DE2515011C2 - Process for the production of symmetrical olefins - Google Patents

Description

The invention relates to a process for the production of symmetrical olefins according to the preceding claims and can be used with advantage in particular for the production of trans-p'-carotene and Use Dimestrol.

At present, higher molecular weight olefins are usually only available to technology as non-uniform products. because the known manufacturing processes provide mixtures of isomers and homologues in many cases, the cannot, or only with difficulty, be broken down into uniform olefins. Accordingly, the already existed Wish. To synthesize Qkfine by Ädditionsreakuanen of aldehydes and ^ or ketones, with compounds should be formed in place of the C = O groups. those in the starting aldehydes or ketones present would contain new C = C bonds. However, the previously known methods for Carrying out such reactions have the disadvantage that they are complex. For example, it is known that the Provitamin A., / - Carolin, by multi-step processes, such as those in US Pat. No. 3,078,256 by Wittig and employees have been described to produce. It becomes a quaternary phosphonium halide in it the corresponding phosphonium ylide reacted and this with a suitable aldehyde to form p "-carotene reacted. Apart from the fact that these known processes are complex in nature, Many of the reaction components required for this are compounds that are difficult for their part are available. For example, the quaternary phosphonium halides. those in the aforementioned Procedures are required, as are other comparable compounds, such as those used as intermediates in similar processes for the preparation of p'-carotene. for example in US-PS 36 22 633: 34 08 414 and 36 00 473 have been described, are produced by means of processes that are already relatively complex per se.

Other known methods for the synthesis of trans-p'-carotene and similar carotenoids. the multilevel and are complex are disclosed, for example, in U.S. Patents 2,846,487 and 2,846,475, 3,000,982 and 3,441,623 US-PS 29 45 069, US-PS 30,07 976 and 34 08 406 described.

The invention now solves the problem of synthesizing symmetrical olefins by a process which in many cases starts out from readily available reaction components and is comparatively cheap Yields.

The process according to the invention can be used particularly advantageously for the synthesis of trans-p'-carotui and Dimestrol (λ. λ -Diethy 1-4.4 -dimetho \\ stilben or Diethy Isiilböstroldimethyiäiher).

The process according to the invention is a reductive coupling reaction of ketones or Aldehydes with reactive divalent titanium. Ti (II). with the formation of the corresponding symmetrical olefins, according to the following general reaction scheme:

C = O + Ti (II)

= C + TiO ₂

The reactive titanium (II) can be conveniently obtained by reducing Ti (III) or Ti (IV) with the reducing agents mentioned particularly lithium aluminum hydride. The reaction component is preferably added to this to the Ti (II) solution So one has a simple one-step method for the synthesis of the corresponding symmetrical olefins are available

In the process according to the invention, the titanium compound used as a reaction component also reacts an aldehyde or ketone in such a way that a reductive coupling of the aldehyde · or ketone molecules takes place, the C = O groups of the starting substances being replaced by C = C bonds. Exemplary of benzophenone, this reaction can be illustrated, for example, as follows:

C = O

The reactive divalent titanium is preferably formed by reducing Ti (III) or Ti (IV) with a the reducing agents lithium aluminum hydride, zinc. Magnesium, calcium hydride or lithium borohydride and

in any case prepares the reactive Ti (II) compound in such a way that soluble or partially soluble salts! '

of higher quality titanium, for example TiCIj or TiCL ₁ . slurried in a suitable inert, dry, organic solvent, such as tetrahydrofuran, under inert conditions, for example in a nitrogen or argon atmosphere, and treated with one of the aforementioned reducing agents. The reaction components are usually refluxed for a while so that the reactive titanium (II) compound is formed.

The aldehyde solution or the ketone is then reacted with the Ti (II) -haItigen reaction solution and that Mixture then acidified. Then you can use the symmetrical olefin as a reaction product Customary procedures and generally win in yields of up to 95%.

It is true that the reaction mechanism of the process according to the invention has not yet been detailed theoretically be clarified. The previous idea is that reactive divalent titanium is a Electron donates to a molecule of the ketone or aldehyde, so that an anion radical is formed, which accordingly the classic pinacol reaction dimerized to a dialcohol as an intermediate. The dialcohol then reacts with another Ti (II) to form a cyclic intermediate which then " decomposed to form the olefin product and T1O2. This probable course of the reaction can be seen in a semantic way play as follows:

0-Ti (III) Ο ^θ O ^e

\ T ₁ (I ₀ \ / \ /

C = O> C > - C - C - vi

/ ' Il

Ti (II)

25 Ti

OO

C = C + TiO ₂ 1 —C - C -

/ \ Il

If the reaction is carried out with an insufficient amount of reducing agent, the Isolate pinacol intermediates from the reaction mixture. Furthermore, if you have a pinacol with treated with reactive Ti (II) solution, win olefins. It is also known that Ti (III) in turn Ketones does not attack, and it is also known that Ti (II) is sufficiently strong Reducing agent acts so that a pinacol reaction can be brought about:

Ti (II) - Ti (III) + e-; 0.37 volts.

It must be noted that the reaction mechanism on which the process according to the invention is based is based on the presence of reactive Ti (II). This reactive Ti (II) is replaced by the one discussed here Reduction process produced. The reactive Ti (II) should not be divalent with known compounds Oxidized Ti can be confused with TiCb. T1CI2 is a completely insoluble one polymeric mass and is completely inactive. It is necessary for the method according to the invention, a soluble and to prepare reactive Ti (II) as mentioned.

The process according to the invention can be applied to aldehydes and ketones of all types, including cyclic aldehydes and ketones, because under the reaction conditions used there is no risk of ring cleavage taking place in these cyclic compounds. \

\ The novel process has the further orteil ^v that no problems with regard to possible \

\ Impurities of the reaction products by the oxide formed by the condensation occur as they

'exist, for example, in the ylid syntheses. In contrast to the phosphine formed in ylide syntheses

oxide, which is an organic substance and therefore also dissolves in the solvent required for the reaction product, the titanium oxide obtained in the process according to the invention is an insoluble substance that remains as a solid in the reaction mixture when the reaction product present in the reaction mixture in dissolved form is isolated therefrom . Separation problems are therefore excluded. The reaction products are obtained in such a purity that they can be used for pleasure purposes as well as pharmaceuticals 60 \ can.

25 15 Oil

A slurry of titanium trichloride (1.54 g, 10.0 mmol) in 30 ml of dry tetrahydrofuran was prepared in an inert atmosphere (nitrogen or argon) and powdered lithium aluminum hydride (190 mg _→ 5.0 mmol) was carefully added. The resulting solution was stirred for two hours at room temperature to allow the Ti (II) reactant to form; a solution of retinal (1.42 g, 5.0 mfnol) in 5 ml of dry tetrahydrofuran was added. The solution was stirred for a further 15 hours at room temperature and then poured into 50 ml of 2 η aqueous hydrochloric acid. The solution was extracted several times with ether, the ether extracts were combined, washed with saturated sodium chloride solution, dried over magenta

' Sium sulfate dried and concentrated by removing the solvent in a rotary evaporator. Of the

The residue was purified by chromatography on Si'ikageS. Elution with. Hexane yielded 1.14 g (85 / o yield) of beta-carotene, which is determined by thin-layer chromatography against an authentic comparison sample, based on the characteristic ultraviolet spectrum and identified by its melting point, m.p. 180-182 ° C became.

Example II
Beta carotene

It was made by dissolving titanium tetrachloride (1.10 ml, 10.0 mmol) in 25 ml of dry tetrahydrofuran in A solution was prepared in an inert gas atmosphere (nitrogen or argon). Lithium aluminum hydride was carefully added to this (190 mg, 5.0 mmol) and the resulting solution to form the active Ti (II) reaction components Stirred for two hours at room temperature Then a solution of retinal (1.42 g, 5.0 mmol)

35 in 5 ml of dry tetrahydrofuran added, and the reaction mixture at room temperature overnight Then the solution was poured into 50 ml of 2 η aqueous hydrochloric acid and extracted several times with ether The ether extracts were combined, washed with saturated aqueous sodium chloride solution, over Dried magnesium sulfate and concentrated by removing the solvent on a rotary evaporator The residue was further purified by chromatography on silica gel, eluting with hexane • 40 1.0 g (75% yield) of beta-carotene obtained, which by thin layer chromatography against a authentic comparative sample and by determining the melting point, melting point 180-182 °.

Example III
Beta carotene

In an inert atmosphere (nitrogen or argon) a slurry of titanium trichloride {770 mg, 5.0 mmol) in 20 ml of dry tetrahydrofuran, and magnesium turnings (120 mg, 5.0 mmol) The resulting mixture was left under overnight to form the Ti (II) reactant Refluxed and a solution of retinal (710 mg, 2.5 mmol) in 5 ml of dry tetrahydrofuran was added After the solution had been refluxed for two hours, it was added to Poured 50 ml of 2 η aqueous hydrochloric acid and extracted several times with ether. Dk ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and removed by removal of the solvent concentrated in a rotary evaporator. The residue was chromatographed on Silica gel purified. Elution with hexane gave beta-carotene, UO mg (20% yield), which was determined by thin layer chromatography compared to an authentic comparative example and based on the characteristic Ultravio lett spectrum was identified.

Example IV

Beta carotene

Magnesium turnings (243 mg, 10.0 mmol) were slurried in 20 ml of dry tetrahydrofuran in an inert gas atmosphere (nitrogen or argon), and a solution of titanium tetrachloride (0.55 ml, 5.0 mmol) in 3 ml of dry benzene was added added quickly The resulting solution was stirred at 50 ° overnight to form the active Ti (II) reaction component, and a solution of retinal (70 mg, 2.5 mmol) in 5 ml of dry tetrahydrofuran was added. After refluxing for a further two hours, the solution was allowed to cool to room temperature, poured into 50 ml of 2 η aqueous hydrochloric acid and

extracted them with ether. The ether extracts were combined with saturated aqueous sodium chloride solution washed, dried over magnesium sulfate and removed by removing the solvent in a rotary evaporator concentrated. The residue was purified by chromatography on silica gel. Elution with hexane gave 130 mg (20% yield) of a product, which by thin layer chromatography against an authentic ver _ same sample and identified as beta-carotene on the basis of the characteristic ultraviolet spectrum.

Example V

Beta carotene

In an inert atmosphere (nitrogen or argon) a slurry of titanium trichloride (770 mg, 5.0 mmol) in 20 ml of dry tetrahydrofuran, and zinc dust (325 mg, 5.0 mmol) was added. The resulting mixture was passed over to form the Ti (II) reactants Treated overnight at the reflux condenser and a solution of retinal (710 mg, 2.5 mmol) in 5 ml of dry tetrahydrofuran adds. After the reflux condenser had been refluxed for a further two hours, the Solution poured into 50 ml of 2 η aqueous hydrochloric acid and extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated by removing the solvent in a rotary evaporator. The residue was Purified by chromatography on silica gel: elution with hexane gave 400 mg (60% yield) of beta-carotene. that by means of thin-layer chromatography against an authentic comparison sample and based on the characteristic Ultraviolet spectrum was identified.

Example Vl
Beta carotene

In an inert atmosphere (nitrogen or argon), zinc dust (654 mg, 10.0 mmol) in 20 ml of dry Slurried tetrahydrofuran, and a solution of titanium tetrachoride (0.55 ml, 5.0 mmol) in 3 ml of dry Benzene added quickly. The resulting solution was used to form the active Ti (II) reactant Treated overnight on the reflux condenser and a solution of retinal (710 mg, 2.5 mmol) in 5 ml added dry tetrahydrofuran. After two hours of reflux condenser treatment was, the solution was cooled to room temperature, poured into 50 ml of 2 η aqueous hydrochloric acid and with Ether extracted The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and removed by removing the solvent in a rotary evaporator concentrated The residue was purified by chromatography on a silica gel column. The elution with Bexan gave 430 mg (65% yield) of beta-carotene which crystallized in a flask. By thin layer chromatography compared to an authentic comparative sample and by comparing the melting point of a recrystallized one Sample, m.p. 180-182 °, the beta-carotene was identified

Example VII

Dimestrol

(ar ^ t'-diethyM ^ '- dimethoxystilbene;
Diethylstilbestrol dimethyl ether)

v

A slurry of titanium trichloride (1 ^ 4 g, 10.0 mmol) in 30 ml of dry tetrahydrofuran and carefully powdered lithium aluminum hydride (190 mg, 5.0 mmol) given. The resulting solution "was two hours at room temperature stirred The Ti (II) reaction component formed. Then it became a solution of para-methoxypropiophenone (820 mg, 5 mmol) in 5 ml of dry tetrahydrofuran added. The reaction mixture became four Treated hours on the reflux condenser, and then poured into 50 ml of 2 η aqueous hydrochloric acid. The solution was> * ■ extracted several times with ether, the ether extracts were combined with saturated aqueous sodium chloride solution washed, dried over magnesium sulfate and removed by removing the solvent in a rotary evaporator concentrated The residue was purified by chromatography on alumina and there were 630 mg (85% yield) of dimestrol obtained; M.p. 124 °.

Example VIII

Dimestrol

(a ^ r'-diethyl-4,4'-dimethoxystilbene;

Diethylstilbestrol dimethyl ether)

In an inert gas atmosphere (nitrogen or argon), zinc dust (654 mg, 10.0 mmol) in 20 ml was dry Slurried tetrahydrofuran and a solution of titanium tetrachloride (0.55 ml, 5.0 mmol) in 3 ml of dry Benzene added. The resulting mixture was passed over to form the active Ti (II) reactant Treated at the reflux cow overnight, and a solution of para-methoxypropiophenone (500 mg, 3.0 mmol) in 5 ml of dry tetrahydrofuran was added. After twelve hours on the reflux condenser had been treated, the solution was cooled to room temperature in 50 ml of 2η aqueous hydrochloric acid

25 15 Oil

poured and extracted with ether. The ether extracts were combined with saturated aqueous sodium |

chloride solution, dried over magnesium sulfate and removed by removing the solvent in a rotary I

concentration evaporator. The residue was purified by chromatography on silica gel, and s

410 mg (-31%) obtained at Dimetrol, which by the IR absorption spectrum. Nuclear Magnetic Resonance Spectrum And |

Mass spectrum was identified. Mp. 124 ^s .

Example IX ö

Cyclohepiylidenecycloheptane

A slurry of titanium trichloride (1.23 g. 8.0 mmol) in 30 ml of dry was in a nitrogen atmosphere Tetrahydrofuran prepared and carefully powdered lithium potassium hydride (152 mg. 4.0 mmol) given. The resulting solution was allowed to form the Ti (II) reactant for one hour at room temperature stirred and a solution of cycloheptanone (450 mg. 4.0 mmol) in 5 ml of tetrahydrofuran was added. The reaction mixture was refluxed for 4 hours and then dissolved in 50 ml of 2 η aqueous Poured hydrochloric acid. The solution was extracted several times with ether, the ether extracts combined with saturated aqueous sodium chloride solution, dried over magnesium sulfate and, by removing the | Solvent concentrated in a rotary evaporator. The product obtained (400 mg. 95% yield) was pure"; Cyclohepiylidenecycloheptane. It was based on its spectral properties (infrared spectrum, mass

Spectrum, nuclear magnetic resonance spectrum). fs

Example X Tetraphenylethylene

In a nitrogen atmosphere, a slurry of titanium trichloride (3.10 g, 20.0 mmol) in 40 ml of dry Tetrahydrofuran prepared and carefully powdered lithium aluminum hydride (380 mg, 10.0 mmol) added. The resulting solution was allowed to form the Ti (II) reactant at room temperature for one hour stirred, and it was a solution of benzophenone (!, 82 g, 10.0 mmol) in 5 ml of dry Tetrahydrofuran added. The reaction mixture was refluxed for fifteen hours,

then poured into 50 ml of 2π aqueous hydrochloric acid and extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated by removing the solvent in a rotary evaporator. The crystalline residue persisted from 1.55 g (95% yield) of tetraphenylethylene, which based on its spectral properties (infrared and ultraviolet spectrum) and by its melting point, m.p. 220-221 °.

Example XI Cyclododecanylidenecyclododecane

C = O »> C = C

In a nitrogen atmosphere, a slurry of titanium trichloride (3.10 g, 20.0 mmol) in 40 ml of dry tetrahydrofuran was prepared and powdered lithium aluminum hydride (380 mg, 10.0 mmol) was carefully added. The resulting solution was stirred at room temperature for one hour to form the Ti (II) reactant, and a solution of cyclododecanone (1.82 mg, 10.0 mmol) in 10 ml of dry tetrahydrofuran was added. The reaction mixture was refluxed for twelve hours, then poured into 50 ml of 2 η aqueous hydrochloric acid and extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated by removing the solvent in a rotary evaporator identified by its melting point. F. 150-152 ⁰ C.

Example XII
Adamamtylidenadamantane

Tl (II) = 0

A suspension of titanium trichloride (3.10 g. 20.0 mmol) in 40 ml of dry tetrahydrofuran was prepared in a nitrogen atmosphere and powdered lithium aluminum hydride (380 mg. 10.0 mmol) was carefully added. The resulting solution was stirred at room temperature for one hour to form the Ti (II) reaction component, and a solution of adamantanone (1.50 g, 10.0 mmol) in 10 ml of dry tetrahydrofuran was added. The reaction mixture was refluxed for twelve hours and then poured into 50 ml of 2 η aqueous hydrochloric acid. The solution was extracted several times with ether. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated by removing the solvent on a rotary evaporator. The residue obtained was purified further by chromatography on silica gel. 1.15 g (85% yield) of adamantylidene adamantane were obtained by elution with hexane, based on its spectral properties (infrared spectrum, mass spectrum and nuclear magnetic resonance spectrum) and its melting point. M.p. 185-186 ^; . was identified.

Example XIII
Beta carotene

A solution was prepared by dissolving titanium tetrachloride (1.10 ml. 10.0 mmol) in 25 ml of dry tetrahydrofuran in an inert atmosphere (nitrogen or argon). It was added lithium borohydride (110 mg, \ 1 5.0 mmol) was added and the resulting solution stirred for two hours at 50 ^r. A solution of Reiinal (1.42 g.

5.0 mmol) in 5 ml of dry tetrahydrofuran was added, and the reaction mixture took four hours

Treated reflux. The solution was then poured into 50 ml of 2 η aqueous hydrochloric acid and repeatedly with Ether extracted. The ether extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and removed by removing the solvent in a rotary evaporator

concentrated. The residue was purified further by chromatography on silica gel. By elution with hexane

0.3 g (60%) of beia-carotene were obtained, which by comparison rni; an aisicntischei; Sample has been identified. 180-182 ^:.

Example XIV
Beta carotene

It was made by dissolving titanium tetrachloride (1.10 ml, 10.0 mmol) in 25 ml of dry tetrahydrofuran prepared a solution under an inert gas atmosphere (nitrogen or argon). Calcium hydride (420 mg, 10.0 mmol) and the resulting solution stirred for two hours at room temperature. A solution from Retinal (1.42 g, 5.0 mmol) in 5 ml of dry tetrahydrofuran was then added and the reaction mixture treated for three hours on the reflux condenser. The solution was then dissolved in 50 ml of 2 η aqueous hydrochloric acid poured and extracted several times with ether. The Atherexiracts were combined with saturated aqueous Washed sodium chloride solution, dried over magnesium sulfate and removed by removing the solvent concentrated in a rotary evaporator. The residue was purified further by chromatography on silica gel Elution with hexane gave 1.0 g (75%) of beta-caroline, which was compared with thin-layer chromatography an authentic comparative sample and was identified on the basis of the melting point, melting point 180-182 °.

Claims (3)

25 15 Oil claims: 1. A process for the preparation of symmetrical olefins, characterized in that aldehydes and / or ketones are reacted by means of a Ti (II) obtained by reducing a titanium having a higher oxidation state than Ti (II) with lithium aluminum hydride, which is dissolved in an inert dry solvent . Zn. Mg. CaH ₂ or LiBH _{4 has been produced} in an inert atmosphere. 2. The method according to claim 1, characterized in that the inert dry solvent is tetrahydrofuran is used. 3. The method according to claim K, characterized in that the starting aldehyde is retinal or the starting ketone para-mathoxypropiophenone is used.