JPS591477A - Preparation of tocopherol and ubiquinone, intermediate product of said method and application thereof - Google Patents

Abstract

PURPOSE:To obtain ubiquinone or convert the ubiquinone into vitamin E, etc. in the presence of an acidic catalyst, by separating the metallic carbonyl part from a reaction product of a carbonyl-alkenylcarbene-metallic complex with an enyme, and oxidizing the resultant comound. CONSTITUTION:A carbonyl-alkenylcarbene-metallic complex having substituent groups R1 and R2 linked to the alkenyl group and an ether type substituent group R3 (R1 is CH3 or OCH3; R2 is H, CH3 or OCH3; R3 is CH3, C2H5, SiR3, etc.), e.g. the compound of formula I , is reacted with a compound of formula II (R4 is H or CH3; R5 is [(CH2)3CHCH3]3CH3, etc.) to give a compound of formula III, etc., and the metallic carbonyl part is then separated therefrom to afford a compound of formula IV, etc. The resultant compound of formula IV, etc. is then oxidized to give ubiquinone, which is if necessary converted into tocopherol or vitamin E in the presence of an acidic catalyst. The compounds of formulas IIIand IV are novel substances.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing tocopherol and ubiquinone,
Concerning intermediate products of this method and their applications.

Tocopherol s ”h K d,!-α tocopherol p
The entire industrial synthesis of vitamin E is based on P.

Research published by P. Karrer in 1938-1940 (e.g., P. Karrer, H.
Fritzsohe.

B. H. Ringar, H. 8alomon, I
Helv. Ohim. Aota21, 520 (193E
Dating back to 1), the method is based on the condensation of trimethylhydroquinone with dinitol or iso-7itol.

For this purpose, acidic condensing agents such as formic acid, dinitrite chloride or boron trisulfide etherate are required (German Patent No. 7 13,7 49, 1939;
1,972, 1958) Instead of trimethylhydroquinone, trimethylbenzoquinone can also be used in the presence of steel/zinc powder and formic acid (M, Kaj
iwara.

D, 8akamoto, 8.0hta, Hat
arooyolas 14.

1995 (1980)).

A basic condensing agent such as pyrrolidine is used in the reaction of -12-acetyl-5,5,6-trimethylhydroquinone with 7'arnesylacetone, and the product is transferred to the next reduction and hydrogenation step. Similarly, it becomes d, r-) conerol (H, J, Kabbe, H.

Haitzer, 8ynthesia 1978
, 888).

Instead of phytol or inphytol, 3.7. I
L15-Tetramethyl-1,5-hexadecanediol can also be condensed with trimethylhydroquinone in the presence of acidic catalysts (zncl!2, BF, -0Et2) (L, Blaha, J, HOdrOVa).

J, Weiahat, 0ollaation 0
zachosloo, Oham.

Oommun, 24, 2023 (1959);
M, Matsui, S, Kitamura,
l Agr, Biol, Ohem.

(Tokyo) 2 9 p 9 7 8 (
1965) ).

The production of trimethylhydroquinone, which is used almost exclusively as starting product, involves a series of reaction steps (6,5-dimethylphenol or 1,2,4-)limethylbenzene (
starting from pseudocumen) is necessary. The total yield known from the literature is below 50%.

A relatively successful four-step synthesis of trimethylhydroquinone with an overall yield of 60% from 4-methoxy-3-buten-1-yne in addition to sulfanilic acid as the starting product in 60 to 70% yield. 4-methoxy-3- obtained with
Requires buten-2-one.

Conventional methods cannot be transformed into natural vitamin E production. The synthesis of naturally occurring d-α-tocopherol is possible only via a 2R-configuration prechroman monomer (e.g. 2-formyl chroman), which is difficult to carry out at home; Join the chains (H, Mayar-P, 5ohudal, IR, R
uegglo, Ialer.

Halv, Ohim, Aota 4 6. 6 5
0. 9 6 5 (+965);N, 0ohen
, R, J le opresti, G%3auoy,
JJ+-Amer.

0hern, Boc,, 1 0 1, 6
7 I O (1979); Barnard, R.
M, I3ohmid, Halv, Ohim
, Aota 6 2゜2584 (1979))
.

Therefore, it can be carried out in a flexible manner, avoiding the relatively difficult to convert hydroquinone enzyme derivatives, to produce the desired tocopherols and even vitamin G or ubiquinone. You will need a way to do this. In this case, it must also be possible to generate systems with OH- or ester groups in the side chains. More detailed aspects of this subject will become clear from the following explanation.

This controversial issue can be resolved by the method mentioned at the beginning, which is based on the substituents R1 and R2 attached to the alkenyl group and the ether type substituent R.
3; R2=H.

5' 1 3%O
H, OOH, and R, = OH6,0□H5, OOH
A carbonyl-alknylcarbene-gold N complex having the formula (2), 5iR3 or 5iR3, where R is alkyl, aryl or alkylaryl, is represented by formula (2), 5 where R4=H, OH5; R5 =((OH2)50
HOH, ]50H3, CCaa2)2aH= 0), 0
Means H2X, X=H, 0H1CjH.

000R6, where R6 is lower alkyl, is reacted with enyne, then the metal carbonyl moiety is separated from the generated reaction product (3), and the metal-free product (4) ) to ubiquinone (7) R, or metal-free raw material -(
4) In the presence of an acidic catalyst, the rare tocopherol or vitamin g1c H of the formula B - Kfl groups R1, B2, R2H and B5 C, the above I16
It is characterized by having the meaning of .

As a carbonyl-alkenylcarbene-metal complex,
Preference is given to the complexes of the sixth subgroup, with particular preference being given to chromium-carbonyl enzyme conductors. Within the scope of the present invention, compounds which can be designated as particularly high-yielding are pentacarbonyl-chromium complexes of the formula r'
1 where [residues R1, R2 and town are listed above or generally in chromium carbonyl derivatives, 111i!
or a plurality of carbonyl groups, as is known from the carbene chemistry of chromium carbonyls, for example, preferably hydrogen atoms are partially or completely replaced by lower alkyl groups [9
can be replaced by other donor ligands, such as phosphine residues, amine residues, etc. Similarly 1
The carbonyl group is replaced by an aromatic ligand such as benzene, cyclopentadienyl, etc.

Carbene complexes can be obtained by methods known per se, for example the synthesis of pentacarbonyl-chromium-carbene complexes is proposed. It can be prepared in a yield of 70 to 80% from commercially available hexacarbonylchromium and 1-lithioalkune and electrophilic alkylating agents (oxonium salts, dialkyl sulfates, trialkylhalogensilanes, acyl compounds@). can. This synthesis is carried out stereoregularly with respect to the 0=O-21 bond. 1-Lithioalkenes are readily obtained from 1-halogenalkenes and lithium or lithium-alkyl compounds (F, G, Borjwall
, Ph, 8. Landia, J., Amar, Ohem,
8oc, 79, 1595 (1957), “D
, 5eabaoh, H., Neumann, Ohem
, Bar, 107.

847 (1974)).

2-lithio-1,2-dimethoxyethylene is, for example,
O, N, 8kold, 8ynth, Oommun,
197 #.

from glyoxal by 119, or similar lcR,
R, 8ohmidt1B, 8ahinid, Tet
◎ Carbene complex of metal of subgroup 6 obtained by Kanosu conversion of dimethoxyethylene according to R, Tett, 1977゜5585, and % chromium carbonyl-carbene chemical t'z, &s scum (e.g. nitrogen, argon, etc.) The complexes presented here are generally red in color and their melting points are below the OC.

The preparation of the indicated alkynes, obtained for example from prenyl bromide and the corresponding alkynyl-Grinard reagents, is described in European Patent No. 0. Of No. 5,456 (
Application No. 0010822.8).

The course of the process according to the invention is illustrated, for example, in the reaction scheme below, in which a pentacarbonyl carbonyl fermentation derivative is cited as the metal carbene complex.

The reaction of compounds (1) and (2) in the reaction scheme below is suitably carried out in a donor solvent such as a dialkyl ether, THF and the like.

The reaction temperature is preferably 20 to 60C.

The reaction is conveniently carried out under protective gas.

The separation of metal carbonyl residues can be carried out over a wide temperature range and GO pressure range, for example in the separation of chromium carbonyl residues, from ambient temperature to about 800 bar at pressures of 40 to 200 bar.

The yield values presented in the reaction scheme above are not optimized. Additionally, some of the partially listed reactants, such as boron tribromide and zinc chloride, are not exclusive to the starting compounds chosen, provided that alternatives are suitable. . The same naturally applies for the separation of metal carbonyl residues in the presence of -carbon oxide, which can also be carried out under other conditions.

The reaction between cardinyl-alkenylcarhene-gold 14H body (1) and alkyn-ene (2) is preferably carried out using a protective gas,
For example, argon, jfii! It is performed in the presence of elements such as elements.

Ring closure to hydroquinone occurs in a domain regular manner in 1-alkynes. The large alkyne 11 substituent is in the 1-position relative to the hydroquinone-○H group.

2-Alkynes react stereoselectively, the relatively long side chains appearing predominantly adjacent to the hydroquinone-〇H group (isomer ratio approximately 2-3=1).

and doruquinone ligands are liberated in the presence of donor ligands (L=00, amines such as phosphine, pyridine, polyvinylpyridine, aromatics). The starting compound again via the ion compound,
For example, it becomes hexacarbonylchromium and is therefore recycled and used for the preparation of carbene complexes. (Scheme 2% Formula %) (Recovery of Donor Ligand, e.g. Polyvinylpyridine) The stereogenic form of hydroquinone heptanoether can be prepared as known per se by acidic catalysis, e.g. Lewis rIR (B Br, , 1101., etc.). It becomes tocopherol by this method. This reaction reacts with chlorinated hydrocarbons, e.g. 0HOI!
,,0H20/2 etc. (will be implemented)
e.g. temperatures between 0 and sac).

By oxidation (e.g. by silver oxide (1)), European%
It is described in Patent Specification No. 0015 456.

The oxidation can also be carried out in a manner known per se, for example by 9 gas.

Scheme 3 %Formula % From the reaction scheme 2 presented above, the separation of the metal carbonyl moieties from the reaction products is preferably carried out by means of pressurized carbon monoxide, with the excess carbonyls conveniently formed being It is clear that it is recycled again to form the carbonyl-alkenylcarbene-gold Jts complex C1)w.

Reaction generation? ! The oxidation of +(4) (scheme 3) is carried out with mild oxidizing agents, such as silver oxide, in which case the desired ubiquinone is obtained. Ko(')Ma
In the reaction, R1 = R2 = 0OH3 and R4 = H or (3H, ? means It can be obtained by changing K to 5, which is tIL.

The metal-free reaction product (4), which generally exists as an isomeric mixture (see compounds 4a and 4b in Scheme 1 above), produces a deetherified intermediate that is then hydrohalogenated. Via compound (5), the deposited tocopherol or vitamin E is generated. Deetherification is preferably carried out with boron tribromide, but by adding this compound, deetherification can be simultaneously performed with hydrogenation. This is because the reaction of the ether is reliably carried out quantitatively.By adding Km excess of this reagent or by cooling other Lewis acids, such as zinc halide, the intermediate compound (5)'a' ) It can be converted into coferol or vitamin g.

An advantage of 9 is that the reaction of compound (4) to (d) can be carried out in one reactor.

The scope of the present invention includes formulas (3) and (4) shown here.
] are involved as encompassed by -g. The invention therefore provides that the metal can be chromium, molybdenum or tungsten, with the formula (
3) tricarbonyl (hydroquinone monoether)-
The present invention relates to the metal-free conductor of formula (4), preferably containing chromium in the Kanasu complexes and in the above-mentioned compounds.The invention therefore relates to tricarbonyl [hydroquinone monoethers of formula (3)]. Cochromium complex, H R5 where R4, R2, R5, R4 and R5 shall have the meanings given above.

The present invention further relates to hydroquinone-monoether compounds of formula (4), ie OR3 and R4, R2, R3, R4 and R5 shall have the meanings indicated.

Finally, it is within the scope of the present invention to use the compounds of formulas (3) and (4) as described above for the production of ubiquinone, tocopherol and %vitaz7ic.

By using the process according to the invention or the new intermediate products according to the invention, the desired types of ubiquinone and tocopherol can be obtained in a simple manner within the framework of a single synthesis. The method is distinguished by high reaction yields, and is additionally free from the use of trisubstituted hydroquinone derivatives, which require a series of reaction steps and result in poor overall yields. It is. Finally, by repeating step a,
Thus, by reusing the metal carbonyl during the production of the starting compound (1), the process is carried out very efficiently. Its advantages are also clear from the reaction scheme presented.

The course of the method according to the invention will become clearer from the following embodiments.

Embodiment 3. To 6.6 J/(30 mmol) of hexacarbonylchromium in oow of tetrahydrofuran (or diethyl ether) is added 40 C in the presence of a protective gas.
An equimolar amount of an ethereal solution of Z-2-lithio-2-alkene, cooled to -500, is added thereto. that time,
The color changes to yellow-orange. After keeping it at -40C for 1 hour,
Remove solvent. The residue was suspended in 50 d of water and 200 d
Pour the pentane from d onto it and add 6 more 4.5# trimethyloxonium tetrafluoroborate, the color immediately changes to deep red. The pentane phase is dried over sodium sulfate and evaporated. Upon cooling, red crystals are obtained.

The 7 sil metallides are also liberated as tetraalkylammonium salts and alkylated with triethyloxonium tetrafluoroborate, acyl halides (acetyl ffl, benzoyl chloride) or trimethylsilyl chloride in homogeneous phase in methylene chloride.

H,0 0,4H1,0rNO6 molecular weight 549.5 Analysis value calculation: 0 48.14 H5,48Or 14.8
9 N4.01 actual measurement: 4B, 00 5.55
14.76 5.97rR (OH201!2):
2055 ta, 1903 vs'H-NMR (acetone-D6): 4.57Cqq+1)
, 3.480112), 1.65 ((1,3), 1.
52 (s, 5)014H7, OrMO6 molecular weight 549
．． 5 Analysis value calculation: 048.14 N5.48 Or 14.
89 N4.01 guess: 47.96 5.31
14.82 4.10 engineering R (CH20I!2):
2050 ml, 1 9 57 ah, 1 9
08 sh.

1896 va' H-NMR (acetone-D6): 5.92
(qqe l) 5.48 (s, 12), 1.69
Cei, 5), 1.50 CB, 5) OHOrO molecular weight 290.2 1110 6 N8: m/e 290.262.234.206.1
78.150 (100%) Engineering R (hexane): 2064 m11960 g
, 1949 vs'H-NMR (acetone-D6J
: 5.7!5 (QQI I) 4.67 (a, 3
), 1-86 (ei q , 5 ), L85 (br
, 3) OHOrO molecular weight 290.2 1104 M8 e Of / l! 1 290.262.234
．． 206.178.150 (100%) XR (hexane): 2065m, 1965 a,
1949 va'H-NMR (acetone-06):
5.17 (qQIIJ4.52 (m, 5), 1.9
3 (dq, 5), L55 (dq, 5) 0, 5H,
60r06131 Molecule 548.3M8:ID
/6 54B, 520.292.264.236.20
B (100%) 'H-NMR (acetone-D,): 7.13 (
qQI 1), 1.90 (dq, ri, 1.57 (d
Q, 5J, 0.07 (a, 9) H, 0 0,, H160r0681 Molecular weight 34 B, 5MS
m ml / 548.520.292.264.
266.20B (100%) 'u-Nul Acetone-D6): 4.8M (q
QI 1), 2.05 (dq, 5), 1.93 (d
qj), 0.46 (1,9)0, . H80r06
Molecular weight 276.2M8: m/a 276.248
．． 220.192.164.136 (100%) IR (hexane): 2068 m, 1967
g, 1951 vs Example:) Licarbonyl (4
-Methoxy-5(21゜5,d-)dimethyl-2(3)
・Phytyl-phenol) chromium 00H6 154 dissolved in t-butyl methyl ether 1,16
1 (4 mmol) of pentacarbonyl (IC-2
-bunanyl-methoxycarben) chromium at 55C
6.10°14.1 of 6 m (4.4 m mol)
Add 8-tetramethyl-5-nonadecen-2-yne (methyl-phytyl-acetylene) drop by drop. After 1 hour, the heating medium is removed and the residue is chromatographed on silica gel. The yellow zone is eluted in each case with methylene chloride/pentane and then with ether. In the rapidly moving zone, 2-phytyl-complex (62% yield) or
Also, in the zone that gradually moves, 6-phytyl-isomer (
Yield: 27%). Overall yield was 89%.

OHOrO molecular weight 580.7 5525 M2S: m/e 5 8 0.4 9 6, 444
IR (hexane): 1960m, 1885va'H
-NMR (benzene-D6): 2-phytyl-complex (3a): 42z-(==O
H containing 124 (OOH,), 404 (1'-0H2),
2.04, t97c5A-OH,), 180(5-OH
15), 156 (5/-OH,), 12B (OH2, O
H), 1ll(OH,)3-phytyl complex (5b):
5.0? (=OH), 329 (00) 15 people 4?6 (
1'-0H2 people 187 (5,6-OH,), t69c5
-OH, ), t 57 (t27COH2 with 5'-OH
, OH), α89COH,) Nitricarbonyl (
4-methoxy-5t23,5-dimethyl-2(,3)
-phytyl-phenol)-10mH 052Hs o OrOs Molecular weight 566.7 Overall yield 80% MS: m/e 566.482.430 IR (hexane): 1961 m, 1885 vs Preparation of compound of type (4)) Example: Separation with Carbon Monoxide in the Presence of a Donor Ligand 501 Ll of 1 rm mol of hydroquinone monoether-complex in ether are heated to saC under 85 bar of carbon monoxide for 65 hours.

After reducing the pressure and cooling to -40C, hexacarbonylchromium precipitates. After filtration and removal of the solvent, a yellow-orange oil remains.

4-Methoxy-3[21,5,6-drimethyl-2(3
) -Phytyl-phenol (4) (yield 95%) k 0H3 0HO molecular weight 444.7 50 52 2 MS: m/e 445.452.41B'H-NM
R (chloroform-D): e.g. 2-phytyl compound
5.25 (=OH), 5.92 (OOH,), 3.
70 (+'-0H2), 2.45 (5,6-OH,
), 2.370.90 (OH,) 0H5 Ether separation and ring closure to chroman Example: aa! -Production of α-tocopherol (6) (
(through (5)) 10117 glue OOplum j, o 2+++
! 0,51 dissolved in chloroform of 51 at 1-800 in hydroquinone methyl ether compound of 1101
of boron tribromide. After gradually returning to room temperature, pour into water and extract with ether. Evaporation of the ether extract gave the 2-(6′-promo 5′, 7
', 11', + 5'-tetramethylhexadecyl)-5,5,6-drimethyl-1,4-benzohydroquinone (compound 5J was obtained, and heating the compound to 120 C (with anhydrous zinc chloride) resulted in a quantitative (1, l
! -α-tocopherol, which is identified by the identification sample.

The total yield was determined to be 96% by 'H-NMR spectroscopy.

Oxidation example to ubiquinone (7) = 5,6-simethoxy3-methyl-2-103
1 ta mol of 4,5°6-drimethoxy-2,3-methyl-phytyl-7enol, commonly known as IJ ether, is stirred with 2 mmol of silver(1) oxide and excess magnesium sulfate. Add 10 m of ether, filter, then evaporate the filtrate to ether/pentane:
100) KJ: When subjected to chromatography using silica gel, a yellow oil is obtained, but its 'H-NMR
The spectrum is identical to that of 5,6-simethoxy-3-methyl-2-phytyl-benzoquinone (53% yield).

Claims (1)

[Claims] t fmiRl and R2 attached to the alkenyl group and an ether type substituent R3, where R4=OH3,00H"
R=H10HOOH, and R,=OH,,5'
2 3'OHOOR or SiR
, and R is alkyl, aryl or alkylaryl, a carbonyl-alkenylcarbene-metal complex having the formula % 0H, 0OOR, and R6 is lower alkyl. Then, the metal carbonyl moiety is separated from the generated reaction product (5), and the generated metal-free product (4) is reacted with ubiquinone (
7) or in the presence of an acidic catalyst, the metal-free product (4) can be converted to the desired tocopheroid of formula (6) and tamin g7. M method for toco7epole and ubiquinone, in particular vitamin g, characterized in that the residues R,, R2, R4 and R5 have the meanings given above. 2. Process according to claim 1, characterized in that a chromium-carbonyl derivative is specified as the carbonyl-alkenylcarbene-metal complex. (5) Carbonyl-alknylcarbene-metal complex (1)
w, t'F, characterized in that the compound of formula (1) is specified as w, t'F Claim 1
Or the method according to paragraph 2. 4. Carbonyl-alkenylcarbene-metal complex (1
) with enyne is carried out under an atmosphere of protective gas. 5. Separation of the metal carbonyl moiety from the reaction product (6) is performed using pressurized carbon monoxide, and in some cases, the metal carbonyl moiety produced is further added to the production step of the carbonyl-alknylcarbene-metal complex (1). A method according to JjjK according to one or more of the claims. & A process according to the patent claims or further claims, characterized in that the oxidation of the reaction product (4) is carried out with silver oxide. Z Converting the reaction product (4) to the desired tocopherol or bitane compound (6) through the intermediate compound (5), which is deetherified by hydrohalogenation.
A method according to one or more of the preceding claims, where i+mold. 8. The reaction is tribromide! A method according to item 7 of the scope of the patent Hatake Seikama, characterized in that it is carried out in seven steps. 9. A process according to claim 7 or claim 8, characterized in that the deetherified intermediate compound (5) is converted into tocopherol or vitamin E (6) with zinc chloride. 1α of the reaction product (4) The process according to claim 1, 7, 8 or 9, characterized in that the conversion to cofluor or vitamin g is carried out in a single reactor process. A tricarbonyl-(hydroquinone monoether) monotetrame complex of H R3 \where R1, R2, R5, R4 and R5 have the meanings shown in claim #!1. 12. Hydroquinocymomonoether compound of formula (4), H R5 , R2, R6, R4 and R5 have the meanings shown in claim 1. 15 , the application of compounds of general formulas (3) and (4) to the production of ubiquinone, toco7erol and especially vitamin g.