DE1941543C - Benzo square bracket to square bracket to thiophene-acetic acid - Google Patents

Description

represents in which X represents a hydrogen atom, a halogen atom or a methyl group, as well as their pharmaceutically acceptable salts.

denotes in which R ^{3 is} a phenyl radical of the general formula

represents, in which X is a hydrogen atom, a halogen atom or a methyl group, as well as their pharmaceutically suitable salts.
According to the general formula

Corresponding benzo [b] thiophene-acetic acids and their salts are produced by hydrolysis a compound of the general formula

denotes in which R ^{3 is} a phenyl radical of the general formula R ²
R ¹ -CH-Y

in which R ¹ and R ^{2 have} the meaning given and Y represents a radical which can be hydrolyzed to a carboxyl group. Such residues are z. B. the cyano, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carbamyl, alkyl-substituted carbamyl, trihalomethyl, amidino, alkyl-substituted, amidino, haloformyl,

-C-NHNH ₂ -, --C-NHOH-,

NOH

The invention relates to benzo [b] thiophene-acetic acids of the general formula

R ²
R ¹ -CH-COOH

55 - C —O-alkyl-, -C-NH ₂ -,

NH NH

-C-NHNH ₂ -, —C —halogen-

and the

in which R ^{1 is} a hydrogen atom or a C, -Q-alkyl group and R ^{2 is} a 4-phenylbenzo [b] thiophene- (2) -, 7-cyclohexyl- or 7-picnylbenzo [b] thiophen- (3) -, 2 -Phenylbenzo [b] thiophene (6) -, 7-cyclohexyl or optionally 7-phenylbenzo [b] thiophene (4) group substituted in the 2-position by a methyl group,

- C -C (halogen) ₃ group

The exact nature of Y is not critical as this residue is converted into a carb during the process

oxyl group is converted. Therefore, the group Y can optionally have one or more substituents such as a halogen atom, a lower alkyl, lower alkoxy, nitro, carboxy or alkoxycarbonyl group contain. In those cases in which the group Y is basic, it can also be in the form of a Acid addition salt can be used. Compounds in which Y is the cyano group or an alkoxycarbonyl group are the preferred starting materials for this process because they are readily available and can be hydrolyzed to carboxyl derivatives in high yields.

The hydrolysis can be carried out under both acidic and alkaline conditions with the help of an acidic or alkaline hydrolyzing agent will. Alkaline conditions are preferred and should be used for certain groups Y, e.g. B. the

/
- C — QHal ^ group,

! Only to be applied. The hydrolysis ! -, poor in water or in an aqueous solution of • • lerten, water-miscible organic solvents, such as an aliphatic alcohol, dioxane, tetrahydrofuran, ethylene glycol, propylene glycol or a lower alkyl ether of ethylene glycol or diethylene glycol are carried out to which an acid or base has been added to render the medium acidic or alkaline. Suitable Bases are e.g. B. alkali hydroxides, hydroxides of alkaline earths, alkali carbonates, alkali alcoholates and trialkylammonium hydroxides. Suitable acids are e.g. B. mineral acids, strong organic acids, such as p-To- ! uolsulfonic acid and acidic ion exchange resins. Be

preferred agents are alkali hydroxides such as sodium hydroxide or potassium hydroxide. The hydrolyzing agent is usually used in a significant overshot.

The hydrolysis is carried out so that a solution or suspension of the starting material in one Solvent containing an acid or base is heated until the group Y is substantially is completely hydrolyzed. The time required

ίο and temperature is different and depends on the type of starting material of the general formula II used and the basic one used or acidic agent. In general, however, the reaction will take place at a temperature between 25 and 200 ° C or carried out at the temperature at which the solvent boils under reflux. The reaction time here is 1 to 75 hours. If you have one of the preferred basic hydrolyzing agents is used, the reaction is normally carried out at a temperature between 60 and 125 "C and is within less than 24 hours essentially complete. If the hydrolysis is carried out under alkaline conditions, if the hydrolysis product is present in the reaction mixture in the form of a salt! it can be in this form or after treatment with an acid, in particular with a mineral acid, are isolated. Do you lead the If hydrolysis occurs under acidic conditions, the hydrolysis product is in the reaction mixture as an acid before and can be isolated in this form or by subsequent treatment with a base in salt form. The required starting materials can be produced in various ways, e.g. B. can be different 7 - phenylbenzo [b] thiophene - (4) - ethyl acetate prepared according to the following reaction scheme will.

\
O C-

Il /

BrCH ₂ -COC ₂ H ₅ C ₂ H ₅ O

Zn

H,

Cat.

HO-CH, -CH, -CH

C-CH, -CH

H-X

PBr ₃

1. LiAlH ₄
2. hydrolysis

C ₂ H ₅ O

BrCH ₂ -CH ₂ -CH

NaCN

NC-CH, -CH, -CH

KOH

(F ₃ C-CO) ₂ O F ₁ C-COOH

C-CH ₁ -CH ₂ -CH

R ¹

CH-C-OCH,

R ¹

! Il

CH-C-OC ₂ H ₅

230 ⁰ C

Another synthetic route for the preparation of dihydrobenzothiophene-4- (5 H) -ones is described under Example H.

Also, various 3-phenylbenzo [b] thiophene- (7) acetonitriles can be used according to the following Reaction scheme can be prepared:

S-CH ₂ -C

CH ₃

PCl ₅ H ₃ PO ₄

CH, Br

N-bromosuccinimide

O

Il Il

Q ₁ H ₅ -COOCQ ₁ H ₅

CH,

¹ S ''

CH ₇ -CN

Furthermore, ii-alkyl-.l-phcnylbenzoCbJthiophene-fVl-acetonitriles required as starting materials can be used accordingly the following equation:

Close

2. R ¹ HaI

CH ₂ -CN

The benzo [b] thiophene-acetic acids of the general formula I form salts with pharmaceutically suitable inorganic and organic bases. Suitable bases include sodium, potassium, calcium, aluminum hydroxide, sodium carbonate and potassium bicarbonate. Choline. 2-hydroxyethylamine, ammonia and diethylamine. Preferred salts are those of the alkalis and alkaline earths as well as the ammonium or amine salts. The salts and acids differ in solubility in polar solvents, but are equivalent for the intended use. The compounds according to the invention in which R ^{1 is} a C ₁ -C ₄ -alkyl group can optionally also be obtained in optically active form by breaking down an optically inactive acid into its optical antipodes by fractional crystallization of a salt formed with an optically active base .

The compounds according to the invention are new. They are used as medicines, especially anti-inflammatory Means, because on the one hand they alleviate and prevent the symptoms associated with inflammation or, on the other hand, suppress the occurrence of inflammation. Your anti-inflammatory activity can be with the help of an in Archives Internationales de Pharmacodynamie et de therapy. Vol. 116, p. 261 to 292. 1958, test method described. • This test has, e. B. for aminopyrine. Antipyrine and aspirin has been shown to be a reliable indicator of anti-inflammatory activity proven a connection.

The following are the activities of some representative compounds of the invention as they do determined by this standard test procedure. In the table is the Activity given in values for the minimum dose that is sufficient to prevent erythema from occurring to stop.

Anti-inflammatory activity

connection least
effective
dose
mg leg 4-phenylbenzo [b] thiophene- (2) -
acetic acid
7-phenylbenzo [b] thiophene- (3) -
acetic acid
7-phenylbenzo [b] thiophene- (4) -
acetic acid
7- (m-TolyI) -benzo [b] thiophene- (4) -
acetic acid 6.2
0.1
0.1
3.1

CH-CN

R ¹

connection

»I-methyl-7-phenylbenzo [b] thio-

phen (4) acetic acid 0.4

2-phenylbenzo [b] thiophene-6-acetic acid 12.5

3-phenylbenzo [b] thiophene-7-acetic

acid 0.4

3- (p-Fluorophenyl) benzo [b] thiophene-7-acetic acid 3.1

u-Butyl-3-phenylbeiizo [b] thiophene-

7-acetic acid 6.2

4-phenylbenzo [b] thiophene-7-acetic

acid 0.2

2-methyl-7-phenylbenzo [b] thiophene-.J ₅ 4-acetic acid 0.4

7-Cyclohexylbenzo [b] thiophene-3-acetic acid 3.1

<i-methyl-7- (o-fluorophenyl) -benzo [b] -

thiophene-4-acetic acid 0.4

r / -Methyl-3-phenylbenzo [b] thio-

phen-7-acetic acid 0.4

Aminopyrine> 38

Antipyrin \ (comparison) 100

Aspirin J 28

example 1

20 cm ^{3 of} an aqueous 5.3 N potassium hydroxide solution are added to a solution of 6.7 g of 4-phenylbenzo [b] thiophene (2) acetonitrile in 100 cm ^{3 of} ethanol and 25 cm ^{3 of dioxane, and the resulting mixture is added for 18 hours} heated to reflux and evaporated under reduced pressure. The residue is treated with a mixture of water and ether, the aqueous layer is separated off, washed with ether and acidified with dilute hydrochloric acid. The acidic mixture is then extracted with ether and the extracts are washed with water until neutral and dried. The dried solution is then evaporated. The black oily residue obtained is purified by chromatography on a column of 120 g of silica gel. The column is first eluted with benzene. these eluates being discarded. It is then eluted with a mixture of 10% ether in benzene. the eluates combined and evaporated. The residue obtained is redissolved in benzene, the benzene solution treated with activated charcoal and after

209 644/318

least

effective

dose

mg / kg

evaporated to dryness after filtering off. 4-Phenylbenzo [b] thiophenyl (2) acetic acid is obtained in this way from 140 to 143 ° C. after successive recrystallizations from aqueous ethanol. benzene and benzene-hexane.

Example 2

A solution of 11.7 g of potassium hydroxide in 50 ecm Water becomes a solution of 11.7 g of 7-phcnylbcnzo [b] thiophyn- (3) -acetic acid ethyl ester given in 100 cvm ethanol, the resulting mixture heated under reflux for 1 hour and then under reduced pressure Pressure evaporated. The residue is dissolved in water, the aqueous solution is washed with ether and acidified with dilute hydrochloric acid. The 7-phenylbenzo [b] thiophene- (3) acetic acid which precipitates is isolated and recrystallized from benzene to hexane. F. 137 to 138 ° C.

In the same way there is obtained: 2-methyl-7-phenylbenzo [b] thiophene- (4) -acetic acid; F. 132 to 134 ° C after recrystallization from benzene.

Example 3

A solution of 10 g of potassium hydroxide in 25 ecm of water becomes a solution of 8.3 g of 7-phenylbenzo [b] thiophene- (4) -acetic acid ethyl ester given in 100 ecm of ethanol, the resulting mixture for 2 hours heated to reflux and then evaporated under reduced pressure. The residue is in water dissolved, the aqueous solution washed with ether and acidified with dilute hydrochloric acid. The acidified Mixture is extracted with ether. Then the ethereal solution is washed with water, dried and evaporated. A black solid residue of 7-phenylbenzo [b] thiophene- (4) -acetic acid is obtained, which by chromatography on silica gel, as described in Example 1, purified and removed Benzene-hexane is recrystallized. F. 128.5 to 129.5 ° C.

To a solution of 2.68 g of 7-phenylbenzo [b] thiophenylacetic acid 10 ecm of an aqueous 1.On sodium hydroxide solution are added to 10 ecm of hot ethanol given and the resulting solution evaporated to dryness under reduced pressure. You get that Sodium 7-phenylbenzo [b] thiophene (4) acetate.

To a warm solution of 2.90 g of sodium 7-phenylbenzo [b] thiophene (4) 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, then filtered to the unlös ¹ HChE sodium chloride to separate, and the filtrate was evaporated under reduced pressure to dryness. The 7-phenylbenzo [b] thiophene- (4) -acetic acid choline salt is obtained.

The following benzo [b] thiophene acetic acids are analogous receive:

60

connection 159.5 F. ° C 161.5 a-methyl-7-phenylbenzo [b] thio- phen ^ 4) acetic acid 129 until 131 d-propyl-7-phenylbenzo [b] thio- phen (4) acetic acid 125 until 126 7- (o-fluorophenyl) -benzo [b] thio- phen (4) acetic acid 143 until 144.5 7- (m-toly 1 (-benzo [b] thio- phen (4) acetic acid until

Compound F. C

n-methyl-7- (o-f! uorphenyl) -

bcnzo [b] -thiophcn- (4) -acetic-

acid 116 to 117.5

.i-ethyl-7- (o-fluorophenyl) -

bcnzo [b] lhiophcn- (4) -cssig-

acid c 138.5 to 139.5

ri.2-Dimethyl-7-phenylbcnzo [b] -

thiophene (4) acetic acid 93 to 95

7-cyclohexyl benzo [b] thio-

phen (3) acetic acid 135 to 136

Example 4

A mixture of 2.4 g of 2-phenylbenzo [b] thiophene- (6) acetonitrile, 2.6 g of potassium hydroxide and 75 ecm of diethylene glycol are heated to 130 ° C for 18 hours, then cooled and poured into water. The aqueous solution is diluted with hydrochloric acid acidified. The acidified mixture is extracted with ethyl acetate. The combined extracts are then washed with water, dried and evaporated. 2-Phenylbenzo [b] thiophene- (6) -acetic acid is obtained from F. 225 to 226.5C after recrystallization from ethyl acetate.

Example 5

A solution of 108 g of potassium hydroxide in 300 ecm of water becomes a solution of 108 g of 3-phenylbenzo [b] thiophene- (7) acetonitrile given in 21 ethanol, the resulting mixture heated under reflux for 18 hours and then under reduced pressure evaporated. The residue is treated with a mixture of water and ether, the aqueous layer separated, washed with ether and acidified with dilute hydrochloric acid. The acidified mixture will then extracted with ether, the extracts washed with water until neutral and dried. The dried one ethereal solution is evaporated and the oily residue obtained by chromatography over a silica gel, like door da »product de; Example 1 described, cleaned. The one from Elua solid obtained from 10% ether in benzene is 3-phenylbenzo [b] thiophene- (7) -acetic acid of F. 129 bi: 130 C after recrystallization from benzene.

The following phenylbenzo [b] thiophen-acetic acids are obtained analogously:

connection F. ⁰ C 153.5 a-methyl-3-phenylbenzo [b] thio- phen (7) acetic acid 162 to 164 154 a-Ethy 1-3-pheny lbenzo [b] thio- phen (7) acetic acid 155 to 157.5 162 a-Butyl-3-phenylbenzo [b] thio- Dhen- (7) acetic acid 94.5 to 95.5 3- (p-fluorophenyl) -benzo [b] thio- phen (7) acetic acid 152 to 3- (p-chlorophenyl) benzo [b] thio- phen (7) acetic acid 152 to 3- (p-bromophenyl) -benzo [b] thio- phen- (7! -acetic acid 159 to

continuation

connection

4-phenylbenzo [b] thiophene

(7) acetic acid

4- (m-Fluorophynyl) -benzo [b] thio-

phen (7) acetic acid

4- (o-chlorophenyi) -benzo [b] thio-

phen (7) acetic acid

4- (m-chlorophenyl) benzo [b] thio-

phen (7) acetic acid

«-Methyl-4-phenylbenzo [b] thio-

phen (7) acetic acid

u-Ethyl-4-phenylbenzo [b] thio-

phen (7) acetic acid

a-methyl-7-phenylbenzo [b] thio-

phen (3) acetic acid

F. "C

139.5 to 141.5

123 to 124.5

158 to 161

131.5 to 133.5

132 to 134.5

158 to 160

122 to 124

10

5 Manufacture of the raw materials

A. 2-Benzoylthiophenc
1. 2- (o-Fluorobenzoyl) 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 liter of benzene, the temperature being kept below 10 ° C. The resulting mixture is ^{stirred for 1 hour below 10 °} C. and for 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-fluorobenzoyl) thiophene, boiling point ₇ :

connection

Separation of Optical Isomers

A solution of 43.4 g of a -methyl-3-phenylbtnzo [b] thiophene- (7) -acetic acid (Example 5) in 300 ecm warm ethyl acetate is added to a solution of 18.6 g u-phenethylamine in 75 ecm ethyl acetate and the resulting mixture was allowed to stand at room temperature for 2 days. The crystalline salt that separates out is collected on a filter and the filtrate saved. The salt is recrystallized 4 times from ethyl acetate-methanol. Each crystallization solution is left to stand at room temperature for 2 days. The mother liquors are combined with the first filtrate and this solution is saved for later use. The salt, F. obtained after recrystallization 4maligem 154 to 157.5 ⁰ C, extracted with ether, followed by washing the ether extracts with 5% hydrochloric acid and with water to neutrality. dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The oily residue obtained is recrystallized from a hexane / benzene mixture and gives d - ^ - methyl - 3 - phenylbenzo [b] thiophene - (7) - acetic acid; M.p. 102.5 to 105 "C; [u]? + 100 ° (1.02% in chloroform).

The stored ethyl acetate-methanol solution is evaporated to dryness and the solid obtained is mixed with an excess of 5% hydrochloric acid. The acidic mixture is extracted with ether, the ether extracts are washed with 5% hydrochloric acid and then with water until neutral, dried and evaporated to dryness. A-methyl-3-phenylbenzo [b] thiophene- (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, added to a solution of 8.1 g of da-phenethylamine in 35 ecm 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 obtained in this way, mp 156.5 to 158 ^° C., is then treated further with 5% hydrochloric acid and the acidic mixture as described above. 1 - α - methyl - 3 - phenylbenzo [b] thiophene - (7) - acetic acid is obtained; F. 103 to 105.5 ⁰ C; [α] 'S -96.5 ° C (1.03% in chloroform).

2. 2- (m-Toluyl) thiophene

3. 2-Benzoyl-5-methyl-thiophene

Kp.

103 to 110 ° C / 0.07

(0.15 mm Hg)
135 to 150 ° C / 1.2 (1.5 mm Hg)

B. 3-Phenyl-3- (2-thienyl) acrylic acid ethyl ester
1. Ethyl 3- (o-fluorophenyl) -3- (2-thienyl) acrylic acid

A crystal of iodine is added to a mixture of 104.5 g of 2- (o-fluorobenzoyl) thiophene, 101.5 g of bromoacetic ester, 40 g of zinc and 600 ecm of benzene and the resulting mixture is refluxed for 90 minutes. It is then cooled and decomposed with dilute hydrochloric acid. The organic phase is separated off, washed with water, a saturated aqueous solution of sodium bicarbonate and again with water until neutral, dried and concentrated. The residue is distilled and gives 3- (o-fluorophenyl) -3- (2-thienyl) acrylic acid ethyl ester, bp. ₀₇ _! _l ; 143bisl45 ^c C.

connection

2. 3- (m-Tolyl) -3- (2-thienyl) acrylic acid ethyl ester

3. 3- (5-Methyl-2-thienyl) -3-phenyl-acrylic acid ethyl ester

Kp.

120 to 130 ° C
(0.15 to 0.25 mm Hg)

160 to 190 ⁰ C
(1.2 to 4mmHg)

C. 3-Phenyl-3- (2-thienyl) propionic acid ethyl ester
1. 3-Phenyl-3- (2-thienyl) propionic acid ethyl ester

A mixture of 161 g of 3-phenyl-3- (2-thienyl) -acrylic acid ethyl ester, 13 g of 20% palladium on carbon and 1 methanol is treated ^{at 27 ° C with hydrogen at an initial pressure of 3.52 kg / cm 2,} until sufficient hydrogen has been absorbed to reduce the double bond. The mixture is then filtered and the filtrate is distilled. He holds 3 - phenyl - 3 - (2 - thienyl) - propionic acid ethyl ester ^K Po, 2-o.3: 117 to 130 ° C.

connection

2. Ethyl 3- (o-fluorophenyl) -3- (2-thicnyl) propionate

3. Ethyl 3- (m-Tolyl) -3- (2-thienyl) propionate ....

4. Ethyl 3- (5-methyl-2-thienyl) -3-phenylpropionate ..

Kp.

112 to. L 15 C

(0.1 to 0.2 mm Hg)

139 to 160C (1.5 to 2.0 mm Hg)

115 to 135 C (0.4 to 0.6 mm Hg)

D. 3-Phenyl-3- (2-thienyl) -propane-1-oils 1. 3-Phenyl-3- (2-thienyl) propane-1 oil

A solution of 151.9 g of ethyl 3-phenyl-3- (2-thienyl) propionate in 750 ecm of dry ether is added dropwise to a suspension of 22.2 g of lithium aluminum hydride in 450 ecm of dry ether and the resulting mixture is refluxed for 90 minutes. It is then cooled and decomposed by treatment with ethyl acetate and water. The organic phase is separated off, washed with a saturated aqueous sodium chloride solution and dried. The dried solution is distilled and gives 3-phenyl-3- (2-thienyl) -propan-l-ol, boiling point _{() (} , _ _{0. 7} : 119 to 165 ° C.

connection

2. 3- (o-Fluorophenyl) -3- (2-thienyl) propan-1-ol

3. 3- (m-Tolyl) -3- (2-thienyl) propan-1-ol

4. 3- (5-methyl-2-thienyl) -3-phenyl-propan-1-ol

Kp.

91 to 150 C (0.4 to 0.5 mm Hg)

102 to 140C (0.30 to 0.35 mm Hg)

128 to 135 ° C (0.2 to 0.5 mm Hg)

E. 3-Phenyl-3- (2-thienyl) -propyl-bromide 1. 3-Phenyl-3- (2-thienyl) -propyl-bromide

A solution of 51 g of phosphorus tribromide in 400 ecm of ether is added dropwise to a solution of 111.4 g of 3-phenyl-3- (2-thienyl) propan-l-ol in 600 ecm of ether, the temperature being 0 to 10 ° C is held. 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, 5% sodium hydroxide and again with water until neutral and then dried. The dried solution is distilled and gives 3-phenyl-3- (2-thienyl) -propyl-bromide, bp ₀ , 4-o. ₅ : '32 to 138 ° C.

connection

2. 3- (o-fluorophenyl) -3- (2-thic-
~ nyD-propyl-bromide

3. 3- (m-Tolyl) -3- (2-thienyl) propyl bromide

Kp.

UO to 168 ° C (0.3 to 0.4 mm Hg)

109 to 160 ° C (0.3 to 0.4 mm Hg)

connection

4. 3- (5-Methyl-2-thienyl) -3-phenyl-propyl-bromide

Kp.

138 to 145 ° C
(0.2 to 1.0 mm Hg)

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

The following connections are made accordingly:

2. 4- (o-FluorophenyI) -4- (2-thienyl) -butyronitrile (oil)

3. 4- (m-Tolyl) -4- (2-thienyi) -butyronitrile (oil)

4. 4- (5-Methy] -2-thienyl) -4-phenyl-butyronitrile (oil)

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

A mixture of 72.5 g of 4-phenyl-4- (2-thienyl) butyroiiitrile. 75 g of potassium hydroxide, 400 ecm of water and 750 ecm of ethanol are refluxed overnight heated. It is then concentrated in order to separate off most of the solvent, and the Treated residue with a mixture of water and Äthei. The aqueous phase is separated and mil acidified with dilute hydrochloric acid. The precipitating 4-phenyl-4- (2-thienyl) butyric acid is isolated and recrystallized from benzene-hexane; M.p. 94 to 95 ° C

connection

2. 4- (o-Fluorophenyl) -4- (2-thienyl) -

buttic acid c

3 4- (m-Tolyl) -4- (2-thienyl) -

shoulder acid

4. 4- (5-Methyl-2-thienyl) -4-phenylbutyric acid

F. ⁰ C

90 to 91

100.5 to 103

oil

H. Dihydrobenzo [b] thiophen-4- (5H) -one
1. 2-Methyl-6,7-dihydrobenzo [b] thiophen-4 (5H) -one

To a mixture of 98.2 g of 2-methylthiophene, 150 g / i-carbomethoxypropionyl chloride and 1 l of benzene, 260.5 g of tin chloride are added dropwise with stirring, the temperature being kept below 10 ° C. The resulting mixture is stirred for 1 hour under half of 10 ⁰ C and 2 '/> hours at Raumtemperatu and then decomposed with dilute Salzsäun. The organic phase is separated off, washed with water, saturated aqueous sodium bicarbonate solution and again with water until neutral, dried and concentrated. This gives 2 - methyl - 5 - (3 - carbomethoxypropionyl) thiophene which can be used without further purification

500 ml of 3.6 N sodium hydroxide solution are added to a solution of 173.3 g of 2-methyl-5- (3-carbomethoxypropionyl) thiophene in 750 ml of ethanol and the resulting mixture is refluxed for 90 minutes. It is then concentrated in order to separate off the ethanol, and the aqueous residue is washed with ether and acidified with dilute hydrochloric acid. 2 - methyl - 5 - (3 - carboxypropionyl) - thiophene precipitates, which is isolated and dried; F. 101 to 105 ⁰ C.

A mixture of 147.8 g of 2-methyl-5- (3-carboxypropionyl) -thiophene, 147.8 g of potassium hydroxide, 115 cc of hydrazine hydrate and 900 cc of diethylene glycol is heated in a water separator equipped with a device so long as at 100 ⁰ C, until no more water separates out. The mixture is then heated to approximately 200 ° C. for a further 4 hours. After cooling, the resulting mixture is diluted with 2 liters of water and the aqueous mixture is acidified with hydrochloric acid. The acidified mixture is extracted with ether, the ether extracts are combined, washed with water, dried and concentrated. The residue is distilled and gives 4 - (2 - methyl-5-thienyl (-butyric acid, boiling point _o .3 ₅ -o.5 ^: Π 4 to 120 ⁰ C.

138 g of trifluoroacetic anhydride are added dropwise to a solution of 120.7 g of 4- (2-methyl-5-thienyl) butyric acid in 180 ecm of trifluoroacetic acid and the resulting mixture is refluxed overnight. It is then concentrated to separate off the solvent and the residue is dissolved in ether. The ethereal solution is washed with 5% aqueous sodium hydroxide solution and with water until neutral, dried and distilled. 2 - methyl - 6,7 - dihydrobenzo [b] thiophen - 4 (5H) - one is obtained; Bp. ₀₆ : 81 to 89 ⁰ C.

2. 7-phenyl-6,7-dihydrobenzo [b] thiophen-4 (5H) -one

To a solution of 52.8 g of 4-phenyl-4- (2-thienyl) -butyric acid in 400 ecm trifluoroacetic acid 45.5 g of trifluoroacetic anhydride were added dropwise and the resulting mixture was 1 hour at room temperature touched. Then another 2 ecm of trifluoroacetic anhydride are added added, the mixture stirred at room temperature overnight, then refluxed for 1 hour and concentrated. The residue is dissolved in ether and the ethereal solution with 2.5% aqueous sodium hydroxide solution and then washed with water, dried and concentrated. 7-Phenyl-6,7-dihydrobenzo [b] -thiophen-4 (5H) -one is obtained, F. 65.5 to 68.5 ° C after recrystallization from hexane.

3. According to 2, 7- (o-fluorophenyl) -6,7-dihydrobenzo [b] thiophen-4 (5H) -one, b.p. _O4 : 140 to 175 ° C. is obtained.

4. In line 1 is obtained 7- (m-tolyl) -6,7-dihydrobenzo [b] thiophen-4 (5H) -one, bp ₀₁₅ _ _030. 150 to 152 ° C.

5. 7 - methyl - 6,7 - dihydrobenzo [b] thiophen-4 (5 H) -one, Kp _{0th. 8} _, _ ,: 93 to 95 ° C is obtained by the following sequence of reactions. 3- (2-thienyl) -crotonsäureäthylester is hydrogenated according to the method described under C and yields 3- (2-thienyl) -buttersäureäthylester, bp ₀₂ _. _03: 63 to 69 ° C. The ethyl 3- (2-thienyl) -butyric acid ethyl ester is reduced with lithium aluminum hydride and then hydrolyzed according to the method given under D. To give 3 - (2 - thienyl) - butan - 1 - oil, bp ".2-o..v 70-83 ⁰ C. The 3- (2-thienyl) -bulan-l-ol according to the below E given method reacted with phosphorus tribromide and gives 3- (2-thienyl) butyl bromide, bp ₀₂ _p. ₄ : 64 to 80 ^° C. This intermediate product is then reacted with sodium cyanide in aqueous acetone-ethanol according to the process given under E and the 4- {2-thienyl) valeronitrile is subjected to basic hydrolysis according to the process given under G. 4- (2-thienyl) valeric acid is obtained, which is finally made to react with trifluoroacetic anhydride in trifluoroacetic acid in accordance with the process given under H.

6. According 2 obtained -one 2-methyl-7-phenyl-6,7-dihydrobenzo [b] thiophen-4 (5H), bp. _{O2. 04} :

150 to l55 ° C.

I. Phenyl-substituted dihydrobenzo [b] thiophenes 1 2-methyl-4-phenyl-6,7-dihydrobenzo [b] thiophene

To a solution of phenylmagnesium bromide, which consists of 42.5 g of bromobenzene, 6.5 g of magnesium and 200 ecm Ether was prepared, a solution of 39.3 g of 2 - methyl - 6,7 - dihydrobenzo [b] thiophene-4 (5th H) -one was added dropwise to 300 ecm of ether with stirring, and the resulting mixture was at room temperature for 18 hours touched. The mixture is then hydrolyzed by treatment with dilute hydrochloric acid, which separated organic phase, with water, saturated aqueous sodium bicarbonate solution and again with Washed water until neutral, dried and evaporated to dryness. To the oily residue 100 ecm of acetic anhydride are added, the resulting solution is refluxed for 2 hours, cooled and poured into water. The aqueous mixture becomes alkaline with 50% sodium hydroxide made and the alkaline mixture extracted with ether. The combined ethereal extracts become with Washed water until neutral, dried and evaporated to dryness. Become the residue 200 ecm of absolute ethanol, 16 g of carboxymethyltrimethyltrimethy ammonium chloride - hydrazide (Girard's reagent T) and 16 ecm acetic acid and the The resulting mixture was refluxed for 1 hour. Then 200 ecm of ethylene glycol are added and the mixture concentrated to separate the ethanol. The concentrated solution is extracted with ether, the ether extracts with water, saturated aqueous sodium bicarbonate solution and again with Washed 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] thiophene is obtained, which is trapped at 0.6 mm Hg between 105 and 175 ° C.

2.

connection R-C 60 _a) 4-phenyl-7-methyl-6,7-dihydro- benzo [b] thiophene 87 to 93 b) 4- (m-fluorophenyl) -7-methyl- 6,7-dihydrobenzo [b] thiophene 63.5 to 67 65 c) 4- (o-chlorophenyl) -7-methyl- 6,7-dihydrobenzo [b] thiophene oil d) 4- (m-chlorophenyl) -7-methyl- 6,7-dihydrobenzo [b] lhiophene oil

209 644 / 3L8

J. Phenylbenzo [b] thiophenes

1. 2-Methyl-4-phenylbenzo [b] thiophenes

A mixture of 44.2 g of 2-methyl-4-phenyl-6,7-dihydrobenzo [b] thiophene and 6.56 g of sulfur is heated to 222-232 ° C. for 30 minutes, 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 180 ^° C. at 0.6 mm Hg is collected. On standing this liquid solidifies and gives 2 - methyl - 4 - phenylbenzo [b] thiophene; F. 68 to 69.5 ° C after recrystallization from methanol.

connection

F.-c

76 until 78 ° 210 C. oil ^! 190 (*
87 until ° C) (K |
102 until ⁰ C)

a) 4-Phenyl-7-methylbenzo- [b] thiophene

b) 4- (m-Fluorophenyl) -7-methylbenzo [b] thiophene

c) 4- (o-Chlorophenyl) -7-methylbenzo [b] thiophene

d) 4- (m-Chlorophenyl) -7-methylbenzo [b] thiophene

3. 3-Phenyl-7-methylbenzo [b] thiophene

132 g of phosphorus pentoxide are added in individual portions to 100 ecm of phosphoric acid. After cooling the resulting solution at 40 ⁰ C. 12.1 g of 2 - added acetophenone - [(o - tolyl) - thio]. 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, saturated sodium bicarbonate solution and again with water until neutral, then dried and evaporated to dryness. 3-Phenyl-7-methyl-benzo- [b] thiophene is obtained as a yellow oil which is collected between 97 and 142 ° C. at 0.5 to 0.7 mm Hg.

4. 3- (p-Fluorophenyl) -7-methylbenzo [b] thiophene

A mixture of 14.3 go-thiocresol, 25.0 g p-fluorophenacyl bromide and 60 ecm of pyridine is refluxed for 6 hours, cooled and poured into 21 ice water poured. The aqueous mixture is acidified with dilute hydrochloric acid, the precipitating 2 - [(o-tolyl) -lhio] -p-fluoroacetophenone isolated, dried and recrystallized from benzene-hexane, m.p. 49 to 5PC. This Intermediate product is cyclized according to 3 and gives 3- (p-fluorophenyl) -7-methylbenzo [b] thiophene, F. 54.5 to 55.5 "C, after recrystallization from aqueous ethanol.

5. According to 4 one obtains 3- (p-chlorophenyl) -7-methylbenzo [b] th.iophcn, F. 79 to 81.5 "C, after recrystallization from aqueous ethanol, whereby initially 2 - [(o-tolyl) thio] -p-chloroacetophynone, m.p. 56.5 to 58.5 C, after crystallization from benzene-hexane arises.

6 According to 4 one obtains 3- (p-bromophenyl) -

7-methylbenzo [b] thiophene, m.p. 82 to 92 ° C (aqueous

Ethanol) where initially 2 - [(o-Tolyl) -thio] -p-bromo-

acetophenone, m.p. 59 to 61.5 ° C (benzene-hexane) is formed.

7. 3-Methyl-7-phenylbenzo [b] thiophene

45.7 g of chloroacetone are added dropwise to a solution of 92.0 g of 2-mercaptobiphenyl in 500 ecm of pyridine

ίο and the resulting mixture under reflux for 1 hour heated. It is then evaporated to separate off the solvent and the residue in Ether dissolved. The ethereal solution is mixed with water, a few times with dilute hydrochloric acid and again with

is water washed until neutral. The solution is then dried and evaporated to dryness. I- (2-DiphenyJyJthio) -2-propanone, mp 85 to 86 ° C., is obtained after recrystallization from ethanol. This intermediate (38.0 g) is then added at 400 g

Phosphorus oxide cyclized in 300 ecm phosphoric acid according to 3. 3-Methyl-7-phenylbenzo [b] thiophene is obtained by distillation as an oil, which is collected between 124 and 1,52 ° C. at 0.15 to 0.2 mm Hg.

K. (Bromomethyl) phenylbenzo [b] thiophenes
1. 2-Bromomethyl-4-phenylbenzo [b] thiophenes

7.95 g of recrystallized N-bromosuccinimide and 100 nig of dibenzoyl peroxide are added to a solution of 10.0 g of 2-methyl-4-phenylbenzo [b] -thiophene in 100 ecm of carbon tetrachloride, and the resulting mixture is heated under reflux for 5 hours is irradiated with the light of a flood lamp. It is then filtered off and the Filtral evaporated to dryness. The residue is triturated with hexane and the hexane mixture is cooled in a dry ice-acetone bath. This gives 2-bromomethyl-4-phenylbenzo [b] thiophene; F. 84 to 90 ⁰ C.

2. 2-Phenylbenzo [b] thiophene-6-methyl-bromide

A mixture of 9.5 g of 2-phenyI-6-methylbenzo- [b] thiophene (for the preparation of this compound s.

J. Chem. Soc, 1956, p. 4791), 7.9 g of N-bromosuccinimide, 100 mg of dibenzoyl peroxide and 215 ecm of benzene is refluxed overnight, with it is irradiated with a radiant heater. After cooling, the mixture is used to separate insolubles filtered, the filtrate washed with 5% sodium hydroxide solution and then with water, dried and concentrated. The residue is extracted with benzene and the benzene extracts evaporated. 2-Phenyl-benzo [b] thiophene- (6) -methyl-bromide is obtained as an oil, which can be used without further purification can be used.

3. The following substances are obtained analogously as oils, which can be used without further cleaning:

a) 3-phenylbenzo [b] thiophene- (7) -methyl bromide,

b) 3- (p-fluorophenyl) -benzo [b] thiophene- (7) -methyl bromide,

c) 3- (p-chlorophenyl) -benzo [b] thiophene- (7) -methyl bromide,

d) 3- (p-bromophenyl) -benzo [b] thiophene- (7) -methyl bromide,

e) 4-Phenylbenzo [b] thiophene- (7) -methyl-bromide,

f) 4- (m-fluorophenyl) -beiizo [b] thiophene- (7) -methyl bromide,

g) 4- (o-chlorophenyl) benzo [b] thiophene (7) methyl bromide,

h) 4- (m-chlorophenyI) -benzo [b] thiophene- (7) -methyl-

bromide,
i) 7-Phenylbenzo [b] thiophene (3) methyl bromide.

L. Phenylbenzo [b] thiophene acetonitrile

1. 4-Phenylbenzo [b] thiophene- (2) acetonitrile

A mixture of 8 g of 2 - bromomethyl - 4 - phenylbenzo [b] thiophene, 100 ecm of a bezol-wet quaternized chloromethylated styrene-divinylbenzene copolymer resin, which is in the [CN ~] form (such as that known under the trademark Amberlite IRA-400; for the preparation of the cyanide form of this resin see J. Org. Chem. Vol. 28, p. 698, 1963), and 200 ecm Benzene is refluxed for 12 hours and then cooled down. The solution is then decanted from the solid resin, and the resin is washed with benzene and the washing solutions are combined with the decanted solution. All of the benzene solution is then washed with water, dried and evaporated. 4-Phenylbenzo [b] thiophene (2) acetonitrile is obtained as an oil that can be used without further purification.

2. 2-Phenylbenzo [b] thiophene- (6) -acelonitrile

A mixture of 3.3 g of 2-phenylbenzo [b] thiophene- (6) -methyl bromide, 0.6 g of sodium cyanide, 25 ecm of acetone, 25 ecm Ν, Ν-dimethylformamide and 5 ecm water is refluxed for 6 hours and then concentrated to remove the solvent. the The residue is treated with ether and ethyl acetate, the resulting mixture is washed with water and dried and evaporated to dryness. Solid 2-phenylbenzo [b] thiophene- (6) -acetonitrile is obtained, which can be used without further purification.

3. 3-Phenylbenzo [b] thicphen- (7) acetonitrile

A mixture of 153 g of 3-phenylbenzo [b] thiophene- (7) -methyl bromide, 26.4 g of sodium cyanide, 150 ecm of water and 1500 ecm of acetone is stirred overnight at room temperature and then concentrated in order to separate off the solvent. The residue is treated with ether and the ethereal mixture washed with water, dried and evaporated. A brown oily residue of 3-phenylbenzo [b] thiophene- (7) -acetonitrile is obtained, which is purified by chromatography over aluminum oxide and recrystallized from ethanol; F. 107.5 to HO ¹ C.

4. The following phenylbenzo [frlthiophenacetonitriles receive:

a) 3- (p-Fluorophenyl) -ben7o [b] thiophene- (7) -acetonitrile,

b) 3- (p-chlorophenyl) -benzo [b] thiophene- (7) -acetonitrile,

e) 3- (p-bromophenyl) -benzo [b] thiophene- (7) -acetonitrile,

d) 4-phenylbenzo [b] thiophene- (7) acetonitrile,

e) 4- (m-fluorophenyl) -benzo [b] thiophene- (7) -acetonitrile,

f) 4- (o-Chlorophenyl) -benzo [b] thiophene- (7) -acetonitrile,

g) 4-im-chlorophenyl) -benzo [b] thiophene- (7) -aceto-

nitrile,
h) 7-phenylbenzo [b] thiophene (3) acetonitrile.

M. '"- Alkyl-phenylbenzo [b] thiophene acetonitrile
1. α-Methyl-3-phenylbenzo [bjthiophene- (7) acetonitrile

To a suspension of 1.6 g of a 53.4% dispersion of sodium hydride in mineral oil in 15 ecm Dimethyl sulfoxide is a solution of 8.0 g of 3-phenylbenzo [b] thiophene- (7) acetonitrile under a nitrogen atmosphere dripped into 55 ecm of dimethyl sulfoxide, the reaction temperature below 35 ° C is held. The resulting mixture is kept under a nitrogen atmosphere for 5 hours at room temperature touched. 9.1 g of methyl iodide are then added, the temperature being kept below 25.degree will. The reaction mixture is now at room temperature under a nitrogen atmosphere overnight touched. It is decomposed by treatment with dilute hydrochloric acid and the acetic acid mixture with Ether extracted. The ether extracts are mixed with water, with saturated aqueous sodium bicarbonate solution and washed again with water, dried and evaporated to dryness. A-methyl-3-phenylbenzo [b] thiophene- (7) acetonitrile is obtained as an oil that can be used without further purification.

The following compounds are obtained analogously:

2. a-Ethyl-3-phenylbenzo [b] thiophene- (7) -acetonitrile,

3. a-Butyl-3-phenylbenzo [b] thiophene- (7) -acetonitrile,

4. «-Methyl-4-phenylbenzo [b] thiophene- (7) acetonitrile,

5. «-Ethyl-4-phenylbenzo [b] thiophene- (7) -acetonitrile,

6. a-Methyl-7-phenylbenzo [b] thiophene- (3) acetonitrile.

N. Phenylbenzo [b] thiophene acetic acid ester
1. 7-Phenylbenzo [b] thiophene (3) acetic acid ethyl ester

10.0 g of 2- (diphenylyl) thiol are added to a solution of 2.9 g of sodium methylate in 100 ecm of methanol. After stirring for 10 minutes, a solution of 8.85 g of ethyl 4-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, the ether extracts 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. 132 g of phosphorus pentoxide are added in portions to 100 cc of phosphoric acid and (2-diphenylylthio) -acetessigsäureäthylester added after cooling the resulting solution at 40 ⁰ C, 15.5 g of 4-. The reaction mixture is heated for 2 hours at 6O ⁰ C, cooled and poured into water. The aqueous mixture is extracted with ether. The combined ether extracts are washed with water, with saturated aqueous sodium bicarbonate solution and again with water until neutral, dried and evaporated to dryness. 7-Phenylbenzo [b] thiophene (3) acetic acid ethyl ester is obtained as an oil which can be used without further purification.

2. 7-Phenylbenzo [b] lhio ₁ -3hen- (4) -acetic acid ethyl ester

To a mixture of 6.5 g of 7-phenyl-6,7-dihydrobenzo [b] thiophert-4 (5H) -one, 5.8 g bromoacetic acid

¹ U,

ethyl ester, 2.8 g zinc and 50 ecm benzene becomes a crystal Given iodine and the mixture heated under reflux for 2 hours. Then another 2 g of bromoacetate are added and 1 g of zinc were added and the reaction mixture was refluxed for a further 2 hours. The The mixture is then nitrated in order to separate off the excess zinc, and the filtrate with diluted Hydrochloric acid. Water, dilute aqueous sodium bicarbonate solution and washed again with water until neutral. It is then dried and evaporated. The residue is dissolved in 100 ecm acetic anhydride, the resulting solution for 1 hour Heated to reflux and evaporated. The residue is extracted with ether, the ether extracts with saturated aqueous sodium bicarbonate solution and water washed until neutral, dried and evaporated. The residue obtained in this way is dissolved in 100 ecm of absolute ethanol. To this 4 g of (carboxymethyl) trimethylammonium chloride hydrazide and 4 ecm of acetic acid are added to the solution and the resulting mixture! Heated under reflux for an hour. Then ethylene glycol is added and the mixture was concentrated to separate off the ethanol. The concentrated solution is then extracted with ether and the ether extracts with water, saturated aqueous sodium bicarbonate solution and again with water washed until neutral, dried and evaporated. 7-phenyl-6,7-dihydrobenzo- [b] thiophene- (4) -acetic acid ethyl ester is obtained.

The intermediate product obtained in this way (8.5 g) is mixed with 1.0 g of sulfur and heated to 226 bis for 1 hour 230 C heated, with 7 - phenylbenzo [b] thiophene (4) acetic acid ethyl ester as described earlier Dehydration process occurs.

According to 2 the following connections are obtained:

3. a-Methyl-7-phenylbenzo [b] thiophene- (4) -acetic acid ethyl ester;

4. u-Propyl-7-phenylbenzo [b] thiophene- (4) -acetic acid ethyl ester;

5. 7- (o-Fluorophenyl) -benzo [b] thiophene- (4) -acetic acid ethyl ester;

6. 7- (m-Tolyl) -benzo [b] thiophene- (4) -acetic acid ethyl ester;

7. u-methyl-7- (o-fluorophenyl) -benzo [b] thiophene (4) -acetate, Kp.j ₀ -i _x: 168-205 ⁰ C; oil;

8. (i-Ethyl-7- (o-fluorophenyl) -benzo [b] thiophene-

(4) -acetate, Kp.j ₀ _ _12: 175 to 220 ° C; oil:

9. 2-Methyl-7-phenyl-benzo [b] thiophene (4) -essigsäureäthyiester, oil, bp _O3 173 to 230 ° C;. the dehydrated product is in this case before the

Distillation by chromatography in benzene

cleaned over neutral alumina; 10. u, 2-Dimethyl-7-phenylbenzo [b] thiophene- (4) -acetic acid ethyl ester.

O. 7-Cyclohexylbenzo [b] thiopheneacetic acid ethyl ester

1.7- Cyclohexylbenzo [b] thiophene · (3) - ethyl acetate, oil, boiling point ₀ . _5-0 .6: 160 to 20FC, N 1 is obtained analogously by reaction of o-Cyclohexylthiophenol with 4-Chloracetatessigsäureäthylester in presence of a strong base, then the 4- (o-Cyclohexylphenylthio) -acetessigsäureäthylester reacted with phosphorus pentoxide in phosphoric acid to the reaction will.

Claims (1)

Claim: Benzo [b] thiophene-acetic acids of the general formula I. or phenylbenzo [b] thiophene groups in general Formulas R ¹ -CH-COOH in which R ^{1 is} a hydrogen atom or a C _{1 -C 4} -alkyl group and R ^{2 is} 4-phenylbenzo [b] thiophene- (2) -, 7-cyclohexyl- or 7-phenylbenzo [b] -thiophene - (3 ) -, 2 - phenylbenzo [b] thiophene - (6) -, 7-cyclohexyl or optionally 7-phenylbenzofobjthiophene - (4) group substituted in the 2-position by a methyl group, or phenylbenzo [b] thiophene groups of the general formulas IO