U.S. patent application number 11/005113 was filed with the patent office on 2005-12-15 for process for the manufacture of chroman derivatives, especially alpha-tocopherol and alkanoates thereof.
Invention is credited to Bonrath, Werner, Foricher, Yann, Netscher, Thomas, Wildermann, Angela.
Application Number | 20050277777 11/005113 |
Document ID | / |
Family ID | 34959527 |
Filed Date | 2005-12-15 |
United States Patent
Application |
20050277777 |
Kind Code |
A1 |
Bonrath, Werner ; et
al. |
December 15, 2005 |
Process for the manufacture of chroman derivatives, especially
alpha-tocopherol and alkanoates thereof
Abstract
The present invention relates to novel processes for the
manufacture of chroman derivatives such as .alpha.-tocopherol (TCP)
and alkanoates thereof, especially .alpha.-tocopheryl acetate
(TCPA), whereby at least one step of the processes is carried out
in the presence of a Lewis acid or a mixture of a Lewis acid with a
Bronsted acid as the catalyst under pressure, preferably at an
absolute pressure of at least 1.1 bar. As starting materials for
the manufacture of TCP and its alkanoates either a mixture of
2,3,5-trimethylhydroquinone (TMHQ) or
2,3,6-trimethylhydroquinone-1-alkanoate (TMHQA) and a compound
selected from the group consisting of phytol (pH), isophytol (IP)
and (iso)phytol derivatives or
2-phytyl-3,5,6-trimethyl-hydroquinone
(PTMHQ)/3-phytyl-2,5,6-trimethylhydroquinone-1-alkanoate (PTMHQA)
and/or an isomer thereof are used. Suitable Lewis acids are
indium(III) salts and scandium(III) salts. Suitable acid mixtures
are iron/iron(II) chloride/hydrogen chloride and zinc(II)
chloride/hydrogen chloride.
Inventors: |
Bonrath, Werner; (Freiburg,
DE) ; Foricher, Yann; (Riedisheim, FR) ;
Netscher, Thomas; (Bad Krozingen, DE) ; Wildermann,
Angela; (Bad Sackingen, DE) |
Correspondence
Address: |
Kevin C. Hooper, Esq.
BRYAN CAVE LLP
1290 Avenue of the Americas
New York
NY
10104-3300
US
|
Family ID: |
34959527 |
Appl. No.: |
11/005113 |
Filed: |
December 6, 2004 |
Current U.S.
Class: |
549/411 |
Current CPC
Class: |
A61P 3/02 20180101; C07D
311/72 20130101 |
Class at
Publication: |
549/411 |
International
Class: |
C07D 311/74 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 11, 2004 |
EP |
04013713.5 |
Claims
1. A process for the alkenylation of phenols comprising 0 to 4
methyl groups, a total of 1 to 3 hydroxy groups and at least one
unsubstituted position, whereby the unsubstituted position is ortho
to a hydroxy group, with a compound of the formula III and/or IV
34with R.sup.2 being hydroxy, acetyloxy, benzoyloxy or halogen, n
being an integer from 0 to 3, and whereby the reaction is carried
out in an organic solvent in the presence of a Lewis acid or a
mixture of a Lewis acid with a Bronsted acid as the catalyst under
pressure.
2. The process as claimed in claim 1, wherein the phenol has the
formula IIa 35with X.sup.1, X.sup.2 and X.sup.3 being independently
from each other hydrogen or methyl and R.sup.3 being hydrogen,
acetyl, propionyl, pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO,
nicotinoyl or benzoyl, with the proviso that R.sup.3 is only
acetyl, propionyl, pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO,
nicotinoyl or benzoyl, if X.sup.1, X.sup.2 and X.sup.3 are all
methyl.
3. The process as claimed in claim 1, wherein the phenol has the
formula II 36with R.sup.1 being hydrogen, acetyl, propionyl,
pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or
benzoyl.
4. A process for the manufacture of compounds of the formula VIIa
by 37a) (STEP a) optionally reacting a compound of the formula IIa
38with a compound of the formula III and/or IV in an organic
solvent 39b) (STEP b) submitting in an organic solvent a compound
of the formula Ia 40and optionally one or more double bond isomers
thereof, all obtainable by step a), to ring closure to form chroman
derivatives VIIa, with R.sup.2 being hydroxy, acetyloxy, benzoyloxy
or halogen, R.sup.3 being hydrogen, acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl, X.sup.1,
X.sup.2 and X.sup.3 being independently from each other hydrogen or
methyl, with the proviso that R.sup.3 is only acetyl, propionyl,
pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl,
if X.sup.1, X.sup.2 and X.sup.3 are all methyl, and n being an
integer from 0 to 3, whereby at least one of the steps a) and b) is
carried out in the presence of a Lewis acid or a mixture of a Lewis
acid with a Bronsted acid as the catalyst under pressure.
5. A process for the manufacture of chroman derivatives VIIa 41by
reacting of phenols comprising 0 to 4 methyl groups, a total of 1
to 3 hydroxy groups and at least one unsubstituted position,
whereby the unsubstituted position is ortho to a hydroxy group,
with a compound of the formula III and/or IV 42with R.sup.2 being
hydroxy, acetyloxy, benzoyloxy or halogen, and n being an integer
from 0 to 3, whereby the reaction is carried out in an organic
solvent in the presence of a Lewis acid or a mixture of a Lewis
acid with a Bronsted acid as the catalyst under pressure.
6. The process as claimed in claim 1, wherein n in formulas III and
IV is 3.
7. A process for the manufacture of alkanoates of the formula
VIIIa, 43by reacting compounds of the formula VIIc, 44with an
appropriate acylating agent, wherein n is an integer from 0 to 3,
X.sup.1, X.sup.2 and X.sup.3 are independently from each other
hydrogen or methyl, and R is selected from the group consisting of
acetyl, propionyl, pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO,
nicotinoyl, and benzoyl, characterized in that the reaction is
carried out in the presence of a Lewis acid as the catalyst at
reduced pressure or under pressure.
8. The process as claimed in claim 7, wherein X.sup.1, X.sup.2 and
X.sup.3 are methyl and n=3.
9. The process as claimed in claim 1 characterized in that the
Lewis acid used as the catalyst is indium trichloride, indium
tribromide, indium triiodide, indium triacetate, indium
tris[bis(trifluoromethanesulfonamide- )], indium triflate or
scandium triflate.
10. The process as claimed in claim 1 characterized in that the
mixture of a Lewis acid and a Bronsted acid used as the catalyst is
a mixture of ZnCl.sub.2 with HCl or Fe and/or FeCl.sub.2 with
HCl.
11. A process for the manufacture of alkanoates of the formula
VIIIa, 45by reacting the reaction mixture obtained by step b) of
the process according to claim 4 with an appropriate acylating
agent, wherein n is 3, X.sup.1, X.sup.2 and X.sup.3 are methyl, and
R is selected from the group consisting of acetyl, propionyl,
pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2-- -CO, nicotinoyl, and
benzoyl, characterized in that the reaction is carried out in the
presence of a Lewis acid as the catalyst at reduced pressure or
under pressure.
12. The process according to claim 4 characterized in that all
steps are carried out under pressure.
13. The process according to claim 1, characterized in that the
organic solvent is a non-polar aprotic organic solvent.
14. The process according to claim 13 characterized in that the
non-polar aprotic organic solvent is selected from the group
consisting of cyclohexane, hexane, heptane, octane,
1,1,1-trichloroethane, 1,2-dichloroethane, methylene chloride,
methylene bromide, benzene, toluene, o-xylene, m-xylene, p-xylene,
chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and
1,4-dichlorobenzene.
15. A process for the manufacture of alkanoates of
.alpha.-tocopherol, .beta.-tocopherol, .gamma.-tocopherol and
.delta.-tocopherol, comprising reacting an .alpha.-tocopherol,
.beta.-tocopherol, .gamma.-tocopherol and .delta.-tocopherol,
respectively, obtained by a process according to claim 1 with an
acylating agent.
16. A process for the manufacture of alkanoates of
.alpha.-tocopherol, .beta.-tocopherol, .gamma.-tocopherol and
.delta.-tocopherol by reacting .alpha.-tocopherol,
.beta.-tocopherol, .gamma.-tocopherol and .delta.-tocopherol,
respectively, with an acylating agent selected from the group
consisting of the anhydrides and halides of acetic acid, propionic
acid, pivalic acid, succinic acid, nicotinic acid, and benzoic
acid, characterized in that the reaction is carried out in the
presence of an indium(III) salt as the catalyst.
17. A process for the manufacture of formulations of
.alpha.-tocopherol, .beta.-tocopherol, .gamma.-tocopherol,
.delta.-tocopherol or their alkanoates, whereby .alpha.-tocopherol,
.beta.-tocopherol, .gamma.-tocopherol, .delta.-tocopherol or their
alkanoates, respectively, obtained by a process according to claim
1 is used.
18. A process for the manufacture of a compound of the formula X
46by reacting a compound of the formula II 47with a compound of the
formula IX 48in an organic solvent with R.sup.1 being hydrogen,
acetyl, propionyl, pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO,
nicotinoyl or benzoyl, R.sup.2 being hydroxy, acetyloxy, benzoyloxy
or halogen, and n being an integer from 0 to 3, whereby the
reaction is carried out in the presence of a Lewis acid or a
mixture of a Lewis acid with a Bronsted acid as the catalyst under
pressure.
19. A process for the manufacture of compounds of the formula X
with R.sup.1 being acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2-- -CO, nicotinoyl or benzoyl, 49by
reacting a compound of the formula X with R.sup.1 being hydrogen
with an appropriate acylating agent, wherein n is an integer from 0
to 3, characterized in that the reaction is carried out in the
presence of a Lewis acid as the catalyst at reduced pressure or
under pressure.
Description
[0001] The present invention relates to a novel process for the
manufacture of chroman derivatives, especially for the manufacture
of .alpha.-tocopherol (TCP) and alkanoates (TCPA) thereof such as
.alpha.-tocopheryl acetate (TCPAc), whereby at least one step of
the process is carried out in the presence of a Lewis acid or a
mixture of a Lewis acid with a Bronsted acid as the catalyst under
pressure. Preferably the absolute pressure of the reaction is at
least 1.1 bar, more preferably it is from about 1.1 bar to about
20.0 bar, even more preferably it is from about 1.1 bar to about
6.0 bar.
[0002] As starting materials for the manufacture of TCP and its
alkanoates either a mixture of 2,3,5-trimethylhydroquinone (TMHQ)
or 2,3,6-trimethylhydroquinone-1-alkanoate (TMHQA) and a compound
selected from the group consisting of phytol (pH), isophytol (IP)
and (iso)phytol derivatives, or the "open ring" compound
2-phytyl-3,5,6-trimethylhydroqui- none (PTMHQ), a
3-phytyl-2,5,6-trimethylhydroquinone-1-alkanoate (PTMHQA) and/or an
isomer thereof are used.
[0003] As is known, (all-rac)-.alpha.-tocopherol (or as it has
mostly been denoted in the prior art, "d,1-.alpha.-tocopherol") is
a mixture of four diastereomeric pairs of enantiomers of
2,5,7,8-tetramethyl-2-(4',8',12'-t- rimethyl-tridecyl)-6-chromanol
(.alpha.-tocopherol), which is the biologically most active and
industrially most important member of the vitamin E group.
[0004] Many processes for the manufacture of
"d,1-.alpha.-tocopherol" (referred to as such in the literature
reviewed hereinafter) and its acetate by the reaction of
TMHQ/2,3,6-trimethylhydroquinone-1-acetate (TMHQAc) with IP or PH
in the presence of a catalyst or catalyst system and in a solvent
or solvent system are described in the following selected
literature.
[0005] The manufacture of .alpha.-tocopherol by the reaction of
TMHQ with PH or phytyl bromide in the presence of anhydrous
ZnCl.sub.2 is e.g. described in U.S. Pat. No. 2,411,967. According
to DE 196 54 038 A1 TMHQ is reacted with PH or IP to
.alpha.-tocopherol and its acetate in the presence of ZnCl.sub.2
and a proton donor, whereby in the process of U.S. Pat. No.
3,708,505 a combined acid condensation agent comprising a Lewis
acid such as ZnCl.sub.2 and at least one strong acid such as
p-toluene sulfonic acid and sodium bisulfate is used as the
catalyst.
[0006] In EP-A 0 100 471 the reaction of TMHQ with IP or PH in the
presence of a Lewis acid, e.g. ZnCl.sub.2, BF.sub.3 or AlCl.sub.3,
a strong acid, e.g. HCl, and an amine salt as the catalyst system
is described. In the processes of DE-OS 26 06 830 and U.S. Pat. No.
4,191,692 the IP or PH is pretreated with ammonia or an amine
before the reaction with TMHQ in the presence of ZnCl.sub.2 and an
acid is effected.
[0007] In the processes of DE-OS 21 60 103 as well as U.S. Pat. No.
3,789,086 compounds of the following formula 1
[0008] wherein X is hydrogen, alkanoyl or aroyl, and R.sup.1,
R.sup.2 and R.sup.3 are individually hydrogen or methyl, are
reacted with compounds of the following formulae 2
[0009] wherein Y is --CH.sub.2--CH(CH.sub.3)-- or
--CH.dbd.C(CH.sub.3)-- and A is halogen, hydroxy, etherified
hydroxy or esterified hydroxy in the presence of HCl and Fe and/or
FeCl.sub.2 as the catalyst to obtain e.g. .alpha.-tocopherol.
[0010] According to EP-A 0 694 541 TMHQ and IP, PH or a PH
derivative are reacted in the presence of a mineral acid, a Lewis
acid, an acidic ion exchange resin or a triflate, nitrate or
sulfate of Sc, Y or a lanthanide element as the catalyst. The use
of Sc(III) triflate as catalyst for the condensation of TMHQ with
IP is also described in Bull. Chem. Soc. Jpn. 1995, 68,
3569-3571.
[0011] TCP can be converted into its acetate, succinate and further
known application forms by standard methods, e. g. as described in
Ullmann's Encyclopedia of Industrial Chemistry, Vol. A27, 5.sup.th
edition, pages 484 to 485, VCH Verlagsgesellschaft mbH, D-69451
Weinheim, 1996. In contrast to TCP which is labile against
oxidative conditions, the esters (TCPA) are more stable and more
convenient to handle.
[0012] The object of the present invention is to provide a process
for the manufacture of chroman derivatives such as tocols and
tocopherols and of their alkanoates, especially of
.alpha.-tocopherol and its alkanoates, with high selectivities and
yields.
[0013] According to the present invention this object is achieved
by the use of a Lewis acid or a mixture of a Lewis acid with a
Bronsted acid as the catalyst under pressure, preferably at an
absolute pressure of at least 1.1 bar, more preferably at an
absolute pressure of from about 1.1 bar to about 20.0 bar, even
more preferably at an absolute pressure of from about 1.1 bar to
about 6.0 bar. It has been surprisingly found that pressure has a
positive effect on the condensation reaction of phenols such as
TMHQ or TMHQA with compounds such as IP, PH or a derivative thereof
and on the ring closure reaction of PTMHQ or PTMHQA and/or isomers
thereof to produce .alpha.-tocopherol as well as on the acylation
of tocols and tocopherols.
[0014] Therefore, in one aspect, the present invention is concerned
with a process for the manufacture of
2-alkenyl-3,5,6-trimethylhydroquinone (formula I with n=0 to 3;
R.sup.1=hydrogen) and 3-alkenyl-2,5,6-trimethyl- hydroquinone
1-alkanoate (formula I with n=0 to 3; R.sup.1=acetyl, propionyl,
pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or
benzoyl), most preferably a process for the manufacture of
2-phytyl-3,5,6-trimethylhydroquinone (formula I with
R.sup.1=hydrogen and n=3) and
3-phytyl-2,5,6-trimethylhydroquinone-1-alkanoates (formula I with
R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--- CO, nicotinoyl or benzoyl and
n=3), 3
[0015] by reacting 2,3,5-trimethylhydroquinone (formula II with
R.sup.1=hydrogen) and 2,3,6-trimethylhydroquinone-1-alkanoate
(formula II with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--- CO, nicotinoyl or benzoyl),
respectively, 4
[0016] with a compound of the formula III and/or IV in an organic
solvent 5
[0017] whereby R.sup.1 is hydrogen, acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl,
[0018] R.sup.2 is hydroxy, acetyloxy, benzoyloxy or halogen,
and
[0019] n is an integer from 0 to 3, and
[0020] whereby the reaction is carried out in the presence of a
Lewis acid or a mixture of a Lewis acid with a Bronsted acid as the
catalyst under pressure, preferably at an absolute pressure of at
least 1.1 bar, more preferably at an absolute pressure of from
about 1.1 bar to about 20.0 bar, even more preferably at an
absolute pressure of from about 1.1 bar to about 6.0 bar. This
process is referred to as PROCESS 1 hereinafter.
[0021] Concerning the substituent R.sup.1: preferably it is
hydrogen or acetyl, more preferably it is hydrogen.
[0022] Concerning the substituent R.sup.2: preferably R.sup.2 is
hydroxy, acetyloxy, benzoyloxy, chlorine or bromine, more
preferably R.sup.2 is hydroxy, acetyloxy or chlorine, most
preferably R.sup.2 is hydroxy.
[0023] Concerning the integer n: preferably n is 3.
[0024] While in PROCESS 1 of the present invention the production
of (all-rac)-2-alkenyl-3,5,6-trimethylhydroquinone, e.g.
(all-rac)-PTMHQ, or (all-rac)-3-alkenyl-2,5,6-trimethylhydroquinone
1-alkanoate, e.g. (all-rac)-PTMHQA, especially
(all-rac)-3-phytyl-2,5,6-trimethylhydroquino- ne-1-acetate
(PTMHQAc), is preferred, the invention is not limited to the
production of that particular isomeric form and other isomeric
forms can be obtained by using e.g. phytol (formula IV with
R.sup.2.dbd.OH and n=3), isophytol (formula III with R.sup.2.dbd.OH
and n=3) or a derivative thereof as the starting material in the
appropriate isomeric form. Thus, (R,R)-PTMHQ or (R,R)-PTMHQA will
be obtained e.g. when using (R,R)-phytol, (R,R,R)-isophytol,
(S,R,R)-isophytol or (RS,R,R)-isophytol or an appropriate
(iso)phytol derivative.
[0025] PROCESS 1 is also applicable for the alkenylation of phenols
comprising 0 to 4 methyl groups, a total of 1 to 3 hydroxy groups
and at least one unsubstituted position, whereby the unsubstituted
position is ortho to a hydroxy group.
[0026] Therefore, a further object of the present invention is a
process for the alkenylation of phenols comprising 0 to 4 methyl
groups, a total of 1 to 3 hydroxy groups and at least one
unsubstituted position, whereby the unsubstituted position is ortho
to a hydroxy group, with a compound of the formula III and/or IV in
an organic solvent 6
[0027] with R.sup.2 and n having the same meanings and preferences
as above, and
[0028] whereby the reaction is carried out in the presence of a
Lewis acid or a mixture of a Lewis acid with a Bronsted acid as the
catalyst under pressure, preferably at an absolute pressure of at
least 1.1 bar, more preferably at an absolute pressure of from
about 1.1 bar to about 20.0 bar, even more preferably at an
absolute pressure of from about 1.1 bar to about 6.0 bar. This
process is referred to as PROCESS 1A hereinafter.
[0029] Concerning the phenols used in PROCESS 1A as the starting
material:
[0030] Especially suitable phenols have the following formula IIa
7
[0031] with R.sup.3 being hydrogen, acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl, and
X.sup.1, X.sup.2 and X.sup.3 being independently from each other
hydrogen or methyl, with the proviso that R.sup.3 is only acetyl,
propionyl, pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl
or benzoyl, if X.sup.1, X.sup.2 and X.sup.3 are all methyl; i.e.
hydroquinone, 2-methylhydroquinone, 2,3-dimethylhydroquinone,
2,5-dimethylhydroquinone, 2,6-dimethylhydroquinone,
2,3,5-trimethylhydroquinone and
2,3,6-trimethylhydroquinone-1-alkanoates. Preferred from this group
are 2,3,5-trimethylhydroquinone and
2,3,6-trimethylhydroquinone-1-alkanoates, more preferred are
2,3,5-trimethylhydroquinone and
2,3,6-trimethylhydroquinone-1-acetate, the most preferred is
2,3,5-trimethylhydroquinone.
[0032] In another aspect, the present invention is concerned with a
process for the manufacture of compounds of the formula VII,
preferably .alpha.-tocopherol (formula VII with R.sup.1=hydrogen
and n=3) and its alkanoates (formula VII with R.sup.1=acetyl,
propionyl, pivaloyl, HO.sub.2--CH.sub.2--CH.sub.2--CO, nicotinoyl
or benzoyl and n=3) 8
[0033] by
[0034] a) (STEP a) optionally reacting 2,3,5-trimethylhydroquinone
(formula II with R.sup.1=hydrogen) and 2,3,6-trimethylhydroquinone
1-alkanoate (formula II with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl),
respectively, 9
[0035] with a compound of the formula III and/or IV in an organic
solvent 10
[0036] with R.sup.1, R.sup.2 and n having the same meanings and
preferences as above, and
[0037] b) (STEP b) submitting in an organic solvent a
2-alkenyl-3,5,6-trimethylhydroquinone (formula I with
R.sup.1=hydrogen), preferably 2-phytyl-3,5,6-trimethylhydroquinone
(formula I with R.sup.1=hydrogen and n=3), a
3-alkenyl-2,5,6-trimethylhydroquinone 1-alkanoate (formula I with
R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl),
preferably 3-phytyl-2,5,6-trimethylhydroquinone 1-alkanoate
(formula I with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl and n=3)
and optionally one or more double bond isomers thereof, all
obtainable by step a), 11
[0038] to ring closure to form chroman derivatives VII, preferably
.alpha.-tocopherol (formula VII with R.sup.1=hydrogen and n=3) or
its alkanoate (formula VII with R.sup.1=acetyl, propionyl,
pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl
and n=3),
[0039] whereby at least one of the steps a) and b) is carried out
in the presence of a Lewis acid or a mixture of a Lewis acid with a
Bronsted acid as the catalyst under pressure, preferably at an
absolute pressure of at least 1.1 bar, more preferably at an
absolute pressure of from about 1.1 bar to about 20.0 bar, even
more preferably at an absolute pressure of from about 1.1 bar to
about 6.0 bar. This process is referred to in the following as
PROCESS 2.
[0040] Depending on the activity of the catalyst and the reaction
conditions, the reaction of compounds of the formula II with
compounds of the formula III and/or IV proceeds to the final
product of the formula VII, preferably .alpha.-tocopherol and its
alkanoate, so that the compounds of the formula I such as PTMHQ
(formula I with R.sup.1=hydrogen and n=3) and PTMHQA (formula I
with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl and n=3)
are not isolated.
[0041] Therefore, a further aspect of the present invention is the
manufacture of chroman derivatives VII such as .alpha.-tocopherol
(formula VII with R.sup.1=hydrogen and n=3) and its alkanoates
(formula VII with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub- .2--CO, nicotinoyl or benzoyl and n=3)
12
[0042] by reacting 2,3,5-trimethylhydroquinone (formula II with
R.sup.1=hydrogen) and 2,3,6-trimethylhydroquinone 1-alkanoate
(formula II with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--- CO, nicotinoyl or benzoyl),
respectively, 13
[0043] with a compound of the formula III and/or a IV in an organic
solvent 14
[0044] with R.sup.1, R.sup.2 and n having the same meanings and
preferences as above,
[0045] whereby the reaction is carried out in the presence of a
Lewis acid or a mixture of a Lewis acid with a Bronsted acid as the
catalyst under pressure, preferably at an absolute pressure of at
least 1.1 bar, more preferably at an absolute pressure of from
about 1.1 bar to about 20.0 bar, even more preferably at an
absolute pressure of from about 1.1 bar to about 6.0 bar. This
process is referred to in the following as PROCESS 3.
[0046] As starting material in PROCESS 3 also a compound of the
formula IX instead of a compound of the formula III and/or IV
15
[0047] may be used, so that compounds of the formula X 16
[0048] are obtained. R.sup.1, R.sup.2 and n have the same meanings
and preferences as above. To this process it will be referred to in
the following as PROCESS 4.
[0049] While in the PROCESSES 2 and 3 of the present invention the
production of (all-rac)-chroman derivatives such as (all-rac)-TCP
(formula VII with R.sup.1=hydrogen and n=3) and (all-rac)-TCPA
(formula VII with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub- .2--CO, nicotinoyl or benzoyl and
n=3), especially (all-rac)-TCPAc (formula VII with R=acetyl and
n=3), is preferred, the invention is not limited to the production
of that particular isomeric form and other isomeric forms can be
obtained by using e.g. phytol, isophytol or a derivative thereof as
the starting material in the appropriate isomeric form. Thus, e.g.
(RS,R,R)-TCP/(RS,R,R)-TCPA will be obtained when using (R,R)-PTMHQ,
(R,R)-PTMHQA, (R,R)-phytol, (R,R,R)-isophytol, (S,R,R)-isophytol or
(RS,R,R)-isophytol or an appropriate (iso)phytol derivative.
[0050] In an especially preferred embodiment of the invention TMHQ
is reacted with PH (formula IV with R.sup.2.dbd.OH and n=3) and/or
IP (formula III with R.sup.2.dbd.OH and n=3), preferably with IP,
to .alpha.-tocopherol (formula VII with R.sup.1=hydrogen and n=3),
whereby as intermediates compounds of the formula V (see below) and
VI (see below) such as 2-phytyl-3,5,6-trimethylhydroquinone
(formula I with R.sup.1=hydrogen and n=3; as main component),
2-(3,7,11,15-tetramethyl-he-
xadec-3-enyl)-3,5,6-trimethylhydroquinone (formula Va with
R.sup.1=hydrogen) and
2-[3-(4,8,12-trimethyl-tridecyl)-but-3-enyl]-3,5,6--
trimethylhydroquinone (formula VIa with R.sup.1=hydrogen) are
formed. 17
[0051] PROCESSES 2 and 3 can also be carried out by using phenols
of the formula IIa, whereby, beside .alpha.-tocopherol and its
alkanoates, e.g. other tocols (formula VIIa with n=3) and
tocopherols (formula VIIa with n=3) can be obtained. 18
[0052] Therefore, in another aspect, the present invention is
concerned with a process for the manufacture of compounds of the
formula VIIa by
[0053] a) (STEP a) optionally reacting a compound of the formula
IIa 19
[0054] with a compound of the formula III and/or IV in an organic
solvent 20
[0055] with R.sup.2, R.sup.3, n, X.sup.1, X.sup.2 and X.sup.3
having the same meanings and preferences as above, and
[0056] b) (STEP b) submitting in an organic solvent a compound of
the formula Ia and optionally one or more double bond isomers
thereof, all obtainable by step a), to ring closure to form a
compound of the formula VIla, 21
[0057] whereby at least one of the steps a) and b) is carried out
in the presence of a Lewis acid or a mixture of a Lewis acid with a
Bronsted acid as the catalyst under pressure, preferably at an
absolute pressure of at least 1.1 bar, more preferably at an
absolute pressure of from about 1.1 bar to about 20.0 bar, even
more preferably at an absolute pressure of from about 1.1 bar to
about 6.0 bar. To this process it will be referred to in the
following as PROCESS 2A.
[0058] Depending on the activity of the catalyst and the reaction
conditions, step a of PROCESS 2A can also proceed to the final
products, the compounds of the formula VIIa, so that the compounds
of the formula Ia are not isolated.
[0059] Therefore, a further aspect of the present invention is the
manufacture of a compound of the formula VIla 22
[0060] by reacting a compound of the formula IIa 23
[0061] with a compound of the formula III and/or IV in an organic
solvent 24
[0062] with R.sup.2, R.sup.3, n, X.sup.1, X.sup.2 and X.sup.3
having the same meanings and preferences as above,
[0063] whereby the reaction is carried out in the presence of a
Lewis acid or a mixture of a Lewis acid with a Bronsted acid as the
catalyst under pressure, preferably at an absolute pressure of at
least 1.1 bar, more preferably at an absolute pressure of from
about 1.1 bar to about 20.0 bar, even more preferably at an
absolute pressure of from about 1.1 bar to about 6.0 bar. To this
process it will be referred to in the following as PROCESS 3A.
[0064] In still another aspect the invention relates to a process
for the manufacture of compounds of the formula VIIId (if n=3:
tocyl alkanoates and tocopheryl alkanoates), especially
.alpha.-tocopheryl alkanoates (formula VIIId with n=3,
X.sup.1=X.sup.2=X.sup.3=methyl), 25
[0065] by reacting a compound of the formula VIId (if n=3: a tocol
or tocopherol), especially .alpha.-tocopherol (formula VIId with
n=3, X.sup.1=X.sup.2=X.sup.3=methyl), obtained according to the
process of the present invention, 26
[0066] with an acylating agent. In a preferred embodiment the
reaction is carried out in the presence of a Lewis acid as the
catalyst. In another preferred embodiment the reaction is carried
out at reduced pressure, preferably at an absolute pressure of
below 0.9 bar, or under pressure, preferably at an absolute
pressure of at least 1.1 bar (in the following referred to as
PROCESS 5).
[0067] Concerning the symbol n: it is an integer from 0 to 3.
[0068] Concerning the symbols X.sup.1, X.sup.2 and X.sup.3: they
have the same meanings as given above.
[0069] Concerning the substituent R: it is selected from the group
consisting of acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2-- -CO, nicotinoyl or benzoyl;
preferably R is HO.sub.2C--CH.sub.2--CH.sub.2-- -CO or acetyl, more
preferably R is acetyl.
[0070] In a preferred aspect the invention relates to a process for
the manufacture of compounds of the formula VIIIa, preferably of
compounds of the formula VIIIa with n=3 (tocyl alkanoates and
tocopheryl alkanoates), more preferably of .alpha.-tocopheryl
alkanoates (formula VIII with n=3), 27
[0071] by reacting a compound of the formula VIIc, preferably a
compound of the formula VIIc with n=3 (a tocol or tocopherol), more
preferably .alpha.-tocopherol (formula VIIb with n=3), 28
[0072] with an acylating agent characterized in that the reaction
is carried out in the presence of a Lewis acid as the catalyst at
reduced pressure, preferably at an absolute pressure of below 0.9
bar, or under pressure, preferably at an absolute pressure of at
least 1.1 bar (in the following referred to as PROCESS 5A).
[0073] Concerning the symbols n, X.sup.1, X.sup.2 and X.sup.3: they
have the same meanings as given above.
[0074] Concerning the substituent R: it is selected from the group
consisting of acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2-- -CO, nicotinoyl or benzoyl;
preferably R is HO.sub.2C--CH.sub.2--CH.sub.2-- -CO or acetyl, more
preferably R is acetyl.
[0075] In the same way as compounds of the formula VIII and VIIIa
are manufactured compounds of the formula X with R.sup.1 being
acetyl, propionyl, pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO,
nicotinoyl or benzoyl, and n being an integer from 0 to 3, 29
[0076] can also be manufactured by reacting a compound of the
formula X with R.sup.1 being hydrogen and n having the same meaning
as above with an appropriate acylating agent in the presence of a
Lewis acid as the catalyst at reduced pressure, preferably at an
absolute pressure of below 0.9 bar, or under pressure, preferably
at an absolute pressure of at least 1.1 bar. To this process, which
is also an object of the present invention, it will be referred to
as PROCESS 5B in the following.
[0077] While in a preferred embodiment of PROCESS 5A of the present
invention chroman alkanoates of the formula VIIIa such as
(all-rac)-TCPA (formula VIII with n=3; see above), especially
(all-rac)-TCPAc (formula VIII with n=3 and R=acetyl) is produced,
the invention is not limited to the production of that particular
isomeric form and other isomeric forms can be obtained by e.g.
using TCP (formula VIIb with n=3) as the starting material in the
appropriate isomeric form. Thus, e.g. (R,R,R)-TCPA/TCPAc will be
obtained when using (R,R,R)-TCP as starting material, since no
epimerization occurs at reaction temperatures below 120.degree. C.
The same applies for the other compounds of the formula VIIc used
as starting materials such as e.g. tocols and tocopherols, if
n=3.
[0078] In a preferred embodiment the (all-rac)-.alpha.-tocopherol
(formula VIIb with n=3) obtained by PROCESS 2 or 3 is acetylated
after removal of the solvent without further purification with
acetic anhydride and with total conversion, if PROCESS 2 or 3 is
carried out in the presence of a Lewis acid as the catalyst. No
additional catalyst needs to be used as the catalyst (Lewis acid)
is still present from the reaction before. Furthermore, it is a
special advantage that the reaction mixture of the manufacture of
e.g. (all-rac)-.alpha.-tocopherol can be acetylated at the reaction
temperature the mixture already has. When indium(III) salts are
used as the catalysts, the acetylation even proceeds at room
temperature in a short reaction time (up to 10 minutes). After
acetylation (all-rac)-.alpha.-tocopheryl acetate was isolated in
excellent yield [>99.5% based on
(all-rac)-.alpha.-tocopherol].
[0079] Lewis Acids and Mixtures of Lewis Acids with Bronsted
Acids
[0080] Concerning the Lewis acids and/or mixtures of Lewis acids
with Bronsted acids used as the catalyst under pressure in all
PROCESSES 1 to 5B:
[0081] In principle all Lewis acids and mixtures of Lewis acids
with Bronsted acids known to the person skilled in the art as
catalysts for the condensation reaction of TMHQ or TMHQA with IP,
PH or derivatives thereof can be used. Suitable catalysts are e.g.
bortrifluoride (BF.sub.3), a mixture of boric acid (especially
orthoboric acid) and oxalic acid, triflates and heterowolfram
acids. Preferred are Lewis acids, where the radius of the metal
cation varies from about 73 pm to about 90 pm, preferably from
about 73 pm to about 82 pm, such as the radius of Fe.sup.2+ (0.74
.ANG.), Zn.sup.2+ (0.74 .ANG.), In.sup.3+ (0.81 .ANG.) and
Sc.sup.3+ (0.73 .ANG.).
[0082] Especially suitable Lewis acids are indium(III) salts such
as indium(III) halides, indium(III) trifluoromethanesulfonate
(=triflate) [In(SO.sub.3CF.sub.3).sub.3; In(OTf).sub.3] and
indium(III) bis(trifluoromethanesulfonamide)
[In((NSO.sub.2CF.sub.3).sub.2).sub.3; In(NTf.sub.2).sub.3];
scandium(III) salts such as those described on page 5, line 14 to
21 in combination with page 6, line 23 to page 7, line 33 of EP 0
658 552 A1, e.g. scandium(III) fluorosulfonate
[Sc(SO.sub.3F).sub.3], scandium(III) triflate [Sc(OTf).sub.3] and
scandium(III) fluorobenzenesulfonate
[Sc(SO.sub.3C.sub.6H.sub.4F).sub.3]; scandium(III)
bis(trifluoromethanesulfonamide) [Sc(NTf.sub.2).sub.3],
scandium(III) nitrate [Sc(NO.sub.3).sub.3], scandium(III) sulfate
[Sc.sub.2(SO.sub.4).sub.3] and zinc(II)
bis(trifluoromethanesulfonamide) [Zn(NTf.sub.2).sub.2].
[0083] More preferred are InCl.sub.3, In(OTf).sub.3 and
Sc(OTf).sub.3, whereby InCl.sub.3 is the most preferred one. The
indium and scandium salts InCl.sub.3, In(OTf).sub.3 and
Sc(OTf).sub.3 are known compounds which are commercially available,
InCl.sub.3 e.g. from Fluka (No. 57 100), In(OTf).sub.3 and
Sc(OTf).sub.3 e.g. from Aldrich (No. 442 151 and 418 218). They can
be used in solid form, anhydrous or hydrated (of which InCl.sub.3.4
H.sub.2O is an example), as well as in solution or in suspension.
For PROCESS 1 and 2 the catalyst is preferably dissolved or
suspended in water. The concentration of such an aqueous solution
is not critical. Furthermore, all the Lewis acids cited above
tolerate acetic anhydride and other acylating agents as well as
protic solvents such as acetic acid, methanol, ethanol and water.
After the termination of the reaction the Lewis acids used as the
catalysts can be recycled.
[0084] Especially suitable mixtures of Lewis acids with Bronsted
acids are the following systems: zinc(II) compounds/hydrochloric
acid, zinc(II) compounds (preferably ZnCl.sub.2)/gaseous HCl and
Fe(II) chloride/gaseous HCl. The Fe(II) chloride can be prepared in
situ by the reaction of Fe with HCl, which therefore presents an
equivalent system to the system Fe(II) chloride/gaseous HCl.
Suitable zinc(II) compounds are zinc(II) salts such as ZnCl.sub.2,
ZnBr.sub.2 as well as all zinc(II) compounds which form ZnCl.sub.2
under the reaction conditions, e.g. ZnO. If the system
ZnCl.sub.2/hydrochloric acid or ZnCl.sub.2/gaseous HCl is used, it
is preferred to carry out the reaction in the presence of an amine
such as disclosed in the last paragraph on page 4 and the first
paragraph on page 5 of EP 0 100 471 A1, which is hereby
incorporated by reference, or in the presence of an ammonium salt.
Alternatively the reaction is preferably carried out by using the
compound of the formula III or IV such as IP or PH having been
pretreated with an amine or NH.sub.3 as described in DE-OS 26 06
830.
[0085] Manufacture of the Starting Materials
[0086] The starting material TMHQAc may be obtained e.g. by
selective hydrolysis of 2,3,5-trimethylhydroquinone diacetate as
described in EP-A 1 239 045. 2,3,5-Trimethylhydroquinone diacetate
can be prepared e.g. by the acid catalyzed rearrangement of
ketoisophorone in the presence of acetic anhydride or another
acetylation agent as described in EP-A 0 850 910, EP-A 0 916 642,
EP-A 0 952 137 or EP-A 1 028 103.
[0087] The (iso)phytyl compounds can be produced by conventional
processes known to the person skilled in the art. Phytol and its
derivatives represented by the formula IV with n=3 can be used as
E/Z-mixture as well as in pure E- or pure Z-form. Preferred is the
use of phytol and its derivatives represented by the formula IV as
E/Z-mixtures. The most preferred starting material selected from
the (iso)phytyl compounds is IP.
[0088] Of course any other appropriate isomeric form of the
(iso)phytol derivatives can also be used. (R,R)-phytol,
(R,R,R)-isophytol, (S,R,R)-isophytol or (RS,R,R)-isophytol or an
appropriate (iso)phytol derivative e.g. can be used to obtain
(R,R)-PTMHQ/(R,R)-PTMHQA or (RS,R,R)-TCP/(RS,R,R)-TCPA, if
TMHQ/TMHQA is used as the other component.
[0089] The other (di)(methyl)hydroquinones and compounds of the
formula III and IV with n being 0, 1 or 2 can be prepared by
processes known to the person skilled in the art.
[0090] PROCESS 1, STEP a of PROCESS 2, STEP a of PROCESS 2a
[0091] As will be readily apparent, the use of the compound of the
formula II with R.sup.1.dbd.H (=TMHQ;=formula IIa with X.sup.1,
X.sup.2 and X.sup.3=methyl and R.sup.3=hydrogen) as a reactant in
this process of the present invention will result in the production
of a compound of the formula I with R.sup.1=H such as PTMHQ (n=3)
while, when using a compound of the formula II with R.sup.1=acetyl,
propionyl, pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl
or benzoyl (=TMHQA), especially TMHQAc, the respective compound of
the formula I with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl such as
PTMHQA/PTMHQAc (n=3) will be obtained.
[0092] If TMHQ/TMHQA is reacted with a compound of the formula III
and/or IV with n being 3 in both formulas, minor amounts of the
isomers of PTMHQ/PTMHQA, (Z)-
or(E)-2-(3,7,11,15-tetramethyl-hexadec-3-enyl)-3,5,6-t-
rimethylhydroquinone (formula Va with R.sup.1=hydrogen; see
above)/(Z)-
or(E)-3-(3,7,11,15-tetramethyl-hexadec-3-enyl)-2,5,6-trimethylhydroquinon-
e-1-alkanoate (formula Va with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl; see
above) and/or
2-[3-(4,8,12-trimethyl-tridecyl)-but-3-enyl]-3,5,6-trimethylhydroq-
uinone (formula VIa with R.sup.1=hydrogen; see above) and/or
3-[3-(4,8,12-trimethyl-tridecyl)-but-3-enyl]-2,5,6-trimethylhydroquinone--
1-alkanoate (formula VIa with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl; see
above) may be formed as by-products in PROCESS 1 as well as in STEP
a of PROCESS 2 and 2A. If other compounds of the formula III and/or
IV are used where n=0, 1 or 2, also minor amounts of compounds of
the formula V and VI may be formed as by-products. 30
[0093] PTMHQ/PTMHQA and their isomers represented by the formulae
Va and VIa (see above) are intermediates for the production of
.alpha.-tocopherol or its alkanoates (final products).
[0094] Depending on the activity of the catalyst and the reaction
conditions, the reaction proceeds to the final product (steps a and
b of PROCESS 2) or is slowly enough so that these intermediates can
be isolated (only step a of PROCESS 2 is performed). The same
applies for the steps a and b of PROCESS 2a.
[0095] In a preferred embodiment of PROCESS 1 and PROCESS 2 TMHQ is
reacted with PH and/or IP, more preferably with IP.
[0096] Conveniently the reaction is carried out under an inert gas
atmosphere, preferably gaseous nitrogen or argon.
[0097] The reaction is preferably carried out at an absolute
pressure of at least 1.1 bar, more preferably at an absolute
pressure of from about 1.1 to about 20.0 bar, even more preferably
at an absolute pressure of from about 1.1 bar to about 6.0 bar,
even more, more preferably at an absolute pressure of from about
1.7 to about 5.1 bar, most preferably at an absolute pressure of
from about 2.0 to about 3.6 bar.
[0098] The reaction temperature depends on the applied pressure and
solvent because the reaction is carried out under reflux.
Therefore, the reaction temperature is conveniently from about
90.degree. C. to about 170.degree. C., preferably from about
90.degree. C. to about 160.degree. C., more preferably from about
112.degree. C. to about 160.degree. C. and most preferably from
about 125 to about 150.degree. C.
[0099] Suitable organic solvents are aprotic non-polar organic
solvents such as aliphatic hydrocarbons, halogenated aliphatic
hydrocarbons, aromatic hydrocarbons, halogenated aromatic
hydrocarbons and mixtures thereof.
[0100] Preferred examples of aliphatic hydrocarbons are linear,
branched or cyclic C.sub.5- to C.sub.15-alkanes. Particularly
preferred are linear, branched or cyclic C.sub.6- to
C.sub.10-alkanes, especially preferred are hexane, heptane, octane
and cyclohexane or mixtures thereof.
[0101] Preferred examples of halogenated aliphatic hydrocarbons are
mono- or polyhalogenated linear, branched or cyclic C.sub.1- to
C.sub.15-alkanes. Especially preferred examples are mono- or
polychlorinated or -brominated linear, branched or cyclic C.sub.1-
to C.sub.15-alkanes. More preferred are mono- or polychlorinated
linear, branched or cyclic C.sub.1- to C.sub.15-alkanes. Most
preferred are 1,1,1-trichloroethane, 1,2-dichloroethane, methylene
chloride and methylene bromide.
[0102] Preferred examples of aromatic hydrocarbons are benzene,
toluene, o-, m- and p-xylene, 1,2,3-trimethylbenzene, mesitylene,
pseudocumene, naphthalene and mixtures thereof, particularly
preferred is toluene.
[0103] Preferred examples of halogenated aromatic hydrocarbons are
mono-or polyhalogenated benzene. Especially preferred are
chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and
1,4-dichlorobenzene.
[0104] The most preferred non-polar solvents differ from catalyst
to catalyst:
[0105] If InCl.sub.3 is used as the catalyst, toluene and heptane
are the preferred solvents; especially preferred is heptane. If
Sc(OTf).sub.3 is used as the catalyst, the most preferred solvent
is toluene. If the catalyst system
Fe(FeCl.sub.2)/HCl.sub.(g)("(g)"=gaseous) is used, the most
preferred solvent is also toluene.
[0106] If the system ZnCl.sub.2/hydrochloric acid or
ZnCl.sub.2/HCl.sub.(g)("g"=gaseous) is used, it is more preferred
to carry out process 1 or step a) of process 2/2a in the presence
of an amine such as disclosed in the last paragraph on page 4 and
the first paragraph on page 5 of EP 0 100 471 A1, which is hereby
incorporated by reference. The process can also be carried out by
pretreating the compound of the formula III or IV such as IP or PH
with an amine or NH.sub.3 as described in DE-OS 26 06 830. If an
amine is present in an amount of about 0.05 to about 5.0 weight %,
preferably of about 0.1 to about 2.0 weight %--based on the weight
of the compound III or IV, whichever is employed, the most
preferred solvent for carrying out the reaction with the Zn(II)
catalyst system is hexane. If no amine is present, the most
preferred solvent for carrying out the reaction with the Zn(II)
catalyst system is heptane. The molar ratio of the compound of the
formula II or Ia (most preferred: TMHQ or TMHQA(c)) to a compound
of the formula III or IV, whichever is employed, in the reaction
mixture conveniently varies from about 0.95:1 to about 1:1.1,
preferably from about 1:1.01 to about 1:1.05.
[0107] The amount of the aprotic non-polar organic solvent used is
conveniently from about 0.1 ml to about 6.0 ml, preferably from
about 0.15 ml to about 3.0 ml, based on 1 mmol of the compound of
the formula III or IV, whichever is employed.
[0108] The relative amount of catalyst, based on compound III or
IV, whichever is employed, is dependent on the catalyst system used
and the reactants. Conveniently the relative amount of the catalyst
based on compound III or IV, whichever is employed, is at least
0.01 mol %. Generally the relative amount of catalyst varies from
about 0.01 to about 30 mol %. The optimal relative amount of the
catalyst is different from catalyst to catalyst and also depends on
the reactants:
[0109] If InCl.sub.3 is used as the catalyst, it may be preferably
present e.g. in a relative amount of from about 0.1 mol % to about
2.5 mol %, especially preferable in a relative amount of from about
0.1 mol % to about 2.0 mol %, more preferably in a relative amount
of from about 0.1 to about 1.0 mol %, even more preferably in a
relative amount of from about 0.1 to about 0.5 mol %, based on
compound III or IV, whichever is employed.
[0110] If Sc(OTf).sub.3 is used as the catalyst, it may be
preferably present in a relative amount of from about 0.05 mol % to
about 2.0 mol %, preferably in a relative amount of from about
0.075 to about 1.5 mol %, more preferably in a relative amount of
from about 0.1 to about 1.0 mol %, based on compound III or IV,
whichever is employed.
[0111] If Fe and/or FeCl.sub.2 in combination with HCl is used as
the catalyst, it may be present in an amount as described e.g. in
DE-OS 21 60 103 (page 5, end of second paragraph and claim 9) and
in U.S. Pat. No. 3,789,086 (column 3, lines 27-60).
[0112] If Zn(II) and/or ZnCl.sub.2 is used as the catalyst, it may
be present in an amount as described e.g. in the examples 1 to 12
of U.S. Pat. No. 2,411,967, in U.S. Pat. No. 3,708,505 (page 1,
right column, lines 26-44), in DE-OS 196 54 038 (page 2, lines
55-63; page 3, lines 4-6; page 3, line 60 to page 4, line 19; page
4, line 29-38), in EP-A 0 100 471 (page 7, lines 19-24), in DE-OS
26 06 830 (page 4, last two lines to page 5, first two paragraphs),
in U.S. Pat. No. 4,191,692 (second column, lines 49-62).
[0113] In this context the expression "amount of catalyst" is to be
understood as referring to the weight of pure Lewis acid or pure
Bronsted acid present, even though the catalyst may be impure, in
the form of an adduct with a solvent and/or a solution/suspension.
The relative amount of the Bronsted acid depends also on the Lewis
acid used and can be chosen accordingly.
[0114] The reaction can be carried out batchwise or continuously,
and in general operationally in a very simple manner, for example
(i) by adding the compound of the formula III or IV--as such or
dissolved in the solvent, preferably as such--portionwise or
continuously to a mixture of the Lewis acid, the compound of the
formula IIa/II (preferred: TMHQ or TMHQA; most preferred: TMHQ or
TMHQAc) and the solvent. If a catalyst system consisting of a Lewis
acid and a Bronsted acid is employed, the Bronsted acid is added
continuously or batchwise, preferably continuously, to the mixture
of the Lewis acid, the compound of the formula Ia/II (most
preferred: TMHQ or TMHQA(c)) and the solvent.
[0115] It is also possible (ii) to add subsequently the Lewis acid,
preferably as such or as aqueous solution, and the compound of the
formula III and/or IV--as such or dissolved in the non-polar
solvent, preferably as such--to the compound of the formula IIa/II
(most preferred: TMHQ or TMHQA(c)) and the solvent. The Bronsted
acid is then continuously or batch-wise, preferably continuously,
added to this mixture.
[0116] Conveniently, the compound of the formula III or IV is added
continuously to the compound of the the formula IIa/II (most
preferred: TMHQ or TMHQA(c)) within about 15 to about 180 minutes,
preferably within about 30 to about 150 minutes, more preferably
within about 45 to about 130 minutes. The Lewis acid is preferably
added at once, i.e. in its full amount, to the mixture of the
compound of the formula IIa/II (most preferred: TMHQ or TMHQA(c))
and the solvent.
[0117] After completion of the addition of the compound of the
formula III or IV (in the non-polar solvent) the reaction mixture
is suitably heated further at the reaction temperature for about 10
minutes to about 360 minutes, preferably for about 30 minutes to
about 240 minutes. The working-up can be effected by procedures
conventionally used in organic chemistry.
[0118] STEP b OF PROCESS 2, STEP b of PROCESS 2a
[0119] As will be readily apparent, the use of a compound of the
formula II or IIa with R.sup.1 and R.sup.3, respectively, being
hydrogen such as PTMHQ or an isomer thereof as a reactant in the
process of this invention will result in the preparation of a tocol
or a tocopherol such as .alpha.-tocopherol while, when using a
compound of the formula II with R.sup.1 being acetyl, propionyl,
pivaloyl, HO.sub.2C--CH.sub.2--CH.sub.2-- -CO, nicotinoyl or
benzoyl and n being 3 the respective tocyl alkanoate or tocopheryl
alkanoate such as .alpha.-tocopheryl alkanoate will be
obtained.
[0120] For the manufacture of .alpha.-tocopherol or
.alpha.-tocopheryl alkanoate PTMHQ or PTMHQA and optionally one or
more isomers thereof, which are obtained as minor by-products in
the manufacture of PTMHQ or PTMHQA, prepared to any method known to
the person skilled in the art can be used as starting material.
[0121] This ring closure can be carried out using the same
catalysts under substantially the same reaction conditions as
described above for the reaction of compounds of the formula II
(e.g. TMHQ: formula II with R.sup.1=hydrogen; or TMHQA: formula II
with R.sup.1=acetyl, propionyl, pivaloyl,
HO.sub.2C--CH.sub.2--CH.sub.2--CO, nicotinoyl or benzoyl) or IIa
with a compound of the formula III and/or a compound of the formula
IV. Therefore, in cases, where e.g. PTMHQ or PTMHQA and optionally
one or more isomers thereof are produced according to STEP a, it is
sufficient to simply prolong the reaction time of STEP a to realize
STEP b, i.e. to prolong the reaction time for about 30 minutes to
about 240 minutes, to increase the amount of catalyst and/or to
increase the reaction temperature.
[0122] PROCESSES 3 and 3a
[0123] This reaction can be carried out using the same catalysts
under substantially the same reaction conditions as described above
for step a) of PROCESS 2 and 2a. Depending on the kind of catalyst,
the amount of catalyst and the reaction temperature the reaction
stops at the intermediates of the formula Ia/I or proceeds to the
end products of the formula VII/VIla.
[0124] PROCESS 4
[0125] This reaction can be carried out using the same catalysts
under substantially the same reaction conditions as described above
for step a) of PROCESS 2 and 2a. The reaction proceeds to the final
product of the formula X independent from the nature of the
catalyst, the amount of catalyst and the reaction temperature.
[0126] PROCESS 5A
[0127] According to still another aspect of this invention, a
compound of the formula VIIc such as e.g. .alpha.-tocopherol or
.gamma.-tocopherol, or any other tocol as described in DE-OS 21 60
103 on page 5 in the third and forth paragraph may be converted
into its alkanoate (a compound of the formula VIIIa), e.g. its
acetate, by treatment with an acylating agent in the presence of a
Lewis acid as the catalyst at reduced pressure, preferably at an
absolute pressure of below 0.9 bar, or under pressure, preferably
at an absolute pressure of at least 1.1 bar.
[0128] More preferably the absolute reaction pressure varies from
about 0.02 bar to about 0.9 bar (even more preferably from about
0.1 bar to about 0.9 bar, most preferably from about 0.2 bar to
about 0.9 bar) and from about 1.1 bar to about 10.0 bar (even more
preferably from about 1.1 bar to about 6.0 bar, even more, more
preferably from about 1.1 bar to about 5.0 bar, most preferably
from about 1.1 bar to about 3.0 bar).
[0129] Therefore, the invention is also directed to a process for
the manufacture of tocyl alkanoates in the presence of a Lewis acid
as the catalyst at reduced pressure, preferably at an absolute
pressure of below 0.9 bar, or under pressure, preferably at an
absolute pressure of at least 1.1 bar.
[0130] The acylation in accordance with that aspect of the
invention can be carried out using acylating agents conventionally
used in the acylation of tocopherols such as anhydrides or
halides.
[0131] Examples of these are anhydrides or halides of alkanoic
acids such as acetic acid, propionic acid, pivalic acid, succinic
acid, nicotinic acid and benzoic acid. Preferably, acetic anhydride
or acid chloride, especially acetic anhydride, are/is used.
[0132] The molar ratio of the compound of the formula VIIc to the
acylating agent in the reaction mixture conveniently varies from
about 1:1 to about 1:5, preferably from about 1:1 to about 1:3,
more preferably from about 1:1.1 to about 1:2.
[0133] Suitable Lewis acids are the ones named above.
[0134] The amount of the Lewis acid used as the catalyst is based
on the lesser molar amount of reactant, i.e. the compound of the
formula VIIc or the acylating agent, and can be in the range of
from about 0.006 mol % to about 2.0 mol %, preferably from about
0.0075 mol % to about 1.5 mol %, more preferably from about 0.01
mol % to about 1.0 mol %, in the batchwise mode of operation. For
continuous operation, the amount of catalyst will be adjusted to
the size of the reactor and the flow of the reactants. It will be
appreciated that the determination of the appropriate figures based
on the figures for batchwise operation is within normal skill. As
in the other processes of the invention the Lewis acid is added at
once, i.e. in its full amount. Preferably the catalyst is added as
an aqueous solution or suspension.
[0135] The temperature of the acylation is dependent on the
catalyst system used and the temperature the reactants (resulting
from former process steps) already have. The acylation reaction can
be generally carried out at temperatures from about 20 to about
200.degree. C., preferably from about 60 to about 180.degree. C.,
more preferably from about 80 to about 160.degree. C. When
indium(III) salts are used as the catalysts, the acylation reaction
is preferably carried out at temperatures below 120.degree. C.,
more preferably from about 15 to about 120.degree. C., most
preferably at room temperature, i.e. from about 15 to about
40.degree. C.
[0136] The reaction can be carried out essentially in the absence
of an additional organic solvent, which is preferred.
[0137] "Essentially in the absence of an additional organic
solvent" in the context of the present invention means that
essentially no organic solvent is present during the reaction and
that no organic solvent is deliberately added. It might, however,
be possible that traces of organic solvent are present in the
starting materials or the catalyst as impurities. In other words,
the reaction is carried out in substance; i.e. no other compound
except the compound of the formula VIIc, the acylating agent and
the catalyst is intendedly used for the reaction, so that at the
beginning of the reaction the amount of any substance except for
the starting material, the compound of the formula VIIc and the
acylating agent, and except for the catalyst in the reaction
mixture is <5 weight %, preferably <3 weight %, more
preferably <0.5 weight %, and that no further compound is added
during the reaction
[0138] Alternatively it is also possible to carry out the reaction
in the presence of an additional organic solvent, e.g.
pyridine.
[0139] The reaction is conveniently carried out under an inert gas
atmosphere, preferably gaseous nitrogen or argon.
[0140] It is a particular feature of the acylation according to the
present invention that when using chiral tocols and tocopherols,
e.g. (enantiomeric pure) (R,R,R)-.alpha.-tocopherol, the acylation
proceeds substantially without epimerization in the presence of
indium(III) salts as the catalysts and at a temperature below
120.degree. C., e.g. from about 20.degree. C. to about 120.degree.
C. Thus, if e.g. (R,R,R)-.alpha.-tocopherol is used as starting
material for PROCESS 5A, (R,R,R)-.alpha.-tocopheryl alkanoate is
obtained.
[0141] In especially preferred embodiments of PROCESS 5A
.alpha.-tocopherol (formula VIIb with n=3; see above),
.beta.-tocopherol (formula VII c with X.sup.1=X.sup.3=CH.sub.3,
X.sup.2=H and n=3), .gamma.-tocopherol (formula VII c with
X.sup.2=X.sup.3=CH.sub.3, X.sup.1=H and n=3) and .delta.-tocopherol
(formula VII c with X.sup.1=X.sup.2=H, X.sup.3=CH.sub.3 and n=3),
preferably .alpha.-tocopherol and .beta.-tocopherol, more
preferably .alpha.-tocopherol, are/is acylated to the appropriate
tocopheryl alkanoates (compounds of the formula VIII/VIIIa with n=3
and R, X.sup.1, X.sup.2 and X.sup.3 having the same meanings and
preferences as above). More preferred the appropriate acetates are
manufactured, especially with indium(III) salts (preferences see
above) as the catalysts and at a temperature below 120.degree. C.,
preferably at room temperature, i.e. a temperature between 15 and
40.degree. C.
[0142] PROCESS5B
[0143] It can be carried out using the same catalysts under
substantially the same reaction conditions as described above for
PROCESS 5A.
[0144] Process for the Manufacture of Formulations of
.alpha.-tocopherol or its Alkanoates
[0145] The .alpha.-tocopherol or its alkanoate obtained by one of
the processes of the present invention can further be formulated by
any method known to the person skilled in the art, e.g. as those
disclosed in U.S. Pat. No. 6,162,474, US 2001/0009679, U.S. Pat.
No. 6,180,130, U.S. Pat. No. 6,426,078, U.S. Pat. No. 6,030,645,
U.S. Pat. No. 6,150,086, U.S. Pat. No. 6,146,825, U.S. Pat. No.
6,001,554, U.S. Pat. No. 5,938,990, U.S. Pat. No. 6,530,684, U.S.
Pat. No. 6,536,940, US 2004/0053372, U.S. Pat. No. 5,668,183, U.S.
Pat. No. 5,891,907, U.S. Pat. No. 5,350,773, U.S. Pat. No.
6,020,003, U.S. Pat. No. 6,329,423, WO 96/32949, U.S. Pat. No.
5,234,695, WO 00/27362, EP 0 664 116, US 2002/0127303, U.S. Pat.
No. 5,478,569, U.S. Pat. No. 5,925,381, U.S. Pat. No. 6,651,898,
U.S. Pat. No. 6,358,301, U.S. Pat. No. 6,444,227, WO 96/01103 and
WO 98/15195.
[0146] The following Examples illustrate the invention further.
EXAMPLES
[0147] In the following examples minor amounts of the following
by-products were obtained:
[0148] PTMQ: phytyltrimethylquinone: 31
[0149] PTD: phytadienes=dehydrated by-products of IP (easily
separable);
[0150] BZF: benzofuranes: 32
[0151] Phytyl-toluene compounds and their double-bond isomers
(easily separable): 33
[0152] The analysis of the products was done by gas chromatography
(GC) using an internal standard.
[0153] Jeffsol EC50.RTM. is a solvent mixture available from
Huntsman Corp., PO Box 15730 Austin, Tex., USA/Antwerp 2030,
Belgium, which consists of ethylene carbonate and propylene
carbonate in the volume ratio 1:1.
[0154] If examples were carried out at "atmospheric pressure"
(comparative examples), this indicates that the reaction was
carried out at a pressure from about 0.96 bar to about 1.03
bar.
Examples 1-32
[0155] Processes with InCl.sub.3 or In(OTf).sub.3 as the
Catalyst
Examples 1-14
[0156] Preparation of PTMHO
Examples 1-3
[0157] InCl.sub.3 as the Catalyst
[0158] 12.88 mmol of TMHQ and 8.58 mmol of IP were reacted in the
solvent or solvent system given in Table 1 in the presence of
InCl.sub.3 as the catalyst (amounts of the catalyst given in Table
1) and at atmospheric pressure. The reaction time was 2 hours. For
further details and the results see Table 1.
Examples 4 and 5
[0159] In(OTf).sub.3 as the Catalyst
[0160] 12.88 mmol of TMHQ and 8.58 mmol of IP were reacted in a
mixture of 20 ml of heptane and 20 ml of Jeffsol EC 50.RTM. in the
presence of increasing amounts (see Table 1) of In(OTf).sub.3 as
the catalyst and at atmospheric pressure. For further details about
the reaction conditions and the results see Table 1.
1TABLE 1 The amount of THMQ was 12.88 mmol in all cases, the amount
of IP was 8.58 mmol in all cases. Yield of PTMHQ Amount Reaction
[%] - of catalyst Reaction time based on Example Catalyst [mol %]
Solvent temperature [hours] IP 1 InCl.sub.3 0.1 20 ml of Jeffsol
94.degree. C. 2 47.2 EC50 .RTM. + 20 ml of heptane 2 InCl.sub.3 2.0
20 g of butyl acetate reflux 2 60.2 3 InCl.sub.3 2.0 20 g of
diethylketone reflux 2 80.3 4 In(OTf).sub.3 0.01 20 ml of Jeffsol
94.degree. C. 12 58.7 EC50 .RTM. + 20 ml of heptane 5 In(OTf).sub.3
1.0 20 ml of Jeffsol 22.degree. C. 100.5 90.5 EC50 .RTM. + 20 ml of
heptane
Examples 6 and 7
[0161] InCl.sub.3 as the Catalyst
[0162] Varying amounts of TMHQ were reacted with 17.17 mmol of IP
in 45 ml of toluene at 110.degree. C. in the presence of 1.0 mol %
of InCl.sub.3-- based on IP--as the catalyst and at atmospheric
pressure. Further details and the results are presented in Table
2.
Example 8
[0163] In(OTf).sub.3 as the Catalyst
[0164] TMHQ (38.63 mmol) and IP (25.75 mmol, 97%, added during 1
hour) were reacted in a molar ratio of 1.5:1 in the presence of 1.0
mol % of In(OTf).sub.3 as the catalyst (amount based on IP) at
22.degree. C. and at atmospheric pressure. For further details and
the results see Table 2. After separation of the heptane phase and
washing of the heptane phase with Jeffsol EC50.RTM. (60 ml) the
resulting mixture (suspension in heptane) was filtered under
vacuum. The pasty nearly colorless solid was analysed by GC.
Example 9
[0165] In(OTf).sub.3 as the Catalyst
[0166] TMHQ (24.691 g, 161.1 mmol) and IP (38.833 ml, 107.4 mmol,
97%, added during 1 hour) were reacted in a molar ratio of 1.5:1 in
the presence of 1.0 mol % of In(OTf).sub.3 as the catalyst (amount
based on IP) at 22.degree. C. and at atmospheric pressure. For
further details and the results see Table 2. After separation of
the heptane phase and washing of the heptane phase with Jeffsol
EC50.RTM. (250 ml) the resulting suspension in heptane was filtered
under vacuum. The pasty nearly colorless solid was analysed by
quantitative GC.
2TABLE 2 The amount of catalyst was 1.0 mol % - based on IP - in
all cases. Example 6 7 8 9 Amount of 17.17 25.76 38.63 161 TMHQ
[mmol] Amount of IP 17.17 17.17 25.75 107 [mmol] Catalyst
InCl.sub.3 InCl.sub.3 In(OTf).sub.3 In(OTf).sub.3 Solvent Toluene
Toluene 60 ml of Jeffsol 250 ml of Jeffsol EC50 .RTM. + EC50 .RTM.
+ 60 ml of 250 ml of heptane heptane Reaction 110.degree. C.
110.degree. C. 22.degree. C. 22.degree. C. temperature Reaction
time 10 2 92 192 [hours] Yield of 63.9 73.6 88.7 59.7 PTMHQ - based
on IP
Examples 10-14
[0167] 200 mmol of TMHQ were reacted with 200 mmol of IP (examples
10 and 13) and 203 mmol of IP (examples 11, 12 and 14),
respectively, in the presence of increasing amounts of
In(OTf).sub.3 (example 10) or InCl.sub.3 (examples 11-14) as the
catalyst in 100 ml of an organic solvent. Examples 10 and 14 were
carried out under pressure, whereby examples 11-13 were carried out
at atmospheric pressure. For the reaction temperature, the
pressure, the reaction time and the type of solvent see Table
3.
3TABLE 3 The amount of solvent was 100 ml in all cases. The amount
of TMHQ was 200 mmol in all cases. In the examples 11, 12 and 14 a
molar excess of IP of 1.5 mol % based on the amount of TMHQ was
used. The yield of PTMHQ is based on IP. Catalyst Amount and its
Yield of of IP amount Reaction Pressure Reaction PTMHQ Example
[mmol] [mol %] Solvent temperature [bar] time [%] 10 200 0.001
Toluene 137.degree. C. 2 3 hours 35.0 In(OTf).sub.3 11 203 0.25
InCl.sub.3 Heptane 98.degree. C. 1 4 hours 61.2 12 203 0.5
InCl.sub.3 Heptane 98.degree. C. 1 3 hours 48.8 13 200 1.0
InCl.sub.3 Heptane 98.degree. C. 1 2 hours 43.4 14 203 2.0
InCl.sub.3 CH.sub.2Cl.sub.2 40.degree. C. + 4 23 hours + 52.9
86.degree. C. 22 hours
Examples 15-29
[0168] Preparation of (all-rac)-TCP
Examples 15-16
[0169] Preparation of (all-rac)-TCP at Atmospheric Pressure
[0170] In a 250 ml Buchi reactor or an autoclave equipped with a
stirrer, a thermometer, a pressure indicator, a Dean-Stark
separator, and a reflux condenser 30.447 g (200 mmol) of TMHQ
(99.97%), certain amounts of InCl.sub.3 (see Table 4; amounts based
on IP) and 100 ml of toluene were heated at 114.degree. C. under a
continuous nitrogen flow and under an absolute pressure of 1.0 bar.
74.035 ml (200 mmol) of IP (94.6%) were added at a feed rate of
1.234 ml per minute. Approximately 3.6 ml water were collected
until the end of the reaction. After completion of the addition the
reaction mixture was stirred for 1 hour at 114.degree. C. and
cooled down to room temperature. The reaction mixture was
concentrated under reduced pressure (45.degree. C. at 95 to 15
mbar). (all-rac)-TCP was obtained as a viscous oil. For the results
see Table 4.
Examples 17-18
[0171] Preparation of (all-rac)-TCP Under Pressure
[0172] Examples 15 and 16 were repeated, but the reaction was
carried out at 137.degree. C. under an absolute pressure of 2 bar.
After 1 hour at 137.degree. C. the reaction mixture was cooled down
to room temperature and once at room temperature the pressure was
released. For the results see Table 4, 5 (example 18 only) and 12
(example 18 only).
Example 19
[0173] Preparation of (all-rac)-TCP Under Pressure
[0174] In a 250 ml Buchi reactor or an autoclave equipped with a
stirrer, a thermometer, a pressure indicator, a Dean-Stark
separator, and a reflux condenser, 30.447 g (200 mmol) of TMHQ
(99.97%,), 5 ml of InCl.sub.3 (0.2 M aqueous solution, 0.5 mol %, 1
mmol) and 100 ml of heptane were heated at 147.degree. C. under a
continuous nitrogen flow and under an absolute pressure of 3.4 bar.
75.304 ml (203 mmol) of IP (94.6%) were added at a feed rate of
0.605 ml per minute. Approximately 3.6 ml water were collected
until the end of the reaction. After completion of the addition the
reaction mixture was stirred for 1 hour at 147.degree. C. and
cooled down to room temperature. Then the pressure was released.
The reaction mixture was concentrated under reduced pressure
(45.degree. C. at 110 to 15 mbar). (all-rac)-TCP was obtained as a
viscous oil (91.51 g). The yield was 92.0%--based on IP. For the
results see Table 4, 6, 7, 8 and 12.
4TABLE 4 Comparison between experiments at atmospheric pressure and
under pressure in toluene with InCl.sub.3 as the catalyst. The
conversion of IP was 100% in all cases. Amount Yield of of Reaction
Pres- TCP [%] = Ex- catalyst temperature sure Selectivity ample
Catalyst [mol %] Solvent [.degree. C.] [bar] for TCP [%] 12
InCl.sub.3 0.5 heptane 98 1.0 18.5 15 InCl.sub.3 0.5 toluene 114
1.0 59.8 16 InCl.sub.3 2.0 toluene 114 1.0 90.1 17 InCl.sub.3 0.5
toluene 137 2.0 81.2 18 InCl.sub.3 2.0 toluene 137 2.0 95.7 19
InCl.sub.3 0.5 heptane 147 3.4 92.0
Examples 20 and 22 (*)
[0175] Preparation of (all-rac)-TCP with InCl.sub.3 as the Catalyst
in Different Solvents and Under Pressure
[0176] 200 mmol of TMHQ and 203 mmol of IP (corresponding a molar
excess of 1.38 mol %--based on the amount of TMHQ) were reacted in
100 ml of toluene at 137.degree. C. or in 100 ml of heptane at
147.degree. C. The IP was added during 120 minutes. Afterwards the
mixture was reacted for further 60 minutes. All yields and
selectivities (given in Table 5) are based on IP. See also Table
6.
Examples 21, 23 and 24
[0177] Preparation of (all-rac)-TCP with Different Amounts of
Indium Salts as the Catalyst and Under Pressure
[0178] 200 mmol of TMHQ and 200 mmol of IP were reacted in 100 ml
of toluene at 137.degree. C. or in 100 ml of heptane at 147.degree.
C. The IP was added during 60 minutes. Afterwards the mixture was
reacted for further 60 minutes. All yields and selectivities (given
in Table 5) are based on IP.
5TABLE 5 Influence of the counterion of the indium salt. The amount
of catalyst was 2.0 mol %, based on IP, in all cases. The
conversion of IP was 100% in all cases. Yield of IP addition TCP
[%] = time Pressure Selectivity Example Catalyst Solvent [hour/s]
[bar] for TCP [%] 18 InCl.sub.3 Toluene 1 2.0 95.7 20* InCl.sub.3
Toluene 2 2.0 95.5 21 InCl.sub.3 Heptane 1 3.4 89.5 22* InCl.sub.3
Heptane 2 3.4 93.9 23 In(OTf).sub.3 Toluene 1 2.0 72.3 24
In(OTf).sub.3 Heptane 1 3.4 65.6 *molar excess of IP of 1.38%
[0179] With InCl.sub.3 excellent yields were obtained in both
solvents, heptane and toluene. The selectivity for the formation of
the desired 6-membered ring product (all-rac)-TCP with this
catalyst was very high compared to results with In(OTf).sub.3 as a
difference of 28 to 30% for the selectivity was observed.
[0180] It was also found that in heptane a small excess of IP
(+1.38 mol %) led to a much better yield (see Table 5, example 22)
than carrying out the reaction with equimolar amounts of IP and
TMHQ. In fact, (all-rac)-TCP could be isolated in 93.9% yield after
work-up. It has to be emphasized that at atmospheric pressure a
TMHQ/IP ratio of 1.5/1 had to be used whereas, under pressure, an
equimolar ratio was sufficient to produce the desired chroman ring
compound (all-rac)-TCP in excellent yield.
[0181] It is noteworthy that the proportion of TMHQ used for these
reactions under pressure was twenty-fold higher than at atmospheric
pressure (4 mol/L instead of 0.2 mol/L) and it did not affect the
yield of the reaction.
Example 25
[0182] Preparation of (all-rac)-TCP with InCl.sub.3 as the Catalyst
and Under Pressure
[0183] 200 mmol of TMHQ and 203 mmol of IP were reacted in 100 ml
of toluene at 137.degree. C. The IP was added during 120 minutes.
The reaction mixture was then further reacted for another 60
minutes. The yield--based on IP--is given in Table 6. See also
Table 7.
Example 26
[0184] Preparation of (all-rac)-TCP with InCl.sub.3 as the Catalyst
and Under Pressure
[0185] 200 mmol of TMHQ and 203 mmol of IP were reacted in 100 ml
of toluene at 137.degree. C. The IP was added during 120 minutes.
The reaction mixture was then reacted for further 566 minutes. The
yield--based on IP--is given in Table 6.
Example 27
[0186] Preparation of (all-rac)-TCP with InCl.sub.3 as the Catalyst
and Under Pressure
[0187] 200 mmol of TMHQ and 203 mmol of IP were reacted in 100 ml
of heptane at 147.degree. C. The IP was added during 120 minutes.
The reaction mixture was then further reacted for another 120
minutes. The yield--based on IP--is given in Table 6.
6TABLE 6 Influence of the amount of InCl.sub.3. The conversion of
IP was 100% in all cases. Amount Yield of TCP [%] = Selectivity of
InCl.sub.3 Pressure for TCP Example [mol %] Solvent [bar] [%] 12
0.5 Heptane 1.0 18.5 19 0.5 Heptane 3.4 92.0 20 2.0 Toluene 2.0
95.5 22 2.0 Heptane 3.4 93.9 25 0.5 Toluene 2.0 90.2 26 0.25
Toluene 2.0 85.1 27 0.25 Heptane 3.4 81.5
[0188] When the amount of InCl.sub.3 was reduced to 0.25 mol %
(all-rac)-TCP was still obtained in good yield (see Table 6,
examples 26 and 27). However a longer reaction time (e.g. up to 566
minutes in toluene, example 26) was needed to obtain nearly total
ring closure.
[0189] It appeared that best results were obtained (selectivity
(yield)) for (all-rac)-TCP using a catalyst amount of 0.5 mol % to
2% InCl.sub.3, especially in heptane. In toluene and in heptane,
the desired chroman product (all-rac)-TCP could be isolated in 90.2
up to 96.0% yield.
Example 28
Preparation of (all-rac)-TCP in Cyclohexane at an Absolute Pressure
of 4.0 Bar
[0190] 200 mmol of TMHQ and 203 mmol of IP were reacted in 100 ml
of cyclohexane at 135.degree. C. and under an absolute pressure of
4.0 bar in the presence of 0.5 mol % of InCl.sub.3--based on IP.
The IP was added during 120 minutes. Afterwards the mixture was
reacted for further 380 minutes. The yield of (all-rac)-TCP given
in Table 7 is based on IP.
Example 29
[0191] Preparation of (all-rac)-TCP in Hexane Under Pressure
[0192] 200 mmol of TMHQ and 203 mmol of IP were reacted in 100 ml
of hexane in the presence of 0.5 mol % of InCl.sub.3--based on IP.
The IP was added during 120 minutes at 125.degree. C. and under an
absolute pressure of 4.0 bar. Afterwards the mixture was reacted
for further 180 minutes at 125.degree. C. and under an absolute
pressure of 4.0 bar and further 206 minutes at 135.degree. C. and
under an absolute pressure of 5.1 bar. The yield of (all-rac)-TCP
given in Table 7 is based on IP.
7TABLE 7 Influence of the solvent. The conversion of IP was 100% in
all cases. Yield of TCP Temperature [%] = Selectivity of the
Pressure for TCP Example Solvent reaction mixture [bar] [%] 19
Heptane 145.degree. C. 3.4 92.0 25 Toluene 137.degree. C. 2.0 90.2
28 Cyclohexane 135.degree. C. 4.0 86.6 29 Hexane 125/135.degree. C.
4.0/5.1 75.1
[0193] One of the advantages of heptane compared to toluene was the
absence of by-products such as phytyl-toluene compounds due to the
solvent.
Examples 19(-a)-19-e
[0194] Reproducibility
[0195] All reactions were carried out in 100 ml of heptane with 200
mmol of TMHQ, 203 mmol of IP, 0.5 mol % of InCl.sub.3 under an
absolute pressure of 3.4 bar and at 147.degree. C. IP as added
within 120 minutes. The reaction time was 60 minutes. All yields
are based on IP. The results are summarized in Table 8.
8TABLE 8 Test of reproducibility, total conversion of IP: Yield of
TCP [%] = Selectivity for TCP Example [%] 19 (-a) 92.0 19-b 91.8
19-c 90.6 19-d 92.3 19-e 91.2
[0196] An excellent reproducibility was found as only a 1.04%
maximum variation of the yield was observed with an average yield
of 91.6% over five experiments.
Examples 30-37
[0197] Processes with Sc(OTf).sub.3 as the Catalyst
Examples 30-31
[0198] Preparation of (all-rac)-TCP with Azeotropic Removal of
Water
[0199] In a Buchi reactor with a Dean-Stark separator 200 mmol of
TMHQ and 200 mmol of IP were reacted in 100 ml of toluene in the
presence of 0.1 mol % of Sc(OTf).sub.3--based on IP. The IP was
added during 60 minutes at the temperature and at the pressure
given in Table 9. Afterwards the mixture was reacted for further 60
minutes at the same temperature and pressure. The yield and
selectivity of (all-rac)-TCP given in Table 9 is based on IP.
Example 32
[0200] Preparation of (all-rac)-TCP without Azeotropic Removal of
Water
[0201] In an autoclave reactor 200 mmol of TMHQ and 200 mmol of IP
were reacted in 100 ml of toluene in the presence of 0.1 mol % of
Sc(OTf).sub.3--based on IP. The IP was added during 60 minutes at
an absolute pressure of 3.6 bar and at a temperature of 140.degree.
C. Afterwards the mixture was reacted for further 60 minutes at the
same temperature and pressure. The yield and selectivity of
(all-rac)-TCP given in Table 9 is based on IP.
Example 33
[0202] Preparation of (all-rac)-TCP without Azeotropic Removal of
Water
[0203] In a 250 ml autoclave reactor equipped with a mechanical
stirrer, a thermometer and a pressure indicator 34.396 g (221 mmol)
of TMHQ (98%), 1 mmol of Sc(OTf).sub.3 (0.5 mol %--based on IP) and
50 ml of toluene were heated at 140.degree. C. under nitrogen
atmosphere and under an absolute pressure of 5.6 bar. 72.350 ml
(200 mmol) of IP (97%) were added at a feed rate of 2.412 ml per
minute. After completion of the addition the reaction mixture was
stirred for one hour at 140.degree. C., cooled down to room
temperature and when room temperature was reached the pressure was
released. The reaction mixture was concentrated under reduced
pressure (45.degree. C. at 95 to 15 mbar). A viscous oil (94.76 g)
was obtained and analysed by quantitative GC. The yield of
(all-rac)-TCP was 81.4% - based on IP.
Examples 34 and 35
[0204] Preparation of (all-rac)-TCP with Azeotropic Removal of
Water
[0205] Examples 30 and 31 were repeated, but instead of 0.1 mol %
of Sc(OTf).sub.3 1.0 mol % of Sc(OTf).sub.3 were used. The yield
and selectivity of (all-rac)-TCP, based on IP, is given in Table
9.
Example 36
[0206] Example 35 was repeated but the reaction was carried out at
a higher temperature and at a higher pressure. For details and the
results see Table 9 and 12.
Example 37
[0207] Preparation of (all-rac)-TCP without Azeotropic Removal of
Water
[0208] Example 32 was repeated, but instead of 0.1 mol % of
Sc(OTf).sub.3 1.0 mol % of Sc(OTf).sub.3 were used. The yield and
selectivity of (all-rac)-TCP, based on IP, is given in Table 9.
9TABLE 9 Comparison between experiments at atmospheric pressure and
under pressure in toluene with Sc(OTf).sub.3 as the catalyst. Yield
of Amount Temperature TCP [%] = of Azeotropic Pres- of selectivity
Sc(OTf).sub.3 removal sure reaction for Example [mol %] of water
[bar] mixture TCP [%] 30 0.1 yes 1.0 110.degree. C. 78.2 31 0.1 yes
2.0 137.degree. C. 74.5 32 0.1 no 3.6 140.degree. C. 72.6 33 0.5 no
5.6 140.degree. C. 81.4 34 1.0 yes 1.0 110-117.degree. C. 80.7 35
1.0 yes 2.0 137.degree. C. 81.6 36 1.0 yes 2.2 150.degree. C. 84.0
37 1.0 no 3.6 140.degree. C. 78.8
Examples 38-47
[0209] Processes with Fe/HCl as the Catalyst
Example 38
[0210] Preparation of (all-rac)-TCP in a Buchi Reactor
[0211] In a 500 ml Buchi reactor equipped with a stirrer, a
thermometer, a pressure indicator, a Dean-Stark separator and a
reflux condenser 91.3 g (595 mmol) of TMHQ (99.5%), 0.16 g (2.86
mmol) of iron powder and 137 g of toluene were heated to
140.degree. C. under a continuous argon flow and under an absolute
pressure of 1.9 bar. When the temperature of the reaction mixture
was 140.degree. C. hydrogen chloride was added to the reaction
mixture at a feed rate of 0.333 g per minute for the next 5 hours
(30 minutes of saturation, 4 hours addition of IP and 30 minutes
further reaction afterwards; altogether 100 g of gaseous HCl were
used during these 5 hours). After 30 minutes under hydrogen
chloride flow at 136.degree. C. and under an absolute pressure of
2.05 bar, 187.9 g (616 mmol) of IP (97.5%) were added at a feed
rate of 0.78 g per minute. During the addition of IP (4 hours) the
temperature of the reaction mixture increased from 136.degree. C.
to 146.degree. C. Approximately 14 ml of aqueous phase were
collected until the end of the reaction. After the addition of IP
was completed the reaction mixture was stirred for further 30
minutes at 146.degree. C., then the hydrogen chloride flow was
stopped, replaced by an argon flow and the solution was cooled down
to room temperature. When room temperature was reached the pressure
was released. The reaction mixture was concentrated under reduced
pressure (45.degree. C. at 95 to 15 mbar). A viscous oil (270.2 g)
was obtained and analysed by quantitative GC. The yield of
(all-rac)-TCP was 91.5%--based on IP.
Examples 39-42
[0212] Preparation of (all-rac)-TCP Under Pressure
[0213] Example 38 was repeated with the same amounts of TMHQ, IP
and Fe. The amount of HCl and the time for the addition of IP were,
however, different. The pressure, under which the reaction was
carried out was also slightly different in the examples 39-41. For
further details and the results see Table 10 and 13 (examples 41
and 42 only).
Examples 43-46
[0214] Preparation of (all-rac)-TCP at Atmospheric Pressure
[0215] In a Buchi reactor with a Dean-Stark separator 600 mmol of
TMHQ and varying amounts of IP(see Table 10) were reacted in 137 g
of toluene (only example 48 and 49: 171.1 g toluene) in the
presence of varying amounts of iron powder and fed gaseous HCl (see
Table 10). The gaseous HCl was added with a feed rate of 0.333 g
per minute to the TMHQ in toluene. The mixture of TMHQ and toluene
was saturated with HCl during 30 minutes before the IP was added
during the time given in Table 10 and at an absolute pressure of
1.0 bar under a continuous HCl flow. After the complete addition of
IP the mixture was reacted for further 30 minutes at the same
temperature and pressure and the continuous HCl flow. Then the HCl
flow was stopped and the reaction mixture worked-up. The yield and
selectivity of (all-rac)-TCP given in Table 10 is based on IP.
Example 47
[0216] Preparation of (all-rac)-TCP Under Pressure
[0217] Example 46 was repeated but the reaction was carried out
under an absolute pressure of 2.1 bar instead of 1.0 bar. Further
details and the results are shown in Table 10.
10TABLE 10 Comparison between experiments at atmospheric pressure
(examples 43-46) and under pressure (examples 38-42 and 47) in
toluene (under reflux) with Fe/HCl as the catalyst; the conversion
of IP was 100% in all cases. All yields and selectivities are based
on IP. Yield of IP TCP [%] = TMHQ/IP Amount addition Pres-
Selectivity Ex- [mmol/ of Fe HCl time sure for ample mmol] [mol %]
[10.sup.-3 kg] [hour/s] [bar] TCP [%] 38 595/617 0.5 100.1 4 2.1
91.5 39 595/617 0.5 139.3 6 2.0 91.6 40 595/617 0.5 41.0 1 2.0 93.2
41 595/617 0.5 39.9 1 2.0 92.0 42 595/617 0.5 60.2 2 2.1 93.2 43
600/616 0.5 60.0 2 1.0 26.0 44 600/617 0.5 99.9 4 1.0 89.4 45
600/617 0.5 138.9 6 1.0 89.6 46 600/570 13.7 59.9 2 1.0 7.2 47
600/570 13.7 59.9 2 2.1 92.7
Examples 48-53
[0218] Processes with ZnCl.sub.2/HCl as the Catalyst
Example 48
[0219] Preparation of (all-rac)-TCP in Heptane in the Absence of an
Amine at Atmospheric Pressure
[0220] 322 mmol of TMHQ and 320 mmol of IP were reacted in 163.3 g
of heptane under reflux in the presence of ZnCl.sub.2 and gaseous
HCl as the catalyst (amounts see Table 11). The reaction was
carried out at 1.0 bar. Further details and the results are given
in Table 11.
Example 49
[0221] Preparation of (all-rac)-TCP in Heptane in the Absence of an
Amine Under Pressure
[0222] Example 48 was repeated, but the reaction carried out under
an absolute pressure of 2.1 bar and not at 1.0 bar. Further details
and the results are given in Table 11.
Example 50
[0223] Preparation of (all-rac)-TCP in Hexane in the Presence of an
Amine Under Pressure
[0224] In a 500 ml Buchi reactor equipped with a stirrer, a
thermometer, a pressure indicator, a Dean-Stark separator and a
reflux condenser 60 g (394 mmol) of TMHQ (99.5%), 12.5 g (91.7
mmol) of ZnCl.sub.2, 1.2 g of tridecylamine and 177.7 g of hexane
were heated to 92.degree. C. under a continuous argon flow and
under an absolute pressure of 2.2 bar. When the temperature of the
reaction mixture had reached 92.degree. C. gaseous hydrogen
chloride was added to the reaction mixture at a feed rate of 0.035
g per minute to saturate the reaction mixture with HCl. (The HCl
flow was continued during the addition of IP and the further
reaction time, i.e. gaseous HCl was added during 2.5 hours.) After
30 minutes under hydrogen chloride flow at 94.degree. C. and at an
absolute pressure of 2.2 bar, 122.6 g (403 mmol) of IP (97.5%) were
added at a feed rate of 2.05 g per minute. During the addition of
IP the temperature of the reaction mixture increased from
94.degree. C. to 100.degree. C. Approximately 7.4 ml of an aqueous
phase were collected until the end of the reaction. After all IP
was added the reaction mixture was stirred for further 60 minutes
at 102.degree. C., then the hydrogen chloride flow was stopped (A
total of 5.3 g of hydrogen chloride were used during the 2.5
hours.), replaced by an argon flow and the solution was cooled down
to room temperature. When room temperature was reached, the
pressure was released. The reaction mixture was concentrated under
reduced pressure (45.degree. C. at 110 to 15 mbar). A viscous oil
(176.88 g) was obtained and analysed by quantitative GC. The yield
of (all-rac)-TCP was 94.9%--based on IP.
Example 51
[0225] Preparation of (all-rac)-TCP in Hexane in the Presence of an
Amine Under Pressure
[0226] Example 50 was repeated, but instead of 403 mmol of IP 404
mmol of IP were added and instead of 5.3 g of gaseous HCl 49.9 g of
gaseous HCl were used. For further details and the results see
Table 11.
Example 52
[0227] Preparation of (all-rac)-TCP in Hexane in the Presence of an
Amine at Atmospheric Pressure
[0228] Example 51 was repeated with the amounts of TMHQ, IP,
ZnCl.sub.2, tridecyl amine and gaseous HCl given in Table 11. The
reaction, however, was not carried out at 2.2 bar, but at 1.0 bar.
The results are presented in Table 11.
Example 53
[0229] Preparation of (all-rac)-TCP in Heptane in the Presence of
an Amine at Atmospheric Pressure
[0230] Example 51 was repeated with the amounts of TMHQ, IP,
ZnCl.sub.2, tridecyl amine and gaseous HCl given in Table 11. The
reaction, however, was not carried out in hexane, but in heptane.
The results are presented in Table 11 and 13.
11TABLE 11 Comparison between experiments at atmospheric pressure
(1.0 bar) and under pressure (2.1-2.2 bar) in heptane under reflux
(examples 48, 49 and 53) or hexane under reflux (examples 50-52)
with ZnCl.sub.2/HCl.sub.(g) as the catalyst. IP was added during
one hour in all cases. All yields and selectivities are based on
IP. The conversion of IP was 100% in all cases. Amount of Yield of
TCP ZnCl.sub.2 Tridecyl [%] = Selectivity TMHQ/IP [mol %] - amine
HCl Pressure for TCP Example [mmol/mmol] based on IP [10.sup.-3 kg]
[10.sup.-3 kg] [bar] [%] 48 322/320 18.3 0 39.9 1.0 75.9 49 322/320
18.3 0 40.0 2.1 86.6 50 394/403 22.7 1.2 5.3 2.2 94.9 51 394/404
22.7 1.2 49.9 2.2 94.1 52 394/402 22.8 1.2 50.0 1.0 77.8 53 394/400
22.8 1.2 49.9 2.2 91.0
Examples 18, 19-d, 23
[0231] Amount of By-Products
[0232] For these five experiments the precise analytical data
concerning the by-products are given in Table 12.
12TABLE 12 Detailed results and comparison of selectivity for Lewis
acids as the catalyst. Example 18 19-d 23 34 36 Amount of 200/200
200/203 200/200 200/200 200/200 TMHQ to IP [mmol/mmol] Catalyst
InCl.sub.3 InCl.sub.3 In(OTf).sub.3 Sc(OTf).sub.3 Sc(OTf).sub.3
Amount of 2.0 0.5 2.0 1.0 1.0 catalyst [mol %] Solvent toluene
heptane toluene toluene toluene Temperature of 137 147 137 110-117
150 the reaction mixture [.degree. C.] Pressure [bar] 2.0 3.4 2.0
1.0 2.2 Time for the 60 126 60 60 60 addition of IP [minutes] Crude
product 94.42 92.96 101.4 90.22 94.69 [10.sup.-3 kg] Assay of DHTC
0.00 0.15 0.00 0.00 0.00 according to GC [%] Assay of BZF 0.33 0.31
7.43 3.83 2.70 according to GC [%] Assay of TCP 87.28 86.84 61.45
76.72 76.40 according to GC [%] Yield of TCP [%] 95.7 93.7 72.3
80.7 84.0
[0233] As already stated, InCl.sub.3 shows a higher selectivity for
the formation of TCP than In(OTf).sub.3 and Sc(OTf).sub.3.
13TABLE 13 Detailed results and comparison of selectivity for a
mixture of Bronsted with Lewis acids as the catalyst Example 41 42
53 Amount of TMHQ to IP 595/617 595/617 394/400 [mmol/mmol]
Catalyst Fe + HCl Fe + HCl ZnCl.sub.2 + HCl + tri- decyl amine
Amount of catalyst [mol %] 0.5 Fe 0.5 Fe 23.0 ZnCl.sub.2 Amount of
gaseous HCl [g] 39.9 60.2 49.9 Solvent toluene toluene heptane
Temperature of the 135-146.degree. C. 137-147.degree. C.
106-109.degree. C. reaction mixture Pressure [bar] 2.0 2.1 2.2 Time
for the addition of IP 60 minutes 120 minutes 60 minutes Crude
product [10.sup.-3 kg] 271.2 270.9 176.69 Assay of DHTC according
to 0.54 0.39 0.05 GC [%] Assay of BZF according to 0.24 0.38 1.23
GC [%] Assay of TCP according to 90.0 91.3 88.9 GC [%] Yield of TCP
[%] 92.0 93.2 91.0
Example 54
[0234] Preparation of (all-rac)-3,4-dehydro-.alpha.-tocopherol
[0235] 15.22 g (99.2 mmol) of TMHQ (99.2%), 29 mg (0.5 mmol) of
iron powder and 70 ml of toluene were added to a 200 ml flask
equipped like the Buchi reactor and the resulting beige suspension
was stirred at 750 rounds per minute. The reaction mixture was
heated to 111.degree. C. at a constant heating rate of 2 K per
minute. HCl was added at a flow rate of 33.8 ml per minute and
argon was added at a flow rate of 3.5 ml per minute. After 45
minutes the reaction temperature of 111.degree. C. had been reached
and 31.01 g (102.4 mmol) of 1,2-dehydroisophytol (97.3%; from
Teranol in Lalden, Switzerland) were added at a feed rate of 0.138
g per minute during 225 minutes. During the addition of the
1,2-dehydroisophytol toluene was slowly distilled off in order to
keep the volume of the solution constant during all the reaction.
The reaction temperature also increased from 111.degree. C. to
157.degree. C. After completion of the addition of
1,2-dehydro-isophytol the reaction mixture was stirred at this
temperature for 45 minutes and cooled down to room temperature.
When the heating was switched off, the HCl flow was stopped and
replaced by a stronger argon flow. After 1 hour the temperature of
the reaction mixture was 60.degree. C. The reaction mixture was
then concentrated under reduced pressure (60.degree. C. at 300 to
18 mbar). The resulting oil was further concentrated under reduced
pressure (60.degree. C. at 0.3 to 0.1 mbar) during more than 2
hours to yield the crude product (45.6 g). A qualitative GC
analysis of the crude product showed that it contained mainly TMHQ
(25.6%) and (all-rac)-3,4-dehydro-.a- lpha.-tocopherol (21.1%). The
crude product was purified by two successive column
chromatographies (first with ethyl acetate/hexane=1/9 (v/v; silica
gel 60 (Merck), particle size 0.063-0.2 mm) and finally with ethyl
acetate/hexane=1/19 (v/v)) to yield
(all-rac)-3,4-dehydro-.alpha.-tocophe- rol (5.23 g, GC 81.7%, 10.0%
isolated yield, 44.1% yield based on conversion).
* * * * *