JPH0339067B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a process for the production of tocopherols and in particular d-α-tocopherol, as well as intermediate products of the process and applications thereof. The industrial total synthesis of tocopherols, especially d,l-α-tocopherol (vitamin E), began in 1938-
P. Karrer's research published in 1940 (e.g.
P. Karrer, H. Fritzsche, BHRingier, H.
Salomon, Helv. Chim. Acta 21 , 520 (1938)) and the method is based on the condensation of trimethylhydroquinone with phytol or isophytol. For this purpose,
An acidic condensing agent such as formic acid, zinc chloride or boron trifluoride etherate is required (German Patent No. 713,749, 1939; German Patent No. 731,972, 1938). Instead of trimethylhydroquinone, trimethylbenzoquinone can also be used in the presence of copper/zinc powder and formic acid (M.KaJiwara, D.
Sakamoto, S. Ohta, Heterocycles 14 , 1995
(1980)). A basic condensing agent such as pyrrolidine is used in the reaction of 2-acetyl-3,5,6-trimethylhydroquinone with phalnesylacetone, and the product is similar in the subsequent reduction and hydrogenation steps. nid,
becomes l-tocopherol (HJKabbe, H.
Heitzer, synthesis 1978 , 888). instead of phytol or isophytol, 3.
7,11,15-tetramethyl-1,3-hexadecanediol is also suitable for acidic catalysts (ZnCl ₂ , BF ₃ .
In the presence of OEt ₂ ), it can be condensed to trimethylhydroquinone (L.Bla′ha, J.
Hodrov′a, J. Weichet, Collection Czechosloc.
Chem.Commun. 24 , 2023 (1959); M.Matsui, S.
Kitamura, Agr.Biol.Chem. (Tokyo) 29 , 978
(1965)). The production of trimethylhydroquinone, which is used almost exclusively as starting product, involves a series of reaction steps (3,5-dimethylphenol or 1,2,4-
(starting from trimethylbenzene (pseudocumene)) is required. The total yield known from the literature is below 30%. A relatively new four-step synthesis of trimethylhydroquinone with an overall yield of 60% to 70% from 4-methoxy-3-buten-1-yne in addition to sulfanilic acid as the starting product. 4-methoxy-3-buten-2-one obtained in Conventional methods cannot be transformed into natural vitamin E production. Naturally occurring d-α
The synthesis of -tocopherols is only possible via 2R-configured chroman precursors (e.g. 2-formyl chroman), which have hitherto been difficult to obtain, to which isoprene side chains are attached (H.
Mayer, P. Schudel, R. Ru¨egg, O. Isler, Helv.
Chim. Acta 46 , 650, 963 (1963); N. Cohen, R.J.
Lopresti, G. Saucy, J. Amer. Chem. Soc., 101 ,
6710 (1979); R. Barner, M. Schmid, Helv.
Chim. Acta 62 , 2384 (1979)). The invention is based on the problem of developing a process for producing tocopherols and in particular natural vitamin E that can be carried out in a flexible manner without using trialkylhydroquinones. In particular, the method must be able to synthesize natural d-alpha-tocopherol, which outperforms the racemic d,l-product by as much as 35% in biological activity. (vitamin testing method,
(3rd edition, Interscience, 1966). More detailed aspects of this problem will become clear from the description below. This problem is solved by developing a method as mentioned at the beginning, which requires substituents R ₁ and R ₂ on the alkenyl group and an ether-type substituent R ₃ , where R ₁ = CH ₃ , OCH ₃ ; R ₂ = H,
CH ₃ , OCH ₃ and R ₃ = CH ₃ , C ₂ H ₅ , COR or
_represents a carbonyl-alkenylcarbene-metal complex having the formula
(9), Here R ₄ = H, CH ₃ ; R ₅ =
[(CH ₂ ) ₃ CHCH ₃ ] ₃ CH ₃ ,

[Formula], where X=H, OH, COOR _{6 and} R ₆ = lower alkyl, is reacted with an alkynol, and then the metal carbonyl moiety is separated from the reaction product (10) formed. ,
Deetherification of the metal-free product (11)
It is characterized by cyclization to the desired tocopherol in the presence of an acidic catalyst. The metal atoms included in the carbonyl-alkenylcarbene-metal complexes (1) used according to the invention generally represent metals of subgroup 6, of which chromium is again particularly preferred. It is. A particularly favorable synthesis result is Eq. was obtained when specifying the compound. In this compound, one or more carbonyl groups are replaced by other ligands, such as phosphine ligands, amine ligands, in which the hydrogen atoms are generally re-alkylated or arylated, or, for example, benzene, cyclo By π-bonded aromatics such as pentadienyl,
Can be replaced. Such and other ligands are known from carbene chemistry. The reaction of the carbonyl-alkenylcarbene-metal complex with the alkynol is generally carried out in the presence of a protective gas. Examples of the protective gas include nitrogen and argon. As solvents, donor solvents such as dialkyl ethers,
THF etc. are preferably considered. The reaction is between 20 and
The reaction takes place at a high rate in a temperature range of 80°C. The raw material carbene complex (1) can be produced by a method known per se, which will be explained in more detail using a chromium pentacarbonyl complex. In the above case, one starts from commercially available hexacarbonylchromium and 1-lithioalkenes and electrophilic alkylating agents (e.g. oxonium salts, dialkyl sulfates, trialkylhalogensilanes, acyl compounds); )
can be obtained in yields of about 70 to 90%. The synthesis occurs stereoregularly around the C=C- double bond.
1-Lithioalkenes are prepared from 1-halogen alkenes and lithium or lithium-alkyl compounds (FG Bordwell, Ph.S. Landis, J.
Amer.Chem.Soc. 79 , 1593 (1957); D. Seebach,
H. Neumann, Chem. Ber. 107 , 847 (1974)). Carbene complexes of chromium generally exhibit red crystals, some with melting points below 0° C., and can be stored cold for long periods in the presence of protective gases (nitrogen, argon, etc.). Although the preparation of alkynols is carried out starting from alkyn-enes, the above-mentioned synthesis from prenyl bromide and alkynyl-Grinard reagents
European Patent Specification No. 0015436 (Hoff-man-La
Roche) (Publication No. 00 100 822.8). The alkyne-ene is a peracid, e.g. m
- oxidized by chloroperbenzoic acid to give an epoxy-alkyne, which is easily reduced, for example by _LiAlH4 , to the desired alkynol. The reaction of carbonyl-alkenylcarbene-metal complexes with alkynols takes place with almost quantitative yields, although the reaction products still contain metal carbonyl moieties. The reaction products represent pure enantiomers or racemic mixtures, regardless of the nature of the starting alkynol. If the alkynol is added in purely enantiomeric form, the product (10) is likewise formed in enantiomerically pure form. The reaction product (10) is the product (11)
is released from the metal carbonyl moiety.
Generally, the reaction is carried out using pressurized carbon monoxide in this case, but the metal carbonyl produced here can be returned to produce the raw material carbonyl-alkenylcarbene-metal complex (1).
This variant makes it possible to carry out the method particularly advantageously or rationally. A metal-free hydroquinone monoether product (11) is also obtained in near quantitative yield. This metal-free product (11) can be deetherified in various ways. It can be determined, for example, by the nature of the ether residue R ₃ and can be carried out using hydrolysis, hydrogenolysis or using Lewis acids.
When the ether type substituent is an acyl residue,
Removed by hydrolysis. R ₃ is e.g. SiR ₃
If (R ₃ =lower alkyl), this residue is removed by hydrogenolysis or, if R ₃ =lower alkyl, by boron tribromide. De-etherification is also carried out in high yields, for example in the range of 80-96%. The hydroquinone derivative (12) is then cyclized to the desired tocopherol, preferably with an acidic catalyst such as boron trifluoride-etherate, p-toluenesulfonic acid, formic acid, and the like. The process according to the invention is shown in the following reaction scheme 1, in which a pentacarbonylchromium-carbene complex is used as the metal carbene complex. However, the designation of this particular carbene is only for the purpose of understanding the process and is in no way intended to limit the process according to the invention. R ₁ = CH ₃ , OCH ₃ R ₂ = H, CH ₃ , OCH ₃ R ₃ = CH ₃ , C ₂ H ₃ , COR, SiR ₃ R = alkyl, aryl, alkylaryl R ₄ = H, CH ₃ X = H, OH, COOR ₆ R ₆ = lower alkyl The synthesis according to the invention is therefore of particular interest, since the reaction is carried out in a stereoisomerically selective manner;
This is because it allows the synthesis of natural d-α-tocopherol immediately. This should become clear from reaction scheme 2 shown below. It is worth noting that in Scheme 2 above, the inol reacts by conversion (ring closure to chroman) in the condensation step. Therefore,
Starting from 6S-ynol, the conversion in the condensation step allows a new way to obtain natural 2R-α-tocopherol (vitamin E). The enantiomer 6S- (or 6R-)inol is produced by stereoselectively alkylating a ketone with, for example, an axially symmetric metal alkyl compound (D. Seebach, Organometallic Compounds in Organic Synthesis, Wageningen Symposium, Netherlands, March 18/19, 1982). When the corresponding en-yne (2) is stereoselectively oxidized to (8), the enantiomer 6S- or 6R
-Inol can also be obtained. The present invention also includes intermediates between formulas (10) and (11), where (10) still includes a metal tricarbonyl moiety. Therefore, the present invention particularly relates to compounds of formula (10), includes. Similarly, hydroquinone monoether of formula (11) according to the invention, is included. Finally, according to the present invention, hydroquinone monoethers (11) and their metal tricarbonyl-substituted derivatives (10) for the production of tocopherols, especially vitamin E.
is also claimed. The invention will be further elucidated by the embodiments presented below, which should not be construed as limiting the invention. Embodiments Preparation of metal-carbene complexes (1), e.g. pentacarbonyl(E-2-alkenylcarbene)chromium-complexes (1) To 6.6 g (30 mmol) of hexacarbonylchromium in 300 ml of tetrahydrofuran (or diethyl ether), At −40° C., an ether solution of an equimolar amount of Z-2-lithio-2-alkene, cooled to −30° C., is added dropwise in the presence of a protective gas. In that case, the color changes to yellow-orange. After standing at -40°C for 1 hour, remove the solvent. The residue is suspended in 50 ml of water, 200 ml of pentane is poured over it and a further 4.5 g of trimethyloxonium tetrafluoroborate are added, the color immediately changing to deep red. Dry the pentane phase with sodium sulfate,
Evaporate. Upon cooling, red crystals are obtained. The acylated metal compounds are also liberated as tetraalkylammonium salts, in homogeneous phase in methylene chloride, triethyloxonium tetrafluoroborate, acyl halides (acetyl chloride,
benzoyl chloride) or trimethylsilyl chloride. C ₁₄ H ₁₉ CrNO ₆ molecular weight 349.3 Analysis value Calculated: C48.14 H5.48 Cr14.89 N4.01 Actual measurement: 48.00 5.56 14.76 3.97 IR (CH ₂ Cl ₂ ): 2033m, 1903 vs ¹ H-NMR (acetone-D ₆ ):4.37(qq,1),
3.48 (s, 12), 1.65 (d, 3), 1.52 (s, 3) C ₁₄ H ₁₉ CrNO ₆ molecular weight 349.3 Analysis value Calculated: C48.14 H5.48 Cr14.89 N4.01 Actual measurement: 47.96 5.31 14.82 4.10 IR (CH ₂ Cl ₂ ): 2030m, 1937sh, 1908sh, 1896vs ¹ H-NMR ( Acetone- _D6 ): 5.92 (qq, 1) 3.48
(s, 12), 1.69 (d, 3), 1.50 (s, 3) C ₁₁ H ₁₀ CrO ₆ Molecular weight 290.2 MS: m/e290, 262, 234, 206, 178, 150 (100
%) IR (hexane): 2064m, 1960s, 1949vs ¹ H-NMR (acetone-D ₆ ): 5.73 (qq, 1) 4.67
(s, 3), 1.86 (dq, 3), 1.83 (br, 3) C ₁₁ H ₁₀ CrO ₆ Molecular weight 290.2 MS: m/e290, 262, 234, 206, 178, 150 (100
%) IR (hexane): 2065m, 1963s, 1949vs ¹ H-NMR (acetone- _D6 ): 5.17 (qq, 1) 4.52
(s, 3), 1.93 (dq, 3), 1.55 (dq, 3) C ₁₃ H ₁₆ CrO ₆ Si Molecular weight 348.3 MS: m/e 348, 320, 292, 264, 236, 208 (100
%) ¹ H-NMR (acetone-D ₆ ): 7.13 (qq, 1),
1.90 (dq, 3), 1.57 (dq, 3), 0.07 (s, 9) C ₁₃ H ₁₆ CrO ₆ Si Molecular weight 348.3 MS: m/e 348, 320, 292, 264, 236, 208 (100
%) ¹ H-NMR (acetone-D ₆ ): 4.83 (qq, 1),
2.03 (dq, 3), 1.93 (dq, 3), 0.46 (s, 9) C ₁₀ H ₈ CrO ₆ Molecular weight 276.2 MS: m/e 276, 248, 220, 192, 164, 136 (100
%) IR (hexane): 2068m, 1967s, 1951vs Epoxidation of enine Example 5 Preparation of 6-epoxy-6,10,14,18-tetramethyl-2-nonadescine (8) 3.44 in 50 ml of methylene chloride 4.50 g of 6,10,14,18-tetramethyl-5-nonadecen-2-yne dissolved in 20 ml of methylene chloride are added dropwise to 1 g of 3-chloroperbenzoic acid (77% purity) at 0°C. . After stirring for 2 hours, it is filtered and the filtrate is washed with 10% sodium sulfite solution and 5% sodium bicarbonate solution and extracted with ether. The concentrated organic phase is chromatographed on silica gel. Using methylene chloride as eluent, 4.25 g of colorless oil are obtained (91% yield). C ₂₃ H ₄₂ O Molecular weight 334.6 MS: m/e 334, 319, 305, 281, 151, 137, 124 ¹ H-NMR (CDCl ₃ ): 2.87 (5-H), 2.34
(CH ₂ ), 1.75 (≡C-CH ₃ ), 1.40 (CH ₂ ), 1.23,
1.18 (CH ₂ , CH), 0.83 (CH ₃ ) ¹³ C-NMR (benzene-D ₆ ): 77.4, 75.0 (≡C
−); 61.1, 60.0

[Formula] Epoxide Reduction Example 6, Preparation of 10,14,18-tetramethyl-2-nonadecin-6-ol (9) To 0.45 g of lithium aluminum hydride suspended in 30 ml of ether was added 10 ml of lithium aluminum hydride. 2.04 g of 5,6-epoxy-6,10,14,18 dissolved in ether
-Tetramethyl-2-nonadesine is added. Heat under reflux for 4 hours, decompose excess lithium aluminum hydride with water while cooling with ice,
Acidify with 0.1 ml of sulfuric acid and extract with ether.
The concentrated ether extract is purified on silica gel using pentane/methylene chloride/ether. 1.78 g of colorless oil are obtained from the ether eluate (yield 87%). C ₂₃ H ₄₄ O Molecular weight 336.6 MS: m/e 336, 321, 307 IR: 3390 (OH) ¹ H-NMR (CDCl ₃ ): 3.53 (OH), 2.28 (CH ₂ ),
1.79 (≡C-CH ₃ ), 1.68 (CH ₂ ), 1.23, (CH ₂ ,
CH), 0.88 ( _CH3 ) tricarbonyl (hydroquinone monoether)
Chromium complex (10) Example: Tricarbonyl (4-methoxy-3(2),
5,6-trimethyl-2(3)-(3'-hydroxy-3',7',11',15'-tetramethyl-hexadecyl)phenol)-chromium dissolved in 20 ml of t-butyl methyl ether. 1.65 g of pentacarbonyl(E-2-butenyl-methoxy-carbene)-chromium and 2.10 g of 6,
10,14,18-tetramethyl-2-nonadecine-6
-heat to 50° C. for 2 hours. Remove the solvent and chromatograph on silica gel.
Methylene chloride is used to elute the yellow zone containing the tricarbonylchromium complex (yield 2.95
g, 87%). C ₃₃ H ₅₄ CrO ₆ Molecular weight 598.7 MS: m/e 598, 514, 462 IR (hexane): 3400 (OH), 1954s, 1881s,
1872s(CO) ^1H -NMR (benzene- _D6 ): 2-(3'-hydroxy-3',7',11',15'-tetramethyl-hexadecyl)-phenol complex 3.35 ( _OCH3 ), 2.50
( _CH2 ), 2.11, 2.07 ( _CH3 ), 1.53 ( _CH2 ), 1.27
(CH ₂ , CH), 0.90 (CH ₃ ) Hydroquinone monoether-ligand separation example: Separation in the presence of carbon monoxide 1 mmol of hydroquinone monoether complex dissolved in 50 ml of ether was heated at 100 bar. Heat to 70° C. for 8 hours under carbon oxide. After reducing the pressure, the solution is cooled to -40°C and separated from the precipitated hexacarbonylchromium. Concentrate the filtrate to leave a yellow oil. Example 4 - Methoxy-3(2),5,6-trimethyl-2
(3)-(3′-hydroxy-3′,7′,11′,15′-tetramethyl-hexadecyl)phenol (yield 95
%) C ₃₀ H ₅₄ O ₃ molecular weight 462.6 MS: m/e 462, 447 IR: 3390 (OH) ¹ H-NMR (benzene-D ₆ ): 3.29 (OCH ₃ ), 2.48
( _CH2 ), 2.16, 2.12 ( _CH3 ), 1.60 ( _CH2 ), 1.27
(CH ₂ , CH), 0.88 (CH ₃ ) Separation of ether and ring closure to chroman (step (12) to (6)) Example d, Preparation of l-α-tocopherol (6) In 10 ml of chloroform 1 mmol of hydroquinone monomethyl ether compound (11a, b) dissolved
0.5 dissolved in 3 ml of chloroform at −78°C.
Add ml of boron tribromide. Gradually warm to room temperature, pour into water and extract with ether. Evaporate the ether extract, add 20 ml of heptane and excess anhydrous zinc chloride and heat to 70° C. for 3 hours.
Purification on silica gel using pentane/ether gives d,l-α-tocopherol (87% yield).

Claims (1)

[Claims] 1 Formula (1) Here R ₁ = CH ₃ , OCH ₃ ; R ₂ = H, CH ₃ ,
OCH ₃ and R ₃ = CH ₃ , C ₂ H ₅ , COR or SiR ₃ , R is alkyl, aryl or alkylaryl, carbonyl-
The alkenylcarbene-chromium complex is expressed by formula (9) Here R ₄ = H, CH ₃ ; R ₅ = [(CH ₂ ) ₃ CHCH ₃ ]
₃ CH ₃ , [Formula], where X = H, OH, COOR ₆ and R ₆ = lower alkyl, is reacted with an alkynol, and then the reaction product shown by formula (10) is produced. thing (Here, R ₁ to R ₅ are the same as above) The metal carbonyl moiety is separated from the product to obtain a metal-free product represented by formula (11). (Here, R ₁ to R ₅ are the same as above.) This is then deetherified and cyclized to the desired tocopherol in the presence of an acidic catalyst.
Method for producing tocopherol. 2. Process according to claim 1, characterized in that the reaction of the carbonyl-alkenylcarbene-chromium complex (1) with the alkynol (9) is carried out in the presence of a protective gas. 3 Separation of the metal carbonyl moiety from the reaction product (10) is carried out using pressurized carbon monoxide and, in some cases, the metal carbonyl formed is separated from the reaction product (10). The method according to claim 1 or 2, characterized in that the method is returned to the step of producing. 4. Claims 1 to 4, characterized in that the deetherification of the metal-free product (11) is carried out by hydrolysis, hydrogenolysis or using Lewis acids. The method described in any one of Item 3. 5 Ring closure of the product obtained by deetherification of the metal-free product (11) to the desired tocopherol with boron trifluoride-etherate, p-toluenesulfonic acid or formic acid. A method according to any one of claims 1 to 4, characterized in that: 6 Alkynol (9) as 6S- and/or 6R-
2. A method according to claim 1, characterized in that it is used in the enantiomeric form of .