ring closure of benzoquinones containing unsaturated side chains using basic catalysts

Abstract

The present invention relates to the formation of a compound of formula (I) by a ring closure reaction of a compound of formula (II) in the presence of a catalytic amount of base. It has been found that this reaction is very efficient, for example providing an efficient route to the synthesis of 3,4-dehydro-α-tocotrienol, α-tocotrienol and α-tocopherol, respectively.

Description

Technical Field

[0001] This invention relates to the field of synthesis of chromanes and chromenes, particularly the synthesis of 3,4-dehydrotocopherol, 3,4-dehydrotocotrienol, tocopherol, and tocotrienol. Background Technology

[0002] Vitamin E and its esters are an important class of tropane compounds. The synthetic pathway of tropanes is through the corresponding tropenes.

[0003] There are different pathways for the formation of chromones.

[0004] Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963) disclosed the formation of 3,4-dehydrotocotrienols via a ring-closure reaction of geranyl-geranyltrimethylbenzoquinone in a pyridine-mediated process involving the formation of a ring-closed chromene, where pyridine is present in large quantities (corresponding to a massive excess relative to benzoquinone). The use of pyridine is highly unfavorable, especially in large quantities, as it is a carcinogenic and highly flammable compound in animals. Furthermore, the resulting reaction mixture is complex, requiring a complicated derivatization process to form dehydrotocotrienol p-phenylazobenzoate for separation, followed by purification by crystallization. This process uses the very expensive and highly toxic chemical 4-(phenylazo)benzoyl chloride, making the overall process extremely unfavorable.

[0005] Also, Dötz KH and others. Chem. Ber. 115, 1278-1285 (1982) and Terashima K. et al., Bioorganic & Medicinal Chemistry 10, 1619-1625 (2002) discloses a cyclization reaction by reflux of the corresponding benzoquinone in a large molar excess of pyridine.

[0006] WO 2015 / 028643 A1 discloses the intramolecular hydrogenation of chiral arylalkynes to form chromenes via Au(I) or Ag(I) catalysis. Gold and silver catalysts are very expensive. Summary of the Invention

[0007] Therefore, the problem to be solved by the present invention is to provide a method for providing chromene and chromane, which avoids the use of large amounts of pyridine or general bases.

[0008] The method according to claim 1 solves this problem. It has been particularly discovered that, in the ring-closing reaction of formula (II) benzoquinone, a catalytic amount of base can be used to produce formula (I) chromene. In particular, it has been found that strongly basic catalysts are particularly suitable as catalytic bases for the above-described ring-closing reaction. Studies have shown that compounds of formula (I) can be obtained with very high conversions and yields.

[0009] This method provides a very advantageous synthetic route for the chromanes of formula (III) or (IV) as described in claim 8 or 9.

[0010] Other aspects of the invention pertain to the subject of the other independent claims. Particularly preferred embodiments are the subject of the dependent claims. Detailed Implementation

[0011] In a first aspect, the present invention relates to a method for preparing a compound of formula (I),

[0012]

[0013] The method includes a ring-closing step of compound (II) in the presence of a basic catalyst to produce compound (I).

[0014]

[0015] in

[0016] n = 0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12;

[0017] R 1 Indicates hydrogen or methyl;

[0018] R 3 and R 4

[0019] Either they represent hydrogen, methyl, or methoxy groups independently of each other.

[0020] They either collectively represent -CH-CH-CH-CH- and form aromatic groups;

[0021] Any with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and

[0022] Any wavy line represents a carbon-carbon bond independently of each other, and when connected to a carbon-carbon double bond, it is in either the Z or E configuration.

[0023] The characteristic feature is that the molar ratio of the alkaline catalyst to the compound of formula (II) is 1:1,000 to 1:5, particularly 1:100 to 1:10.

[0024] For clarity, some terms used in this article are defined as follows:

[0025] In this article, "C x-y "-alkyl" refers to an alkyl group containing x to y carbon atoms, for example, C 1-3 -alkyl refers to an alkyl group containing 1 to 3 carbon atoms. Alkyl groups can be straight-chain or branched. For example,

[0026] -CH(CH3)-CH2-CH3 is considered a C4-alkyl group.

[0027] In this document, if the same symbol or group label exists in multiple formulas, the definition of the group or symbol in a particular formula also applies to other formulas containing the same label.

[0028] In this article, the term "independently" means that, in the context of substituents, molecules, or groups, the same designated substituents, molecules, or groups can appear simultaneously in the same molecule with different meanings.

[0029] In this paper, any dashed lines in the formula represent bonds where substituents are bonded to the rest of the molecule.

[0030] In this article, any chemical formula with a dashed line ( The bonds in the carbon-carbon bond can be represented independently as either a carbon-carbon single bond or a carbon-carbon double bond.

[0031] In any chemical formula described herein, the wavy line represents a carbon-carbon bond, which, when attached to a carbon-carbon double bond, is in either the Z or E configuration. In all molecules, the carbon-carbon double bond is preferably in the E configuration.

[0032] pK a The negative logarithm to the base 10 of the acid dissociation constant (pKa = -log) is commonly referred to as the acid dissociation constant. 10 K a When organic acids have multiple protons, the pK used in this paper... a It relates to the dissociation constant of the last proton. For example, for a base with two basic sites, "pk a "with pK" a2 Related to pK a It was measured under standard temperature and pressure.

[0033] Compound of formula (II)

[0034] The compound of formula (II) is a substance known to those skilled in the art, and its synthesis method is also known.

[0035]

[0036] In a preferred embodiment, the substituent R3 and R 4 This indicates a methoxyl group. In this embodiment, any group with a dashed line (...) The bond in () preferably represents a carbon-carbon double bond, and most preferably an E configuration.

[0037] Ubiquinone is a key representative of this embodiment. Based on the number of isoprene-like groups in the side chain, ubiquinone is designated as ubiquinone-2 (n=0), ubiquinone-3 (n=1), ubiquinone-4 (n=2), ubiquinone-5 (n=3), ubiquinone-6 (n=4), ubiquinone-7 (n=5), ubiquinone-8 (n=8), ubiquinone-9 (n=9), ubiquinone-4 (n=2), ubiquinone-5 (n=3), ubiquinone-6 (n=4), ubiquinone-7 (n=5), ubiquinone-8 (n=6), ubiquinone-9 (n=7), and ubiquinone-10 (n=8). Ubiquinone is also known by its former name, Coenzyme Q. Ubiquinone-10 (n=8) (= Coenzyme Q10) is a particularly preferred species in this embodiment.

[0038] In another preferred embodiment, the substituent R 3 and R 4 Indicates H or methyl. R 3 =R 4 =CH3 is the preferred choice.

[0039] R is the preferred choice 1 = R 3 = R 4 = CH3.

[0040] Preferably, n=2. More preferably, all expressions in equation (II) with dashed lines (...) All the bonds in the carbon-carbon double bonds are carbon-carbon double bonds, preferably all of which are E configuration.

[0041] In this embodiment, the compound of formula (II) is preferably a compound of formula (II-BB).

[0042]

[0043] In another preferred embodiment, the substituent R 3 and R 4 They collectively represent -CH-CH-CH-CH- and form aromatic groups. The compound in this embodiment is represented as follows:

[0044] .

[0045] In this embodiment, R 1 Preferably, it represents methyl.

[0046] Vitamin K1 (phylloquinone) is one example of this implementation method.

[0047] Methylnaphthoquinone (MK), also known as vitamin K2, is another important representative of this embodiment.

[0048] Any with dashed lines ( The bond in () preferably represents a carbon-carbon double bond, and preferably has an E configuration.

[0049] Based on the number of isoprene-like groups in the side chain, methylnaphthoquinone is represented as MK-2 (n=0), MK-3 (n=1), MK4 (n=2), MK-5 (n=3), MK-6 (n=4), MK-7 (n=5), MK-8 (n=6), MK-9 (n=7), MK-10 (n=8), MK-11 (n=9), MK-12 (n=10), and MK-13 (n=11).

[0050] MK-4 (n=2) is a particularly preferred species in this embodiment.

[0051] If any has a dashed line ( The bond in the dashed line represents a carbon-carbon double bond, and those skilled in the art would expect a risk of secondary ring formation (through the existing carbon-carbon double bond). Since this has not been observed, it is particularly preferred that at least one bond marked with a dashed line is a carbon-carbon double bond. Therefore, this method is especially effective in yielding α-tocotrienols containing three double bonds in the side chain. α-Tocotrienols are an important compound in natural vitamin E.

[0052] alkaline catalyst

[0053] The method includes a ring-closing step of the compound of formula (I) in the presence of an alkaline catalyst ("cat") to produce the compound of formula (I), such as Figure 1 The reaction scheme is shown in step a).

[0054] The alkaline catalyst is preferably a hydroxide or carbonate of an alkali metal or alkaline earth metal, especially an alkali metal hydroxide.

[0055] Furthermore, the preferred alkaline catalyst is an organic amine, especially an organic tertiary amine.

[0056] The basic catalyst is a base. Not all bases are equally effective for this invention. Preferably, the basic catalyst is not pyridine. It has been shown that the conjugate acid of the basic catalyst has a pK value measured in water. a A value between 8.6 and 15.7, and particularly between 9 and 15.7, is especially suitable. This implies that the pK of the alkaline catalyst is... b The value is preferably between 5.4 and 0, and particularly between 5 and 0.

[0057] PK of corresponding acids aA few examples:

[0058]

[0059] In one embodiment, the alkaline catalyst is an organic amine, particularly selected from the group consisting of: 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (=DBN), 1,4-diazabicyclo[2.2.2]octane (=DABCO), 1-azabicyclo[2.2.2]octane (=quinine ring), and sparteine, preferably selected from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU), and 1-azabicyclo[2.2.2]octane (=quinine ring).

[0060] In another embodiment, the alkaline catalyst is preferably a hydroxide or carbonate of an alkali metal or alkaline earth metal, particularly an alkali metal hydroxide. In this embodiment, the most preferred alkaline catalyst is NaOH or KOH.

[0061] The base must not be a hydride, such as sodium hydride, because hydrides form molecular hydrogen when in contact with compounds of formula (II). The formation of hydrogen poses a significant safety hazard in the closed-loop process and in general handling procedures.

[0062] When the base is used in solid form, a phase transfer agent is preferably used, especially a quaternary ammonium salt, particularly a quaternary ammonium salt of the formula [NR4]X, where R is C 2-18 -alkyl, especially C 3-8 -alkyl, where X is a halide. Preferably, the phase transfer agent is tetrabutylammonium halide, especially tetrabutylammonium bromide. The amount of the phase transfer agent is preferably 0.1 to 10 mol%, especially 0.5 to 2 mol%, relative to the compound of formula (II).

[0063] In another embodiment, water may also be present if the alkaline catalyst is an alkali metal hydroxide.

[0064] The ring-closing step is preferably carried out in a hydrocarbon solvent, particularly toluene.

[0065] When using a hydrocarbon solvent, the solvent is preferably used in an amount such that the solution having the compound of formula (II) is between 0.05 mol and 5 mol, more preferably between 0.1 mol and 1 mol, relative to the compound of formula (II).

[0066] In the presence of water, it is preferred that the closed-loop reaction be carried out in a two-phase system, namely an aqueous phase and an organic phase, particularly an aqueous phase and an organic solvent phase.

[0067] The key point to emphasize is: alkaline substances... catalytic The presence of a quantity, i.e., the basic catalyst relative to compound (II) no It exists not in stoichiometric amounts, but in significantly lower amounts, i.e., the molar ratio of the basic catalyst to the compound of formula (II) is preferably 1:1,000 to 1:5, particularly 1:100 to 1:10.

[0068] The closed-loop step is typically carried out under stirring, preferably at a temperature between 40 and 200°C, more preferably between 90 and 150°C, more preferably at the reflux temperature of the organic solvent if an organic solvent is used, and / or at a pressure between 1 bara and 10 bara. Furthermore, the reaction is preferably carried out under an inert atmosphere, preferably under nitrogen.

[0069] It has been shown that the above method can successfully produce compound (I).

[0070]

[0071] In particular, the above method can simply isolate the desired compound of formula (I) without any complex derivatization, and subsequent purification by crystallization and final chemical transformation of the derivative to the desired compound, as is the case with Schudel, Mayer, Isler, Helv. Chim. Acta The method disclosed in 46, 2517-2526 (1963) is the same.

[0072] Particularly preferred embodiments of the compounds of formula (I) are compounds of formulas (IA), (IB), and (IC), with preferred embodiments being compounds of formulas (I-AA), (I-BB), (I-CC1), and (I-CC2):

[0073]

[0074]

[0075] The most preferred compounds are those of formula (I-As).

[0076]

[0077] The most preferred compound is the (I-Cis) compound.

[0078]

[0079] The compound of formula (I) obtained as described above can be hydrogenated using a hydrogenating agent.

[0080] In one embodiment, only the carbon-carbon double bonds in the ring are hydrogenated during hydrogenation, while the carbon-carbon double bonds of the alkene are not hydrogenated ("partial hydrogenation"). This hydrogenation yields a compound of formula (III), such as... Figure 1 As shown.

[0081]

[0082] Particularly preferred embodiments of the compounds of formula (III) are compounds of formulas (III-A), (III-B) and (III-C), and more preferably compounds of formulas (III-AA), (III-BB), (III-CC1) and (III-CC2):

[0083]

[0084]

[0085] The most preferred compound is the (III-Cis) compound.

[0086]

[0087] In another embodiment, in this hydrogenation reaction, all the carbon-carbon double bonds of the olefin are hydrogenated ("complete hydrogenation"), thereby hydrogenating to obtain a compound of formula (IV), such as Figure 1 As shown.

[0088]

[0089] Particularly preferred embodiments of the compounds of formula (IV) are compounds of formulas (IV-A), (IV-B), and (IV-C), with compounds of formulas (IV-A), (IV-BB), and (IV-CC) being more preferred:

[0090]

[0091]

[0092] The most preferred compounds are those of formula (IV-Cs).

[0093]

[0094] Therefore, in another aspect, the present invention also relates to a method for preparing compounds of formula (III),

[0095]

[0096] The method includes the following steps:

[0097] a) Prepare compound (I) by the method detailed above;

[0098]

[0099] Any of them with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and

[0100] Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z or E configuration when it is attached to a carbon-carbon double bond;

[0101] b) The compound of formula (I) is partially hydrogenated using a hydrogenating agent suitable for partial hydrogenation to produce the compound of formula (III).

[0102] The hydrogenating agent used in step b) is one that hydrogenates only the carbon-carbon double bond in the ring of formula (I). Sodium / ethanol is particularly suitable as a hydrogenating agent, such as Schudel, Mayer, and Isler. Helv. Chim. Acta 46, 2517-2526 (1963), especially the last paragraph on page 2524.

[0103] Therefore, in another aspect, the present invention also relates to a method for preparing a compound of formula (IV),

[0104]

[0105] The method includes the following steps:

[0106] a) Prepare compound (I) by the method detailed above;

[0107]

[0108] Any of them with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and

[0109] Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z or E configuration when connected to a carbon-carbon double bond;

[0110] b') Hydrogenation of compound (I) with the aid of a hydrogenating agent produces compound (IV).

[0111] The hydrating agent used in step b') is one that can hydrogenate all the carbon-carbon double bonds in the ring of formula (I). Hydrogen gas in the presence of group 7, 8, 9 or 10 transition metals is particularly suitable as a hydrating agent, especially selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co and Ni, more preferably Pd.

[0112] The heterogeneous transition metal catalyst is preferably a heterogeneous supported transition metal catalyst.

[0113] In this embodiment, the transition metal is supported on a carrier; that is, palladium is attached to / or deposited on the carrier. The carrier is a solid material.

[0114] The support is preferably carbon or an inorganic support. Preferred inorganic supports are oxides or carbonates. Preferred oxides are oxides of Si, Al, Ce, Ti, or Zr, particularly oxides of Al or Si. Particularly preferred are silicon dioxide, aluminum oxide, titanium dioxide, and cerium oxide.

[0115] If the support is Ce, the preferred oxide is CeO2. Preferably, the oxides of Al are Al2O3 and AlO(OH). Al2O3 is particularly preferred.

[0116] Hydrogenation is preferably carried out under pressure, particularly at a hydrogen pressure of 2-20 bar. More preferably, hydrogenation is carried out at a temperature of 0°C to 100°C.

[0117] Compositions containing the compound of formula (II) and the basic catalyst itself are also an object of this invention.

[0118] Therefore, in another aspect, the present invention relates to a composition comprising:

[0119] i) Compound of formula (II)

[0120]

[0121] in

[0122] n = 0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12;

[0123] R 1 Indicates hydrogen or methyl;

[0124] R 3 and R 4

[0125] Either they represent hydrogen, methyl, or methoxy groups independently of each other.

[0126] They either collectively represent -CH-CH-CH- and form aromatic groups;

[0127] Any with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and

[0128] Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z or E configuration when it is attached to a carbon-carbon double bond;

[0129] and

[0130] ii) Alkaline catalyst;

[0131] The basic catalyst is characterized in that the molar ratio of the alkaline catalyst to the compound of formula (II) is 1:1,000 to 1:5, particularly 1:100 to 1:10.

[0132] The compound of formula (II) and the basic catalyst, and their preferred embodiments, have been discussed in detail above with respect to the method.

[0133] In this invention, it was found that a catalytic amount of alkali can be used for effective closure in the above-mentioned closure step.

[0134] Therefore, in another aspect, the present invention relates to the catalytic use of a base in the ring-closing reaction of a compound of formula (II) to produce a compound of formula (I).

[0135]

[0136] in

[0137] n = 0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12;

[0138] R 1 Indicates hydrogen or methyl

[0139] R 3 and R 4

[0140] Either they represent hydrogen, methyl, or methoxy groups independently of each other.

[0141] They either collectively represent -CH-CH-CH-CH- and form aromatic groups;

[0142] Any with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and

[0143] Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z or E configuration when connected to a carbon-carbon double bond.

[0144] The method has been discussed in detail above, including the compound of formula (II), the base catalyst, the ring-closing step, and their preferred embodiments.

[0145] Further investigation revealed that compounds of formula (IA), (IC), (III-A), (III-C), (IV-A), or (IV-C) possess antioxidant properties.

[0146] Therefore, in another aspect, the present invention relates to the use of compounds of formula (IA) or (IC) or (III-A) or (III-C) or (IV-A) or (IV-C) as antioxidants.

[0147]

[0148]

[0149] in

[0150] R 1 It indicates hydrogen or methyl.

[0151] Compounds of formula (IA) or (IC) or (III-A) or (III-C) or (IV-A) or (IV-C) and their preferred embodiments have been discussed above in detail with respect to the method.

[0152] Several compounds disclosed herein are novel. They are not only novel but also inventive because they are suitable for the disclosed methods and uses.

[0153] Therefore, in another aspect, the present invention particularly relates to compounds of formula (I-As), (I-Cis), (III-Cis), or (IV-Cs).

[0154]

[0155] And among them

[0156] R 1 Indicates hydrogen or methyl;

[0157] Any with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and

[0158] Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z or E configuration when connected to a carbon-carbon double bond.

[0159] Example

[0160] The following experiments further illustrate the invention.

[0161] Formation of (E)-2-(4,8-dimethylnon-3,7-dien-1-yl)-2,5,7,8-tetramethyl-2H-chromen-6-ol

[0162] 2.0 g (4.74 mmol) of 4-hydroxy-2,3,6-trimethyl-5-((6E)-3,7,11-trimethyldodec-2,6,10-trien-1-yl)phenylacetate was mixed with 50 mL of diethyl ether and cooled to 5 °C. Lithium aluminum hydride (2 M, in THF) (2.96 mL, 5.92 mmol) was then added, and the reaction was carried out at 0–24 °C for 3.5 hours. The reaction was then stopped by adding 40 mL of 4 N HCl. The organic phase was washed once with 40 mL of brine and 0.2 g of sodium dithionite, and then dried over MgSO4. After filtration and evaporation, 2,3,5-trimethyl-6-((6E)-3,7,11-trimethyldodec-2,6,10-trien-1-yl)phenyl-1,4-diol was isolated in 85% yield.

[0163] 2,3,5-Trimethyl-6-((6E)-3,7,11-trimethyldodec-2,6,10-trien-1-yl)phenyl-1,4-diol was dissolved in diethyl ether (7.5 mL), and 1.5 equivalents of silver oxide and 46 μL of acetic acid were added. The mixture was stirred at room temperature for 2 hours. After purification by filtration and chromatography (neutral silica gel), 2,3,5-trimethyl-6-((6E)-3,7,11-trimethyldodec-2,6,10-trien-1-yl)cyclohexane-2,5-dien-1,4-dione was isolated in 88% yield.

[0164] 2,3,5-trimethyl-6-((6E)-3,7,11-trimethyldodec-2,6,10-trien-1-yl)cyclohexyl-2,5-dien-1,4-dione (1.27 g (3.29 mmol)) and 18 ml of toluene and 0.15 ml (0.988 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU) were added and stirred under reflux (110°C) for 20 hours to produce (E)-2-(4,8-dimethylnon-3,7-dien-1-yl)-2,5,7,8-tetramethyl-2H-chromen-6-ol in 86.5% yield.

[0165] Experiment Series 1

[0166] Geraniylgeraniyltrimethylbenzenequinone (97% purity) (0.5 g (1.183 mmol)) and 6 ml of toluene, along with the corresponding amounts of alkaline catalyst given in Table 1, were added. The mixture was stirred under reflux (110°C) for the reaction times shown in Table 1 to give 2,5,7,8-tetramethyl-2-(4,8,12-trimethyldecadec-3,7,11-trien-1-yl)-2H-chromen-6-ol (3,4-dehydro-α-tocotrienol). The conversion and yield are shown in Table 1.

[0167]

[0168] Table 1. Different alkaline catalysts

[0169] 1 DMAP = 4-(dimethylamino)pyridine; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; TEA = triethanolamine

[0170] 2 H. Ripin; DA Evans (2002). "PKA's of Nitrogen Acids".

[0171] https: / / organicchemistrydata.org / hansreich / resources / pka / pka_data / evans_pKa_table.pdf

[0172] 3 https: / / www.aatbio.com / data-sets / pka-and-pkb-reference-table

[0173] 4 na = Not applicable

[0174] The results in Table 1 show that all bases used at catalytically high amounts can form the desired product, 3,4-dehydro-α-tocotrienol. Most examples demonstrate that very high conversions and yields exceeding 94% can be obtained. Furthermore, Examples 7, 8, and 9 in Table 1 show that their conjugate acid has a pK... a Certain basic catalysts with concentrations below 8.6 result in lower conversion and yield. Experiments also show that pyridine conversion is particularly low at certain catalytic concentrations. A comparison of Examples 2 and 3 demonstrates that extremely high conversion and yield can still be achieved despite a tenfold reduction in catalyst concentration.

[0175] Partial hydrogenation

[0176] According to Schudel, Mayer, Isler Helv. Chim. ActaThe process disclosed in the last paragraph on page 2524 of 46, 2517-2526 (1963) quantitatively hydrogenates the 3,4-dehydro-α-tocotrienol (=2,5,7,8-tetramethyl-2-(4,8,12-trimethyldecacarbon-3,7,11-trien-1-yl)-2H-chromen-6-ol) prepared above to α-tocotrienol (=2,5,7,8-tetramethyl-2-(4,8,12-trimethyldecacarbon-3,7,11-trien-1-yl)chromen-6-ol), the characteristics of which can be verified by nuclear magnetic resonance.

[0177] Fully hydrogenated

[0178] According to Kabbe and Heitzer, Synthesis The last paragraph on page 888 of 1978; 12, 888-889 quantitatively hydrogenates the 3,4-dehydro-α-tocotrienol (=2,5,7,8-tetramethyl-2-(4,8,12-trimethyldecacarbon-3,7,11-trien-1-yl)-2H-chromen-6-ol) prepared above to α-tocopherol (=2,5,7,8-tetramethyl-2-(4,8,12-trimethyldecaalkyl)-chromen-6-ol), the characteristics of which can be verified by nuclear magnetic resonance.

[0179] Experiment Series 2

[0180] In another series, 0.46 g (1.098 mmol) of geranylgeranyltribenzylquinone (97% purity) and the amounts of toluene shown in Table 2, along with 5.49 μmol DBU (1 / 200), were added and stirred under reflux (110°C) for 24 hours to give 2,5,7,8-tetramethyl-2-(4,8,12-trimethyldecadec-3,7,11-trien-1-yl)-2H-chromen-6-ol (3,4-dehydro-α-tocotrienol), with conversions and yields shown in Table 2.

[0181]

[0182] Experiment Series 3

[0183] In another series, 0.46 g (1.098 mmol) of gerany-gerany-gerany-geranytrimethylbenzoquinone (97% purity) and 6 ml of toluene and 4.7 mg of ground solid NaOH (0.1098 mmol, 10 mol% (relative to gerany-gerany-geranytrimethylbenzoquinone)) were added in the presence of 3.5 mg tetrabutylammonium bromide (1 mol% relative to gerany-gerany-geranytrimethylbenzoquinone), and the mixture was stirred under reflux (110°C) for the reaction times shown in Table 2, producing 2,5,7,8-tetramethyl-2-(4,8,12-trimethyldecacarbon-3,7,11-trien-1-yl)-2H-chromen-6-ol (3,4-dehydro-α-tocotrienol), with conversions and yields shown in Table 3.

[0184]

Claims

1. A method for preparing compounds of formula (I), The method includes a ring-closing step of compound (II) in the presence of a basic catalyst to produce compound (I). in n = 0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12; R 1 Indicates hydrogen or methyl; R 3 and R 4 Either they represent hydrogen, methyl, or methoxy groups independently of each other. They either collectively represent -CH-CH-CH-CH- and form aromatic groups; Any with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and Any wavy line represents a carbon-carbon bond independently of each other, and when connected to a carbon-carbon double bond, it is in either the Z or E configuration. Its features are, The molar ratio of the alkaline catalyst to the compound of formula (II) is 1:1,000 to 1:5; and The pK of the conjugate acid of the alkaline catalyst measured in water. a The value is between 8.6 and 15.

7.

2. The method according to claim 1, characterized in that, The molar ratio of the alkaline catalyst to the compound of formula (II) is 1:100 to 1:

10.

3. The method according to claim 1, characterized in that, The pK of the conjugate acid of the alkaline catalyst measured in water. a The value is between 9 and 15.

7.

4. The method according to claim 1, characterized in that... R 1 = R 3 = R 4 = CH3.

5. The method according to any one of claims 1 to 4, characterized in that, The alkaline catalyst is either an organic amine, a metal hydroxide, or a carbonate.

6. The method according to any one of claims 1 to 4, characterized in that, The alkaline catalyst is an organic tertiary amine or an alkali metal hydroxide.

7. The method according to any one of claims 1 to 4, characterized in that, The alkaline catalyst is selected from 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1-diazabicyclo[2.2.2]octane (quinine ring), and cytisine.

8. The method according to any one of claims 1 to 4, characterized in that, The alkaline catalyst is selected from 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU) and 1-azabicyclo[2.2.2]octane (=quinine ring).

9. The method according to any one of claims 1 to 4, characterized in that, Compound (I) is a compound of formula (I-BB), and compound (II) is a compound of formula (II-BB).

10. The method according to any one of claims 1 to 4, characterized in that, The ring-closing step is carried out in a hydrocarbon solvent.

11. The method according to any one of claims 1 to 4, characterized in that, The ring-closing step is carried out in toluene.

12. A method for preparing compounds of formula (III), The method includes the following steps: a) Prepare the compound of formula (I) according to the method of any one of claims 1-11. Any of them with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z or E configuration when connected to a carbon-carbon double bond; b) By using a hydrogenating agent suitable for partial hydrogenation, the compound of formula (I) is partially hydrogenated to produce the compound of formula (III).

13. A method for preparing compounds of formula (IV), The method includes the following steps: a) Prepare the compound of formula (I) according to the method of any one of claims 1-11. Any of them with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z or E configuration when connected to a carbon-carbon double bond; b') Hydrogenation of compound (I) with the aid of a hydrogenating agent produces compound (IV).

14. A composition comprising: i) Compound of formula (II) in n = 0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12; R 1 Indicates hydrogen or methyl; R 3 and R 4 Either they represent hydrogen, methyl, or methoxy groups independently of each other. They either collectively represent -CH-CH-CH-CH- and form aromatic groups; Any with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as carbon-carbon single bonds or carbon-carbon double bonds. as well as Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z or E configuration when connected to a carbon-carbon double bond; and ii) Alkaline catalyst; Characterized by the fact that the molar ratio of the alkaline catalyst to the compound of formula (II) is 1:1000 to 1:5; and the pK of the conjugate acid of the alkaline catalyst measured in water. a The value is between 8.5 and 15.

7.

15. The composition according to claim 14, characterized in that, The molar ratio of the alkaline catalyst to the compound of formula (II) is 1:100 to 1:

10.

16. The composition according to claim 14, characterized in that, The pK of the conjugate acid of the alkaline catalyst measured in water. a The value is between 9 and 15.

7.

17. The composition according to claim 14, characterized in that, Compound (II) is a compound of formula (II-BB).

18. The catalytic use of bases in the ring-closing reaction of compounds of formula (II) to produce compounds of formula (I), in n = 0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12; R 1 Indicates hydrogen or methyl; R 3 and R 4 Either they represent hydrogen, methyl, or methoxy groups independently of each other. They either collectively represent -CH-CH-CH-CH- and form aromatic groups; Any with dashed lines ( The bonds in the carbon-carbon bonds can be represented independently as either carbon-carbon single bonds or carbon-carbon double bonds; and Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z or E configuration when connected to a carbon-carbon double bond; Its features The pK of the conjugate acid of the base measured in water. a The value is between 8.6 and 15.7, and The molar ratio of the base to the compound of formula (II) is from 1:1000 to 1:

5.

19. The use according to claim 18, characterized in that, The molar ratio of the alkaline catalyst to the compound of formula (II) is 1:100 to 1:

10.

20. The use according to claim 18, characterized in that, The pK of the conjugate acid of the alkaline catalyst measured in water. a The value is between 9 and 15.7.

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