DE1249879B - Process for the preparation of basic substituted 4H-benzo [4, 5] cyclohepta [1, 2-b] thiophenes - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

co7d

-SD

German KL: 12 q - 26

Number: 1249 879

File number: S 94649IV b / 12 q

Filing date: December 16, 1964

Opened on September 14, 1967

The invention relates to a method of manufacture of 4H-Benzo [4,5] cyclohepta [1,2-b] thiophene of the general formula I

, R ⁴

v _R 3

CH- CH- CH- N (Ri R ²

and their acid addition salts, in which R ¹ and R ^{2 are} either a hydrogen atom or a low molecular weight alkyl group, R ³ and R ^{4 are} each a low molecular ^{weight alkyl group or R 4 is} a low molecular weight alkyl group, R ³ and R ' ^{2 are} a tri or tetramethylene group or R ¹ and R ^{3 form} a di- or trimethylene group, each of the substituents R ¹ and R ^{2 being} a hydrogen atom. to

According to the invention, these compounds of general formula I and their acid addition salts are obtained in modification of the process according to patent 1,225,660 in that one converts the corresponding 4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-ols of the general formula II

Il

CH ₂ -CH-CH-N <

R ¹

in which R ¹ , R ² , R ³ and R ^{4 have} the meaning given, splits off water in a manner known per se and the bases obtained are optionally converted into their acid addition salts.

The procedure is carried out, for example, as follows:

From the compounds of the formula II, which can be obtained as described below, The products of the process of general formula I are produced by the action of water-releasing agents won. As dehydrating agents such. B. mineral acids, strong organic acids, acetic anhydride, Thionyl chloride or phosphorus oxychloride can be used. The transfer of the so The bases obtained in their acid addition salts are carried out by treatment with organic or inorganic ones Acids in a manner known per se. Preferred method for making basic

substituted

4H-Benzo [4,5] cyclohepta [1,2-b) thiophenes

Addendum to the patent: 1 225 660

Applicant:

SANDOZ A. C, Basel (Switzerland)

Representative:

Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Named as inventor:

Dr. Ernst Jucker, Ettingen;

Dr. Anton Ebnöther, Reinach:

Dr. Jean-Michel Bastian, Birsfelden;

Dr. Erwin Rissi, Basel;

Dr. Andre btoll, Birsfelden (Switzerland)

Claimed priority:
Switzerland of December 20, 1963 (15 711),
dated May 22, 1964 (6699)

Salts are for example the hydrochlorides. Hydrobromides, phosphates, sulfates, malonates, fumarates. Maleates. Tartrates, malates, hexahydrobenzoates or p-toluenesulfonates.

The starting compounds of the formula II used can be obtained as follows:

2-Thenyl diethyl phosphonate is condensed in an anhydrous organic solvent and in the presence of an alkaline condensing agent with o-phthalaldehyde acid, reduces the resulting 2- (2-Thienyl- (2) -vinyl] -benzoic acid to form 2- [2-thienyl- (2) -ethyl] -benzoic acid and subjects this to an intramolecular ring closure, the 9,10-di-

70 »« 47/547

bydro-4H-benzof4,5) cyclohcpta [1,2-b] thiophen-4-one of formula III

III

is obtained.

As a reducing agent, for example, sodium amalgam in an aqueous alcohol and as a condensing agent polyphosphoric acid or sulfuric acid can be used for ring closure.

The introduction of the double bond in the 9,10-position takes place z. B. in such a way that you 9,10-dihydro-4 H - benzo [4,5] cyclohepra [1,2-b] thiophen - 4 - one with Bromosuccinimide in absolute carbon tetrachloride and in the presence of catalytic amounts of benzoyl peroxide heated and then purified by diatomaceous earth and freed from the solvent Reaction product heated with a trialkylamine.

Then a Grignard solution - obtained as described below - becomes the general Formula IV

Shark - Mg - CH ₂ - CH - CH - N - R ⁴

DJ T? - R 3

at 0 to 30 ^: C with the 4H-benzo [4.5] cyelohepta [l, 2-b] thiophen-4-one dissolved in the same solvent and the mixture is advantageously stirred for some time at room temperature or then heated to the boil.

The intermediates thus obtained are z. B. hydrolyzed by treatment with ice-cold aqueous ammonium chloride solution to compounds of general formula II, which can be isolated in a manner known per se.

To prepare the Grignard compounds of general formula IV, tetrahydrofuran is used or diethyl ether covered magnesium shavings with a solution of a basic substituted haloalkyl derivative added to tetrahydrofuran or diethyl ether. As basic substituted haloalkyl derivatives can e.g. B. used: 3-dialkylaminopropyl halides, such as 3-dimethylamino or 3-diethylaminopropyl halides, 3-dimethylamino-2-methylpropyl balogenides, l-alkyl-piperidyl- (3) - or l-alkyl-pyrrolidyH3) -methyl halides, or 1-alkylpyrrolidyl- (2) - or l-alkyl-piperidyl- (2) -äthylhalogenidc, where the halides chlorides, bromides or Iodides and, as alkyl radicals, methyl, ethyl or isopropyl radicals are possible.

The formation of the Grignard compound is preferably achieved by adding a small amount of ethylene bromide, Ethyl bromide or methyl iodide and a trace of iodine were promoted. The reaction mixture is optionally heated under reflux to complete the reaction. Instead of magnesium shavings copper-magnesium alloy (according to G i 1 m a n) can also be used.

The process products and their salts with pharmaceutically acceptable organic or inorganic Acids are valuable drugs and are characterized by low toxicity, e.g. B. by a strong neuroleptic and antidepressant effects. So they inhibit the spontaneous as well as the through Amphetamine administration increased motor activity, also conditional and emotional Reactions of the test animals. However, the compounds also have anticholinergic and reserpine antagonistic properties Properties and potentiate the effects of noradrenaline. The process products can therefore be used to treat mental illnesses, e.g. B. Psychoses and Neuroses, as well various forms of depression are used. All temperatures are given in the examples in degrees Celsius and are uncorrected.

Example I.

A solution of 4 g of 4- (3-dirncthylaminopropyl) is heated - 4H - bcnzo ^ .Slcycloheptall ^ -blthiophen-4-ol in 250 ecm acetic anhydride to the boil for 6 hours. After distilling off about 200 ecm solvent, the residue is poured into 1200 ecm water with stirring and the aqueous solution is filtered Solution by highly purified diatomaceous earth, makes it strongly alkaline and with 20% sodium hydroxide solution extract the alkaline solution three times with ether. The combined, washed with water and over Magnesium sulphate dried ether extracts are then evaporated. The residue obtained is distilled in a high vacuum, the 4- (3-dimethylammo-propylidene) -4H-benzo [4,5] cyclohepla [1,2-b] -thiophene transitions at 160 to 165 / 0.1 mm Hg.

Malonate: a solution of 3.8 g of base in 10 ecm A bite solution of 1.4 g of malonic acid in 10 ecm of isopropanol is added to isopropanol After cooling, the precipitated Sal / is filtered. away. The malonate melts after recrystallization from ethanol — isopropanol at 142 to 143 ' (Decomposition).

The 4H-benzo- [4,5] cyclobcpta [1,2-b] thiophen-4-ol used as the starting material was made as follows:

a) 2-thenyl diethyl phosphonate

133 g thenyl chloride (b.p. 73 to 75715 mm Hg) are heated to 150 ", whereupon 175 g of freshly distilled triethyl phosphite are added at this temperature with stirring slowly added dropwise and stirred for a further 2 hours to 160 to 170 ' heated. The reaction mixture is then distilled in a high vacuum; 2-thenyl diethyl phosphonate boils at 120 to 124 ° / 0.06 mm Hg.

b) 2- [2-thienyl- (2) -vinyl] -benzoic acid

To a solution of 117 g of 2-thenyl diethylphosphonate 30 g of powdered, well-dried dimethylformamide are added to 200 ecm of freshly distilled dimethylformamide Sodium methylate, the solution being heated to 45 to 50 °. Then you put the flask in an ice bath and a solution of 80 g of o-phthalaldehyde acid in 200 ecm of dimethylformamide is added dropwise in such a way that that the temperature remains between 35 and 40 ', and then stirs for another 30 to 60 minutes Room temperature further. The reaction solution is then cooled with 1600 ecm of water (temperature 10 to 15 ') added, whereby a red oil separates. It is then made alkaline with potassium carbonate, the oil dissolving again, and shaking the red-brown solution three times with benzene and carefully adjusts the aqueous solution at 10 to 15 ° with hydrochloric acid to pH 4. After a few hours im

The precipitated acid is filtered off in the refrigerator, dried and recrystallized from benzene. The 2- [2-thienyl- (2) -vinyl] -benzoic acid melts at 133 up to 135 °.

The mother liquor is extracted three times with methyl chloride, the organic phase over Dried sodium sulfate and evaporated at 15 mm Hg. The residue is crystallized from benzene, a further portion of acid having a melting point of 133 ° to 135 ° is obtained.

c) 2- [2-thienyl (2) ethyl] benzoic acid

7.5 g of sodium are melted under anhydrous toluene, which is followed by frequent shaking 375 g of pure mercury are added dropwise so that the toluene boils. The mixture is then heated with stirring to 120 to 140 and cools to 50 as soon as all the toluene has distilled off. The homogeneous amalgam it is then poured over with a solution of 20 g of 2- [2-thienyl- (2) -vinyl] -benzoic acid in 150 ecm 95% ethanol and shake the mixture for 30 minutes. The mercury is then separated off and washed it twice with ethanol and diluted the combined ethanolic solutions with 1200 ecm of water. the The solution is filtered through highly purified diatomaceous earth, acidified with hydrochloric acid and cooled to 5 °. After a few hours, the precipitated acid is filtered off and crystallized from chloroform-hexane. 110-111 °.

d) 9,10-dihydro-4H-benzo [4,5] cyclo-

hepta [1,2-b] thiophen -4-one

59 ecm of 84% phosphoric acid and 86 g of phosphorus pentoxide are first stirred for 125 to 130 minutes for 30 minutes. Then 20 g of pulverized 2- [2-thienyl- (2) -ethyl] -benzoic acid are introduced within 30 minutes at this temperature. The reaction mixture is stirred for a further 2 hours at 125 to 130, poured into 1000 ecm of water, the solution filtered through highly purified diatomaceous earth and extracted three times with methylene chloride. The organic phase is washed with 2N sodium carbonate solution, dried over magnesium sulfate, the solvent is evaporated and the residue is distilled in a high vacuum, the 9,10-dihydro-4H-benzo [4,5] -cyclohepta [1,2-b] thiophen-4-one passes as a green oil at 125 to 1407 0.05 mm Hg, n'i - 1.6559.

e) 4H-Benzo [4,5] cyclohepta [1,2-b] thiophen-4-one

For the introduction of the double bond in the 9,10 position the procedure is such that a mixture of 32.1g of the dihydro compound obtained, 26.7 g N-bromosuccinimide and 0.3 g of benzoyl peroxide in 250 ecm of absolute carbon tetrachloride for 4 hours heated to boiling. After cooling to 50 °, the reaction mixture is filtered through highly purified Diatomaceous earth and evaporate the solvent at 15 mm Hg. The oily residue obtained is then heated for 2 hours with 200 ecm of triethylamine with stirring. After evaporation of unchanged triethylamine, the residue is mixed with 250 ecm of methylene chloride and the solution obtained washed three times with 2η hydrochloric acid and twice with water. After drying the solution over magnesium sulfate, the solvent is removed under reduced pressure. The residue is then distilled in a high vacuum, the 4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one at 173 to 18070.1 mm Hg passes as an oil and crystallizes on cooling. F. 109 to 110 ° after recrystallization from ethanol.

0 4- (3-dimethylaminopropyl) -4H-benzo [4.5] cycloheptafl , 2-b] lhiophen-4-ol

2.2 g of magnesium activated with iodine are covered with a layer of 15 ecm of absolute tetrahydrofuran and mixed with a few drops of ethyl bromide. To

ίο Onset of the reaction one leaves a solution of 10.8 g of 3-dimethylaminopropyl chloride in 20 ecm absolute Tetrahydrofuran is added dropwise so that the solvent boils, and the mixture is then heated 1 hour left to simmer. It is then left with cooling at 20 ° for 15 minutes a solution of 8.2 g of 4H-benzo [4,5] cyclohepta [1,2-b] -thiophen-4-one add dropwise in 30 ecm of absolute tetrahydrofuran and heat to boiling for a further 30 minutes. After cooling, the reaction mixture is dissolved in 250 ml of saturated aqueous ammonium chloride solution poured, 200 ecm of methylene chloride added and the whole thing filtered through highly purified Diatotneenerdc. After the organic phase has been separated off, the aqueous portion is washed twice with methylene chloride extracted, washed the combined methyl chloride solutions with water, over magnesium sulfate dried and evaporated at 15 mm Hg. The crystalline residue is made from ethanol or ethanol-hexane recrystallized. F. 121 to 122 °.

Example 2

oily 4-12 - [1 - methyl - pipendyl - (2)] - ethyP, -4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-ol (manufactured as described below) is in 200 ecm Hydrochloric acid (1: 1) dissolved, the acidic solution washed twice with ether and then with sodium hydroxide solution made strongly alkaline with cooling. This aqueous solution is extracted three times with methylene chloride, the methylene chloride extracts washed with water, dried over magnesium sulfate and evaporated at 15 mm Hg. The oily residue is dissolved in isopropanol and with an isopropanolischcn Salicylic acid solution added. After cooling, the precipitated 4-f2- [l-methylpiperidyl - (2)] - Ethylidene) - 4H - benzo [4,5] cyclohcpta- [1,2-b] thiophene salicylate filtered off and from isopropanol recrystallized. F. 167 to 168 ".

The 4- | 2- (l-methylpiperidyl- (2)] ethyl} -4H-benzo [4.5] cyclohepta [l, 2-b] - required as starting material thiophen-4-ol was obtained as follows:

2.2 g of magnesium activated with iodine are coated with 15 ecm of tetrahydrofuran and a few drops of ethylene bromide are added. After the start of the reaction, a solution of 12.6 g of 2- [l-methyl-piperidyl- (2)] -ethyl chloride in 15 ecm of tetrahydrofuran is added dropwise in such a way that the solvent boils, and the mixture is then heated to the boil for a further Vk hours. A solution of 8.2 g of 4H-benzo [4.5] cyclohpla [l, 2-b] thiophen-4-one in 20 ecm of tetrahydrofuran is then added dropwise over the course of 15 minutes at 20 "and heated with stirring for a further ³ / 4 hours to 40.

After cooling, the reaction mixture is in

250 ecm 2O% ammonium chloride solution poured. diluted with 200 ecm of methylene chloride and filtered through highly purified diatomaceous earth. After this The aqueous phase is separated off from the organic phase

Part shaken three times with methylene chloride, the combined methylene chloride extracts washed with water, dried over sodium sulfate and with 15 mm Hg evaporated.

Claims (1)

Claim: Process for the preparation of basic substituted 4H-benzo [4,5] cyclohepta [1,2-b] thiophenes the general formula / R4 CH- CH- CH- N (R ¹ R ² 15 in which R ¹ and R ^{2 are} either hydrogen or a low molecular weight alkyl group and R ³ and R ^{4 are} each a low molecular weight alkyl group or R ^{4 is} a low molecular weight alkyl group, R ² and R ^{3 are} a tri- or tetramethylene group or R ¹ and R ^{3 form} a di- or trimethylcngruppc, where in each case one of the substituents R ¹ and R ^{2 is} a Η atom, as well as their acid addition salts in a modification of the process according to patent 1,225,660. Characterized in that instead of 9,10 - dihydro - 4H-Benzo ^^ Jcycloheptafl, 2-b] -thiophen-4-ols from the corresponding 4H-benzo [4,5] cyclohepta [l, 2-b] thiophene-4-ols in a manner known per se and splits off water the bases obtained in this way are optionally converted into their acid addition salts.