WO2012171652A1

WO2012171652A1 - Synthesis of vitamin e

Info

Publication number: WO2012171652A1
Application number: PCT/EP2012/002537
Authority: WO
Inventors: Georg Emil FRÀTER
Original assignee: Ximo Ag
Priority date: 2011-06-17
Filing date: 2012-06-15
Publication date: 2012-12-20

Abstract

The present invention relates to methods for synthesizing vitamin E, and to intermediates thereto.

Description

SYNTHESIS OF VITAMIN E

FIELD OF THE INVENTION

[0001] The present invention relates to methods for synthesizing vitamin E, and to intermediates thereto.

BACKGROUND OF THE INVENTION

[0002] Vitamin E, also known as alpha-tocopherol, is an important lipid-soluble antioxidant. Vitamin E has many biological functions. Although the antioxidant function is considered to be the most important function vitamin E is best known for, there are other functions that have also been recognized to be of importance. For example, alpha -tocopherol is known to have a regulatory effect on enzymatic activities and an effect on gene expression.

[0003] Vitamin E is found in certain food products as pure alpha-tocopherol, i.e., a single stereoisomeric form. In contrast, synthetically produced vitamin E is typically racemic alpha- tocopherol (a mixture of 8 stereoisomers) or contains a mixture of alpha- and beta-tocopherals. See Thomas Netscher " Synthesis of Vit.E" in Vitamins and Hormones Vol.76, 155-202 ( 2007). Accordingly, there remains a need to provide methods for preparing alpha-tocopherol as its single steroisomer as found in nature.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0004] Methods and intermediates of the present invention are useful for preparing vitamin E, referred to herein as compound 1, the structure of which is depicted below:

As is readily apparent, vitamin E, 1, has an absolute configuration of (R), (R), (R) at the 3 chiral centers. [0005] Provided methods are also useful for preparing racemic vitamin E (racemic tocopherol), depicted below:

or any of the 8 stereoisomers thereof.

[0006] In certain embodiments, a provided method is depicted in Scheme 1, set forth below: Scheme 1

[0007] In Scheme 1 above, R is a hydroxyl protecting group, X is a leaving group, rac refers to racemic, (R) refers to the R-configuration of the molecule, and (S) refers to the S- configuration of the molecule. [0008] In one aspect, the present invention provides methods for preparing vitamin E according to the steps depicted in Scheme 1, above. At step S-l, a mono-protected hydroquinone, 2 (4-protected hydroxy-2,3,5-trimethylphenol), is alkylated with diyne 3 (3- methylpenta-l ,4-diyn-3-ol) to form intermediate 4 (2-PGoxy-l ,3,4-trimethyl-5-(3-methyl-penta- l,4-diyn-3yloxy)benzene). Diyne 3 can be prepared, for example, by methods substantially similar to those described by D. Buser, et. al., Molecules, 2002, 7, 341. Conditions for step S-l are substantially similar to those described in detail in Bell et al. Synthesis (1995), 707, and Danishefsky et al. JACS, ( 2000), 122, 6160-67.

[0009] Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Examples of suitably protected hydroxyl groups include, but are not limited to, esters, carbonates, sulfonates allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of suitable esters include formates, acetates, proprionates, pentanoates, crotonates, and benzoates. Specific examples of suitable esters include formate, chloroacetate, trifluoroacetate, methoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4- (ethylenedithio)pentanoate, pivaloate (trimethylacetate), crotonate, 4-methoxy-crotonate, benzoate, 2,4,6-trimethylbenzoate. Examples of suitable carbonates include 9-fiuorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p- nitrobenzyl carbonate. Examples of suitable silyl ethers include trimethylsilyl, triethylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl ether, and other trialkylsilyl ethers. Examples of suitable alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, trityl, t-butyl, and allyl ether, or derivatives thereof. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyran-2-yl ether. Examples of suitable arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O- nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl ethers. In certain embodiments, R is a hydroxyl protecting group removable by hydrogenation. In some embodiments, R is benzyl. [0010] As defined above, X is a leaving group. Suitable leaving groups are well known in the art, e.g., see, "Advanced Organic Chemistry," Jerry March, 5th Ed., pp. 351-357, John Wiley and Sons, N.Y. Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, and optionally substituted arylsulfonyloxy. Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl (mesyl), tosyl, triflate, nitro- phenylsulfonyl (nosyl), and bromo-phenylsulfonyl (brosyl). In certain embodiments, X is halogen. In other embodiment, X is an optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, or optionally substituted arylsulfonyloxy group. In some embodiments, X is -OC(0)CF₃, chloro, or bromo.

[0011] At step S-2, intermediate 4 is subjected to thermal rearrangement to form racemic ethynyl-chromene 5 (6-protected hydroxy-2-ethynyl-2,5,7,8-tetramethyl-2H-chromene). Suitable temperature ranges for achieving thermal rearrangement of 4 include about 100 to about 200 °C, about 150 to about 200 °C, about 160 to about 190 °C, or about 170 to about 180 °C. Suitable conditions for step S-2 are readily available to one of skill in the art and include those described by Harfenist et al. JOC (1972),37, 841; and Anderson et al. JOC ( 1974),39, 881.

[0012] Ethynyl-chromene (rac) 5 is reduced to vinyl-chromene (rac) 6 (6-PGoxy-2, 5,7-8- tetramethyl-2-vinyl-2H-chromene) at step S-3. One of ordinary skill in the art will recognize that methods are suitable for reducing the triple bond of intermediate (rac) 5 to form the double bond of (rac) 6. In some embodiments, the reduction step is achieved via hydrogenation. In some embodiments, hydrogenation is achieved via catalytic reduction in the presence of palladium (e.g, Pd on carbon or Pd(OH)₂ on carbon) under a hydrogen atmosphere.

[0013] At step S-4, racemic vinyl-chromene (rac) 6 is treated with 4-methylhepta-l ,6-diene, 7, (the metathetic equivalent of 4-methylcyclopent-l-ene, 8) in the presence of a chiral metathesis catalyst to form (R)-9 leaving the S-isomer of 6 unreacted. One of ordinary skill in the art will recognize that this important step achieves resolution of the R- and S-isomers of 6 while simultaneously incorporating 5 carbons of the vitamin E "side-chain" under desymmetrization of compound 7.

[0014] Chiral metathesis catalysts suitable for achieving the enantioselective reaction between 7 (or 8) and (rac)-6 to form (R)-9 are known in the art and include those described by Meek, et al. "Catalytic Z-selective olefin cross-metathesis for natural product synthesis," Nature 471 461 -466 (201 1), the entirety of which is hereby incorporated herein by reference. Such catalysts are also described in US 6, 121 ,473, US 200801 19678, US 201 10077421 , US 201 10015430, and US 201 1 -0065915, the entirety of each of which is hereby incorporated by reference.

[0015] As described above, the chiral metathesis reaction at step S-4 selectively reacts with the R-isomer of intermediate 6 thereby leaving the S-isomer of 6 unreacted. In this regard, the chiral metathesis reaction results in the resolution of racemic 6. The unreacted S-isomer of 6 can be reracemized in order to form rac-6 which can be recycled into the process. Scheme 2, below, depicts a method for racemization of (S)-6 to form rac-6 which can then be recycled into the process of Scheme 1 at step S-4 to ultimately prepare vitamin E, 1.

Scheme 2

(S)-6 (R)-6

[0016] In an alternative embodiment, the rac-6 isolated via the racemization process depicted in Scheme 2 can be utilized in the metathesis reaction at step S-4 using a non-chiral metathesis catalyst thereby resulting in rac-vitamin E. Thus, in this alternative embodiment, any metathesis catalyst can be employed to couple rac-6 to 7 (or 8) to form rac-9. The resulting rac-9 can then be taken on to rac-vitamin E via the remaining steps of Scheme 1.

[0017] At step S-5, (R)-9 is combined with 10 ((R)-3,7-dimethylocta-l,6-diene, commercially available) under metathesis conditions to form intermediate 11 (which is a mixture of (R)-6-protected hydroxy-2,5,7,8-tetramethyl-2-((l E,4R,6E,8R)-4,8, 12-trimethyltrideca- 1,6,1 1 -trienyl)-2H-chromene and (R)-6-protected hydroxy-2,5,7,8-tetramethyl-2- ((lZ,4R,6Z,8R)-4,8,12-trimethyltrideca-l ,6, l l-trienyl)-2H-chromene). One of ordinary skill in the art will appreciate that any metathesis catalyst is suitable for the reaction at step S-5, including those described by Meek, et al., by Schrock and Hoveyda in numerous publications, and those that are commercially available (e.g, from Sigma Aldrich). Such suitable metathesis catalysts include those referred to as "Grubbs" catalysts (i.e., those metathesis catalysts having ruthenium metal) and those referred to as "Schrock" catalysts (i.e., those metathesis catalysts having tungsten or molybdenum metal such as those described in detail in US 6, 121 ,473, US 200801 19678, US 201 10077421 , US 201 10015430, and US 201 1 -0065915).

[0018] Finally, at step S-6, the hydroxyl protecting group is removed and the double bonds of intermediate 11 are reduced to form vitamin E, 1. One of ordinary skill in the art would recognize that, depending on the choice of hydroxyl protecting group, deprotection and olefin reduction may be performed in the same step. For example, when the R group of 11 is benzyl, reduction of the olefin would simultaneously deprotect the hydroxyl group. Accordingly, in certain embodiments, the present invention provides a method of forming vitamin E comprising the step of simultaneously reducing the olefin and deprotecting the hydroxyl group of 11. Thus, in certain embodiments, the R group of 11 is a hydroxyl protecting group that is removed by reduction, e.g. hydrogenation or transfer hydrogenation. For example, reduction of the double bond and deprotection of a benzyl group is achieved in the same reaction by catalytic reduction with Pd-C under a hydrogen atmosphere. In an alternate method, the removal of R and olefin reduction at step S-6 may be performed in a stepwise fashion using methods known to one of ordinary skill in the art.

[0019] In other embodiments, a provided method is depicted in Scheme 3, below:

Scheme 3

[0020] In Scheme 3 above, R is a hydroxyl protecting group, X is a leaving group, rac refers to racemic, (R) refers to the R-configuration of the molecule, and (S) refers to the S- configuration of the molecule.

[0021] In one aspect, the present invention provides methods for preparing vitamin E according to the steps depicted in Scheme 3, above. At step S-1, a mono-protected hydroquinone, 2 (4-protected hydroxy-2,3,5-trimethylphenol), is alkylated with enyne 12 (3- methylhex-5-en-l-yn-3-ol) to form intermediate 13 (2-protected hydroxy- 1 , 3,4-trimethyl-5-(3- methylhex-5-en-l-yn-3-yloxy)benzene). In some embodiments, step S-1 is performed in the presence of a base. One of ordinary skill would recognize that the displacement of a leaving group by an amino moiety is achieved either with or without the presence of a suitable base. Such suitable bases are well known in the art and include organic and inorganic bases. In certain embodiments, step S-1 is performed in the presence of K₂C0₃, KI, and catalytic Cul, in DMF at 50-80 °C.

[0022] At step S-2, intermediate 13 is subjected to thermal rearrangement to form racemic allyl-chromene 14 (2-allyl-6-protected hydroxy-2,5,7,8-tetramethyl-2H-chromene). Suitable temperature ranges for achieving thermal rearrangement of 13 include about 100 to about 200 °C, about 150 to about 200 °C, about 160 to about 190 °C, or about 170 to about 180 °C.

[0023] At step S-3, racemic allyl-chromene (rac) 14 is treated with 3-methylcyclo-prop-l- ene, 15, (the metathetic equivalent of 3-methyl-l,4-pentadiene) in the presence of a chiral metathesis catalyst to form (R)-16 ((R)-6-protected hydroxy-2,5,7,8-tetramethyl-2((R,E)-4- methylhexa-2,5-dienyl)-2H-chromene) leaving the S-isomer of 14 unreacted. One of ordinary skill in the art will recognize that this important step achieves resolution of the R- and S-isomers of 14 while simultaneously incorporating 4 carbons of the vitamin E "side-chain" under desymmetrization of compound 15. [0024] As described above, the chiral metathesis reaction at step S-3 selectively reacts with the R-isomer of intermediate 14 thereby leaving the S-isomer of 14 unreacted. In this regard, the chiral metathesis reaction results in the resolution of racemic 14. The unreacted S-isomer of 14 can be re-racemized in order to form (R)-14 which can be recycled into the process. Scheme 4, below, depicts a method for racemization of (S)-14 to form rac-14 which can then be recycled into the process of Scheme 3 at step S-3 to ultimately prepare vitamin E, 1.

Scheme 4

(S)-14 (R)-14

[0025] In an alternative embodiment, the rac-14 isolated via the racemization process depicted in Scheme 4 can be utilized in the metathesis reaction at step S-3 of Scheme 3 using a non-chiral metathesis catalyst to form rac-vitamin E. Thus, in this alternative embodiment, any metathesis catalyst can be employed to couple rac-14 with 15 to form rac-16. The resulting rac- 16 can then be taken on to rac-vitamin E via the remaining steps of Scheme 3.

[0026] Compound 15 (3-methylcyclo-prop-l-ene) can be prepared according to Scheme 5, below, using methods substantially similar to those described by R. Koster, et. al., Angew. Chem. 1970, 82, 839; Angew. Chem. Int. Ed. 1970, 9, 810.

Scheme 5

3-methylcycloprop-1 -ene

[0027] At step S-4, (R)-16 is combined with dimethyl- 1-nonene or dimethyl- 1,7-nonadiene, 17, wherein the dotted bond represents a single or double bond, under metathesis conditions to form intermediate 18 ((R)-6-protected hydroxy-2,5,7,8-tetramethyl-2-((lE,4R,6E,8R)-4,8,12- trimethyltrideca- 1,6, 1 l-trienyl)-2H-chromene). Methods for preparing 17 are described in: (R)- 4,8-dimethylnon-l-ene: H. Lebel, et. al., J. Am Chem Soc. 2004, 126, 320; and (1-nonane) (R)- 4,8-dimethylnona-l ,7-diene: E. Negishi, et. al., Angew. Chem. Int. Ed. 2002, 41(12), 2141.

[0028] One of ordinary skill in the art will appreciate that any metathesis catalyst is suitable for the reaction at step S-4, including those described by Meek, et al., by Schrock and Hoveyda in numerous publications, and those that are commercially available (e.g, from Sigma Aldrich). Such suitable metathesis catalysts include those referred to as "Grubbs" catalysts (i.e., those metathesis catalysts having ruthenium metal) and those referred to as "Schrock" catalysts (i.e., those metathesis catalysts having tungsten or molybdenum metal such as those described in detail in US 6,121 ,473, US 200801 19678, US 201 10077421, US 201 10015430, and US 201 1- 0065915).

[0029] Finally, at step S-5, the hydroxyl protecting group is removed and the double bonds of intermediate 18 are reduced to form vitamin E, 1. One of ordinary skill in the art would recognize that, depending on the choice of hydroxyl protecting group, deprotection and olefin reduction may be performed in the same step. For example, when the R group of 18 is benzyl, reduction of the olefin would simultaneously deprotect the hydroxyl group. Accordingly, in certain embodiments, the present invention provides a method of forming vitamin E comprising the step of simultaneously reducing the olefin and deprotecting the hydroxyl group of 18. Thus, in certain embodiments, the R group of 18 is a hydroxyl protecting group that is removed by reduction, e.g. hydrogenation or transfer hydrogenation. For example, reduction of the double bond and deprotection of a benzyl group is achieved in the same reaction by catalytic reduction with Pd-C under a hydrogen atmosphere. In an alternate method, the removal of R and olefin reduction at step S-5 may be performed in a stepwise fashion using methods known to one of ordinary skill in the art.

[0030] In some embodiments, reactions described above are performed in a suitable medium. A suitable medium is a solvent or a solvent mixture that, in combination with the combined compounds, may facilitate the progress of the reaction therebetween. The suitable solvent may solubilize one or more of the reaction components, or, alternatively, the suitable solvent may facilitate the agitation of a suspension of one or more of the reaction components. Examples of suitable solvents useful in the present invention are a protic solvent, a halogenated hydrocarbon, an ether, an ester, an aromatic hydrocarbon, a polar or a non-polar aprotic solvent, or any mixtures thereof. Such mixtures include, for example, mixtures of protic and non-protic solvents such as benzene/methanol/water; benzene/water; DME/water, and the like. These and other such suitable solvents are well known in the art, e.g., see, "Advanced Organic Chemistry", Jerry March, 5th edition, John Wiley and Sons, N.Y.

[0031] In certain embodiments, the metathesis catalyst is selected from catalysts A to S having the following formulas:

[0032] In some embodiments, the metathesis catalyst is:

[0033] In some embodiments, the metathesis catalyst is:

wherein each X is independently Br or I.

[0034] In some embodiments, the metathesis catalyst is:

J

 [0035] In some embodiments, the present invention provides a method for preparing (R),(R),(R)-tocopherol (vitamin E). One of ordinary skill in the art will recognize that the present stereoselective methods can be performed in a manner in which racemic tocopherol is produced. For example, in steps where a chiral metathesis catalyst is indicated, one could utilize a non-chiral (i.e., non-stereoselective) metathesis catalyst thereby forming racemic tocopherol.

[0036] In another embodiment, a provided method for preparing (R),(R),(R)-tocopherol (vitamin E) makes use of (rac) 6 of Scheme 1, however, said compound is obtained via a reaction sequence that differs from steps S-l to S-3 of Scheme 1.

[0037] Accordingly, a provided method for preparing (R),(R),(R)-tocopherol (vitamin E) makes use of triene 20:

[0038] In compound 20, R is a hydroxyl protecting group, wherein R has the meaning as defined for the hydroxyl protecting group R with respect to Scheme 1 above.

[0039] Triene 20 may be prepared according to known methods starting from known compounds, respectively compounds, which may be prepared according to known methods. In one embodiment, diyne 3 of Scheme 1 is reacted with a respectively substituted phenol to afford the respective O-alkylated phenol 19. Subsequently, the diyne groups are partially hydrogenated to afford triene 20 as depicted in Scheme 6: Scheme 6

19 20

[0040] Conditions for the alkylation of an appropriate phenol with diyne 3 to compound 19 are substantially similar to those described in detail in Bell et al. Synthesis (1995), 707 or Danishefsky et al. JACS (2000), 122, 6160-67. In one embodiment, the hydrogenation of the O- alkylated phenol 19 to triene 20 may be performed by catalytical hydrogenation using e.g. a Lindlar catalyst. Such catalysts and reaction conditions for performing the reaction are known in the art. Compound 20 may be obtained from compound 19 in a yield of more than 85 %, preferably more than 90 %.

[0041] In one embodiment, compound 20 may be catalytically converted to compound (rac)- 6 using a metathesis catalyst as depicted in Scheme 7. In one embodiment, a non-chiral metathesis catalyst is used. Such catalysts and conditions for performing such reaction are well known in the art, e.g. those as disclosed in section [0017] above.

Scheme 7

rac. 6

[0042] Subsequent to the conversion, a reaction sequence similar to the sequence as depicted in Scheme 1 via steps S-4 to S-6 may be performed to afford target compound 1 as depicted in Scheme 8: Scheme 8

[0043] In another embodiment, if a chiral metathesis catalyst is used for the conversion of compound 20, the conversion may proceed enantioselectively, thus under desymmetrization. Then, (R)-6 may be formed exclusively or at least predominantly as depicted in Scheme 9:

Scheme 9

20 (R)-6

[0044] Chiral metathesis catalysts suitable for achieving the enantioselective conversion of compound 20 to compound (R)-6 are known in the art and include chiral Mo- or W-based catalysts. These catalysts include those as e.g. described in sections [0014] and [0031] to [0034] above.

[0045] Subsequent to the conversion of compound 20 to compound (R)-6, compound (R)-6 may be processed to target compound 1 via steps S-4 to S-6 in a manner analogous to the reaction sequence as depicted in Scheme 1. This reaction sequence is depicted in Scheme 10:



Claims

CLAIMS We claim:

1. A method of preparing (R),(R),(R)-Vitamin E comprising the steps depicted in Scheme 1 Scheme 1

2. A method of preparing (R),(R),(R)-Vitamin E comprising the steps depicted in Scheme 3:

Scheme 3

3. A compound selected from:

wherein R is a hydroxyl protecting group.

4. A c

wherein R is a hydroxyl protecting group.

5. A method of preparing racemic Vitamin E comprising the steps depicted in Scheme 1 wherein at step S-4 a non-stereoselective metathesis catalyst is utilized.

6. A method of preparing racemic Vitamin E comprising the steps depicted in Scheme 3 wherein at step S-3 a non-stereoselective metathesis catalyst is utilized.

7. A method of preparing (R),(R),(R)-Vitamin E comprising the step depicted in Scheme 7:

Scheme 7

8. The method of claim 7, further comprising after the step depicted in Scheme 7 the steps depicted in Scheme 8:

9. A method of preparing (R),(R),(R)-Vitamin E comprising the step depicted in Scheme 9:

Scheme 9

20 (R)-6

10. The method of claim 9, further comprising after the step depicted in Scheme 9 the steps depicted in Scheme 10:

Scheme 10

1 1. The method of any one of claims 7 to 10, further comprising prior to the step depicted in Scheme 7 or Scheme 9 the step depicted in Scheme 6:

Scheme 6

19

12. A compound selected from

20 wherein R is a hydroxyl protecting group.

13. A method of preparing compound 20 from compound 19 comprising hydrogenation of compound 19 as depicted in Scheme 6.

14. A method of preparing compound (rac) 6 or (R)-6 from compound 20 comprising the step depicted in Scheme 7 using a non-chiral metathesis catalyst, or comprising the step depicted in Scheme 9 using a chiral metathesis catalyst.