WO2000061526A1

WO2000061526A1 - Method for carrying out the transition metal-catalyzed dimerization or codimerization of alkenes in compressed carbon dioxide which serves as a solvent

Info

Publication number: WO2000061526A1
Application number: PCT/EP2000/002569
Authority: WO
Inventors: Walter Leitner; Andreas Wegner
Original assignee: Studiengesellschaft Kohle Mbh
Priority date: 1999-04-08
Filing date: 2000-03-23
Publication date: 2000-10-19
Also published as: CA2369607A1; EP1165468A1; JP2002541229A; DE19915904A1

Abstract

The invention relates to a method for carrying out the transition metal-catalyzed dimerization or codimerization of alkenes. The inventive method is characterized in that the dimerization or codimerization is carried out in compressed carbon dioxide which serves as a solvent. The invention also relates to methods in which the compressed carbon dioxide is used as a solvent for the dimerization or codimerization and for the successive processing of the products. The invention especially relates to the use of such methods in order to produce anti-inflammatory and pain-relieving pharmaceuticals.

Description

Process for transition metal-catalyzed dimerization or codimensation of alkenes in compressed carbon dioxide as a solvent

The present invention relates to processes for transition-metal-catalyzed dimerization or codimerization of alkenes, characterized in that the dimerization or codimerization is carried out in compressed carbon dioxide as a solvent. Furthermore, the invention relates to methods in which the compressed carbon dioxide is used as a solvent for dimerization or codimerization and for the subsequent processing of the products. In particular, the invention relates to the use of such methods in the manufacture of anti-inflammatory and analgesic pharmaceuticals.

It is known that alkenes can be dimerized or codimerized using transition metal-containing catalysts. The codimerization of substituted alkenes with ethene is particularly interesting from an economic point of view [German Patent 20 39 125, Studiengesellschaft kohl mbH (priority 1970); US Patent 3,978,147 Studiengesellschaft kohl mbH (priority 1973); US Patent 4,098,834 Studiengesellschaft kohl mbH (priority 1976); F. Petit et al, Bull. Soc. Chim. 1979, 11-415]. If vinylaromatics (e.g. styrene, p-methoxystyrene, 2-methoxy-6-vinylnaphthalene) are used as substituted alkenes, 1-butenes substituted with aryl radicals can be obtained in the 3-position, which are intermediates for the preparation of commercially important pharmaceuticals such as For example, ibuprofen and naproxen can serve. Nickel compounds that have been modified with phosphorus ligands and activated with Lewis acids have proven particularly useful as catalysts. The use of chiral phosphorus ligands, especially of azaphospholene 1, enables enantioselective codimerization of alkenes [G. Wilke et al, Angew. Chem. 1972, 1070; B. Bogdanovic et al., Angew. Chem. 1973, 1013; F. Petit et al, J. Chem. Soc. 1980, 937; Buono et al, J. Org. Chem. 1985, 50, 1781; European Patent 0 247 595 A2, Studiengesellschaft kohl mbH (priority 1987); PW Jolly and G. Wilke in Applied Homogeneous Catalysis with Organometallic Compounds 2 (B. Cornils, WA Herrmann, Eds.), VCH-Wiley 1996, 1024]. Enantioselective control is of particular importance for the products that serve as intermediates for pharmaceuticals. However, the known processes have serious disadvantages. The reactions are carried out at very low temperatures (-70 ° C to -55 ° C). This requires a very high amount of energy to cool the reaction mixture. In addition, a large excess of chlorine- and aluminum-containing compounds are used as Lewis acids for activation. Their use can be partially avoided by using weakly coordinating anions [TV RajanBabu et al., J. Am. Chem. Soc. 1998, 120, 459]. The decisive disadvantage is the use of liquid, organic solvents, with the best results being achieved in methylene chloride. Such toxicologically questionable solvents have to be completely separated in a complex manner, in particular for intermediates in the synthesis of pharmaceuticals. The subsequent disposal of these solvents leads to considerable environmental pollution.

Supercritical carbon dioxide (scCO ₂ ) has already been described as a toxicologically safe and easy-to-remove solvent for chemical synthesis using transition metal-containing catalysts [R. Noyori et al., Science 1995, 269, 1065]. However, the possible use in dimerization or codimerization has not yet been recognized. In particular, only very small number of cycles of less than 20 have been observed for other reactions with nickel-containing catalysts in scCO ₂ , since nickel phosphine complexes in particular can be rapidly decomposed by reaction with CO ₂ [D. Walther et al, Z. anorg. general Chem. 1998, 624, 602].

We now describe a new process for the transition-metal-catalyzed dimerization or codimerization of alkenes, characterized in that compressed (liquid or supercritical) carbon dioxide is used as the solvent. The process presented here enables the codimerization of alkenes and substituted alkenes, in particular vinyl aromatics, without the use of ecologically and toxicologically questionable, liquid, organic solvents. In addition, the reactions can be carried out without the addition of chlorine and aluminum-containing compounds at reaction temperatures in the range from -30 ° C to + 100 ° C, in particular from 0 ° C to + 60 ° C. Surprisingly, we find that even nickel-containing phosphine catalysts have a high activity, selectivity and service life under these conditions. Even at + 40 ° C 5500 mmol substrate per mmol nickel are implemented. These results are Amazingly, even better than the results of comparable experiments in methylene chloride under otherwise identical conditions. Due to the variable solution properties of supercritical carbon dioxide with pressure and temperature [Zosel et al., Angew. Chem. Int. Ed. Engl. 1978, 702 and M. McHugh, V. Krukonis, Supercntical Fluid Extraction, Butterworth Publishers, 1986], it is also possible, with suitable selection of the external parameters, to selectively separate the desired products from the reaction mixture, the catalyst being recovered in active form .

In the present invention, the solvent used is compressed (liquid or supercritical) carbon dioxide. The total pressure is in the range of 15-500 bar, preferably 35-300 bar.

The reactions are carried out at temperatures in the range from -30 to + 100 ° C., preferably at temperatures from 0 to + 60 ° C.

The reaction time is not subject to any particular restriction and depends on the course of the reaction, which can be investigated using suitable analysis methods (e.g. GC, NMR). The reaction time is usually in the range from 2 minutes to 24 hours and depends, among other things, on the ratio of substrate to catalyst. The ratio of The substrate to catalyst can be varied within very wide limits of 100-100,000, particularly preferably 300-10,000.

Any compounds and salts of transition metals, in particular nickel and palladium, can be used as the source of the transition metal. The compounds and salts can e.g. B. from the group Ni (cod) ₂ (cod = 1,5-cyclooctadiene), Ni (acac) ₂ (acac = acetylacetonate), NiCl ₂ , NiBr ₂ , PdCl ₂ , PdBr ₂ , Pd (acac) ₂ , Pd (dba) ₂ (dba = dibenzylidene acetone), or Pd (CH ₃ COO) ₂ can be selected. Particularly preferred metal sources are hydrido or allyl complexes, such as, for example, [Ni (C ₃ H ₅ ) Cl] ₂ or complex 2.

The transition metal compounds can be modified by monodentate or multidentate phosphorus ligands, e.g. B. PPh ₃ , Ph ₂ P (CH ₂ ) _n PPh ₂ (n = 1-6), P (OPh) ₃ , PR ₃ , P (OR) ₃ or P (NR ₂ ) ₃ , where R is a straight-chain, can be branched or cyclic alkyl radical. The use of chiral phosphorus ligands, such as. B. mddp, nmddp, Norphos, Chiraphos, Binap, Binaphos, mop, Diop, DuPHOS, Glyphos or bppm, enables the enantioselective control of the reaction. [A list of further ligands and an explanation of the acronyms can be found in the literature: H. Brunner, W. Zettlmeier, Handbook of Enantioselective Catalysis, Vol. II, VCH-Wiley 1993]. Compound 1 is particularly efficient. The catalysts modified with ligands can be formed in situ in the reaction mixture from the metal sources and the phosphorus ligands or can be used in the form of isolated complexes (for example 2). The ratio of ligand to metal can be varied within a wide range and is typically between 0.1 and 100, preferably between 0.5 and 10.

Lewis acids as described previously in the literature can be used as cocatalyst [F. Petit et al., Bull. Soc. Chim. 1979 11-415; G. Wilke et al., Angew. Chem. 1972, 1070; F. Petit et al., J. Chem. Soc. 1980, 937; Buono et al., J. Org. Chem. 1985, 50, 1781; European Patent 0 247 595 A2, Studiengesellschaft kohl mbH (priority 1987); PW Jolly and G. Wilke in Applied Homogeneous Catalysis with Organometallic Compounds 2 (B. Cornils, WA Herrmann, Eds.), VCH-Wiley 1996, 1024]. The Lewis acid can be a compound of the general composition RJVl'X ,,, where R is an alkyl or aryl radical, X is a halogen, M ^{1 is} an element of the 3rd, 4th or 5th main group and m and n are integers between 0 and 5 and the sum of m and n of the maximum valence of M ¹ corresponds. Aluminum sesquichloride or methylalumoxane can also be used as Lewis acid.

Salts of weakly coordinating anions can also be used as cocatalyst [for definition of weakly coordinating anions, see: SH Strauss, Chem. Rev. 1993, 93, 927]. Examples of weakly coordinating anions are compounds of the type [M'R'R ² R ³ R ⁴ ] ^" , where M ^{1 is} a metal of the 3rd main group and where R ¹ , R ² , R ³ and R ^{4 are} the same or can be different radicals, can be selected independently of one another and can be composed of a halogen atom or straight-chain, branched, cyclic or aromatic (C, -C ₂₀ ) hydrocarbons, in which one or more carbons can be replaced by heteroatoms and which can be replaced by halogen atoms. , Hydroxyl, alkoxy, acyl, phenoxy, acyloxy, alkoxycarbonyl or phenoxycarbonyl groups, where the radicals R ¹ , R ² , R ³ or R ⁴ can be linked to one another to form rings or condensed ring systems. The weakly coordinating anion can also be a compound of the type [M ³ R'R ² R ³ R ⁴ R ⁵ R ⁶ ] ^" , where M ^{3 is} an element of the 5th main group and the definition of the radicals R ¹ , R ² , R ³ R ⁴ , R ⁵ , R ⁶ corresponds to the above definition for R ¹ - R ⁴ t. Furthermore, the weakly coordinating anion can be a compound of the general formula [M ⁴ (OM ⁵ F ₅ ) ₆ ] \ where M ^{4 is} an element of the 5th main or subgroup and M ^{5 is} an element of the 6th main or subgroup , his. Perchlorate [ClO ₄ ] ^" or anions of the general formula [RSO ₃ ] \ where R is a halogen or hydrogen atom, a (C, -C ₁₀ ) alkyl group, a halogen-substituted (C _r C, ₀ ) alkyl group can also be used , an aryl group, a halogen-substituted aryl group, an arylalkyl group or a halogen-substituted arylalkyl group.

The amount of cocatalyst used is not particularly limited. The ratio of cocatalyst to transition metal can be up to 1000, for the weakly coordinating anions a ratio of 0.2-10 is preferably set. Straight-chain or branched, cyclic or acyclic, aromatic or non-aromatic unsaturated hydrocarbons can be used as alkenes. The alkenes can also contain several double bonds in a conjugated or non-conjugated arrangement. The alkenes can also have one or more substituents such as. B. CF ₃ , halogen, alkoxy, acyloxy, carboxy, carbonyl, amine, amide, nitro, alkynyl, hydroxy, phenoxy, alkoxycarbonyl or phenoxycarbonyl, thiol and sulfide. Codimerization and enantioselective codimerization of substituted and unsubstituted vinyl aromatics with ethene are particularly preferred.

The amount of alkene used is not particularly limited, but is usually 0.1-1000 mmol per 100 g CO ₂ , preferably 15-600 mmol per 100 g CO ₂ . When using gaseous alkenes, the partial pressure of the alkene can be in the range from 0 to 300 bar.

When carrying out the reactions, the procedure is expediently such that an isolated complex of metal source and phosphorus ligands or the two separate components are dissolved in a liquid substrate (for example styrene). This solution is added to the cocatalyst, which is introduced together with CO ₂ and a second substrate (e.g. ethene) in a high-pressure reactor at the reaction temperature. Other procedures can also be used depending on the technical requirements and the physical state of the substrates.

The present invention is to be described in more detail with the aid of the following selected examples, without the use of the method being in any way restricted thereby. In particular, the workup is intended for the laboratory scale and can be used in an industrial application such. B. can be replaced by suitable methods of separation with compressed carbon dioxide [G. Brunner, Gas Extraction, Steinkopff-Verlag, Darmstadt, 1994].

Examples

The comparison of Examples 1-3 with the control experiments in Examples 4-5 illustrates the positive effect of CO ₂ over methylene chloride. example 1

Na [B (C ₆ H ₃ (CF ₃ ) ₂ ) ₄ ] (33.4 mg, 35.5xl0 ^{~ 3} mmol) was placed under argon atmosphere in a stainless steel high-pressure reactor with a viewing window (V = 27 mL), PTFE stirring core, and holes for temperature sensors, needle and ball valve. A solution of 2 (5.4 mg, 6.3x10 ^"3 mmol) in styrene (0.45 g, 4.37 mmol) was weighed into a metering device which was connected to the reactor via the ball valve. Ethene (1.1g, 39.3 mmol ) and filled into the reactor with the aid of a compressor CO ₂ (14.6 g) The reaction mixture was heated with stirring to 40 ° C. The metering device was also filled with CO ₂ (7.1 g) and heated to about 60 ° C. By opening of the ball valve, the styrene was introduced into the reactor, and after stirring for 15 minutes, the reactor was depressurized within 20 minutes, passing the gas stream through a trap cooled to -55 ° C. 0.2282 g of condensate was removed from the with toluene The trap and 0.3931 g of crude product were flushed out of the high-pressure reactor with acetone (in total 100% of theory) The gas chromatographic analysis of the combined solutions gave a product with the composition 77.2% 3-phenyl-1-butene, 13.2% 2-phenyl-2- but and 9.2% substances with a molecular weight higher than 136. By gas chromatography, the enantiomeric excess of 3-phenyl-1-butene was determined to be 83.2%.

Examples 2-3

Examples 2-3 (see Table 1) were analogous to Example 1, with a variation of

Reaction temperature carried out.

Example 4

50 mL CH ₂ C1 _{2 were} cooled to 10 ° C in a 500 ml glass flask with an internal thermometer, dropping funnel and gas inlet tube. Na [B (C ₆ H ₃ (CF ₃ ) ₂ ) ₄ ] (410 mg, 0.463 mmol) and 2 (100 mg, 0.115 mmol) were added and ethene was introduced. Styrene (27.5 g, 0.265 mmol) was added dropwise in the course of 30 minutes, during which the temperature rose to 35 ° C. Ethene was introduced for a further 30 minutes with stirring. Subsequent introduction of NH ₃ ended the reaction. After recondensation in The solvent was distilled off in an oil pump vacuum. The product was analyzed by gas chromatography and contained 57.2% 3-phenyl-1-butene with an enantiomeric excess of 81.4%.

Example 5

Analogously to Example 4, the reaction temperature being controlled at 23 ° C.

Table 1

Example substrate solvent temperature 3-phenyl -1-butene ee

(° C) (%) '° ^<

1 styrene scCO ₂ 40 77.2 83.2

2 styrene liquid CO ₂ 23 71.4 85.6

3 styrene liquid CO ₂ 1 82.9 86.2

4 styrene CH ₂ C1 ₂ 35 57.2 81.4

5 styrene CH ₂ C1 ₂ 23 70.5 84.6

Examples 6-9

Examples 6-9 (see Table 2) were carried out analogously to Example 1, with variation of the substrates and the reaction temperature.

Table 2

Example substrate solvent temperature 3-aryl-1-butene ee

(° C) (%) (%)

6 4-chlorostyrene scCO ₂ 40 80.5> 70

7 4-chlorostyrene liquid CO ₂ 24 87.0> 80

8 4-isobutylstyrene scCO ₂ 35 44.4 89.4

9 4-isobutylstyrene liquid CO ₂ 20 71.4 76.6 Examples 10-12

Examples 10-12 (see Table 3) were analogous to Example 1, with the variation of

Cocatalyst and the reaction temperature carried out.

Table 3

Example cocatalyst cocatalyst / Ni solution temperature 3-phenyl-l-ee medium (° C) butene (%) f χ

1 [B (C ₆ H ₃ (CF ₃ ) ₂ ) ₄ ] ^' 2.8 scCO ₂ 40 77.2 83.2

10 [OSO ₂ CF ₃ ] ^" 7.5 scCO ₂ 40 1.0 nb

11 [Al (OC (Ph) (CF ₃ ) ₂ ) ₄ ] - 3.9 liquid CO ₂ 22 33.0 76.0

12 C1 ₃ A1 ₂ (C ₂ H ₅ ) ₃ 1.5 liquid CO ₂ 1 92.9 70.2

Example 13

Na [B (C ₆ H ₃ (CF ₃ ) ₂ ) ₄ ] (28.2 mg, 31.8xl0 ^"3 mmol) was placed under an argon atmosphere in a stainless steel high-pressure reactor with a viewing window (V = 225 mL), PTFE stirring core, and holes for temperature sensors, needle and ball valve. A solution of 2 (1.5 mg, 1.73xl0 ^"3 mmol) in styrene (3.64 g, 34.9 mmol) was weighed into a metering device, which was connected to the reactor via the ball valve. Ethene (16 g, 571 mmol) and, with the aid of a compressor, CO ₂ (142 g) were introduced into the reactor via the needle valve. The reaction mixture was heated to 40 ° C with stirring. The metering device was also filled with CO ₂ (10 g) and heated to about 60 ° C. The styrene was introduced into the reactor by opening the ball valve. While stirring was carried out for 24 hours, samples were taken from the reaction mixture at regular intervals and analyzed directly by gas chromatography. At the start of the reaction, 1300 mmol of substrate per mmol of nickel were reacted in one hour. A total of 5500 mmol substrate reacted per mmol nickel. The only product observed was 3-phenyl-1-butene with an enantiomeric excess of 79.6%. Example 14-19 (see Table 4)

Like example 1, but the reaction temperature was 28 ° C. After relaxing and removing all the volatile substances in an oil pump vacuum at 40 ° C., the stainless steel high-pressure reactor was charged again with the same weights of styrene, ethene and CO ₂ as before, without exchanging the catalyst or cocatalyst. This process was repeated four more times.

Table 4

Example repeat 3-phenyl-1-butene ee

14 84.3 83.4

15 1 88.8 83.0

16 2 89.0 81.4

17 3 76.6 80.2

18 4 30.5 79.8

19 5 8.5 79.4

Claims

claims

1. A process for transition metal-catalyzed dimerization or codimerization of alkenes, characterized in that the dimerization or codimerization is carried out in compressed carbon dioxide as a solvent.

2. The method according to claim 1, wherein straight-chain or branched, cyclic or acyclic, aromatic or non-aromatic unsaturated hydrocarbons are used as alkenes, wherein the alkenes can also contain several double bonds in a conjugated or non-conjugated arrangement and can be substituted with substituents from the group CF ₃ , halogen, alkoxy, acyloxy, carboxy, carbonyl, amine, amide, nitro, alkynyl, hydroxy, phenoxy, alkoxycarbonyl or phenoxycarbonyl, thio and sulfide.

3. The method according to claim 1-2 for the codimerization of substituted or unsubstituted vinyl aromatics and ethene.

4. The method according to claim 1-3, wherein the dimerization or codimerization is enantioselective.

5. The method according to claim 1-4, wherein a combination of transition metal source and phosphorus ligand is used as the transition metal catalyst.

6. The method according to claim 5, wherein compounds or salts of the elements palladium or nickel are used as transition metal source.

7. The method according to claim 5, wherein monodentate or multidentate phosphorus compounds are used as the phosphorus ligand.

8. The method of claim 7, wherein the phosphorus compound is a chiral phosphorus compound.

9. The method of claim 5, wherein the transition metal source and the phosphorus ligand are added individually to the reaction mixture.

10. The method of claim 5, wherein the transition metal source is a complex compound containing the phosphorus ligand.

11. The method according to claim 1-10, wherein the transition metal catalyst is activated by a suitable cocatalyst.

12. The method of claim 11, wherein the cocatalyst is a Lewis acid.

13. The method according to claim 12, wherein the Lewis acid is a compound of the general composition R ^ M'X ,,, where R is an alkyl or aryl radical, X is a halogen, M ^{1 is} an element of the 3rd, 4th or 5th main group and m and n are integers between 0 and 5 and the sum of m and n corresponds to the maximum valence of M ¹ .

14. The method according to claim 12, wherein aluminum sesquichloride is used as Lewis acid.

15. The method according to claim 12, wherein methylalumoxane is used as Lewis acid.

16. The method of claim 11, wherein the cocatalyst is the salt of a weakly coordinating anion.

17. The method according to claim 16, wherein the weakly coordinating anion is a compound of the type [M ² R'R ² R ³ R ⁴ ] ^" , wherein M ^{2 is} an element of the 3rd main group and the radicals R ¹ , R ² R ³ R ^{4 can be} identical or different, can be selected independently of one another and can be constructed from the group of halogens or straight-chain, branched, cyclic or aromatic (C, -C ₂₀ ) hydrocarbons, in which one or more carbons can be replaced by heteroatoms and with halogen, hydroxy, alkoxy, acyl, phenoxy, acyloxy, alkoxycarbonyl or Phenoxycarbonyl groups can be substituted and the radicals R ¹ , R ² , R ³ or R ⁴ can be linked to one another to form rings or condensed ring systems.

18. The method according to claim 16, wherein the weakly coordinating anion is a compound of the type [M ³ R'R ² R ³ R ⁴ R ⁵ R ⁶ ] ^" , where M ^{3 is} an element of the 5th main group and the radicals R ¹ , R ² , R ³ R ⁴ , R ⁵ , R ^{6 can be} identical or different, can be selected independently of one another and can be constructed from the group of halogens or straight-chain, branched, cyclic or aromatic (C, -C ₂₀ ) - Hydrocarbons in which one or more carbons can be replaced by heteroatoms and which can be substituted with halogen, hydroxyl, alkoxy, acyl, phenoxy, acyloxy, alkoxycarbonyl or phenoxycarbonyl groups and where the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ or R ⁶ can be connected to one another to form rings or condensed ring systems.

19. The method according to claim 16, wherein the weakly coordinating anion is a compound of the type [M ⁴ (OM ⁵ F ₅ ) ₆ ] ^" , where M ^{4 is} an element of the 5th main or subgroup and M ^{5 is} an element of 6. Main or sub group is.

20. The method according to claim 16, wherein the weakly coordinating anion is a compound of the general formula [RSO ₃ ] ^" , where R is a halogen or hydrogen atom, a (C, -Cι ₀ ) alkyl group, a halogen-substituted (C , -C ₁₀ ) alkyl group, an aryl group, a halogen-substituted aryl group, an arylalkyl group or a halogen-substituted arylalkyl group.

21. The method of claim 16, wherein the weakly coordinating anion is [ClO ₄ ] ^" .

22. The method according to claim 1-21, wherein the reaction temperature is in the range of -30 to + 100 ° C.

23. The method according to claim 1-22, wherein the total pressure is 15-500 bar.

24. The method of claim 22-23, wherein the compressed carbon dioxide is in the supercritical state.

25. The method according to claim 1-24, wherein the work-up of the reaction mixture is carried out by separation by means of compressed carbon dioxide.

26. The method of claim 25, wherein the products are separated from the catalyst by extraction with supercritical carbon dioxide.

27. The method of claims 25-26, wherein the catalyst is recovered in active form.

28. The method according to claim 25-27, wherein the reaction and the material separation are combined in an integrated process.

29. The method according to claim 1-28, wherein the products are used as intermediates for the production of pharmaceuticals.

30. The method according to claim 29, wherein the products are used for the production of anti-inflammatory and pain-relieving pharmaceuticals.

31. The method according to claim 30, wherein the products are used for the production of ibuprofen.

32. The method of claim 30, wherein the products are used for the production of naproxen.