Method for Producing Carotenoids

Tag : sodium ethoxide



A process for preparing carotenoids, in which the process includesreacting a dialkoxy dialdehyde in a double Wittig condensation witha phosphonium salt of or in a double Wittig-Horner condensationwith a phosphonate. The carotenoids include, for example,.beta.-carotene, zeaxanthin, canthaxanthin, astaxathin, lycopeneand croceptin, which are useful as nutraceuticals, food colorants,and feed additives.

Inventors: Ernst; Hansgeorg (Speyer, DE), Henrich; Klaus(Ha.beta.loch, DE), Keller; Andreas (Speyer, DE)
Assignee: BASF Aktiengesellschaft (Ludwigshafen, DE)

Appl. No.: 10/532,207
Filed: November 17, 2003
PCT Filed: November 17, 2003
PCT No.: PCT/EP03/12804
371(c)(1),(2),(4) Date: April 22, 2005
PCT Pub. No.: WO2004/048323
PCT Pub. Date: June 10, 2004
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Foreign Application Priority Data
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Nov 22, 2002 [DE] 102 54 809

Current U.S. Class: 568/343 ; 560/183; 568/378; 568/673; 568/824
Current International Class: C07C 45/68 (20060101); C07C 35/18(20060101); C07C 49/543 (20060101); C07C 69/73 (20060101); C07C43/03 (20060101)

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References Cited [Referenced By]
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U.S. Patent Documents

5455362 October 1995 Ernst et al.
5654488 August 1997 Krause et al.
6150561 November 2000 Kreienbuhl et al.
6743954 June 2004 Ernst et al.
6747177 June 2004 Ernst et al.

Foreign Patent Documents

0 908 449 Apr., 1999 EP

Primary Examiner: Witherspoon; Sikarl A.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier &Neustadt, P.C.

Claims


We claim:
1. A process for preparing carotenoids, which comprises reacting adialkoxy dialdehyde of the general formula I ##STR00018## whereinR.sup.1 is C.sub.1-C.sub.6-alkyl, in a double Wittig condensationwith a phosphonium salt of the formula II or in a doubleWittig-Horner condensation with a phosphonate of the formula III##STR00019## wherein the substituents in formulas II and III,independently of one another, are defined as follows: R.sup.2 is##STR00020## R.sup.3 is aryl; R.sup.4 to R.sup.6 areC.sub.1-C.sub.6-alkyl; and X.sup.- is an anion equivalent of aninorganic or organic acid.
2. The process according to claim 1, wherein X.sup.- is the anionequivalent of an acid selected from the group consisting ofhydrohalic acid, sulfuric acid, phosphoric acid, formic acid,acetic acid and sulfonic acid.
3. The process according to claim 2, wherein X.sup.- is Cl.sup.-,Br.sup.-, C.sub.nH.sub.2n+1-SO.sub.3.sup.- with n =1-4,Ph-SO.sub.3.sup.-, p-Tol-SO.sub.3.sup.- or CF.sub.3-SO.sub.3.sup.-.
4. The process according to claim 1 for preparing a carotenoidselected from the group consisting of astaxanthin, lycopene andcanthaxanthin, which comprises reacting a dialkoxy dialdehyde ofthe formula Ia ##STR00021## with a phosphonium salt of the formulaIIa, ##STR00022## in which the substituents have independently ofone another the following meaning: R.sup.2 is ##STR00023## Ph isphenyl; and Hal is halide.
5. The process according to claim 1, wherein the reaction iscarried out in a C.sub.1-C.sub.6 alcohol using an alkali metal oralkaline earth metal alkoxide as base.
6. The process according to claim 1, wherein the reaction productis thermally isomerized into the all (E) form and isolated byfiltration.
7. Compounds of the formula IV, ##STR00024## wherein R.sup.1 andR.sup.2 are independent of one another and defined in claim 1.


Description


The invention relates to a process for preparing carotenoids, forexample .beta.-carotene, zeaxanthin, canthaxanthin, astaxanthin,lycopene and crocetin, which are in demand as nutraceuticals, foodcolorants and feed additives.
It is known that carotenoids are prepared inter alia by doubleWittig condensation of a C.sub.15 phosphonium salt (C.sub.15--P)with a symmetrical C.sub.10 dialdehyde (Carotenoids, Vol. 2, page89 et seq., Birkhauser Verlag, 1996).
##STR00001##
Depending on the structure of the carotenoid to be prepared, it ispossible for example to react the following C.sub.15 phosphoniumsalts (P1 to P5) in the abovementioned Wittig reaction, where Ph isa phenyl radical and X.sup.- is the anion equivalent of aninorganic or organic acid:
##STR00002##
For the synthesis of crocetin diesters as precursors of the saffronpigment crocetin, C.sub.5 ester phosphonium salts (C.sub.5--P) orC.sub.5 ester phosphonates (C.sub.5-EP) under respectively Wittigor Wittig-Horner condensation with the C.sub.10 dialdehyde (Angew.Chem. 72, 911 (1960); Chem. Ber. 93, 1349 (1960)).
##STR00003##
The C.sub.10 dialdehyde required for these synthetic processes is acrystalline substance which is only slightly soluble in manysolvents. Carotenoid syntheses using C.sub.10 dialdehyde musttherefore usually be carried out in chlorinated hydrocarbons suchas dichloromethane or trichloromethane or in oxiranes as solventsor co-solvents (Carotenoids, Vol. 2, pages 92 et seq.;Birkhauser-Verlag, 1996). The use of such solvents for preparingfood additives is objectionable from the toxicological viewpoint.
This is why various processes have been proposed, inter alia inEP-A-0 733 619 and EP-A-0 908 449, for carrying out theseindustrial processes in toxicologically less objectionable solventssuch as, for example, lower alcohols. However, all these processesstill require the preparation and isolation, and handling andmetering, of the crystalline C.sub.10 dialdehyde. Handling ofsolids is, however, associated with high capital costs and thushigh production costs.
One possibility for avoiding this disadvantage is disclosed inEP-A-0 509 273.
The process described therein employs 2,5-dihydrofuran of theformula (1), which is in the form of an oil and which is preparedby reacting a 2,5-dialkoxy-2,5-dihydrofuran (2) with an alkylpropenyl ether (3), as synthetic equivalent for the C.sub.10dialdehyde.
##STR00004##
However, this process has the following disadvantages. The statedyields of (1) are from 38 to 56% of theory, which is insufficientfor industrial implementation. Other publications confirm thatanalogous processes generally give only low yields of bisalkylationproduct (1) (J. Gen. Chem. USSR, 32, 4, 1082 f. (1962); TetrahedronLett. 42, 10, 2003 f. (2001)). The only example indicated of acarotenoid synthesis was the reaction of (1) to give.beta.-carotene in an overall yield of 52%. This process isindustrially and economically unattractive because the availabilityof (1) is poor and the yield is low.
It was therefore an object of the present invention to provide aprocess for preparing carotenoids which does not have thedisadvantages of the prior art described at the outset.
This object has been achieved by a process for preparingcarotenoids which comprises reacting a dialkoxy dialdehyde of thegeneral formula I
##STR00005## with R.sup.1=C.sub.1-C.sub.6-alkyl, in a double Wittigcondensation with a phosphonium salt of the formula II or in adouble Wittig-Horner condensation with a phosphonate of the formulaIII
##STR00006## in which the substituents have independently of oneanother the following meaning:
##STR00007## R.sup.3 aryl; R.sup.4 to R.sup.6 C.sub.1-C.sub.6-alkyland X.sup.- an anion equivalent of an inorganic or organic acid.Alkyl radicals which may be mentioned for R.sup.1 and R.sup.4 toR.sup.6 are branched or unbranched C.sub.1-C.sub.6-alkyl chainssuch as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl. Preferred alkyl radicals areC.sub.1-C.sub.4-alkyl groups, particularly preferably methyl,ethyl, n-propyl and 1-methylethyl, very particularly preferablymethyl and ethyl.
The term aryl for R.sup.3 refers to conventional aryl radicalsoccurring in phosphines and phosphonium salts, such as phenyl,tolyl, naphthyl, optionally substituted in each case, preferablyphenyl.
The radical X.sup.- is an anion equivalent of inorganic or organicacid, preferably a strong inorganic or organic acid.
The term strong acid comprises hydrohalic acids (especiallyhydrochloric acid and hydrobromic acid), sulfuric acid, phosphoricacid, sulfonic acids and other inorganic or organic acids with acomparable degree of dissociation. Strong organic acids also meanin this connection C.sub.1-C.sub.6-alkanoic acids.
Anions which should be particularly preferably mentioned are thoseof an acid selected from the group consisting of hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, formic acid,acetic acid and sulfonic acids. Very particular preference is givento Cl.sup.-, Br.sup.-, C.sub.nH.sub.2n+1--SO.sub.3.sup.- (withn=1-4), Ph-SO.sub.3.sup.-, p-Tol-SO.sub.3.sup.- orCF.sub.3--SO.sub.3.sup.-.
A preferred embodiment of the process of the invention relates tothe preparation of a carotenoid selected from the group consistingof astaxanthin, lycopene and canthaxanthin, which comprisesreacting a dialkoxy dialdehyde of the formula Ia
##STR00008## with a phosphonium salt of the formula IIa,
##STR00009## in which the substituents have independently of oneanother the following meaning:
##STR00010## Ph phenyl; Hal halide, preferably Cl.sup.- orBr.sup.-.
The Wittig or Wittig-Horner reactions generally take place underthe conditions described for these reactions (Carotenoids, Vol, 2,pages 79 et seq., Birkhauser-Verlag, 1996, and references citedtherein; and EP-A-0 733 619). The reaction can be carried out forexample in a system consisting of an inert organic solvent such as,for example, chlorinated hydrocarbons or cyclic or open-chainethers in combination with an alkali metal or alkaline earth metalalkoxide, preferably a solution in the corresponding alkanol. Analternative possibility in this case too is to employ an oxirane,preferably 1,2-epoxybutane, in a manner known per se as latent baseand cosolvent in combination with a lower alkanol.
All bases customary for Wittig condensations, e.g. alkali metalhydroxides such as sodium hydroxide, potassium hydroxide or lithiumhydroxide; alkali metal hydrides such as sodium hydride orpotassium hydride, can be used as base.
However, it is preferred to use a solvent in which the desiredfinal product is slightly soluble but the triphenylphosphane oxideresulting as coproduct from the Wittig reaction is readily soluble.
Suitable for this purpose are in particular lower alcohols,preferably C.sub.1-C.sub.6 alcohols, for example methanol, ethanol,n-propanol, isopropanol, n-butanol or tert-butanol, particularlypreferably methanol. The base advantageously used in this case analkali metal or alkaline earth metal alkoxide, preferably Namethoxide. Triphenylphosphine oxide and inorganic salts can beremoved by diluting the mixture with water.
The condensation normally takes place at temperatures between-30.degree. C. and +50.degree. C., preferably between -20 and+30.degree. C., particularly preferably between -10.degree. C. and+25.degree. C., very particularly preferably between 0.degree. C.and +20.degree. C.
It is possible in this connection either to introduce both startingcompounds (phosphonium salt and aldehyde) into the solvent and addthe base thereto, or else add the base to a solution of thephosphonium salt, and only then to add a solution of the aldehyde.
The amount of base employed is normally in the range from 0.8 to 5mol, preferably 1 to 3 mol, per mole of the phosphonium salt II orphosphonate III employed.
Following the Wittig or Wittig-Horner reaction, the products can bethermally isomerized into the all(E) form in a known manner byheating for several hours at temperatures in the range from 70 to120.degree. C., preferably at the boiling point of the solventused, and be isolated in high yield and purity by filtration.
The dialkoxy dialdehyde I or Ia used according to the invention
##STR00011## arises as intermediate in an industrial C.sub.10dialdehyde synthesis starting from a hexaalkoxy derivative V, in asequence of acetal cleavage and elimination, but is not normallyisolated (Carotenoids, Vol. 2, pages 117/118 and 301/302,Birkhauser Verlag, 1996; CH Pat. 321 106). With suitable choice ofthe reaction conditions, the process can be stopped at theintermediate stage of I. I can be isolated and purified bydistillation (J. Gen. Chem. USSR, 34, 1, 64 f. (1964)).
##STR00012##
The dialkoxy dialdehydes of the formula I are readily soluble,stable substances and are in the form of liquids or oils, so thatthe elaborate handling of C.sub.10 dialdehyde solid is dispensedwith. A further advantage of the use of I is that the process forpreparing the C.sub.10 units is shortened by one synthesis stageand one removal of solids.
It has surprisingly been found that the intermediate of the formulaI, preferably Ia, is outstandingly suitable for all theabovementioned Wittig and Wittig-Horner condensations.Intermediates arising in this case are alkoxy derivatives of thegeneral formula IV.
##STR00013##
These intermediate stages can be isolated if desired. However, theelimination to the desired polyene is preferably allowed to proceedunder the reaction conditions, preferably by increasing thereaction temperature.
The invention additionally relates to compounds of the formula IV
##STR00014## in which the substituents have independently of oneanother the following meaning: R.sup.1 C.sub.1-C.sub.6-alkyl;
##STR00015## R.sup.6 C.sub.1-C.sub.6-alkyl.
Preferred compounds are those of the formula IV
##STR00016## in which R.sup.1 is methyl or ethyl, particularlypreferably methyl; and
##STR00017##
The following examples are intended to explain the process of theinvention in more detail.
EXAMPLE 1
Preparation of Astaxanthin
71.9 g (0.125 mol) of astaxanthin C.sub.15 phosphonium salt P5(X.sup.-=bromide) were introduced into 150 ml of methanol. At0.degree. C., 11.4 g of C.sub.10 dial Ia (95% pure; equivalent to0.0475 mol) were added.
Then 24.8 g of a 30% strength solution of sodium methoxide inethanol (=0.137 mol NaOMe) were added dropwise at 0.degree. C. overthe course of 1 h, and the mixture was stirred at 0.degree. C. fora further our and then allowed to reach room temperature. Asolution of 1.5 g (25 mmol) of acetic acid in 115 ml of water wasadded dropwise, and the mixture was heated to reflux (about75.degree. C.) and then stirred under reflux for 20 h. It wasallowed to reach room temperature, and the crystals were filteredoff. The filter cake was washed twice with 100 ml each time of a60:40 (v/v) methanol/water mixture, once with hot water (100 ml)and once with methanol (100 ml; 25.degree. C.) and dried in avacuum drying oven at +50.degree. C.
Final weight: 23.5 g of astaxanthin=83.0% yield (based on Iaemployed); HPLC purity: 99.17%
EXAMPLE 2
Isolation of the Astaxanthin Intermediate Stage IVe
71.9 g (0.125 mol) of astaxanthin C.sub.15 phosphonium salt P5(X.sup.-=bromide) were dissolved in 250 ml of methylene chloride.At 0.degree. C., 11.4 g of C.sub.10 dial Ia (95% pure; equivalentto 0.0475 mol) were added. Then 46.8 g of a 20% strength solutionof sodium ethoxide in ethanol (0.137 mol NaOEt) were added dropwiseat 0.degree. C. over the course of 1 h, and the mixture was stirredat 0.degree. C. for 1 h. Then a solution of 1.5 g of acetic acid in250 ml of water was added dropwise. The organic phase was separatedoff. The aqueous phase was back-extracted twice with 40 ml ofmethylene chloride. The combined organic phases were washed twicewith 125 ml of water each time, dried over sodium sulfate andconcentrated in a rotary evaporator. The bright red pasty residuewas purified by flash chromatography on silica gel (eluent:cyclohexane/methyl tert-butyl ether=4:1 to 1:1).
27.05 g (86.3% of theory) of viscous red oil which, according toH-NMR, C-NMR and IR analysis, contained IVe as mixture ofstereoisomers were obtained. E.sup.1.sub.1 (CHCl.sub.3):335 (260nm); 468 (351 nm).
EXAMPLE 3
Preparation of Zeaxanthin
14.9 g (0.0288 mol) of zeaxanthin C.sub.15 phosphonium salt P3(X.sup.-=chloride) were dissolved in 63 ml of ethanol. 2.85 g ofC.sub.10 dial Ia (95% pure; equivalent to 0.012 mol) and then 16.6g of butylene oxide (1,2-epoxybutane) were added. The mixture wasthen heated under reflux for 20 h. The resulting suspension wascooled to 0.degree. C. and stirred at this temperature for 1 h. Thecrystals were filtered off with suction. The filter cake was washedthree times with 50 ml of ethanol each time and dried in a vacuumdrying oven.
Final weight: 5.52 g of zeaxanthin=81% of theory (based on Iaemployed).