DE4420921A1 - Process for the preparation of benzthiophene derivatives - Google Patents

Description

The application relates to a process for the production of specially substituted Benzothiophene derivatives of the general formula (I)

in which
R¹ C₁-C₆-alkyl, NH-C₁-C₂₀-alkyl, N (C₁-C₂₀-alkyl) ₂, N (C₁-C₂₀-alkyl) (C₁-C₁₀-alkyl), NH-aryl, NH-benzyl and
R² is H, methyl or halogen.

The benzothiophene derivatives of the formula (I) are known and are used as Intermediates for the production of known pharmaceuticals, plant and Material protection agents.

Ways of making benzthiophene derivatives are also known and z. B. in EP 568 289, Tetrahedron Lett. 33, 7499 (1992), Tetrahedron 39, 4153 (1983), J. Org. Chem., 37, 3224 (1972), US-5 169 961, EP 572 712 and J. Chem. Soc. Perkin. Trans. I, 1984, 385. They all stand out  unsatisfactory yields and / or poor accessibility of the starting materials as well as special requirements for the equipment.

The application therefore relates to a process for the production of Compounds of formula (I), characterized in that compound of Formula (III)

with an aldehyde of the formula (II)

in the presence of a base.

The compounds of formula (I) thus obtained can then be given if also without intermediate insulation, d. H. in the form of a one-pot reaction to the known sulfones of the formula (Ia)

be oxidized.

Alkyl here and below preferably represents straight-chain, branched or cyclic alkyl, optionally with one or two oxygen atoms is interrupted, e.g. B. for methyl, ethyl, n-, i-propyl, n-, i-, s-, t-butyl, n-, i-, s-, t- Pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl or their ver  branched structural isomers and for cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, cyclododecyl.

Aryl represents substituted phenyl or naphthyl with 1 to 3 methyl, halogen and / or methoxy substituents.

Halogen stands for F, Cl, Br, I.

Compounds are preferably prepared in which
R¹ is methyl or NH-C₁-C₂₀-alkyl, NH-aryl and
R² mean H.

Compounds in which
R¹ NH-C₁-C₁₀ alkyl and
R² mean H.

The compound in which

and
R² = H are made.

The compounds of formula (II) are commercially available or according to known ones Process can be produced.

The compounds of formula (III) are obtained by z. B. Connection gene of formula (IV)  

in which R³ is hydrogen, C₁-C₆-alkyl, preferably hydrogen, methyl or Ethyl, with compounds of formula (V)

HR¹ (V)

implements, or
Compounds of the formula (VI)

with reagents such as H₂S, NaHS, KHS, Na₂S, K₂S, FeS, potassium disulfide, Sodium disulfide, sodium polysulfide, potassium polysulfide, Na₂ S₂O₃, ammonium sulfide, polysulfide, disulfide, dithiocarbonate.

implements.

The thiol of the formula (III) required can be prepared separately and in isolated or enriched form or as a crude product in solution or as an oil reaction according to the invention are added. The thiol can also in situ be prepared and then directly, d. H. in the form of a one-pot reaction to be processed further. The latter is particularly useful if the Reaction is carried out continuously.  

The invention therefore relates to processes for the preparation of compounds of Formulas (I) and (Ia), where either compounds of the formulas (II) and (III) or from compounds of the formulas (IV) and (V) or (VI).

The reaction temperature for the reaction of the compounds of the formulas (II) and (III) depends on the base used and the desired reac tion speed. Preferably at temperatures from 20 ° C to 200 ° C worked, but in particular at 60 ° C to 180 ° C, preferably at 80 ° C to 160 ° C and particularly preferably at 100 ° C to 140 ° C.

The ratio of (III) to (II) is generally 1: 3 to 3: 1, preferably 1: 1 to 2: 1, particularly preferably 1.1: 1 to 1.8: 1.

The ratio of (III) to the base added is generally 1: 3 to 3: 1, preferably 1: 1 to 2: 1, particularly preferably 1.1: 1 to 1.8: 1. In the case of ver Use of alkali metal sulfides or hydrogen sulfides can also be larger Excess base is used, especially if the same base is used for the preparation of (III) or used for the cleavage of polysulfides to (III) becomes.

It is an essential feature of the present invention that one in counter were one or more basic compounds of the elements lithium, sodium, Magnesium, potassium, calcium, rubidium, strontium, cesium, barium and / or of the ammonium works. As basic compounds such. B. basic reacting salts, oxides, hydrides, hydroxides and alcoholates in question. Example Wise may be mentioned: lithium hydride, sodium hydride, potassium hydride, calcium hydride, Lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, magne sodium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, lithium oxide, sodium peroxide, potassium oxide, potassium peroxide, calcium oxide, barium oxide, Magnesium oxide, strontium oxide, lithium carbonate, lithium hydrogen carbonate, Na trium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen car bonat, rubidium carbonate, rubidium hydrogen carbonate, cesium hydrogen carbonate, Cesium carbonate, lithium cyanide, sodium cyanide, potassium cyanide, rubidium cyanide, Ammonium bicarbonate, ammonium carbonate, ammonium polysulfide, ammo nium carbamate, potassium disulfide, potassium polysulfide, potassium sulfite, potassium hydrogen  sulfide, sodium sulfide, sodium disulfide, sodium polysulfide, sodium hydrogen sulfide and / or their naturally occurring or synthetically obtainable mixtures, such as for example dolomite or magnesium oxide carbonate and / or compounds that Sodium or potassium metal dispersed on the corresponding carbonates Contain form as well as the alcoholates of sodium, potassium, lithium, magnesium or aluminum with the alcohols methanol, ethanol, propanol, isopropanol, Butanol, iso-butanol, sec-butanol, tert-butanol, pentanol, iso-pentanol, neo- Pentanol, sec-pentanol, isopentanol, amyl alcohol.

The alkali carbonates, alkali hydrogen carbonates, alkaline earth oxides, Alkali sulfides, alkali hydrogen sulfides.

The basic reacting compounds can be in anhydrous form or, as far as it is salts that crystallize with water of hydration, even in hydrogenated Form are used. Anhydrous compounds are preferably used.

If appropriate, the process according to the invention can be carried out in the presence of Conduct auxiliary bases, d. H. in the presence of further bases, for example in an amount of less than 0.5 mol, based on the base used.

Examples of such auxiliary bases are: halides of Alkali metals, zeolites, potassium acetate, potassium formate, sodium acetate, titanium alko holates, titanium acid amides, amidine bases or guanidine bases such as 1,5-diazabi cyclo (4.3.0) non-5-ene (DBN), 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU), 7-methyl- 1,5,7-triazabicyclo (4.4.0) dec-5-ene (MTBD), cyclohexyl-tetrabutylguanidine, cyclo hexyl-tetramethylguanidine, N, N, N, N-tetramethyl-1,8-naphthalenediamine, penta methylpiperidine, N, N-dimethylaminopyridine, N-butyl-tetraethylguanidine, N-t- Butyl-N ′, N′-diethylformamidine, tetramethylguanidine, tetraethylguanidine, N-t- Butyl-N ′, N′-dimethylacetamidine, N-cyclohexyl-tetraethylguanidine and N-t-butyl tetraethylguanidine, and 1,4-diazabicyclo (2.2.2) octane (DABCO), tertiary amines such as triethylamine, trimethylamine, N-methylmorpholine, pyridine and tetramethyl ethylenediamine, primary and secondary amines of the same structure as that for Amine, alkyl and aryl metal compounds such as butyl, Methyl, phenyl and neopryl lithium, as well as Grignard reagents.  

Metal catalysts such as the complexes of the salts of Cu, Ni, Pd, Pt or Fe use. These catalysts are in 0.01 to 10 mol% added. As ligands find P (Ph) ₃ and the like, as counterions Halogens, sulfates or phosphates use. The metals are zero, one, two or three valued.

In general, it is advantageous to carry out the process according to the invention in the presence of solvents or diluents. Become solvent used in such an amount that the reaction mixture during remains easily stirrable throughout the process. Preferred solvents come in Question: hydrocarbons such as petroleum ether, benzene, toluene, chlorobenzene, Dichlorobenzene, hexane, cyclohexane, methancyclohexane, pentane, heptane, octane and technical hydrocarbon mixtures, for example so-called white spirits with components with boiling points in the range from 40 to 250 ° C, for example, Ethers such as dimethyl, diethyl, dipropyl, diisopropyl, dibutyl, methyl t Butyl ether, tetrahydrofuran, 1,4-dioxane and polyether of ethylene oxide and / or Propylene oxide, amines such as trimethyl, triethyl, tripropyl, tributylamine, n- Methylmorpholine, pyridine and tetramethylethylenediamine, esters such as methyl, Ethyl and butyl acetate, as well as dimethyl, dibutyl and ethylene carbonate, Nitro compounds such as nitromethane, nitroethane, nitropropane and nitrobenzene, Nitriles such as acetonitrile, propionitrile and benzonitrile as well as compounds such as Tetrahydrothiophene dioxide and dimethyl sulfoxide, tetramethylene sulfoxide, propyl sulfoxide, benzylmethyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, diiso amyl sulfoxide, ketones such as acetone, methyl butyl ketone and methyl ethyl ketone, Polyether of ethylene oxide and / or propylene oxide and N-methylpyrrolidone, N- Methyl caprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidine, octyl pyr rolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, dimethylformamide, Di methylacetamide, formamide, diethylformamide, N-formylpyrolidine, N-formyl morpholine, N-formylpiperidine, N, N'-1,4-diformylpiperazine, dipropylformamide and Dibutylformamide.

However, the process according to the invention can also be carried out without a solvent or but perform in water, especially if you are going for phase transfer Reactions suitable additives, such as quaternary ammo nium salts, polyvinylpyrrolidone, trioctylphosphine oxide and / or acetylacetone.  

Auxiliaries such as cryptands, e.g. B. Crown ether or polyether can be added as a complexing agent.

Mixtures can of course also be used in the process according to the invention of solvents.

The following solvents are particularly preferred: N-methylpyrrolidone, N- Methylcaprolactam, dimethylacetamide, dimethylformamide and dimethyl sulfoxide, which surprisingly leads to particularly good yields of the target compound to lead.

In principle, if components (II), (III) and base are combined, they are all Possibilities of an order of addition possible. Submission is preferred of (III) in the solvent and the addition of the base and / or vice versa des o- Chlorobenzaldehyde (II). The reaction mixture can be added before or after addition the individual components are brought to the desired reaction temperature. Preference is given to heating the solvent / starting material III mixture and adding the compound of formula (II) or the base and adding the portionwise missing component at the reaction temperature or combining of all components and heating up to the reaction temperature.

Since a thiol is used in the reaction, use is one Protective gas atmosphere useful. Hydrogen sulfide, nitrogen, Argon or carbon dioxide. However, when working in large reaction vessels the use of protective gas can also be dispensed with.

Depending on the driving style, the response is usually between 5 Minutes and 480 hours after reaching the reaction temperature. Preferred here - because of the time / space yield - higher reaction temperatures with response times between 10 minutes and 5 hours.

After the reaction has ended, the mixture can be worked up. To In principle, there are different ways.

• a) cooling and stirring the mixture into water. The target connection is then, if appropriate after inoculation, suctioned off as a solid.
• b) Distilling off part to almost all solvent for the purpose Recover them and stir the residue with water or using the residue for further reactions (e.g. oxidation with hydrogen peroxide).
• c) cooling the mixture and isolating the deposited crystals by filtration. In many cases, the mother liquor can be used again same reaction can be used.

The sales that are obtained in the process described above are in usually at 100%.

The thiol (III) can be prepared from the thiol (IV). The reaction is carried out analogously to the manner specified in EP 342 115 or EP 126 013. Here is expediently either without or in the solvent of the worked method according to the invention. Components (IV) and (V) can in a ratio of 1: 2 to 2: 1, but preferably from 0.8 to 1.2, particularly preferably from 0.9 to 1.1 can be used. Find when splitting off water (R³ = H) Diluents and entraining agents such as toluene, xylene, chlorobenzene, dichlorobenzene etc. use.

Without solvent one works preferably from 20 ° C to the boiling point of the Mixture with solvent at the boiling point of the mixture. Preferably the resulting R³OH is removed from the reaction mixture by distillation. There the thiol is sensitive to oxidation, is also here preferably under the above. Shielding gases worked. The reaction may also become catalytic, in particular by base or acid catalysis with HCl, H₂SO₄, NaOH, KOH or the bases and auxiliary bases for the subsequent reaction.

The thiol (III) is prepared from the chloroacetamide (VI) using the reagents mentioned above. It is working with sulfides in the for that  Solvents used process according to the invention, preferably under Use of H₂S preferred.

But also the production of Bunte salts with Na₂S₂O₃ or the reaction with Thiourea derivatives which give the thiol (III) after cleavage are possible (Houben Weyl, production of mercaptones and thiophenols or in DE 28 32 977).

The thiol (III) can also be analogous to the regulations in J. pract. Chemistry 74 25 (1906) 66 174 (1902) or 153, 67 (1939) with alkali or ammonium rhodenide can be obtained according to the following equation.

Since a base is used for this reaction, the last reaction step can can also be carried out in a solvent for the inventive Method is used and (III) is then further implemented in situ.

The following examples serve to illustrate the invention and do not serve to limit their scope of application. The specified levels The target compound is obtained by calibrated HPLC measurements.

The compounds of formula (I) with R 1 = alkyl as above are also after be known methods (e.g. J. Heterocycl. Chem. 27 1709 (1990)) by the reaction with organometallic compounds in the compounds of formula (I) with R¹ = alkyl transferable. This applies in particular to R¹ = Me, starting from MeLi, MeMgBr, MeMgI, MeMgCl. The product is an important intermediate at Production of zibutan (see Synth. Commen., 23 743 (1993)). The hydrolysis of the  The above amides give the free benzothiophene carboxylic acid, which pharma has uses (US 4 101 668).

example 1

173 g III, obtained from the mixture of 1 mole refluxed for 1 h Cyclohexyl and 2-mercaptoacetic acid methyl ester and distilling off the The resulting methanol is placed in 500 ml of DMF (dimethylformamide) and concentrated after one hour of stirring at 25 ° C. reduced pressure. To Add 400 ml of DMF, 138 g of K₂CO₃ (potassium carbonate) are added and rapidly added 70.3 g of 2-chlorobenzaldehyde at 120 ° C. to 140 ° C. It will now 39.3 g of volatile components are condensed and stirred at 150 to 155 ° C for 2 h. After the volatile components have been expelled at about 1 mm, 650 ml of toluene are added added and refluxed after adding charcoal. Filtration and crystallization successively results in three crystal batches.

• A: 94.4 g (40.9%)
• B: 70.0 g (44.6%)
• C: 24.9 g (47.6%)
• Σ: 82.5 g = 63.6% of theory.

The following processing variants lead to similar results:

Refurbishment variants

A: Rotating the mixture in an oil pump vacuum (ÖPV) down to 0% Solvent content, with dist. Record H₂O, edit with Ultra-Turrax, decant and the remaining organic viscous phase with acetone move, work with Ultra-Turrax, vacuum crystals, use a suction filter Rinse CH₂CL₂ and rotate in together with the mother liquor (ML). With CH₂Cl₂ / dest. Extract H₂O, dry the organic phase, evaporate, Public transport drying. Discard all aqueous phases.

B: Identical variant A, but the ML after spinning in with hexane / acetone Process 1: 1 with Ultra-Turrax, vacuum crystals and dry

C: Identical variant A, but crystals from machining acetone and one rotated ML with toluene, without recrystallized active (A) carbon  

D: Rotating in the batch to 0% solvent content, with CH₂Cl₂ / dest. Extract H₂O using the Ultra-Turrax, dry the organic phase and rotate Discard the aqueous phase, dry the crystals.

B: Identical variant D, but no crystallization of the rotated-in organi the residue (RS), therefore inclusion of the RS with cyclohexane, Bear processing with Ultra-Turrax, suction crystals, with CH₂Cl₂ / dest. H₂O extra here, dry the organic phase, evaporate. Rotate in ML, aqueous Discard phases.

F: Identical variant D, but there is no crystallization of the residue Take up with ethanol, heat to reflux and add dist. H₂O in boiling heat, vacuum crystals, dry. Rotate in ML.

G: Rotate batch to 0% solvent content, RS with dist. H₂O on take, process with Ultra-Turrax, vacuum crystals and at public transport dry, discard aqueous phase.

H: Identical to variant D, but already fall from CH₂Cl₂ / dest. H₂O crystals , vacuum and dry. Drying the organic phase, spinning in, RS process with cyclohexane using Ultra-Turrax, vacuum crystals, dry, Rotate in ML, discard aqueous phases.

I: Identical variant F, but no crystals fall out, but it separates an oil.  

Example 3

346 g of III, obtained as in Example 1, are 1 h at 25 ° C in 1000 ml of DMF stirred and at reduced pressure at 60 ° C 104.6 g of volatile components away. After adding 276 g of K₂CO₃ at 40 ° C, 140.6 g of 2- at 140 ° C Chlorobenzaldehyde added. The mixture is kept at this temperature for 150 min then the volatile components under reduced pressure and extracted with Dichloromethane / water. After suction and concentration, the following are obtained Fraction:

A: 10.58 g (44.2%)
B: 149.15 g (73.6%)
C: 245.4 g (22.6%)
Σ: 169.9 g (66% of theory).

The contaminated crystals can be recrystallized from toluene.

Example 4

346 g III (as example 3) are dissolved in 500 ml DMF at 140 ° C to a Suspension of 276 g K₂CO₃ and 140.6 g 2-chlorobenzaldehyde in 500 ml DMF dripped. After 190 min 140 ° C is worked up as in Example 3. Σ 130.2 g (50% of theory).

Example 5

98.9 g III (as Example 3) are dissolved in 400 ml DMF at 140 ° C and after Add 157.7 g of K₂CO₃ with 100 g of 2,3-dichlorobenzaldehyde. After on Work as in Example 3, 68 g (41% of theory) of 7-chlorobenz thiophene-2-cyclohexylcarboxamide obtained from the melting point 154 to 155 ° C.

Claims (8)

1. Process for the preparation of compounds of formula (I) in which
R¹ C₁-C₆-alkyl, NH-C₁-C₂₀-alkyl, N (C₁-C₂₀-alkyl) ₂, N (C₁-C₂₀-alkyl) (C₁-C₁₀-alkyl), NH-aryl, NH-benzyl and
R² denotes H, methyl or halogen,
characterized in that compounds of the formula (III) with an aldehyde of the formula (II) in the presence of a base. 2. The method according to claim 1, characterized in that the compounds of formula (I) to the sulfones of formula (Ia) without intermediate isolation oxidized. 3. The method according to claim 1, characterized in that one produces compounds of the formula in which
R¹ is methyl or NH-C₁-C₂₀-alkyl, NH-aryl and
R² mean H. 4. The method according to claim 1, characterized in that compounds of the formula (I) are prepared in which
R¹ NH-C₁-C₁₀ alkyl and
R² mean H. 5. The method according to claim 1, characterized in that one has a connection in which and
R² = H. 6. The method according to claim 1, characterized in that the Implementation at temperatures from 20 ° C to 200 ° C.   7. The method according to claim l, characterized in that the ratio the compound of formula (III) to the compound of formula II and the Base is 1: 3 to 3: 1 each. 8. The method according to claim 1, characterized in that the Produces compound of formula III in situ and without intermediate isolation can react further with the compounds of formula (II).