FI60009C - ETT NYTT FOERFARANDE FOER FRAMSTAELLNING AV THERAPEUTISKT VAERDEFULLA 4- (4-PIPERIDYLIDEN) -4H-BENZO (4,5) -CYCLOHEPTA (1,2-B) THIOFEN-10 (9H) -ONER - Google Patents

Description

M3te-T ·} TrI ANNOUNCEMENT

Ma * · · * (} UTLÄGGNI NGSSKRIFT 60009 '(51) Kv.ik.3 / Int.ci.3 c 07 D 409/08 FINLAND —FINLAND (*) Patent application - Patantanattknlng 21+ 3 3/71 (22) Hakamlapllvi - Ansttknlngadag 31.08.71 * '(23) Alkuptivt — Glklghatadag 31.08.71 (41) Tullut Julkiaaktl - Bllvlt offantllg 25.03.72

Patent and Registration Office .... .... _ ...

_ ^ ^, (44) Nlhtlvlkalpanen] a kuLL (outer date -

Patent · och registerstyrelsen Anittkan utlagd och utl.skrlftan publicarad 31.07.81 (32) (33) (31) Pyy4 * «y atuolkaua — Begird prlorltat 21.09.70 0U.02.71 Switzerland-Switzerland (CH) lll20 / 70, 1632/71 (71) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Jean-Pierre Bourquin, Magden / AG, Gustav Schwarb, Allschwil,

Erwin Waldvogel, Aesch, Switzerland-Schweiz (CH) (7l) Oy Kolster Ab (5I) A new method for the treatment of therapeutically valuable 1- (1-piperidylidene) -1H-benzo [3,5] cyclohepta [2-b] thiophene- For the preparation of 10 (9H) -ones - 1- (1-piperidylenyl) -1H-benzo [1,5] -cyclohepta [1,2-b] thiophen-10 (9H) -one is used for the preparation of therapeutically active substances. oner

The present invention relates to a new process for the preparation of therapeutically valuable k- (k-piperidylidene) -1H-benzo [1,5] cyclohepta [1,2-b] thiophene-10 (9H) -ones of formula I

/ Ny-VS> - i i 1

rS

60009 wherein R1 is hydrogen, a chlorine or bromine atom in the 6-position or a chlorine atom in the 7-position or a methoxy group, and R8 is an alkyl group containing a 1-h carbon atom.

According to the invention, compounds of formula I are obtained such that compounds of formula II

R, - I J II

wherein and R 1 are as defined above and X is chlorine or bromine, is treated with strong aqueous non-oxidizing acids.

Suitable strong acids are both inorganic acids, such as sulfuric acid, hydrochloric acid, hydrobromic acid and phosphoric acid, as well as organic acids, such as aliphatic and aromatic sulfonic acid, trifluoroacetic acid, trichloroacetic acid.

For example, the compound of formula II is heated in a 20-70 ° C aqueous solution of a strong acid at about 80-120 °.

The reaction time is 1 1/2 to about 15 hours, depending on the quality and concentration of the acid and the reaction temperature.

If very dilute acids are used, it is expedient to work at higher temperatures, e.g. about 200-230 ° C, and in an autoclave.

The compounds of formula II are moderately or well soluble in aqueous acid solutions. Therefore, the addition of a solvent is usually not necessary.

If a solvent, e.g. an alkanol, is used, it is recommended to keep the amount of solvent as small as possible.

The compounds of the formula I and an analogous process for the preparation of these compounds are known from Finnish Patent Publication No. 52,980. The compounds of the formula I were prepared in two steps from the corresponding compounds of formula II by reacting secondary or tertiary amines obtained or by cleavage of the ethers thus obtained with acids.

This analogous method has the disadvantage that the preparation of amines or ethers in each case gives a mixture of i + H-benzoZ? * »5.7-cyclohepta / i, b -7-thiophenes which are substituted in the 9-position and ^ H-benzo ^ , 5-cyclohepta- [1,2-b] thiophenes substituted at the 10-position in a ratio of about 2: 1.

When using the process according to the invention, only 10-keto compounds are formed, as a result of which the yield can be doubled and the quality substantially improved compared to previously known processes.

In addition, based on the data provided in the literature on the interchangeability of halogens in vinyl halides, it could be assumed that X (in formula II) would not react with virtually any acidic substances. Thus, vinyl as its halides, in contrast to alkyl halides, have little tendency to nucleophilic substitution reactions (halide ion changes to hydroxide ion), e.g., Fieser, "Organische Chemie", Verlag Chemie (1965) »page k02, and Hoben Weyl," Methoden der Organic Chemistry "(i960), Part V / U, page 70 ^.

The interchangeability of halogens in vinyl halides in acidic solution has not been described in the literature. The process according to the invention can be considered surprising, since the reaction proceeds rapidly and the yields are excellent.

Compounds of formula H may be prepared starting from e.g. compounds of formula III,

_x

I '* III

il ™

Ra wherein X, R and R2 are as defined above by cleaving water from them.

For cleavage of water, for example, mineral acids such as sulfuric acid, ethanolic hydrochloric acid, hydrobromic acid or also strong organic acids, acetic anhydride or inorganic acid halides can be used.

By selecting a strong aqueous, non-oxidizing acid as the water-cleaving agent, the compounds of formula III can also be converted directly to the compounds of formula I without isolating the compounds of formula II. Also in these direct process alternatives, it is recommended to keep the amount of possible solvent as low as possible.

k 60009

The starting compounds of formula III are also novel and can be prepared, for example, by administering compounds of formula IV,

O

wherein R 1 and X are as defined above, react with an organomagnesium compound of formula V,

R_-N / “MgHal V

2 V_V

wherein Hal is as defined above and Hal is chlorine, bromine or iodine, and the reaction mixture is hydrolyzed to a compound of formula III.

In practice, a compound of formula III is prepared by dropwise addition of a compound of formula IV in an inert anhydrous organic solvent, e.g. an open chain or cyclic ether such as tetrahydrofuran or diethyl ether, to a mixed magnesium halogen compound of formula V in the same solvent and for another about 1 1/2 hours, preferably at room temperature. Finally, the mixture is hydrolyzed in cold aqueous ammonium chloride solution and extracted with a water-immiscible inert organic solvent, e.g. a chlorinated aliphatic hydrocarbon such as methylene chloride or chloroform.

The compounds of formula IV are also new.

They are prepared by cleavage from compounds of formula VI,

X X

r ^ V-S-S

Ri - j I I VI

o wherein R 1 and X are as defined above, halogen hydrogen (HX, where X is as defined above). This cleavage occurs under alkaline conditions, e.g.

By allowing a potassium hydroxide solution to act on a compound of formula VI in an inert organic solvent such as methanol, or by allowing aqueous bases to act on a compound of formula VI while adding lower alcohols as a solvent, cleavage is accelerated by heating the reaction mixture.

Compounds of formula VI may be prepared, for example, by chlorination or bromination of compounds of formula VII,

R1 'I T Ί) VII

o wherein R.j is as defined above, in an inert organic solvent such as cyclohexane, to the corresponding 9,10-dichloro or 9,10-dibromo compounds. The above 9,10-dibromo compounds obtained from compounds of formula VII can also be obtained, e.g., by reacting compounds of formula VIII, where R is as defined above, with a calculated amount of N-bromosuccinimide. in an inert organic solvent, e.g. a chlorinated aliphatic hydrocarbon such as carbon tetrachloride.

In the following examples, which further illustrate the invention, all temperature values in degrees Celsius follow and are uncorrected.

Example 1: H- (1-Methyl-U-piperidylidene) -UH-benzo [1,5] cyclohepta [1,2-b] thiophen-10 (9H) -one

A mixture of 100 g of 10-bromo-1 + - (1-methyl-H-piperidylidene) -UH-benzo-A, 57-cyclohepta [1,2-b] thiophene base and 900 ml of 50% sulfuric acid is stirred for 1 1/2 for one hour at 100 ° (oil bath temperature 110 °). The reaction solution 6 60009 is cooled to room temperature and poured into 3,000 ml of water. The mixture is then made alkaline by cooling in 1,300 ml of concentrated sodium hydroxide. The separated base is extracted with 1,350 ml of chloroform in small portions. The chloroform extracts are combined, washed with water, dried over sodium sulfate and evaporated in vacuo. The crude 1- (1-methyl-1-piperidylidene) -1H-benzo [1,5] cyclohepta [1,2-b] thiophen-10 (9H) -one base thus obtained is recrystallized from 320 ml of isopropanol. In this way, pure b- (1-methyl - (- (piperidylidene)) - (1H-benzo [b, 5,7-cyclohepta] -1,2-thiophene-10 (9H) -one base is obtained, melting 152-153 ° C.

The starting 10-bromo-4- (1-methyl-U-piperidylidene) -1H-benzo-A, β / cyclohepta [1,2-b] thiophene base can be prepared, e.g., as follows:

A mixture of 129 g of 9,10-dihydro-1H-benzo [5] cyclohepta [1,2-b] thiophen-U-one, 21 g of N-bromosuccinimide, 1.2 g of benzoyl peroxide and 2,000 ml of anhydrous carbon tetrachloride, boil under stirring for 3 hours at reflux. The mixture is filtered hot and the filtrate is concentrated to one third of its original volume. After the mixture has been at room temperature for a few hours, the crystals are filtered off and dried. This crude product is recrystallized from 7 times the amount of chloroform. In this way, pure 10-bromo-9,10-dihydro-1H-benzo [2,7,5-cyclohepta / 1,2-1] thiophen-1 + -one is obtained, melting at 13 DEG-135 DEG C. with decomposition. The microanalysis is consistent with the formula C HgB ^ OS. The structure was determined by NMR spectrum.

VnMR (CDCl 3): 5.68 (1) d (J = 5H7); 6.05 O) d (J = 5H7); 7.2-7.8 (5) m; 8.0-8.25 (1) m.

A mixture of 70 g of 9,10-dibromo-9,10-dihydro-1 + H-benzo [1], 5-cyclohepta-β, 2-b] thiophen-U-one, 31.6 g of potassium hydroxide and 3,200 ml of methanol, heated with stirring for 2 hours at reflux. The mixture is stirred for about 1 hour at 0-5 °, and the crystals are filtered off. The product is recrystallized from 100 times the amount of methanol to give pure 10-bromo-UH-benzoZT4,57-cyclohepta / 1,2-b / thiophen-U-one, melting at 13 DEG-135 DEG. The microanalysis is consistent with the formula C 1 H BrOS.

1 H-NMR (CDCl 3: δ, b-7.8 (5) m, 8.1 (1) d (J = 5.5 H7), 8.5-8.8 (1) m.

To 5 g of iodine-activated magnesium is added 15 ml of anhydrous tetrahydrofuran, and the mixture is heated to reflux. Add 2 g of freshly distilled 1-methyl-ij-chloropiperidine and a few drops of 1,2-libromoethane to start the Grignard reaction. Now, without heating, 7 60009 22.8 g of freshly distilled 1-methyl-4-chloropiperidine dissolved in 30 ml of anhydrous tetrahydrofuran are added dropwise so rapidly that the mixture still boils. After the addition is complete, the reaction mixture is refluxed for an additional 2 hours, after which the magnesium is substantially complete. A warm solution of 30 g of 10-bromo-1 + H-benzo [1, 5,7-cyclohepta] [1,2-b] thiophen-1 + -one in 160 ml of absolute tetrahydrofuran is then added dropwise with cooling at 20-25 °. within an hour. The reaction mixture is stirred for 1 1/2 hours at 20-25 °, then poured into a mixture of 250 g of ice water and 35 g of ammonium chloride, and the separated base is extracted in small portions with a total of 600 ml of chloroform. The chloroform phases are combined and washed with 50 ml of water, dried over sodium sulfate and concentrated in vacuo. The residue is obtained from crude 10-bromo-H- (1-methyl-H-piperidyl) -1 + H-benzo [1H], 5-cyclohepta [1,2-b] thiophene-1- + 011- base, which is worked up immediately.

A solution of 51 g of crude 10-bromo-1 + - (1-methyl-1 + -piperidyl) -1 + H-benzo [5,5] cyclohepta [1,2-b] thiophenol-ol and 1 + 20 ml of 1% ethanolic hydrobromic acid , is heated for 1 hour at 100 ° in an oil bath temperature under reflux. The mixture is concentrated in vacuo and the residue is dissolved in 100 ml of water.

It is made alkaline with concentrated sodium hydroxide solution and the separated base is extracted three times with 100 ml of chloroform. The chloroform extracts are combined and washed with 50 ml of water, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in TO ml of chloroform containing 5% methanol and adsorbed onto 1000 g of silica gel. Elute with chloroform containing 5% methanol. The first 8 L of elution product is discarded, the next 1+ 1 are co-evaporated. An oily evaporation residue is obtained, which is dissolved by boiling in 50 ml of isopropanol and crystallized overnight at 0-5 °. The crystals are filtered off and dried to give pure 10-bromo-1 + - (1-methyl-1-piperidylidene) -1 + H-benzo [η 5,7] cyclohepta / 1,2-b] thiophene base, melting 11 + 9 -150 ° C. The microanalysis is consistent with the formula C 1 H 2 BrNS.

1 H-NMR (CDCl 3): 1.9-2.8 (11) m; 6.95 (D d (J = 5 HT) »7.05-7.5 (6) m.

β 60009

Example 2: 6-Chloro-4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta- [1,2-b] thiophen-10 (9H) -one

A mixture of 10 g of 10-bromo-6-chloro-4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene base and 110 ml of 60% sulfuric acid , stirred for 3 hours at 85-90 °. The reaction solution is poured into 300 g of ice and made alkaline with concentrated sodium hydroxide by cooling at 20 °. The separated base is extracted in small portions with a total of 200 ml of chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated. The solid evaporation residue is recrystallized from 50 ml of ethyl acetate. In this way, pure 6-chloro-4- (1-methyl-4-piperidylidene) -4H-benzo [4,57] cyclohepta / 1,2-b] thiophen-10 (9H) -one base is obtained, m.p. 168-169 °. The microanalysis agrees with the formula C 18 g H 2 gClNOS. The structure was determined by IR, NMR and MS spectra.

From the base 10-bromo-6-chloro-4- (1-methyl-4-piperidylidene) -4H-benzo74,57-cyclohepta [1,2-b] thiophene base, 6-chloro-9,10-dihydro-4H-benzo [4,57] cyclohepta [1,2-b] thiophen-4-one. During the synthesis, the following intermediates were isolated: - 6-chloro-9,10-dibromo-9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one (decomposition point 147-149 °) - 10- bromo-6-chloro-4H-benzo [4,5] cyclohepta [1,2- b] thiophen-4-one (m.p. 198-200 °) -10-bromo-6-chloro-4- (1-methyl-4-piperidyl) -4H-Benzo / 4,5,7-cyclohepta [1,2-b] thiophen-4-ol base (further crude) - 10-bromo-6-chloro-4- (1-methyl-4-piperidylidene) 4H-benzo [4,57] cyclohepta- [3,2-b] thiophene base (m.p. 193-195 °).

Example 3: 7-Chloro-4- (1-methyl-4-piperidylidene) -4H-benzo74,57-cyclohepta- [1,2-b] thiophen-10 (9H) -one

A mixture of 10 g of 10-bromo-7-chloro-4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta / 1,2-b] thiophene base and 100 ml of 60% sulfuric acid is stirred. For 1 1/2 hours at 100-105 °. The reaction mixture is then poured onto 300 g of ice and made alkaline by cooling with concentrated ammonia at 20-25 °. The separated base is extracted in small portions with a total of 300 ml of chloroform. The extracts Q 60009 are combined, washed with water, dried over sodium sulfate and concentrated in vacuo. The evaporation residue is dissolved in chloroform and adsorbed onto 250 g of silica gel. Elute with chloroform containing 5% methanol. The first 0.6 L of elution products are discarded, the next 0.8 L is concentrated. The solid evaporation residue is recrystallized from 1 + of isopropanol.

In this way, pure 7-chloro-1 - - (1-methyl-U-piperidylidene) -UH-benzo-2R, 5-cyclohepta [1,2-b] thiophene-10 (9H) -one base is obtained, melting at 150-151 ° :in. The microanalysis agrees with the formula C 1 H 2 gClNOS. The structure was determined by IR, NMR and MS spectra.

The starting 10-bromo-7-chloro-L- (1-methyl-1 + -piperidylidene) -NH-benzo [?,] [Beta] -cyclohepta [1,2-b] thiophene base is obtained from 7-chloro-9, 10-dihydro-1H-benzo [2,7,5-cyclohepta] -1,2-b] thiophen-1 + -one.

During the synthesis, the following intermediates were isolated: - 7-chloro-9,10-dibromo-9,10-dihydro-1 + H-benzo [4,5-cyclohepta] [1,2-b] thiophen-L-one (crude) - 10- bromo-7-chloro-1H-benzo [2,7,5-cyclohepta] -1,2-b] thiophen-1-one (m.p. 218-220 ° C) -10-bromo-7-chloro-L- (1-methyl-L- piperidyl) -1 + H-benzo [+ +], 5-cyclohepta [1,2-b] thiophene-4-ol base (oily, crude) - 10-bromo-7-chloro-U- (1-methyl-L- piperidylidene) -1 + H-benzoA, 5,5-cyclohepta - [1,2-b] thiophene base (m.p. 1-7-1-9 °).

Example k ·. 6-Bromo-1 + - (1-methyl-N-piperidylidene) -NH-benzo [2,7,5-cyclohepta-C12-2-thiophen-10 (9H) -one

A mixture of 15 g of 6,10-dibromo-1 + - (1-methyl-1 + -piperidylidene) -UH-benzo [b], 5-cycloheptaZ, 2-b7-thiophene base and 160 ml of 6θ% sulfuric acid is stirred for 1 hour. For 1/2 hour at 100 °. The reaction mixture is diluted with 200 ml of water and made alkaline by cooling at 20-25 ° with concentrated ammonia. The separated base is extracted in small portions with a total of 1 + 00 ml of toluene. The extracts are combined, washed with water, dried over sodium sulfate and concentrated in vacuo. The evaporation residue is dissolved in chloroform and adsorbed onto 500 g of silica gel. Elute with chloroform containing 2% methanol. The first 2.5 L of elution products are discarded, the next 2.7 L are concentrated. The solid evaporation residue is recrystallized from 8 times the amount of isopropanol. In this way, pure δ-bromo-1H-1-methyl-1 + -piperidylidene) -UH-benzo [1,1 ', 5-cyclohepta-1,2,2-b] thiophene-10 (9H) -one base is obtained, melting 172-173 ° C. The microanalysis is consistent with the formula C ^ H ^ gBrNOS. The structure was determined by IR and NMR spectra.

The starting 6,10-dibromo-1 + - (1-methyl-1 + -piperidylidene) -1 + H-benzo [5,5-cyclohepta [1,2-b] thiophene base was obtained starting from 6-bromo-9,10-dihydro -1 + H-benzoZi +, 57-cyclohePtaZi, 2-b] thiophene-1 + -one.

10 60009

During the synthesis, the following intermediates were isolated: - 9,10-dihydro-6,9,10-tribromo-1H-benzo [f, 57] cyclohepta [1,2-b] thiophen-4-one (crude) - 6,10-dibromo- N, N-benzo [3,7-cyclohepta] -1H-1'-thiophenyl-l-one (m.p. 177-190 °) - 6,19-dibromo-k- (1-methyl-U-piperidyl) -UH-benzo [5,5-cyclohepta] [1,2-b] thiophene-N-ol base (oily, crude) - 6,10-dibromo-U- (1-methyl-1 + -piperidylidene) -1 + H-benzo [delta], 57-cyclohepta, 2-bJ-thiophene base (mp 185-186 °).

Example 5: 7-Methoxy-1 - ((1-methyl-1 + -piperidylidene) -1H-benzo [5,5-cyclohepta- [1,2-b] thiophen-10 (9H) -one)

A mixture of 8 g of oily 10-bromo-7-methoxy-H- (1-methyl-U-piperidylidene) -N, H-benzo [N, N] cyclohepta [1,2-b] thiophene base and 250 ml of 60 - $ sulfuric acid, stirred for 1 1/2 hours at 100 °. The reaction mixture is poured into 600 g of ice, made alkaline with concentrated ammonia, and the separated base is extracted several times with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated. The evaporation residue is recrystallized once from 5 times the amount of ethyl acetate and once from 10 times the amount of isopropanol. In this way, pure 7-methoxy-1 - - (1-methyl-H-piperidylidene) -1H-benzo [1,] 7-cyclohepta / 1,2-b-thiophen-10 (9H) -one base is obtained, which melts at 157-158 °. The microanalysis agrees with the formula C ^ qH ^^ NO ^ S. The structure was determined by IR, NMR and MS spectra.

The starting 10-bromo-7-methoxy-U- (1-methyl-U-piperidylidene) -UH-benzo [5,5-cycloheptaZ1,2-b] thiophene base was obtained starting from l-methoxyphthalaldehyde acid. During the synthesis, the following intermediates were isolated: - N-methoxy-2- [2- (2-thienyl) vinyl / benzoic acid (m.p. 170-172 °) - 14-methoxy-2- [2- (2-thienyl) ethyl] benzoic acid (crude further processed) - 9,10-dihydro-7-methoxy-1 + H-benzo [5,5] cyclohepta [1,2-b] thiophen-14-one (crude) - 9,10-dibromo-9,10-dihydro-7 ~ methoxy-UH-benzo [+] +,? 7-cyclohepta [1,2-h] thiophen-1,4-one (crude) - 10-bromo-7-methoxy-1H-benzo [1,1'-cyclohepta] -1 [thiophen-U-one (m.p. 182-18 * 4 °) -10-bromo-7-methoxy- [1- (1-methyl-h-piperidyl) -NH-benzoyl] -5,5-cyclohepta] -2- 7-Thiophene - ** - was (crude further processed).

Example 6: * 4- (1-ethyl-k-piperidylidene) -N, H-benzo [5,5-cyclohepta [2,2-b] thio- (phen-10 (9H) -one

A mixture of 10 g of * 4- (1-ethyl- * 1-piperidylidene) -10-bromo- * 4H-benzo-O *, 57 ° C, 2-b / thiophene base and 100 ml 50- $ sulfuric acid, stirred for 11 60009 1 1/2 hours at 100 °. The solution is cooled to room temperature, diluted with 300 ml of water and made alkaline with concentrated ammonia. The separated base is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and concentrated. The residue is recrystallized from 3 times the amount of isopropanol. In this way, pure L- (1-ethyl-L-piperidylidene) -LH-benzo-N-cyclohepta [1,2-h] thiophene-10 (9H) -one base is obtained, melting at 113-115 °. The microanalysis agrees with the formula C 1 H 2 NOS. The structure was determined by IR and NMR spectra.

The starting α- (1-ethyl-L-piperidylidene) -10-chromium-αH-benzo-β * jojycyclohepta [1,2-b] thiophene base (m.p. 130-132 °) was obtained from 9 (10) - bromo-1H-benzo [a, 5-cyclohepta [1,2-b] thiophenyl] -one In the course of the synthesis, isolated 4- (1-ethyl-L-piperidyl) -9 (10) -bromo-1H-benzo [1,5] cyclohepta The T1,2-b7thiophene L-ol base was further treated crude.

Example 7: α- (1-Isopropyl-L-piperidylidene) -LH-benzo [b] 5,5-cyclohepta [1,2-b] thiophen-10 (9H) -one

Proceed as described in Example 6, but using 1Q-bromo-1 + - (1-isopropyl-L-piperidylidene) -αH-benzo [5,5-cyclohepta] -1,2-b] thiophene base as starting material α- (1-ethyl-U-piperidylidene) ) Instead of -10-bromo-1H-benzoA, 5,5-cyclohepta-E, 2-brothiophene base. The hydrogen fumarate of the title compound is recrystallized from ethanol and melts at 225-226 ° with decomposition.

The starting 10-bromo-.alpha .- (1-isopropyl-.alpha.-piperidylidene) -UH-benzo [.alpha.] [Beta] -57-cyclohepta [1,2-b] thiophene base was obtained starting from 10-bromo-1H-benzo [? / 1,2-b7 ~ ^ -one. The 9 (10) -brora-N- (1-isopropyl-.alpha.-piperidyl) -αH-benzo [4,5-cyclohepta [1,2-b] thiophene-L-ol base isolated during the synthesis was further treated crude.

Example 8: α- (1-n-Butyl-.alpha.-piperidylidene) -αH-benzo [5,5] cyclohepta [1,2-b] thiophen-10 (9H) -one

Proceed as described in Example 6, but using 10-bromo-L- (1-n-butyl-t-piperidylidene) -NH-benzo [4] cyclohepta-1,2-b] thiophene base as starting material for U- (1-ethyl (N-piperidylidene) instead of -10-bromo-1 + H-benzo [1,5] cyclohepta [1,2-b] thiophene base. The pure title compound melts at 10t-105 ° (from isopropanol).

The starting 10-bromo-1H + (1-n-butyl-t-piperidylidene) -1H-benzo [3,5-cyclohepta] [1,2-b] thiophene base was obtained from 10-bromo-1H-benzo [-, § 7-cyclohepta / fl, 2-b7thiophen-1 * -one. During the synthesis, the isolated 10-bromo-1- (1-n-butyl-L-piperidyl) -1H-benzo [b], 5-cyclohepta [1,2-b] thiophene-1 + ol base was worked up crude.

12 60009

Example 9: U- (1-methyl-1-piperidylidene) -αH-benzo [b], 5-cyclohepta [1,2-b] thiophen-10 (9H) -one

Proceed as described in Example 6, but using 10-bromo-1 + - (1-methyl-U-piperidylidene) -1 * H-benzo [f] +, 5-cyclohepta [1,2-b] thiophene base as starting material for U- (1-ethyl -li-piperidylidene) -10-bromo-HH-benzo [f], 57-cyclohepta-C, 2-1,7-thiophene base and 25 ~ # sulfuric acid instead of 50- # sulfuric acid to give the title compound after heating for 15 hours, m.p. . 152-153 °.

Example 10: N- (1-methyl-4-piperidylidene) -1H-benzo [5,5-cyclohepta [1,2-b] thiophen-10 (9H) -one

Proceed as described in Example 10, but using 50% methanesulfonic acid instead of 25 ~ # sulfuric acid to give, after heating for 3 hours, the title compound, m.p. 152-153 °.

Example 11: U- (1-methyl-1 + -piperidylidene) -1H-benzo [1,5] cyclohepta-thiophen-10 (9H) -one

Proceed as described in Example 10, but using 50-toluenesulfonic acid instead of 25% sulfuric acid to give, after heating for 15 hours, the title compound, m.p. 152-153 °.

Example 12: U- (1-methyl-1 * -piperidylidene, N, N-cyclohepta [1,2-b] thiophen-10 (9H) -one

The procedure is as described in Example 9, but using 18-hydrochloric acid instead of 25% sulfuric acid to give, after heating for 3 hours, the title compound, m.p. 152-153 °.

Example 13: * + - (1-Methyl-U-piperidylidene) -1H-benzo [5,7,7-cyclohepta [1,2-b] thiophen-10 (9H) -one

Proceed as described in Example 9, but using 63-bromo-hydroacid instead of 25-sulfuric acid to give, after heating for 1 1/2 hours, the title compound, m.p. 152-153 °.

Example 1U: U- (1-methyl-1-piperidylidene) -1 + H-benzo [1,2,5] cyclohepta [1,2-b] thiophen-10 (9H) -one

The procedure is as described in Example 9, but using 30-hydrobromic acid instead of 25-sulfuric acid to give, after heating for 15 hours, the title compound, m.p. 152-153 °.

Example 15: h- (1-methyl-U-piperidylidene) - (1H-benzo [1H], 5,7-cyclohepta [1,2-b] thiophen-10 (9H) -one

The procedure is as described in Example 9, but using 10% phosphoric acid instead of 25% sulfuric acid to give, after heating for 15 hours, the title compound, m.p. 152-153 °.

13 60009

Example 16: U- (±) -methyl-1 + -piperidylidene) -1H-benzo [η 5] cyclohepta [1,2-b] thiophen-10 (9H) -one

Proceed as described in Example 9, but using 50- $ trifluoroacetic acid instead of 25- $ sulfuric acid to give, after heating at 120 ° for 15 hours, the title compound, m.p. 152-153 °.

Example 17: k- (1-Methyl-U-piperidylidene) -1H-benzoyl, 5-cyclohepta [1,2-b] thiophen-10 (9H) -one

Proceed as described in Example 9, but using 50- $ trichloroacetic acid instead of 25- $ sulfuric acid to give, after heating at 100 ° for 15 hours, the title compound, m.p. 152-153 °.

Example 18: 1- (1-Methyl-U-piperidylidene) -1H-benzo [h, 5-7 cyclohepta] thiophen-10 (9H) -one

Proceed as described in Example 9, but using one mole of 10-bromo-1- (1-methyl-1-piperidylidene) -1H-benzo / 5,57-cyclohepta / 1,2-b7-thiophene base per mole of sulfuric acid at 20-fold. in water instead of 25- $ sulfuric acid to give, after heating at 230 ° C for 6 hours at 20 ° C, the title compound, m.p. 152-153 ° C.

Example 19: 1- (1-methyl-N-piperidylidene) -1H-benzo [5,5-cyclohepta] -1,2-thiophen-10 (9H) -one

Proceed as described in Example 18, but using one mole of 10-bromo-H- (1-methyl-N-piperidylidene) -UH-benzo [1,5] cyclohepta [1,2-b] thiophene base 1/2 moles of sulfuric acid in 20 times the amount of water to give, after heating at 230 ° for β-hour at 20 ° C, the title compound, m.p. 152-153 °.

Example 20: 1- (1-Methyl-1-piperidylidene) -1H-benzo [b] cyclohepta [1,2-b] thiophen-10 (9H) -one

Proceed as described in Examples 9 to 19, but using 10-chloro-1- (1-methyl-U-piperidylidene-4H-benzo [b], 5-cyclohepta / 1,2-h] thiophene base 10-bromo-1- (1-methyl -U-piperidylidene) -1 + H-benzo [11,5] cyclohepta [1,2-b] thiophene base to give the title compound, mp 152-153 °.

The starting 10-chloro-U- (1-methyl-1-piperidylidene) -1H-benzo [5,5] cyclohepta / 3,2-h / thiophene base (m.p. 150-152 °) was prepared from 1 + H-benzo [5,5] cyclohepta [1,2-h] thiophene-U-one. During the synthesis, the following intermediates were isolated: - 9 (10) -dichloro-9,10-dihydro-1H-benzo [5,7] cyclohepta [1,2-b] thiophen-1 * -one (crude) 60009-10-chloro -1H-benzo [2,7-cyclohepta] -1,2,7-thiophen-1-one (m.p. 121-126 °) -10-chloro-N- (1-methylpiperidyl) -1H-benzoacyl] cyclohepta, b7thiophene-1-ol (crude)

Example 21; 1- (1-methyl-1-piperidylidene) -1H-benzo [1,5] cyclohepta [1,2-b] thiophen-10 (9H) -one

Proceed as described in Example 9, but using a mixture of 50- $ sulfuric acid and n-butanol (1: 2 by weight) instead of 25- $ sulfuric acid to give, after heating at 100 ° for ΐβ-hour, the title compound, m.p. 152-153 °.

Claims (2)

60009 Claim A new process for the preparation of therapeutically valuable U- (U-piperidylidene) -1H-benzo [f], β-cyclohepta / 1,2-b-thiophene-10 (9H) -ones of formula I ΓΊ K wherein R 1 is hydrogen, 6 -chlorine or bromine atom or a chlorine atom in the T-position or a methoxy group, and R1 is an alkyl group containing 1 to U carbon atoms, characterized in that the compounds of formula II 1. II ΓΊ K wherein and Rg are as defined above and X is chlorine or bromine, treated with strong, aqueous, non-oxidizing acids.