral and dried. The dried solution is then distilled and gives 3-phenyl-3- (2-thienyl) propyl-bromide, b.p. 132 to 138 ° C. / 0.4 to 0.5 mm Hg.

(2) 3- (o-Fluorophenyl) -3- (2-thienyl) propyl bromide, b.p. 110 to 168 ° C / 0.3 to 0.4 mm Hg _f is replaced by the one described in (1) above Method by reaction of 3- (o-fluorophenyl) ~ 3- (2-thienyl) propan-1-ol with phosphorus tribromide. obtain.

(3) 3- (m-Tolyl) -3 ~ (2-thienyl) propyl bromide,

Bp. 109 to 160 ° C / 0.3 to 0.4 m Hg is achieved by the above Method described under (1) by reacting 3-Oa-tolyl) -3- (2-thienyl) propan-1-ol obtained with phosphorus tribromide.

(4) 3- (5-methyl-2-thienyl) -3-phenylpropyl bromide, Bp. 138 to $ 14 ° C / 0.2 to 1.0 mm Hg, is obtained by the above Method described under (1) by reacting 3- (5-methyl-2-thienyl) -3-phenylpropan-1-ol obtained with phosphorus tribromide.

F. 4-Phenyl-4- (2-thieiiyl) butyronitrile (1) 4-phenyl-4- (2-thienyl) butyronitrile

A solution of 18.8 g of sodium cyanide in 100 ecm of water becomes a mixture of 89.7 g of 3-phenyl-3- (2-thienyl) -

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propyl bromide, 400 ecm ethanol and 400 ecm acetone were added. The resulting mixture is refluxed for 20 hours. It is then concentrated to remove the solvent and the residue is dissolved in ether. The ethereal solution is washed with water, dried and evaporated. 4-Phenyl-4- (2-thienyl) butyronitrile is obtained, that can be used without further purification.

. (2) 4- (o-Pluorphenyl) -4- (2-thienyl) 'butyronitrile \ is described in the above (1) Method by the reaction of 3- ⁽¹ oi luorphenyl) -3- (2-thienyl) propyl bromide obtained with sodium cyanide as an oil which can be used without further purification.

(3) 4- (m-Tolyl) -4- (2-thienyl) butyronitrile is made by the method described in (1) above by reaction of 3- (m-tolyl) -3- (2-thienyl) propyl bromide with sodium cyanide obtained as an oil that was used without further purification can be.

(4) 4- (5-Methyl-2-thienyl) -4-phenylbutyronitrile is carried out by the method described in (1) above Reaction of 3- (5-methyl-2-thienyl) -3-phenylpropyl bromide

"obtained with sodium cyanide as an oil, which can be used without further purification.

G. 4-Phenyl-4- (2-thienyl) butyric acids (1) 4-Phenyl-4- (2-thienyl) butyric acid

A mixture of? 2.5 g of 4-phenyl-4- (2-thienyl) butyronitrile, g potassium hydroxide, 400 ecm water and 750 ecm ethanol

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is refluxed overnight. Then will. concentrated to remove most of the solvent and the residue is treated with a mixture of water and ether. The aqueous phase is separated ' and acidified with dilute hydrochloric acid. The precipitating 4-phenyl-4- (2-thienyl) butyric acid is isolated and recrystallized from benzene-hexane, melting point 94 to 95 ° Ο ·

■. (2) 4- (o-Fluorophenyl) -4- (2-thienyl) butyric acid, melting point 90 to 91 ° 0 (after crystallization from aqueous ethanol) is by the method described above under (1) by basic Hydrolysis of 4- (o-fluorophenyl) -4- (2-thienyl) ~ butyronitrile obtained. -

(3) 4- (m-Tolyl) -4- (2-thienyl) butyric acid, m.p. 100.5 up to 103 ° C (after / crystallization from aqueous ethanol); is carried out by the xLurch method described under (1) above basic hydrolysis of 4- (m-Q? olyl) -4- (2-thienyl) butyronitrile obtain. .

(4) 4- (5-Methyi-2-thienyl) -4-phenylbutyric acid is obtained by the method described in (1) above by basic hydrolysis of 4- (5-Hethyl-2-thienyl) -4-johenylbutyronitrile obtained as an oil that can be used without further purification.

H. Dihydrobenzo / "" b_7thiophen-4 (5H) -one

(1) 2-methyl-6,7-dihydrobenzo / ~ b_7 * bhiophen-4 (5H) -one

To a mixture of 98.2 g of 2-methyl-thiophene, 15O g of ß-, Carbomethoxypropionyl chloride and 1 liter of benzene earth 260.5 S

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Tin chloride was added dropwise with stirring, the temperature being kept below 10 ^° C. The resulting mixture. is stirred for 1 hour below 10 ° C and 2 1/2 hours at room temperature and then decomposed with dilute hydrochloric acid. The organic phase is separated off, washed with water, with saturated aqueous sodium bicarbonate solution and again with water until neutral, dried and concentrated. 2-Methyl-5- (3-carbomethoxypropionyl) thiophene is obtained, which can be used without further purification. ·

To a solution ύοώ. 175.5 g of 2-methyl-5- (3 ~ .carbomethoxypropionyl) thiophene in 750 ml of ithane oil are added to 500 ml of 3.6 mm sodium hydroxide solution and the resulting mixture is heated 90% under flowing pressure. It is then concentrated to remove the ethanol and the aqueous; "Büekstand is washed with Xther and; dilute hydrochloric acid • _v acidified It falls 2-methyl-5- (3-carboxy- - - piOplouyl.) T2i £ oph" e2i. from-, "'that isolated and dried'". wiiDd, 'ϊρ.- 101'Ms 105 ° σ ·''',

Sin "öeaiiscii. Iron, - 14? « Ss S -2 »Hethjl - 5- ^ö C3 ~ eai ^s i> ö3sjpropiOa.yl) -tiiiOjrheh ·, '- 147 _s 8 g potassium aydroxidj 1Ί5 scm eydrazine hydrate i? Jad 9 © Ö ecu Biätlijlenglykoi is a icer "apparatus with a water separator - sieve to 100 ° ö © Äiiits'ö ₂ Ms. - · kein- more water separates »ÄnsehlleBenä will be 4 hours to ungefähr- 200 ⁰ G. heated» liach the Atolcülilen is the resultant mixture with 2 1 water and the Terdiisat "aqueous mixture is acidified with hydrochloric acid, The acidified mixture is reacted with. Ither extracted and the ither extracts are combined, washed with water, dried and concentrated. The! Residue is distilled and

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gives 4 -. (2-methyl-5-thienyl) butyric acid, b.p. 114 to 120 ° C / 0.35 to 0.5 mm Hg.

138 g of trifluoroacetic anhydride are added to a solution of 120.7 g of 4- (2-methyl-5-thienyl) butyric acid in 180 ecm of trifluoroacetic acid is added dropwise and the resulting mixture is refluxed overnight. It is then concentrated to remove the solvent and the residue is dissolved in ether. The essential Solution is made with 5% aqueous sodium hydroxide solution and washed with water until neutral, dried and distilled. 2-methyl-6,7-dihydrobenzo / ~ b_7-

thiophen-4 (5H) -one, b.p. 81 to 89 ° C / 0.6 mm Hg.

(2) 7-Phenyl-6,7-dihydrobenzo ^ ~ b_7-thiophen-4 (5H) -one

45.5 g of trifluoroacetic anhydride are added to a solution of 52.8 g of 4-phenyl-4- (2-thienyl) butyric acid in 400 ecm of trifluoroacetic acid added dropwise and the resulting mixture is stirred for 1 hour at room temperature. Afterward another 2 ecm of trifluoroacetic anhydride are added and the mixture is stirred overnight at room temperature, refluxed for 1 hour and concentrated. The residue itfird is dissolved in ether and the ethereal Solution is made with 2.5% aqueous sodium hydroxide solution and then washed with water, dried and constricted. A solid residue of 7-I'henyl-6,7- <3-ihydrobenzo / ~ b_7thiophen-4 (5H) -one is obtained, Mp. 65.5 to 68.5 ° C. after recrystallization from hexane.

'(3) 7- (o-Fluorophenyl) -6,7-dihydrobenzo / "" b_7thiophen-4 (5H) -one, Bp. 140 to 175 ° C / 0.4 mm Hg is obtained by reaction

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of ^ - (Q-Fluorophenyl ^^ - ^ - thieny ^ butyric acid with Trifluoroacetic anhydride in trifluoroacetic acid, according to the method described above under (2) obtain.

(4) 7- (m-Tolyl) -6,7-dihydrobenzo / ~ b_7thiophen-4 (5H) -one, 150 to 152 ° C / 0.15 to 0.30 mm Hg by the one described in (1) above. Method through Reaction of 4- (m-Toiyl) -4- (2-thienyl) -butyric acid with trifluoroacetic anhydride in trifluoroacetic acid obtain.

(5) 7-methyl-6,7-dihydrobenzo / ~ b_7thiophen-4 (5H) -one, Bp 93 to 95 ° C / 0.8 to 1.1-mm Hg is achieved by the obtained the following reaction sequence. Ethyl 3 ~ (2-thienyl) crotonate is loaded according to the above under ^ C. (1). method is hydrogenated and gives ethyl 3- (2-thienyl) butyrate, Bp 63 to 69 ° C / 0.2 to 0.3 mm Hg. The ethyl 3- (2-thien3'-l) butyrate is produced by reaction reduced with lithium aluminum hydride and then hyd'roly / according to the method given under D. (1) above.

receives 3- (2-thienyl) butan-1-ol, boiling point.

70 to 83 ° G / 0.2 to 0.3 mm Hg. The 3- (2-thienyl) butan-1-ol is specified in accordance with the above under E. (1) Method with phosphorus tribroinide reacted and gives 3- (2-thienyl) butyl bromide, b.p. 64 to 80 ° C / 0.2 to -0.4 mm Hg. This intermediate halide product is then treated with sodium cyanide in aqueous acetone-ethanol implemented in accordance with the process given above under F. (1) and the 4- (2-thienyl) valeronitrile product is subjected to the basic hydrolysis according to the method given above under G. (i). Man receives 4- (2-thienyl) valeric acid, which ultimately ent-.

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in accordance with the method given above under H, (1 _f ) is reacted with trifluoroacetic anhydride in trifluoroacetic acid. The desired 7-methyl-6,7-dihydrobenzo / b-7thiophen-4 (5H) -one is obtained.

(6) 2-Methyl-7-phenyl-6,7-dihydrobenzo / "~ b_7thiophen-4. (5H) -one, b.p. 150 to 155 ° ^G / ^O >^2;" to _{0.4 mm Hg 1} obtained by reacting 4- (5-methyl-2-thienyl) -4-phenylbutyric acid with trifluoroacetic anhydride in trifluoroacetic acid by refluxing according to the method given under (2) above.

I. Phenyl-substituted dihydrobenzo / ~ b / thiophenes

2-methyl-4-phenyl-6,7-dihydrobenzo / ~ b_7thiophene

To a solution of phenylmagnesium bromide, which consists of 42.5 g of bromobenzene, 6.5 g of magnesium and 200 ecm Ether has been prepared, a solution of 3953 g of 2-methyl-6,7-dihydrobenzo / ~ b_7thiophen-4 (5H) -one in 300 ecm of ether was added dropwise with stirring and the resulting The mixture is stirred for 18 hours at room temperature. The mixture is then diluted by treating with Hydrochloric acid hydrolyzed and the organic phase is separated off, with water, with saturated ■ aqueous sodium bicarbonate solution and washed again with water to neutrality, dried and to Evaporated dry. Become the oily residue 100 ecm acetic anhydride are added and the resulting The solution is refluxed for 2 hours, cooled and poured into water. The aqueous mixture is with 50% sodium hydroxide made alkaline and the alkaline cal mixture is extracted with ether. The United

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. Ether from trains are washed with water "until neutrality, dried and evaporated to dryness. 200 ecm of absolute ethanol and 16 g of carboxymethyltrimethylammonium chloride hydrazide are added to the residue (Girard's reagent T) and 16 ecm acetic acid are added and the resulting mixture is Heated under reflux for 1 hour - 200 ecm of ethylene glycol are then added added and the mixture is concentrated to remove the ethanol .. The concentrated solution is washed with ether extracted and the ether extracts are washed with water, with saturated aqueous sodium bicarbonate solution and again washed with water until neutral, dried and evaporated to dryness. The residue obtained is then distilled under reduced pressure. 2-methyl-4-phenyl-6,7-dihydrobenzo / ~ b_7thiophene is obtained, which is trapped at 0.6 mm Hg between 105 and 175 ° C.

(2) Follow the general procedure above the following phenyl-substituted dihydrobenzo / ~ b_7thiophenes obtained by reaction of the corresponding starting materials.

(a) 4-Phenyl-7-methyl-6,7-dihydrobenzo / ~ b_7thiophene, Pp. 87 to 93 ° C.

-'.- '(b) 4- (mi ^l luorphenyl) -7-methyl-6,7-dihydrobenzo ^ ~ b_7-thiophene, mp. 63.5 to 67 ° C.

(c) 4- (o-Chlorphe.nyl) -7-methyl-6,7-dihydrobenzo / ~ b_7-thiophene is obtained as an oil without further purification can be used.

(d) 4- (m-Chlorophenyl) -7-methyl-6,7-dihydrobenzo / ~ 'b_7-thiophene is obtained as an oil that can be used without further purification

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can be used.

J. Phenylbenzo / ~ b_7thiophenes

(1) 2-methyl-4-phenylbenzo / "" b_7thiophene

A mixture of 44.2 g of 2-methyl-4-phenyl-6,7-dihydrobenzo / ~ b_7thiophen and 6.56 g of sulfur is JO min heated to 222-232 ⁰ C, cooled and dissolved in benzene. The benzene solution is poured onto a basic alumina chromatography column and the column is eluted with benzene. The benzene eluates are evaporated and the oily residue is distilled under reduced pressure. The fraction which passes between 128 and 18Q ⁰ C at 0.6 mm Hg is collected. This liquid solidifies when it is placed, giving 2-methyl-4-phenylbenzo / b-7thiophene, melting point 68 to 69.5 ° C. after recrystallization from methanol.

(2) Following the above general procedure, the following phenylbenzo / b_7thiophenes are obtained by dehydrogenation the corresponding phenyl-substituted dihydrobenzo / ~ b_7-thiophenes obtain: .

[ (a) 4-Phenyl-7-methylbenzo / ~ b__7thiophenj Mp. 76 to 78 ° C after recrystallization from ethanol.

(b) 4- (m-Fluorophenyl) -7-methylbenzo / b_7thiophene is obtained as an oil which can be used without further purification can be. .

(c) 4- (o-Chlorophenyl) -7-methylbenzo / ~ h_7thiophene

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is obtained as an oil that is between 87 and 210 ° C 1.0 to 1.5 mm Hg is captured,

(d) 4- (m-chlorophenyl) -7-iaethylbenzo / ~ 'b_7thiophen is obtained as an oil which 102-190 ⁰ C is collected in 0.20 to 0.25 Eim Hg.

(3) 3-phenyl-7-methylbenzo / * "b_7thiophene

132 g of phosphorus pentoxide are added in individual portions to 100 ecm of phosphoric acid and, after the resulting solution has cooled to 40 ° C., 12.1 g of 2- (o-tolyl) -thiO _M 7acetophenone are added. The reaction mixture is heated to 60 ° C. for 2 hours, cooled and poured into water. The aqueous mixture is extracted with ether and the combined ether extracts are washed with water with saturated sodium bicarbonate solution and again with water until neutral, dried and evaporated to dryness. To give ^3-I> henyl-7-methylbenzo / ~ _r b_7thiophen as a yellow oil which is collected 97-142 ^G C at 0.5 to 0.7 mm Hg.

(4) 3- (pi ^> luophenyl) -7-methylbenzo / ~ b_7thiophene

A mixture of 14.5 g of o-thiocresol, 25.0 g of p-fluorophenacyl bromide and 60 ecm of pyridine is 6 ^ H ~, heated under reflux, cooled and poured into 2 l of ice water. The aqueous mixture is made up with dilute hydrochloric acid ... leavens and the failing solid. 2- / ~ (o-Tolyl) thio_7-.; ,, p-fluoraeetophenone is isolated, dried and removed Benzene-hexane recrystallized, JBp. 49 to 51 C. This,

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The intermediate product is obtained by reacting with phosphorus pentoxide in accordance with the process given under (3) above cyclized in phosphoric acid and gives 3- (p-fluorophenyl) -7-niethylbenzo / ~ b_7thiophen, M.p. 5.5 to 55.5 ° C after crystallization from aqueous ethanol.

(5) 3- (p-chlorophenyl) -7-methylbenzo / ~ _i b_7thiophen mp. 79 is to 81.5 ° C (after Uinkristallisieren from aqueous ethanol) according to the above under (4) The method by the reaction of o-thiocresol obtained with p-chlorophenacyl bromide, initially 2- / ~ (o-tolyl) -thio_7-p-chloroacetophenone, mp. 56.5 to. 5.8.5 ° C is formed after crystallization from benzene-hexane, which is then cyclized in phosphoric acid by reaction with phosphorus pentoxide.

(0 3- (p-bromophenyl) -7-methylbenzo / ~ b_7thiophene, Mp. 89 to 92 (aqueous ethanol) is replaced by the above under (4) given process by reaction of o-thiocresol with p-bromophenacyl bromide obtained, wherein initially 2- / (o-tolyl) thio_7-p-bromoacetophenone, m.p. 59 to 61.5 ° C (benzene-hexane) is formed, which is then cyclized in phosphoric acid by reaction with phosphorus pentoxide will. ·

(7) 3-Methyl-7-phenylbenzo / ~ b_7thiophene

To a solution of 92.0 g of 2-mercaptqbiphenyl in 500 ecm 45.7 6 chloroacetone are added dropwise to pyridine and the resulting mixture is refluxed for 1 hour. It is then evaporated to remove the solvent and the residue is dissolved in ether.

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The ethereal solution is washed with water, a few times with dilute hydrochloric acid and again with water until neutral. The solution is then dried and evaporated to dryness. 1- (2-Diphenylylthio) -2-propanone, Ip. 85 to 86 ⁰ C after recrystallization 'from ethanol. This intermediate product (38.0 g) is then cyclized by reaction with 400 g of phosphorus pentoxide in 300 ecm of phosphoric acid in accordance with the process given under (3) above. 3-Methyl-7-phenylbenzo / "~ b_7-b thiophene is obtained by distillation as an oil which is collected between 124 and 152 ° C. at 0.15 to 0.2 mm Hg.

K. (Bromomethyl) phenylbenzo / ~ b_7thiophene

(1) 2-Bromomethyl-4-phenylbenzo / ~ b_7thiophenes

7.95 g of recrystallized N-bromosuccinimide and 100 mg of dibenzoyl peroxide are added to a solution of 10.0 g of 2-methyl-4-phenylbenzo ~ Y ~ b 7 "thiophene in 100 ecm of carbon tetrachloride, and the resulting mixture is 5 %. \ - Heated under reflux, irradiating it with light from a flood lamp. It is then filtered off and the piltrate evaporated to dryness. The residue is triturated with hexane and the hexane mixture is cooled in an ice-acetone bath and yielded solid 2-bromomethyl-4-phenylbenzo / ~ b_7thiophen, 84 to 90 ⁰ G. Pp.

(2) 2-Phenylbenzo / "b-7thiophene-6-methyl-bromide

A mixture of 9 »5 g of 2-phenyl-6-methylbenzo /" "b_7thiophene (for the preparation of this compound see J. Chem. Soc, 1956, Page 4791), 7.9 g N-bromosuccinimide, 100 mg dibenzoyl

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peroxide and 21.5 ecm of benzene are refluxed overnight while being irradiated with incandescent light. After cooling, the mixture is filtered to. to remove insoluble solids _f and the filtrate washed with ^5% is / öiger sodium hydroxide solution and then with water and dried and concentrated. The residue is extracted with benzene and the benzene extracts are evaporated. 2-Phenylbenzo / b-7thiophene-6-methylbromide is obtained as an oil which can be used without further purification.

(3) According to the general procedures given above under (1) and (2), which are only changed somewhat in relation to the reaction conditions and the type of isolation of the substances, the following (broinmethyl) phenylbenzo / ~ b / thiophenes are carried out Reaction of the corresponding phenylbenzo / ~ b / thiophenes with, · ■ N-bromosuccinimide obtained. In ^- each case the product is obtained as an oil which can be used without further purification. '.

(a) 3-Phenylbenzo / ~ b_ / thiophene-7-methyl bromide.

(b) 3- (p-Fluorophenyl) benzo / ~ b_ / thiophene-7-iaethyl-brDmid. (c) "3- (p-Chlorophenyl) benzo / ~ b_ / thiophene-7-: methyl bromide. (el) 3- (p-bromophenyl) benzo / ~ b / thiophene-7-methyl-bromide.

(e) 4-P-henylbenzo / ~ b_ / thiophene-7-diethyl bromide *

(f) 4- (m-Fluorophenyl) benzo / ~ b_7thiophene-7-methyl-bromide.

(g) 4- (o-Chlorophenyl) benzo / ~ b 7thiophene-7 ~ methyl bromide. (h) 4 - (Ia ~ chlorophenyl) benzp / " ^r 'b / ^: chiophene-7-2iethyl

(i) 7-Slienyiberizo / ~ b__7thiopheh-3-niethyi-'bromide.

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Ii. PhenyTbenzo / ~ b_7thiophenacetonitrile

(1) 4-Phenylbenzo / ~ b 7thiophene-2-acetonitrile

A mixture of 8 g of 2-bromomethyl-4-phenylbenzo / b_7thiophene, 100 ecm of a benzene-wet quaternized chloromethylated Styrene-divinylbenzene copolymer resin, which is in the ^ ~ CU ~ 7-iOrm (like that under the Trademark Amberlite IRA-400 known; for the production of the cyanide form of this resin see J.Org.Chenu, Volume 28, Page 698., 1963) and 200 ecm of benzene is refluxed for 12 hours and then cooled. The solution is decanted from the solid resin. The resin is washed out with benzene and the washing solutions are made given together with the decanted solution. All of the benzene solution is then washed with water, dried and evaporated. 4-Phenylbenzo / b-7-thiophene-2-acetonitrile is obtained as an oil that can be used without further purification.

(2) 2-Phenylbenzo / b-7thiophene-6-acetonitrile

A mixture of 3 »3 g of 2-phenylbenzo / ~ b 7thiophene-6-methyl bromide, 0.6 g sodium cyanide, 25 ecm acetone, 25 ecm N, IT-dimethylformamide and 5 ecm of water are taken for 6 hours Heated to reflux and then concentrated to remove the solvent. The residue is with ether and Treated ethyl acetate and the resulting mixture washed with water, dried and evaporated to dryness. A solid residue of 2-Phenylbenzp / ~ b_7-thi6phen-6-aeetonitrile is obtained, which can be used without further purification.

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1A-36,641-45 (3) 3-P? Enylbenzo / ~ b-7thiophene-7-acetonitrile

A mixture of 153 S 3-phenylbenzo / ~ "b_7-thiophene-7-methyl bromide, 26.4 g sodium cyanide, 150 ecm water • and 1500 ecm acetone is left overnight at room temperature stirred and then concentrated to remove the solvent. The residue is treated with ether and the ethereal mixture is washed with water and dried and evaporated. A brown oily residue of 3-phenylbenzo / ~ b_7thiophene-7-acetonitrile is obtained, which is purified by chromatography on alumina and recrystallized from ethanol, ip. 107.5 up to 110 ° C.

(4) Following the general procedure described under (1), (2) and (3) above, the following phenylbenzo / ~ b 7thiophenacetonitrile by reaction of the corresponding (Bromomethyl) phenylbenzo / "" b 7 thiophenes obtained with sodium cyanide:

(a) 3- (pi ¹ luophenyl) benzo / ~ b-7thiophene-7-acetonitrile.

(t>) 3- (p-Chlorophenyl) benzo / ~ b_7thiophene-7-acetonitrile.

(q) 3- (p-Bromophenyl) benzo / ~ b-7thiophene-7-acetonitrile.

(d) 4-Phenylbenzo / ~ b-7thiophene-7-acetonitrile.

(e) • 4 ~ (mi ¹ luophenyl) benzo / ~ b 7 "bhiophen-7 ~ acetonitrile.

(f) 4- (o-Chlorophenyl) benzo / ~ b 7thiophene-7-acetonitrile.

(g) 4- (m-Chlorophenyl) benzo _i / ~ b-7thiophene-7-acetonitrile. (h) 7-Kienylbenzo / ~ b-7thiophene-3-acetonitrile.

M. a-Alkyl-phenylbenzo ^ "" b_7thiophene acetonitrile

(1) a-Methyl-3-phenylbenzo / b-7tliiophene-7-acetonitrile

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To a suspension of 1.6. g of a 53? 47 & dispersion of sodium hydride in ^ l ^ * ¹ in 15 cc of dimethyl sulfoxide is added dropwise under a nitrogen atmosphere, a solution of 8.0 g of 3-phenylbenzo ^ ~ b_7thiophen-7-acetonitrile in 55 cc of dimethylsulfoxide, keeping the reaction temperature below 35 G is held. The resulting mixture is stirred under a nitrogen atmosphere for 5 hours at room temperature. Then 9 * 1 g of methyl iodide are added, the temperature being kept below 25 ° C. The reaction mixture is stirred over fold at room temperature under a nitrogen atmosphere. It is then decomposed by treatment with dilute hydrochloric acid and the acetic acid mixture is extracted with ether. The extracts of it are washed with water * with saturated aqueous sodium bicarbonate solution and again with water, dried and evaporated to dryness. A-methyl-3-phenylbenzo / b_7thiophene-7-acetonitrile is obtained as an oil which can be used without further purification.

(2) a-Ethyl-3-phenylbenzo / b-7thiophene-7-acetonitrile is carried out according to the procedure given under (1) above, in which ethyl bromide is used instead of methyl iodide is obtained as an oil without further purification can be used"

(3) a-Butyl-3-phenylbenzo / ~ b_7thiophene-7-acetonitrile * is carried out according to the method given under (1) above, using n-butyl bromide instead of methyl iodide is used as an oil obtained without further purification can be used.

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(4) a-Methyl-4-pheaylbenzo / '* b-7thiophene-7-acetonitrile is carried out according to the "procedure specified under (Ί)" above by reaction of 4-phenylbenzo ^ ~ b_7thiophene-7-acetonitrile obtained with sodium hydride and then with methyl iodide. .

(5) a ~ ethyl-4-phenylbenzo / ~ bJ7thiophene-7-acetonitrile is made by the process given under (1) above by reacting 4-phenylbenzo / b_7thiophene-7-aeetonitrile obtained with sodium hydride and then with ■ ethyl bromide. . -

(6) a-Methyl-7-phenylbenzo / b-7-thiophene-5-acetonitrile is by the process given above under (1) by reaction of 7-phenylbenzo / ~ b_7thiophene-3-acetacitrile obtained with sodium hydride and then with methyl iodide *

N. Phenylbenzo / ~ b 7thiophene-acetic acid ester (ij ethyl-7-phenylbenzo / ~ b-7thiophene-3-acetate

10.0 g of 2- (diphenylyl) thiol are added to a solution of 2.9 g of sodium methylate in Λ 00 ecm of methanol. After stirring for 10 minutes, a solution of 8.85 g of ethyl - ^ - chloroacetoacetate in 200 ecm of methanol is added. The resulting mixture is refluxed for 1 hour, cooled and poured into water. The aqueous mixture is extracted with ether and the ether extracts are washed with a saturated aqueous sodium chloride solution, dried and evaporated. Ethyl 4- (2-diphenylylthio) acetoacetate is obtained as an oil which can be used without further purification.

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I32'g Fhosphorpentoxid are added in portions to 100 cc of phosphoric acid and after cooling the resulting Xösung to 4-0 ⁰ C. 15.5 g of ethyl-4- (2-diphenylylthio) acetoacetate were added. The reaction mixture is heated to 2 ½ l to 60 ° C., cooled and poured into water. The aqueous mixture is extracted with ether. The combined extracts of it are washed with water, with saturated aqueous sodium bicarbonate solution and again with water until neutral, dried and reduced to neutrality The product is evaporated to dryness, giving ethyl 7-phenylbenzo / b-7thiophene-3-acetate as an oil which can be used without further purification.

(2) Ethyl-7-phenylbenzo / b-7thiophene-4-acetate

To a mixture of 6.5 g of 7-rienylr-6,7-dihydrobenzo - / - -> \ - ethyl

- / 'b_ / thiophen-4 (5H; -one, 5 »8 g solid bromoacetic acid, 2.8 g Zinc and 50 ecm of benzene are added to a crystal;] od and the mixture is refluxed for 2 hours.

-Axnyl "■

Then a further 2 g of bromoacetate and 1 g of zinc are added and the reaction mixture is for a further 2 h_ heated to reflux. The "" mixture is then filtered, to remove the excess zinc and the filtrate is diluted with hydrochloric acid with water, with dilute aqueous sodium bicarbonate solution and again with water washed until neutral. It is then dried and evaporated. The residue is dissolved in 100 ecm acetic anhydride dissolved and the resulting solution is refluxed for 1 hour and evaporated. The residue is extracted with ether and the ether extracts are washed with saturated aqueous sodium bicarbonate solution and washed with water until neutral, dried and evaporated. The residue obtained in this way

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is dissolved in 100 ecm absolute ethanol. To this Solution are 4 g (car "boxymethyl) trimethylammonium chloride hydrazide and 4 ecm acetic acid are added and the disfiguring mixture is 1. "TBT" heated under reflux. Ethylene glycol is added to this and the mixture is concentrated in order to remove the ethanol Solution is then extracted with ether and the ether extracts are extracted with water, with saturated aqueous sodium bicarbonate solution and washed again with water until neutral, dried and evaporated. Han receives Ethyl-7-phenyl-6,7-dihydrobenzo / ~ b_7thiophene-4-acetate .. ·

The intermediate above (8.5 g) is added at 1.0 g Sulfur mixed and the mixture is 1 hour on Heated from 226 to 230 ° C and yields ethyl 7-phenylbenzo / ~ b_7-thiophene-4-acetate corresponding to the analogous dehydration process described earlier. ■

Ethyl-a-methyl-7-phenylbenzo / b_7thiophene-4-acetate is prepared in accordance with the process given above under (2) by reacting 7-pkeiiyi-6,7-dihydrobenzo-b_7-thiophen-4 (5H) -one produced with ethyl a-bromopropionate and zinc, initially ethyl-cx-methyl-7-phenyl-6 7 _{r-dihydrobenzo} / ~ arises b_7thiqphen-4-acetate, which is then dehydrated by reaction with sulfur.

(4) Ethyl-a-propyl-7-phenylbenzo / ~ b_7thiophene-4-acetate is prepared in accordance with the process given above under (2) by reacting 7-Pb.enyl-6,7-dihydrobenzo- / ~ b_7thiophene-4 ( prepared 5H) -one with ethyl a-bromovalerate and zinc, said first lthyl-a-propyl-7-phenyl-6, 7-dihydrobenzo / ~ arises b_7tliiophen-4-acetate, which is subsequently dehydrogenated with sulfur.

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(5) Ethyl 7- (o-fluorophenyl) benzo / ~ bJ7thiophene-4-acetate is made in accordance with the procedure given above under (2) by reaction of y-Co-fluorophenyl) - ^,? - dihydrobenzo / "~ b_7thiophen-4 (5H) -one with ethyl bromoacetate

• Lind zinc is produced, initially producing ethyl 7- (o-fluorophenyl) ^r -6,7-dihydrobenzo / ~ b_7thiophene-4-acetate, which is then dehydrated with sulfur.

(6) ethyl-7- (ni-tolyl) benzo / ~ b_7'fchiophen-4-acetate is carried out by the procedure given in (2) above

h by reaction of 7- (m-tolyl) -6,7-dihydrobenzo / ~ b_7-

obtained thiophen-4 (5H) -one with ethyl bromoacetate and zinc, initially 7- (m-tolyl) -6j7-dihydrobenzo / ~ b_7thiophene-4-acetate which is then dehydrated with sulfur.

(7) ethyl-a-methyl-7- (o-fluorophenyl) benzo / ~ b_7-thiophene-4-acetate, that by distillation as oil 'between 168 and 205 ° 0 is captured at 1.0 to 1.1 mm Hg,

according to the process given above under (2) by reaction of 7- (oi ¹ luophenyl) -6,7-dihydrobenzo / ~ b_7 thiophen-4 (5H) -one with ethyl a-bromopropionate and zinc, with ethyl -a-methyl-V-Xo-fluorophenyi) -6,7-dihydrobenzo ^ ~ b__7'fchiophen-4-acetate is formed, which is then dehydrated with sulfur.

(8) Ithyl-a-ethyl-7- (o-fluorophenyl) benzo ^ "" b_7thio ~ phen-4-acetate, which was isolated by distillation as an oil 175-220 ⁰ C at 1.0 to 1.2 mm Hg is obtained by reacting 7- (o-pluophenyl) -6,7-dihydropbenzo ^ ~ b_7-thiophen-4 (5H) -one with ethyl-a-bromobutyrate and zinc according to the process given above under (2)

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th, whereby first ethyl-a-ethyl-7- (o-fluorophenyl.) -6,7-dihydrobenzo / ~ b__7thiophene-4-acetate arises, which is then dehydrated with sulfur.

(9) Ethyl-2-methyl-7-phenylbenzo / ~ b_7thiophene-4-acetate, which is ^{isolated after two distillations as an oil between 173 and 230 0} C / at 0.3 mm Hg, is according to the above under (2) given process by reaction of 2-methyl-7-phenyl-6,7-dihydrobenzo / "" b_7thiophen-4 (5H) -one obtained with ethyl bromoacetate and zinc, initially ethyl-2-methyl-7-phenyl-6,7 -dihydrobenzo / ~ b .__ 7thiophene-4 ~ acetate is formed, which is then dehydrated with sulfur. In this case, the dehydrated product is purified by chromatography in benzene over neutral aluminum oxide before distillation.

(10) Ethyl-α, 2-dimethyl-7-phenylbenzo / ~ b-7thiophene-4-acetate is by the process given under (2) above by reacting 2-methyl-7-phenyl-6,7-dihydrobenzo / ~ b_7-thiophen-4 (5H) -one obtained with ethyl a-bromopropionate and zinc as an oil, which can be used without further purification can, whereby initially a ^ -Dimethyl ^ -phenyl-e ^ -dihydrobenzo / ~ b_7thiophene-4 - acetate which is then dehydrated with sulfur.

0. Ethyl-7-cyclohexylbenzo / ~ b_7thiophenessigsäureester '

(1) Ethyl-7-cyclohexylbenzo / ~ b_7thiophene-3-acetate, which is obtained by distillation as an oil between 160 and 201 ⁰ C at 0.5 to 0.6 mm Hg, is - by an analogous process, such as- under IT. (1) described above by reaction of o-cyclohexylthiophenol with ethyl-4-chloroaceto- '

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Acetate obtained in the presence of a strong base, with the ethyl-4— (o-cyclqhexylphenylthio) aceto ^ abe "-2wi * sch- · product is then reacted with phosphorus pentoxide in phosphoric acid.

. (2) Ethyl-7-cyclohexylbenzo / ~ b_7thiophene-4-acetate is obtained as an oil by the following reaction sequence, which can be used without further purification.

^ -Cyclohexylcarbonylthiophene is according to the method given above under B. (1) with ethyl bromine. acetate reacted to form ethyl 3-cyclohexyl-3- (2-thienyl) aerylate. This intermediate product is then catalytically hydrogenated according to the process given above under C (I) and gives ethyl 3-cyclohexyl-3- (2-thienyl) propionate. This propionic acid ester is then in accordance with the method given above under D. (1.). Lithium aluminum hydride reacted to give 3-cyclohexyl-3- (2-thienyl) propan-1-ol. This intermediate product is reacted with phosphorus tribromide in accordance with the process given under E. (1) above and gives 3-cyclohexyl-3- (2- thienyl) propyl bromide. This Halogenzv / ischenprodukt is then reacted according to the method indicated above under F. (1) with sodium cyanide to react V7obei ^z t ~ Gyclohexyl-4- (2-thienyl) butyronitrile formed. This nitrile mixture product is then reacted with an aqueous base in accordance with the process given above under G. (1) and gives 4- cyclohexyl-4- (2-thienyl) butyric acid. This acid intermediate is in accordance with the method given above under H. (2) with trifluoroacetic anhydride in

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Trifluoroacetic acid reacted and gives 7-cyclohexyl-6,7-dihydrobenzo / ~ b_7thiophen-4 (5H) -one. This intermediate ketone product is then reacted with ethyl bromoacetate and zinc to give ethyl 7-cyclohexyl-6 _} 7-dihydrobenzo / "~ b_7thiophene-4-acetate which is finally dehydrated with sulfur according to the process given under N. (2) above , will.

Claims

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Claims (1)

. BR. ING. F. WUBSTHOFt DIPL. ING. G. VOlJS DH.B.r.PKCHMANIi DR. ING. S. BSHRSNS 'PATXKTANWJtLTS 8 MUNICH SO nuroi ssoaai 1A-36 641 Pat entan s prtiohe Benzo / b ^ / thiopheneacetic acid compounds produced by the ormel W-CH-COQH can be represented, as well as their pharmaceutically acceptable salts; where H ^ is a hydrogen atom or a lower one Is an alkyl group of not more than 4 carbon atoms and W one of the following groups means? Sine 4-phenylbenzoOOthiophene-j ^ a 7-phenylbenzoOOthiophene-3 group of the formula 00 9813 / 18S3 BATH ORIGINAL U-36 641 55 a 7 * -Pheny! benzo00 tbiophen-4-G group of the formula a 2-pheny! benzo 00 thiophene-6 group of the formula a phenylbenzo CbI thiophene-7 * group of the formula a 7-cyclohexylbenzo00thiophene-3 group of the formula CHg CH ₂ CH ₂ CH ₂ ^N CH ₂ ^ 00 98 13/188 ZS-. ■ 1A-36.64I or a T-cyclobexylbenzoCbJtbiopben- ^ - group of the formula in which one of the groups "E ₂ 'and E ^" is a hydrogen atom and the other is a pbenyl group of the formula E. is a hydrogen atom or a methyl group - -4 and X is a hydrogen or halogen atom or a methyl group means. 2o & L «-Metbyi-T-pbenylbenzoCbJtbiophen - ^ - acetic acids 3 φ oL-Metbyl-7- (o-fluoropbenyl) benzoCb3tbiopben-4-acetic acid 4 «ck-Metbyl-7-phenylbenzo £ b3tbiopben-4-acetic acid 5β c ^ -Metbyl-S-pbenylbenzoCblthiophene-T-acetic acid 6. cL-MetbylM-phenylbenzoCblthiophene-T-acetic acid. 0 0 981 3 / 188-3