U.S. patent application number 16/150925 was filed with the patent office on 2019-01-31 for process for preparing biphenyl compounds.
The applicant listed for this patent is Centre national de la recherche scientifique, INSTITUT POLYTECHNIQUE DE BORDEAUX, UNIVERSITE DE BORDEAUX. Invention is credited to Stephane CARLOTTI, Henri CRAMAIL, Etienne GRAU, Stephane GRELIER, Audrey LLEVOT.
Application Number | 20190032098 16/150925 |
Document ID | / |
Family ID | 51799055 |
Filed Date | 2019-01-31 |
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United States Patent
Application |
20190032098 |
Kind Code |
A1 |
GRELIER; Stephane ; et
al. |
January 31, 2019 |
PROCESS FOR PREPARING BIPHENYL COMPOUNDS
Abstract
A process is provided for preparing a compound having the
formula (I): ##STR00001## said process being conducted by: a) the
addition of an oxygen source into a solution of a compound of
formula (II) ##STR00002## in a water-miscible solvent, b) the
addition of a laccase in the solution obtained in a); and c) the
possible recovering of the compound of formula (I) thus
obtained.
Inventors: |
GRELIER; Stephane;
(Parentis-en born, FR) ; CRAMAIL; Henri; (SAINTE
TERRE, FR) ; LLEVOT; Audrey; (BORDEAUX, FR) ;
CARLOTTI; Stephane; (PESSAC, FR) ; GRAU; Etienne;
(TALENCE, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNIVERSITE DE BORDEAUX
INSTITUT POLYTECHNIQUE DE BORDEAUX
Centre national de la recherche scientifique |
BORDEAUX
TALENCE
PARIS |
|
FR
FR
FR |
|
|
Family ID: |
51799055 |
Appl. No.: |
16/150925 |
Filed: |
October 3, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15516318 |
Mar 31, 2017 |
10155969 |
|
|
PCT/EP2015/072957 |
Oct 5, 2015 |
|
|
|
16150925 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 303/28 20130101;
C07C 253/30 20130101; C07C 45/71 20130101; C07C 43/215 20130101;
C12P 7/00 20130101; C07C 255/54 20130101; C12P 7/44 20130101; C12P
7/26 20130101; C12P 7/22 20130101; C07C 69/94 20130101; C12P 7/62
20130101; C07C 41/16 20130101; C12P 7/66 20130101; C07C 49/255
20130101; C12P 7/24 20130101; C07C 67/31 20130101; C07C 51/09
20130101; C07D 303/27 20130101; C07C 41/26 20130101; C07C 67/343
20130101; C12Y 110/03002 20130101; C07C 41/30 20130101; C07C 67/08
20130101; C12P 13/002 20130101; C07C 67/343 20130101; C07C 69/94
20130101; C07C 67/31 20130101; C07C 69/94 20130101; C07C 67/08
20130101; C07C 69/94 20130101; C07C 41/26 20130101; C07C 43/23
20130101; C07C 45/71 20130101; C07C 49/255 20130101; C07C 51/09
20130101; C07C 63/331 20130101; C07C 41/30 20130101; C07C 43/215
20130101; C07C 41/16 20130101; C07C 43/215 20130101; C07C 253/30
20130101; C07C 255/54 20130101 |
International
Class: |
C12P 13/00 20060101
C12P013/00; C07C 45/71 20060101 C07C045/71; C12P 7/62 20060101
C12P007/62; C07C 67/08 20060101 C07C067/08; C07C 255/54 20060101
C07C255/54; C07C 41/26 20060101 C07C041/26; C07C 41/16 20060101
C07C041/16; C07C 41/30 20060101 C07C041/30; C07C 67/31 20060101
C07C067/31; C07D 303/28 20060101 C07D303/28; C12P 7/44 20060101
C12P007/44; C12P 7/00 20060101 C12P007/00; C07C 43/215 20060101
C07C043/215; C12P 7/66 20060101 C12P007/66; C07C 51/09 20060101
C07C051/09; C07C 69/94 20060101 C07C069/94; C07C 67/343 20060101
C07C067/343; C07C 253/30 20060101 C07C253/30; C07D 303/27 20060101
C07D303/27; C12P 7/24 20060101 C12P007/24; C12P 7/26 20060101
C12P007/26; C12P 7/22 20060101 C12P007/22; C07C 43/23 20060101
C07C043/23; C07C 49/255 20060101 C07C049/255; C07C 63/331 20060101
C07C063/331 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 3, 2014 |
EP |
14306566.2 |
Claims
1. A process for preparing a compound having the formula (I):
##STR00057## wherein: R.sub.1 is H or OH; R.sub.2 is a
(C.sub.1-C.sub.6)alkoxy group; R.sub.3 is H or forms a C.dbd.O
group with the carbon atom carrying it; R.sub.4 is R or R'; R being
chosen from the group consisting of: --CHO, --CN, --COR.sub.a,
--COOR.sub.a, --R.sub.a, and (C.sub.2-C.sub.6)alkenyl groups,
R.sub.a being a (C.sub.1-C.sub.6)alkyl group; R' being a
(C.sub.1-C.sub.6)alkoxy group; and wherein, when the bond `a`
linking the cores A and B is a single bond, then the compound of
formula (I) has the following formula (I-1): ##STR00058## and when
the bond `a` linking the cores A and B is a double bond, then the
compound of formula (I) has the following formula (I-2):
##STR00059## said process comprising: a) the addition of an oxygen
source into a solution of a compound of formula (II) in a
water-miscible solvent, said compound of formula (II) having the
following formula: ##STR00060## wherein R.sub.1, R.sub.2, and
R.sub.4 are as defined above in formula (I), and R'.sub.3 is H when
R.sub.1 is OH and R'.sub.3 is OH when R.sub.1 is H, said
water-miscible solvent being chosen from the group consisting of:
dioxane, DMSO, acetone, and mixtures thereof; b) the addition of a
laccase in the solution obtained after a); and c) the recovering of
the compound of formula (I) thus obtained.
2. The process of claim 1, wherein the water-miscible solvent is
acetone.
3. The process of claim 1, wherein the laccase is from Trametes
versicolor.
4. The process of claim 1, wherein the amount of laccase for one
gram of compound of formula (II) is from 1.5 mg to 75 mg.
5. The process of claim 1, wherein the solution of the compound of
formula (II) in a water-miscible solvent is prepared by adding said
compound of formula (II) in said water-miscible solvent, and adding
a buffer solution.
6. The process according to claim 5, wherein the amount of
water-miscible solvent is comprised between 5% and 10% of volume in
comparison with the total volume of the mixture formed by said
solvent and the buffer solution.
7. The process of claim 1, wherein the addition of an oxygen source
according to a) is carried out for a sufficient time to saturate
the solution in dissolved oxygen.
8. The process of claim 1, wherein the solution of the compound of
formula (II) in the water-miscible solvent used for b) is saturated
in oxygen.
9. The process of claim 1, wherein the pH of the solution of the
compound of formula (II) in the water-miscible solvent is comprised
between 4 and 7.
10. The process of claim 1, wherein step c) is a step of recovering
the compound of formula (I) by centrifugation or filtration.
11. The process of claim 1, wherein the amount of laccase for one
gram of compound of formula (II) is from 3 mg to 15 mg.
12. The process of claim 5, wherein the buffer solution is a sodium
acetate buffer.
13. The process of claim 7, wherein the addition of an oxygen
source according to step a) is carried out for 5 minutes.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/516,318, filed Mar. 31, 2017, which is a
371 application of International Application PCT/EP2015/072957,
filed Oct. 5, 2015, and which claims the benefit of European Patent
Office application Serial No. 14306566.2, filed Oct. 3, 2014, all
of said applications incorporated herein by reference.
[0002] The present invention concerns a new process for preparing
biphenyl compounds.
[0003] Aromatic compounds constitute basic chemicals to manufacture
everyday life items. Indeed, they play a key role in
pharmaceutical, perfumes, dyestuff and polymer industries. In
plastic industry, aromatic units offer rigidity, hydrophobicity and
fire resistance to the derived polymers. Aromatic polyesters, such
as poly(alkyleneterephtalate)s are widely commercially used,
especially in food packaging and textile field due to their good
thermomechanical properties. Aromatic polyamides, such as Kevlar
constitute high performance polymers thanks to their high stability
and rigidity. Finally, phenolic compounds constitute a widely used
raw material. For instance, Bisphenol A is an important monomer for
the synthesis of polycarbonates, epoxy resins and a popular
plasticizer for thermoplastic polymers. These compounds are mainly
petroleum based and derived from benzene, xylene and toluene.
[0004] Some aromatic structures can be synthesized from natural
compounds or are directly found in nature but in limited quantity.
The main source of phenolic compound and so aromatic compounds is
lignin, isolated from wood or annual plant, and constitute the
second most abundant renewable polymer after cellulose. Vanillin,
phenol commercially available, can be extracted from lignin and
also obtained by biosynthetic pathway from abundant glucose (K. Li
and J. W. Frost, Journal of the American Chemical Society, 1998,
120, 10545-10546).
[0005] Another way to synthesize bisaromatic compounds is to
dimerize lignin derivatives. Dehydrodivanillin is important as
flavouring agent, antioxidant agent, or in food and cosmetic
industry and was even used in microlithography. It has been
synthesized by oxidative coupling using FeCl.sub.3 or
sodium/potassium persulfate or enzymatically with peroxidases using
between 1 000 and 2 000 units of enzyme.
[0006] Environmental concerns and petrol depletions lead the
plastic industry to find biobased aromatic alternatives.
[0007] Furthermore, the phenolic products as obtained with the
known processes as mentioned above are not suitable as they do not
have a sufficient purity and thus cannot be used in subsequent
polymerization processes.
[0008] The aim of the present invention is thus to provide a
process for the preparation of phenolic compounds with a good
yield, preferably greater than 85%.
[0009] Another aim of the present invention is to provide a process
for obtaining phenolic dimers with high purity, said dimers being
suitable for subsequent polymerization.
[0010] Another aim of the present invention is to provide a green
process for preparing phenolic compounds.
[0011] Therefore, the present invention relates to a process for
preparing a compound having the following formula (I):
##STR00003##
[0012] wherein: [0013] R.sub.1 is H or OH; [0014] R.sub.2 is a
(C.sub.1-C.sub.6)alkoxy group; [0015] R.sub.3 is H or forms a
C.dbd.O group with the carbon atom carrying it; [0016] R.sub.4 is R
or R'; [0017] R being chosen from the group consisting of: --CHO,
--CN, --COR.sub.a, --COOR.sub.a, --R.sub.a, and
(C.sub.2-C.sub.6)alkenyl groups, R.sub.a being a
(C.sub.1-C.sub.6)alkyl group; [0018] R' being a
(C.sub.1-C.sub.6)alkoxy group;
[0019] and wherein, when the bond `a` linking the cores A and B is
a single bond, then the compound of formula (I) has the following
formula (I-1):
##STR00004##
[0020] and when the bond `a` linking the cores A and B is a double
bond, then the compound of formula (I) has the following formula
(I-2):
##STR00005##
[0021] said process comprising the following steps: [0022] a) the
addition of an oxygen source into a solution of a compound of
formula (II) in a water-miscible solvent, said compound of formula
(II) having the following formula:
##STR00006##
[0023] wherein R.sub.1, R.sub.2, and R.sub.4 are as defined above
in formula (I),
[0024] and R'.sub.3 is H when R.sub.1 is OH and R'.sub.3 is OH when
R.sub.1 is H, [0025] b) the addition of a laccase in the solution
obtained after step a); and [0026] c) the possible recovering of
the compound of formula (I) thus obtained.
[0027] The present invention also relates to a process for
preparing a compound having the above-mentioned formula (I-1)
wherein step a) is carried out with a compound having the following
formula (II-1):
##STR00007##
[0028] wherein R and R.sub.2 are as defined above in formula
(I).
[0029] The present invention thus also relates to a process for
preparing a compound having the following formula (I-1):
##STR00008##
[0030] wherein: [0031] R.sub.2 is a (C.sub.1-C.sub.6)alkoxy group;
[0032] R is chosen from the group consisting of: --CHO, --CN,
--COR.sub.a, --COOR.sub.a, --R.sub.a, and (C.sub.2-C.sub.6)alkenyl
groups, R.sub.a being a (C.sub.1-C.sub.6)alkyl group, preferably a
methyl group;
[0033] said process comprising the following steps: [0034] a) the
addition of an oxygen source into a solution of a compound of
formula (II-1) in a water-miscible solvent, said compound of
formula (II-1) having the following formula:
##STR00009##
[0035] wherein R and R.sub.2 are as defined above in formula (I-1),
[0036] b) the addition of a laccase in the solution obtained after
step a); and [0037] c) the possible recovering of the compound of
formula (I-1) thus obtained.
[0038] The present invention also relates to a process for
preparing a compound having the above-mentioned formula (I-2)
wherein step a) is carried out with a compound having the following
formula (II-2):
##STR00010##
[0039] wherein R.sub.1 and R.sub.2 are as defined above in formula
(I).
[0040] The present invention thus also relates to a process for
preparing a compound having the following formula (I-2):
##STR00011##
[0041] wherein: [0042] R.sub.2 is a (C.sub.1-C.sub.6)alkoxy group;
[0043] R' is a (C.sub.1-C.sub.6)alkoxy group;
[0044] said process comprising the following steps: [0045] a) the
addition of an oxygen source into a solution of a compound of
formula (II-2) in a water-miscible solvent, said compound of
formula (II-2) having the following formula:
##STR00012##
[0046] wherein R' and R.sub.2 are as defined above in formula
(I-2), [0047] b) the addition of a laccase in the solution obtained
after step a); and [0048] c) the possible recovering of the
compound of formula (I-2) thus obtained.
[0049] According to a preferred embodiment, the present invention
relates to a process for preparing a compound having formula (I)
(or formula (I-1) or (I-2)), comprising steps a) and b), as
mentioned above, wherein the obtained compound is a
precipitate.
[0050] According to such embodiment, the process according to the
invention comprises a subsequent step for recovering the compound
of formula (I) from the liquid reaction medium, said liquid
reaction medium including the water-miscible solvent. For this
recovering step, one may implement any method known by the skilled
person for isolating a solid product from a liquid medium, such as
in particular centrifugation or filtration.
[0051] According to a preferred embodiment, the method of the
invention comprises, as step c), the recovering of the compound of
formula (I) by the implementation of a filtration and/or
centrifugation step.
[0052] Compounds of Formula (I)
[0053] The process of the invention is implemented to prepare
compounds of formula (I) which could also be named `dimers`.
[0054] In formula (I) as mentioned above, the link `a` between the
cores A and B is defined as a single (--) or a double (.dbd.) bond,
depending on the definitions of the radicals present on these
cores. As represented in this formula, when a is a single bond, the
dotted line is absent and when a is a double bond, the dotted line
represents a bond.
[0055] In a similar way, the dotted lines in the cores A and B
correspond either to a ring of formula
##STR00013##
[0056] (wnen a is a double bond) or to a ring of formula
##STR00014##
[0057] (when a is a single bond).
[0058] In formula (I), the R.sub.1 group of core A and the R.sub.1
group of core B are identical; the R.sub.2 group of core A and the
R.sub.2 group of core B are identical; the R.sub.3 group of core A
and the R.sub.3 group of core B are identical and the R.sub.4 group
of core A and the R.sub.4 group of core B are identical.
[0059] According to an embodiment, in formula (I) or in formula
(I-1), R is chosen from the group consisting of: --CHO, --CN,
--COMe, --COOMe, --Me, and --CH.sub.2--CH.dbd.CH.sub.2.
[0060] According to an embodiment, in formula (I) or in formula
(I-2), R' is methoxy.
[0061] According to an embodiment, in formula (I), (I-1), (I-2),
(II-1) or (II-2), R.sub.2 is a methoxy group.
[0062] According to an embodiment, in formula (II) or in formula
(II-1), R is chosen from the group consisting of: --CHO, --CN,
--COMe, --COOMe, --Me, and --CH.sub.2--CH.dbd.CH.sub.2.
[0063] According to an embodiment, in formula (II) or in formula
(II-2), R' is methoxy.
[0064] The present invention also relates to the preparation of a
compound having the above-mentioned formula (I-1) wherein R.sub.2
is a methoxy group.
[0065] The present invention also relates to the preparation of a
compound having the above-mentioned formula (I-2) wherein R.sub.2
is a methoxy group.
[0066] More particularly, the process of the invention allows the
preparation of one of the following compounds:
##STR00015##
[0067] The process of the invention comprises two main steps a) and
b) as described above.
[0068] Step a) consists in adding an oxygen source into a solution
of a compound of formula (II) in a water-miscible solvent.
[0069] According to the invention, the solution of the compound of
formula (II) in a water-miscible solvent may be prepared by adding
said compound of formula (II) in said water-miscible solvent, and
optionally adding a buffer solution, preferably a sodium acetate
buffer.
[0070] According to an embodiment, the above-mentioned solution of
the compound of formula (II) also comprises a buffer, the amount of
said buffer being such that the pH of said solution is comprised
between 4 and 7. According to a preferred embodiment, the buffer is
sodium acetate.
[0071] In other words, the pH of the solution of the compound of
formula (II) in the water-miscible solvent is preferably comprised
between 4 and 7.
[0072] According to a preferred embodiment, the process of the
invention is carried out at a pH comprised between 4 and 7. This pH
range is appropriate as it corresponds to the pH range wherein the
enzyme laccase is not altered.
[0073] Solvent
[0074] The solvent used for the process of the invention is
suitable for enzymatic processes and is water-miscible.
[0075] According to an embodiment, the water-miscible solvent is
chosen from the group consisting of: dioxane, DMSO, acetone, and
mixtures thereof. Preferably, the water-miscible solvent is chosen
from the group consisting of: DMSO, acetone, and mixtures
thereof.
[0076] The preferred solvents according to the invention are chosen
among the solvents in which the compound of formula (I) is able to
form a precipitate.
[0077] Preferably, the water-miscible solvent is the acetone.
According to an advantageous embodiment, step a) consists in adding
an oxygen source in a solution of a compound of formula (II) in
acetone, said solution being prepared by dissolving a compound of
formula (II) in acetone.
[0078] According to a preferred embodiment, the amount of
water-miscible solvent is comprised between 5% and 10% of volume in
comparison with the total volume of the mixture formed by said
solvent and the buffer solution. Most preferably, the percentage
volume of the water-miscible solvent is 10% in comparison with the
total volume of the mixture formed by said solvent and the buffer
solution.
[0079] Oxygen Source
[0080] As mentioned above, the process of the invention comprises a
step implementing an oxygen source.
[0081] In the present application, the term "oxygen source" refers
to a reactant able to regenerate (re-oxide) the active sites of the
laccase. The "oxygen" refers to dioxygene (O.sub.2).
[0082] Preferably, the oxygen source is a gas comprising oxygen,
such as air or pure oxygen.
[0083] As oxygen source, we may cite pure oxygen (O.sub.2), which
is added, by bubbling at atmospheric pressure or at a pressure of a
few bars, into the reaction mixture comprising, at the start of the
process, a compound of formula (II) and at least one water-miscible
solvent, and if appropriate a buffer solution. This step is carried
out to advantageously have the reaction medium saturated with
dissolved oxygen.
[0084] Air or a mixture of any gas enriched in oxygen may be cited
as oxygen source.
[0085] Step a) of the process of the invention consists in
introducing said oxygen source into the reaction medium, said
medium comprising a compound of formula (II) in solution in a
water-miscible solvent. This introduction or addition may be
carried out at a given moment or for a longer duration, preferably
for a longer duration, the aim being to saturate the reaction
medium in dissolved oxygen.
[0086] Alternatively, the oxygen source may be replaced with any
oxidant able to regenerate (re-oxide) the active sites of the
laccase used in the process.
[0087] According to an embodiment, the oxygen source is pure oxygen
or air. Preferably, the oxygen source is pure oxygen.
[0088] According to an embodiment, this addition step is carried
out for a sufficient time to saturate the solution in dissolved
oxygen. Preferably, the addition of the oxygen source is carried
out for 5 minutes.
[0089] According to a preferred embodiment, after step a), the
solution of the compound of formula (II) in the water-miscible
solvent is saturated in oxygen.
[0090] This saturated solution is then used for step b) which
implements a laccase.
[0091] Laccase
[0092] Laccase (EC 1.10.3.2) is a very well-known class of
oxidative enzyme studied since 1883. These glycoproteins which
belong to the blue copper family of oxidase are found in several
plants and fungus and are involved in lignification and
delignification.
[0093] Laccases generate radical intermediates on phenolic
compounds which can undergo self-coupling reactions. Generally, due
to the delocalization of the radical, this reaction leads to
different binding, and so a low selectivity of the synthesized
compound.
[0094] The laccases which may be used in the process of the
invention are found in plants, fungi and microorganisms.
[0095] Laccases from fungi include in particular laccases of genus
Aspergillus, Neurospora (for example Crassa Neurospora), Podospora,
Botrytis, Collybia, Fomes, Lentinus, Pleurotus, Trametes (for
example Trametes villosa et Trametes versicolor), Rhizoctonia (for
example Rhizoctonia solani), Coprinus (for example Coprinus
cinereus, Coprinus comatus, Coprinus friesii et Coprinus
plicatilis), Psathyrella (for example Psathyrella condelleana),
Panaeolus (for example Panaeolus papilionaceus), Myceliophthora
(for example Myceliophthora thermophila), Schytalidium (for example
Schytalidium thermophilum), Polyporus (for example Polyporus
pinsitus), Phlebia (for example Radiata phlebia), Pycnoporus (for
example Pycnoporus cinnabarinus) or Coriolus (for example Coriolus
hirsutus).
[0096] Laccases from bacteria are for example found in
Bacillus.
[0097] Preferably, the laccase used in the invention is laccase
from Trametes versicolor, marketed by Sigma Aldrich.
[0098] According to an embodiment, the amount of laccase for one
gram of compound of formula (II) is from 3 U to 65 U. According to
the present invention, U refers to the catalytic unit, one U being
defined as the amount of the enzyme that formed 1 .mu.mol of ABTS
radical cation per minute.
[0099] In the present invention, the reference substrate is ABTS
(2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid).
[0100] Preferably, the amount of laccase is 13 U for 1 gram of
compound of formula (II).
[0101] According to an embodiment, the amount of laccase for one
gram of compound of formula (II) is from 1.5 mg to 75 mg,
preferably from 3 mg to 15 mg.
[0102] As mentioned above, step b) consists in adding a laccase
into the solution obtained after step a), said solution being also
named `solution of compound of formula (II) in a water-miscible
solvent saturated in oxygen` or `saturated solution` or `saturated
solution of compound of formula (II)`.
[0103] Once the laccase added, the reaction medium comprising the
laccase and the saturated solution of compound of formula (II), may
be stirred at a temperature comprised between 20.degree. C. and
60.degree. C., and preferably at room temperature.
[0104] According to an embodiment, this stirring step is carried
out for at least one minute to several days, in particular for 5
minutes to 72 hours, and preferably for 24 hours.
[0105] During the stirring, the enzymatic reactions are carried out
and allow the formation of the compound(s) of formula (I) as
mentioned above.
[0106] According to an advantageous embodiment, the process of the
invention (in particular steps a) and b)) is carried out under
pressure. According to an advantageous embodiment, the process is
carried out at atmospheric pressure.
[0107] According to an embodiment, the process of the invention
comprises a subsequent step which consists in filtering the
solution obtained after step b), washing it with water and then
drying under vacuum in order to recover the precipitate. As the
obtained product is in a solid form, it can be recovered by
centrifugation and purified by recrystallization.
[0108] According to an embodiment, when the process comprises a
step of filtering the solution obtained after step b) as mentioned
above, the filtrate may be isolated and recovered. This filtrate is
a liquid solution comprising laccase which could be recycled and
used in the process of the invention.
[0109] Therefore, according to the invention, the laccase used in
step b) may be used as pure laccase or as a solution recovered from
the process of the invention.
[0110] The present invention also relates to the transformation of
the dimers of formula (I-1) and (I-2) as mentioned above.
[0111] The present invention also relates to a process for the
preparation of a compound having the following formula (III):
##STR00016##
[0112] R and R.sub.2 being as defined in formula (I), and
[0113] R.sub.5 being a (C.sub.1-C.sub.6)alkyl group, preferably
methyl,
[0114] said process comprising the steps of: [0115] preparing a
compound of formula (I-1) using the process as mentioned above,
said compound of formula (I-1) being thus prepared from a compound
of formula (II-1) as defined above, [0116] alkylating the compound
of formula (I-1) with a compound R.sub.5X, X being a halogen atom,
preferably I, [0117] and the possible recovering of the compound of
formula (III).
[0118] According to an embodiment, in formula (III), R is --CHO,
--CH.sub.2--CH.dbd.CH.sub.2 or COOR.sub.a, R.sub.a being as defined
above in formula (I), and being preferably methyl.
[0119] According to an embodiment, in formula (III), R.sub.2 is a
methoxy group.
[0120] This process consists thus in alkylating a compound of
formula (I-1) as obtained according to the process as described
above comprising steps a) and b).
[0121] The process of preparation of the compounds of formula (III)
corresponds to the process as mentioned above for preparing a
compound of formula (I-1) which comprises a subsequent alkylation
step of said compound of formula (I-1).
[0122] Preferred compounds of formula (III) have the following
formula (III-1):
##STR00017##
[0123] R being as defined in formula (I),
[0124] and most preferably are chosen from the following
compounds:
##STR00018##
[0125] Preferably, the alkylation step as mentioned above is
carried out with a compound R.sub.5I. According to a preferred
embodiment, this alkylation step is carried out in
dimethylformamide (DMF) with K.sub.2CO.sub.3 at 80.degree. C. for
20 hours, such alkylation conditions being well known from the
skilled person.
[0126] The present invention also relates to a process for the
preparation of a compound having the following formula (IV):
##STR00019##
[0127] R.sub.2 being as defined above in formula (I), and
[0128] R.sub.6 being H or a (C.sub.1-C.sub.6)alkyl group,
[0129] said process comprising the steps of: [0130] preparing a
compound of formula (I-1) with R being CHO, using the process as
mentioned above, [0131] reacting the compound of formula (I-1) with
a hydrogenation agent, such as NaBH.sub.4, in order to obtain a
compound of formula (IV) wherein R.sub.6.dbd.H, [0132] and, if
necessary, alkylating the compound of formula (IV) wherein
R.sub.6.dbd.H with a compound R.sub.5X, X being a halogen,
preferably I, and R.sub.5 being a (C.sub.1-C.sub.6) alkyl group, in
order to obtain a compound of formula (IV) wherein
R.sub.6.dbd.(C.sub.1-C.sub.6) alkyl, [0133] and the possible
recovering of the compound of formula (IV).
[0134] The process of preparation of the compounds of formula (IV)
corresponds to the process as mentioned above for preparing a
compound of formula (I-1) with R.dbd.CHO which comprises a
subsequent reaction of hydrogenating the aldehyde moiety (into a
--CH.sub.2OH group).
[0135] According to an embodiment, in formula (IV), R.sub.2 is a
methoxy group.
[0136] Preferably, the hydrogenation step as mentioned above is
carried out with NaBH.sub.4 as hydrogenation agent or any other
well-known hydrogenation agent. According to a preferred
embodiment, this hydrogenation step is carried out in methanol.
[0137] Preferred compounds of formula (IV) have the following
formula (IV-1):
##STR00020##
[0138] R.sub.6 being as defined above, and being preferably H or
methyl,
[0139] and most preferably are chosen from the following
compounds:
##STR00021##
[0140] The present invention also relates to a process for the
preparation of a compound having the following formula (V):
##STR00022##
[0141] R.sub.2 being as defined in formula (I), and
[0142] R.sub.6 being H or a (C.sub.1-C.sub.6)alkyl group,
[0143] said process comprising the steps of: [0144] preparing a
compound of formula (I-1) with R being COOR.sub.a, using the
process as mentioned above, [0145] reacting the compound of formula
(I-1) with methanol in the presence of a base, such as KOH or any
other source of hydroxide, in order to obtain a compound of formula
(V) wherein R.sub.6.dbd.H, [0146] and, if necessary, alkylating the
compound of formula (V) wherein R.sub.6.dbd.H with a compound
R.sub.5X, X being a halogen, preferably I, and R.sub.5 being a
(C.sub.1-C.sub.6) alkyl group, in order to obtain a compound of
formula (V) wherein R.sub.6.dbd.(C.sub.1-C.sub.6) alkyl,
[0147] and the possible recovering of the compound of formula
(V).
[0148] The process of preparation of the compounds of formula (V)
corresponds to the process as mentioned above for preparing a
compound of formula (I-1) with R.dbd.COOR.sub.a which comprises a
subsequent reaction of reacting the compound of formula (I-1) with
methanol in the presence of a base (which consists in transforming
the COOR.sub.a group into a COOH group).
[0149] According to an embodiment, in formula (V), R.sub.2 is a
methoxy group.
[0150] Preferably, the subsequent step as mentioned above is
carried out with methanol and KOH, in particular for 10 hours at
40.degree. C. According to a preferred embodiment, this
hydrogenation step is carried out in methanol.
[0151] Preferred compounds of formula (V) have the following
formula (V-1):
##STR00023##
[0152] R.sub.6 being as defined above, and being preferably H or
methyl,
[0153] and most preferably are chosen from the following
compounds:
##STR00024##
[0154] The present invention also relates to a process for the
preparation of a compound having the following formula (VI):
##STR00025##
[0155] R.sub.2 being as defined in formula (I),
[0156] R.sub.7 being a (C.sub.2-C.sub.10)alkenyl group, and
[0157] R.sub.8 being a (C.sub.1-C.sub.6)alkyl group,
[0158] said process comprising the steps of: [0159] preparing a
compound of formula (V) with R.sub.6 being a (C.sub.1-C.sub.6)alkyl
group, using the process as mentioned above, [0160] reacting the
compound of formula (V) with an alcohol R.sub.7OH in the presence
of a catalyst, such as PTSA/DMAP, and of N,N'-diisopropyl
carbodiimide, especially in stoichiometric quantities, in order to
obtain a compound of formula (VI), [0161] and the possible
recovering of the compound of formula (VI).
[0162] The process of preparation of the compounds of formula (VI)
corresponds to the to process as mentioned above for preparing a
compound of formula (V) with R.sub.6.dbd.(C.sub.1-C.sub.6)alkyl
group which comprises a subsequent reaction of reacting the
compound of formula (V) with an alcohol R.sub.7OH (which consists
in transforming the COOH group into a COOR.sub.7 group).
[0163] According to an embodiment, in formula (VI), R.sub.2 is a
methoxy group.
[0164] According to an embodiment, in formula (VI), R.sub.8 is a
methyl group.
[0165] Preferably, the step as mentioned above of reacting the
compound of formula (V) with the alcohol R.sub.7OH is carried out
with a PTSA/DMAP catalyst, in particular at room temperature, for
72 hours. According to a preferred embodiment, this step is carried
out in dichloromethane.
[0166] Preferred compounds of formula (VI) have the following
formula (VI-1):
##STR00026##
[0167] R.sub.7 being as defined above,
[0168] A most preferred compound of formula (VI) is the following
compound:
##STR00027##
[0169] The present invention also relates to a process for the
preparation of a compound having the following formula (VII):
##STR00028##
[0170] R.sub.2 being as defined in formula (I), and
[0171] R.sub.8 being a (C.sub.1-C.sub.6)alkyl group,
[0172] said process comprising the steps of: [0173] preparing a
compound of formula (I-1) with R being CHO, using the process as
mentioned above, [0174] alkylating the compound of formula (I-1)
with a compound R.sub.8X, X being a halogen, preferably I, for
obtaining a compound having the following formula (III-1):
##STR00029##
[0175] R.sub.2 and R.sub.8 being as defined above in formula
(VIII), [0176] reacting the compound of formula (III-1) with a
Wittig reagent, in order to obtain a compound having the formula
(VII), [0177] and the possible recovering of the compound of
formula (VII).
[0178] The term `Wittig reagent` is a term well-known in the art
which refers to a triphenyl phosphonium ylide.
[0179] Alternatively, the compound of formula (VII) may be prepared
from a compound of formula (III-1) by implementing a Wittig-Horner
reaction instead of the Wittig reaction as mentioned above.
[0180] The process of preparation of the compounds of formula (VII)
corresponds to the process as mentioned above for preparing a
compound of formula (I-1) with R.dbd.CHO which comprises a
subsequent step of alkylating the compound of formula (I-1) as well
as a subsequent step of reacting the alkylated compound of formula
(III-1) with a Wittig reactant (these steps consist in transforming
the CHO group into a --to CH.dbd.CH.sub.2 group).
[0181] According to an embodiment, in formula (VII), R.sub.2 is a
methoxy group.
[0182] According to an embodiment, in formula (VII), R.sub.8 is a
methyl group.
[0183] Preferably, the step of reacting the compound of formula
(III-1) with a Wittig reactant as mentioned above is carried out in
THF, in particular for 24 hours at room temperature. According to a
preferred embodiment, this step also comprises the use of potassium
tert-butoxide.
[0184] A preferred compound of formula (VII) has the following
formula (15):
##STR00030##
[0185] The present invention also relates to a process for the
preparation of a compound having the following formula (VIII):
##STR00031##
[0186] R' and R.sub.2 being as defined in formula (I-2), and
[0187] n being an integer varying from 1 to 6,
[0188] said process comprising the steps of: [0189] preparing a
compound of formula (I-2), using the process as mentioned above,
[0190] reacting the compound of formula (I-2) with a hydrogenation
agent such as NaBH.sub.4, in order to obtain a compound having the
following formula (VIII-1):
##STR00032##
[0191] R' and R.sub.2 being as defined in formula (I-2), [0192]
reacting the compound of formula (VIII-1) in the presence of a
base, such as KOH, with a compound having the following formula
(IX):
##STR00033##
[0193] n being as defined above, and X being a halogen atom, such
as Cl,
[0194] in order to obtain a compound of formula (VIII), [0195] and
the possible recovering of the compound of formula (VIII).
[0196] The process of preparation of the compounds of formula
(VIII) corresponds to the process as mentioned above for preparing
a compound of formula (I-2) which comprises a subsequent step of
hydrogenating the compound of formula (I-2) as well as a subsequent
step of reacting the compound of formula (VIII-1) with a compound
of formula (IX)(in order to obtain bisepoxide compounds).
[0197] According to an embodiment, in formula (VIII), R.sub.2 is a
methoxy group.
[0198] According to an embodiment, in formula (VIII), R' is a
methoxy group.
[0199] Preferably, the step of hydrogenating the compound of
formula (I-2) is carried out with NaBH.sub.4 in ethanol.
Preferably, the step of reacting the compound of formula (VIII-1)
with a compound of formula (IX) comprises the addition of potassium
hydroxide and tetrabutylammonium bromide.
[0200] A preferred compound of formula (VIII-1) has the following
formula (16):
##STR00034##
[0201] A preferred compound of formula (VIII) has the following
formula (17):
##STR00035##
[0202] The present invention also relates to a process for the
preparation of a compound having the following formula (X):
##STR00036##
[0203] Alk being a (C.sub.1-C.sub.6)alkyl group,
[0204] R.sub.2 being as defined in formula (I-1), and
[0205] R.sub.9 being a (C.sub.2-C.sub.10)alkenyl group,
[0206] said process comprising the steps of: [0207] preparing a
compound of formula (I-1) with R being a (C.sub.1-C.sub.6)alkyl
group, using the process as mentioned above, [0208] reacting the
compound of formula (I-1) with a compound R.sub.7X, X being a
halogen, preferably Br, in the presence of K.sub.2CO.sub.3 in a
solvent such as DMF, [0209] and the possible recovering of the
compound of formula (X).
[0210] The process of preparation of the compounds of formula (X)
corresponds to the process as mentioned above for preparing a
compound of formula (I-1) with R.dbd.(C.sub.1-C.sub.6)alkyl group,
which comprises a subsequent step of reacting the compound of
formula (I-1) with a compound R.sub.7X.
[0211] According to an embodiment, in formula (X), R.sub.2 is a
methoxy group.
[0212] According to an embodiment, in formula (X), Alk is a methyl
group.
[0213] Preferably, the step of reacting the compound of formula
(I-1) with the compound R.sub.7X is carried out in DMF in the
presence of potassium carbonate. Preferably, this step is carried
out for 20 hours at 80.degree. C.
[0214] A preferred compound of formula (X) has the following
formula (19):
##STR00037##
[0215] The present invention also relates to a compound having one
of the above formulae (2), (14), (15), and (19).
[0216] As used herein, the term "(C.sub.x-C.sub.y)alkyl" means a
saturated aliphatic hydrocarbon group, which may be straight or
branched, having x to y carbon atoms in the chain. Preferred alkyl
groups have 1 to about 12, preferably 1 to 10, and more preferably
1 to 6, carbon atoms in the chain. The following alkyl groups may
be cited as example: methyl, ethyl, propyl, butyl, pentyl, hexyl,
heptyl, octyl, nonyl, decyl, dodecyl.
[0217] As used herein, the term "(C.sub.x-C.sub.y)alkylene" (or
"alkylidene") refers to a divalent saturated aliphatic hydrocarbon
radical, comprising from x to y carbon atoms, having preferably
from 1 to 20, in particular 1 to 12 carbon atoms, and more
preferably 2 to 10 carbon atoms. When said radical is linear, it
may be represented by the formula (CH.sub.2).sub.m wherein m is an
integer varying from 1 to 12, and preferably from 2 to 10. The
following alkylene may be cited as example: methylene, ethylene,
propylene, butylene, pentylene, hexylene, heptylene, octylene,
nonylene, decylene, dodecylene.
[0218] As used herein, the term "(C.sub.x-C.sub.y)alkenyl" means an
aliphatic hydrocarbon group containing a carbon-carbon double bond
and which may be straight or branched having x to y carbon atoms in
the chain. Preferred alkenyl groups have 2 to 12 carbon atoms in
the chain; and more preferably about 2 to 10 or 2 to 6 carbon atoms
in the chain. Exemplary alkenyl groups include for example ethenyl,
propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl,
heptenyl, octenyl, nonenyl, decenyl.
[0219] As used herein, the term "alkenylene" means a hydrocarbon
radical having at least one carbon-carbon double bond (straight
chain or branched) wherein a hydrogen atom is removed from each of
the terminal carbons such as ethenylene, propenylene, and the
like.
[0220] As used herein, the term "alkoxy" means an alkyl-O-- group
wherein the alkyl group is as herein described. Exemplary alkoxy
groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and
heptoxy.
[0221] The invention is described in the foregoing by way of
non-limiting examples.
EXAMPLES
[0222] Preparation of Compounds of Formula (I)
[0223] Vanillin, 2-methoxy-4-methylphenol and 2,6-dimethoxyphenol
were supplied by Alfa Aesar; Eugenol was purchased from Sigma
Aldrich and Acetovanillon was bought from Acros organic.
[0224] Enzymatic Dimerization: General Procedure
[0225] A solution of 1.5 g of compound of formula (II) in 20 mL of
acetone was added to 180 mL of NaOAc buffer (0.1 M, pH 5.0). The
solution was saturated in O.sub.2 for 5 min. Laccase from Trametes
versicolor (20 U, 12.4 mg) was added and the reaction was stirred
at room temperature for 24 hours. The precipitate was filtered,
washed with water and dried under vacuum (at 100.degree. C.
overnight). This procedure was adapted on 15 g in the case of
vanillin.
[0226] Kinetic Investigation
[0227] The enzymatic dimerization general procedure is followed
using vanillin and 0.1 mL of dioxane, used as reference is added in
the solution. 0.4 mL of solution is sampled regularly, filtered and
diluted in deuteriated acetone. The samples are analyzed by NMR.
The vanillin conversion is extracted from the ratio of CHO peak
integration at 9.81 ppm and the dioxane peak integration at 3.63
ppm.
[0228] Observations
[0229] After introduction of the laccase, the uncolored solution
turned to yellow, revealing the creation of radicals. After few
minutes, a brown precipitate appeared.
Example 1
Preparation of Compound (1)
##STR00038##
[0231] A solution of 1.5 g of vanillin in 20 mL of acetone was
added to 180 mL of NaOAc buffer (0.1 M, pH 5.0). The solution was
saturated in O.sub.2 for 5 min. Laccase from Trametes versicolor
(20 U, 12.4 mg) was added and the reaction was stirred at room
temperature for 24 hours. The precipitate was filtered, washed with
water and dried under vacuum (at 100.degree. C. overnight).
[0232] Yield: 96%
[0233] Analyses: [0234] Mass: 302.1 (100%), 303.1 (18%), 304.1
(2%); [0235] .sup.1H NMR: .delta. 9.85 (s, CHO), 7.50 (s, 2H Ar),
4.00 (s, OCH.sub.3); [0236] .sup.13C NMR: .delta. 191.04 (CHO),
150.70 (Ar--C), 147.95 (Ar--C), 128.30 (Ar--C), 127.69
(Ar--C),124.52 (Ar--C), 109.10 (Ar--C), 55.88 (OCH.sub.3).
Example 2
Preparation of Compound (2)
##STR00039##
[0238] Compound (2) is prepared from
4-hydroxy-3-methoxy-benzonitrile with a yield of 95%.
[0239] 4-Hydroxy-3-methoxybenzonitrile Synthesis
[0240] 750 mg (5 mmol) of vanillin were dissolved in 15 mL of
acetic acid. 520 mg of NH.sub.2OH.HCl (7.5 mmol) are added and the
mixture was stirred and warmed at 110.degree. C. for 2 h. The
reaction was stopped by adding H.sub.2O, the organic product
extracted using CH.sub.2Cl.sub.2, dried and purified by flash
chromatography (Ethyl acetate/cyclohexane 3/7).
[0241] Dimerization
[0242] A solution of 1.5 g of compound of
4-hydroxy-3-methoxybenzonitrile in 20 mL of acetone was added to
180 mL of NaOAc buffer (0.1 M, pH 5.0). The solution was saturated
in O.sub.2 for 5 min. Laccase from Trametes versicolor (20 U, 12.4
mg) was added and the reaction was stirred at room temperature for
24 hours. The precipitate was filtered, washed with water and dried
under vacuum (at 100.degree. C. overnight).
[0243] Analyses: [0244] Mass: 296.1 (100%), 297,1 (18%), 298.1
(2%); [0245] .sup.1H NMR: .delta. 9.91 (s, 2H, HO), 7.57 (s, 2H,
Ar), 7.42 (s, 2H, Ar), 3.93 (s, 6H, OCH.sub.3); [0246] .sup.13C
NMR: .delta. 148.63 (Ar--C), 147.85 (Ar--C), 128.05 (Ar--C), 124.56
(Ar--C), 119.45 (Ar--C), 114.03 (Ar--C), 100.30 (CN), 56.15
(OCH.sub.3).
Example 3
Preparation of Compound (3)
##STR00040##
[0248] A solution of 1.5 g of compound of acetovanillone in 20 mL
of acetone was added to 180 mL of NaOAc buffer (0.1 M, pH 5.0). The
solution was saturated in O.sub.2 for 5 min. Laccase from Trametes
versicolor (20 U, 12.4 mg) was added and the reaction was stirred
at room temperature for 24 hours. The precipitate was filtered,
washed with water and dried under vacuum (at 100.degree. C.
overnight).
[0249] Compound (3) is prepared from acetovanillone with a yield of
92%.
[0250] Analyses: [0251] Mass: 330.1 (100%), 331.1 (18%), 332.2
(2%); [0252] .sup.1H NMR: .delta. 7.49 (s, 4H, Ar), 3.93 (s, 6H,
OCH.sub.3), 2,56 (s, 6H, C.dbd.OCH.sub.3); [0253] .sup.13C NMR:
.delta. 196.07 (OCH), 149.22 (Ar--C), 147.06 (Ar--C), 127.81
(Ar--C), 124.23 (Ar--C), 124.04 (Ar--C), 109.03 (Ar--C), 55.76
(OCH.sub.3), 26.25 (CH.sub.3).
Example 4
Preparation of Compound (4)
##STR00041##
[0255] A solution of 1.5 g of compound of methylvanillate in 20 mL
of acetone was added to 180 mL of NaOAc buffer (0.1 M, pH 5.0). The
solution was saturated in O.sub.2 for 5 min. Laccase from Trametes
versicolor (20 U, 12.4 mg) was added and the reaction was stirred
at room temperature for 24 hours. The precipitate was filtered,
washed with water and dried under vacuum (at 100.degree. C.
overnight).
[0256] Compound (4) is repared from methylvanillate with a yield of
90%.
[0257] Methylvanillate Synthesis
[0258] 15 g of vanillic acid (0.09 mol) were dissolved in 75 mL of
methanol. 2.1 mL of sulfuric acid were added and the mixture is
stirred and warm to reflux for 8 h. After evaporation of methanol,
the solid is dissolved in 60 mL of ethylacetate, washed with 30 mL
of NaHCO.sub.3 solution, water (2 times) and brine (1 time). The
organic phase is evaporated under reduced pressure.
[0259] Analyses: [0260] Mass: 362.1 (100%), 363.1 (20%), 364.1
(2%); [0261] .sup.1H NMR: .delta. 9.60 (s, 2H, HO), 7.46 (s, 4H,
Ar), 3.90 (s, 6H, OCH.sub.3), 3.80 (s, 6H, OCH.sub.3 ester); [0262]
.sup.13C NMR: .delta. 166.04 (OCH.sub.3ester), 148.60 (Ar--C),
147.27 (Ar--C), 125.25 (Ar--C), 123.93 (Ar--C), 119.21 (Ar--C),
110.89 (Ar--C), 55.97 (OCH.sub.3), 51.75(OCH.sub.3 ester).
Example 5
Preparation of Compound (5)
##STR00042##
[0264] A solution of 1.5 g of compound of 2-methoxy-4-methylphenol
in 20 mL of acetone was added to 180 mL of NaOAc buffer (0.1 M, pH
5.0). The solution was saturated in O.sub.2 for 5 min. Laccase from
Trametes versicolor (20 U, 12.4 mg) was added and the reaction was
stirred at room temperature for 24 hours. The precipitate was
filtered, washed with water and dried under vacuum (at 100.degree.
C. overnight).
[0265] Compound (5) is prepared from 2-methoxy-4-methylphenol with
a yield of 92%.
[0266] Analyses: [0267] Mass: 274.1 (100%), 275.1 (18%), 276.1
(2%); [0268] .sup.1H NMR: .delta. 6.73 (s, 2H, Ar), 6.53 (s, 2H,
Ar), 3.79 (s, 6H, OCH.sub.3), 2.23 (s, 6H, CH.sub.3); [0269]
.sup.13C NMR: .delta. 147.52 (Ar--C), 140.99 (Ar--C), 126.92
(Ar--C),125.68 (Ar--C), 123.04 (Ar--C), 111.61 (Ar--C), 55.85
(OCH.sub.3), 20.65 (CH.sub.3).
Example 6
Preparation of Compound (6)
##STR00043##
[0271] A solution of 1.5 g of compound of 2,6-dimethoxy-phenol in
20 mL of acetone was added to 180 mL of NaOAc buffer (0.1 M, pH
5.0). The solution was saturated in O.sub.2 for 5 min. Laccase from
Trametes versicolor (20 U, 12.4 mg) was added and the reaction was
stirred at room temperature for 24 hours. The precipitate was
filtered, washed with water and dried under vacuum (at 100.degree.
C. overnight).
[0272] Compound (6) is prepared from 2,6-dimethoxy-phenol with a
yield of 90%.
[0273] Analyses: [0274] Mass: 304.1 (100%), 305.1 (18%), 318.1
(2%); [0275] .sup.1H NMR: .delta. 8.32 (s, 2H, HO), 6.82(s, 4H,
Ar), 3,84 (s, 12H, OCH.sub.3).
Example 7
Preparation of Compound (7)
##STR00044##
[0277] A solution of 1.5 g of compound of eugenol in 20 mL of
acetone was added to 180 mL of NaOAc buffer (0.1 M, pH 5.0). The
solution was saturated in O.sub.2 for 5 min. Laccase from Trametes
versicolor (20 U, 12.4 mg) was added and the reaction was stirred
at room temperature for 24 hours. The precipitate was filtered,
washed with water and dried under vacuum (at 100.degree. C.
overnight).
[0278] Compound (7) is prepared from eugenol with a yield of
87%.
[0279] Analyses: [0280] Mass: 327.2 (100%), 326.2 (20%), 328,3
(10%); [0281] .sup.1H NMR: .delta. 6.74 (s, 2H Ar), 6.52 (s, 2H
Ar), 5.94 (q, 2H CH-CH.sub.2), 5.03 (d, 4H CH--CH.sub.2), 3.79 (s,
OCH.sub.3), 3.27 (d, 2H CH.sub.2); [0282] .sup.13C NMR: .delta.
147.80 (Ar--C), 141.62 (Ar--C), 138.38 (CH-CH.sub.2), 129.57
(Ar--C), 125.67 (Ar--C), 122.62 (Ar--C), 115.28 (Ar--C), 105.56
(CH--CH.sub.2), 55.64 (OCH.sub.3), 39.19 (CH.sub.2).
[0283] The above results show several advantages of the process of
the invention: [0284] It is a green reaction.
[0285] Indeed the divanillin formation occurs at room temperature,
under oxygen which could be replaced by air. The solvent used shows
a low toxicity. To ensure the solubility of vanillin into the
reaction medium, the compound was totally dissolved into acetone
(10%) before adding the acetate buffer (90%). [0286] The product
extraction is easy and the purity is high (95%). Indeed, the
solvent conditions allowed the reactant solubility while the so
formed product precipitated. The precipitate was filtered off,
washed with water and analyzed by mass spectroscopy, NMR, and HPLC.
[0287] A low quantity of enzyme is needed and can be reused. The
experiments of the above examples were performed using 20 U of
laccase. This amount is the minimal amount necessary to reach more
than 85% conversion after 24 h. With 5 U or 10 U, 50% conversion is
reached after 24 h.
[0288] The experiments are as follows:
[0289] 5 U: [0290] A solution of 1.5 g of compound of vanillin in
25 mL of acetone was added to 225 mL of NaOAc buffer (0.1 M, pH
5.0). The solution was saturated in O.sub.2 for 5 min. Laccase from
Trametes versicolor (5 U, 3.1 mg) was added and the reaction was
stirred at room temperature for 24 hours. The precipitate was
filtered, washed with water and dried under vacuum (at 100.degree.
C. overnight) and weighted.
[0291] 10 U: [0292] A solution of 1.5 g of compound of vanillin in
25 mL of acetone was added to 225 mL of NaOAc buffer (0.1 M, pH
5.0). The solution was saturated in O.sub.2 for 5 min. Laccase from
Trametes versicolor (10 U, 6.2 mg) was added and the reaction was
stirred at room temperature for 24 hours. The precipitate was
filtered, washed with water and dried under vacuum (at 100.degree.
C. overnight) and weighted.
[0293] 20 U: [0294] A solution of 1.5 g of compound of vanillin in
25 mL of acetone was added to 225 mL of NaOAc buffer (0.1 M, pH
5.0). The solution was saturated in O.sub.2 for 5 min. Laccase from
Trametes versicolor (20 U, 12.4 mg) was added and the reaction was
stirred at room temperature for 24 hours. The precipitate was
filtered, washed with water and dried under vacuum (at 100.degree.
C. overnight) and weighted.
[0295] 50 U. [0296] A solution of 1.5 g of compound of vanillin in
25 mL of acetone was added to 225 mL of NaOAc buffer (0.1 M, pH
5.0). The solution was saturated in O.sub.2 for 5 min. Laccase from
Trametes versicolor (50 U, 31 mg) was added and the reaction was
stirred at room temperature for 24 hours. The precipitate was
filtered, washed with water and dried under vacuum (at 100.degree.
C. overnight) and weighted.
[0297] 100 U: [0298] A solution of 1.5 g of compound of vanillin in
25 mL of acetone was added to 225 mL of NaOAc buffer (0.1 M, pH
5.0). The solution was saturated in O.sub.2 for 5 min. Laccase from
Trametes versicolor (100 U, 62 mg) was added and the reaction was
stirred at room temperature for 24 hours. The precipitate was
filtered, washed with water and dried under vacuum (at 100.degree.
C. overnight) and weighted.
[0299] The results of the above experiments are as follows:
TABLE-US-00001 Laccase units Yield (%) 100 85 50 85 20 87 10 54 5
56
[0300] Kinetic studies were realized and showed a good conversion,
over 85% (not over due to NMR sensitivity) and a very high yield,
over 90% after 24 h. [0301] The fact the divanillin precipitates
while vanillin is still soluble allows the solution to be reused
for a new reaction after filtration of divanillin.
[0302] Refill Procedure
[0303] After 24 h of reaction, the precipitate was filtered and
vanillin was added in the solution which was saturated in oxygen
again. This experiment was repeated 8 times and the yield was still
as high as 95%.
[0304] The following experiment was carried out: [0305] A solution
of 1.5 g of compound of vanillin in 25 mL of acetone was added to
225 mL of NaOAc buffer (0.1 M, pH 5.0). The solution was saturated
in O.sub.2 for 5 min. Laccase from Trametes versicolor (50 U, 31
mg) was added and the reaction was stirred at room temperature for
24 hours. The precipitate was filtered, washed with water and dried
under vacuum (at 100.degree. C. overnight) and weighted. The
filtrate was kept. 1.5 g of vanillin was added in the solution
which was saturated in oxygen again. The reaction was stirred at
room temperature for 24 hours. The precipitate was filtered, washed
with water and dried under vacuum (at 100.degree. C. overnight)
and
TABLE-US-00002 [0305] Yield (%) 1st reaction 84 Refill 1 95 Refill
2 84 Refill 3 93 Refill 4 80 Refill 5 85 Refill 6 95 Refill 7 92
Refill 8 96
[0306] Chemical Modifications of Compounds of Formula (I)
[0307] Sodium borohydride, potassium hydroxide, triphenylphosphine,
allyl bromide were supplied by Alfa Aesar.
[0308] Sodium acetate, acetic acid, laccase, hydroxylamine
hydrochloride, sulfuric acid, iodomethane, 4-toluenesulfonic acid
and N,N'-diisopropylcarbodiimide were purchased to from Sigma
Aldrich.
[0309] 4-dimethylaminopyridine was bought from Acros organic,
potassium carbonate was supplied by Prolabo, potassium
tert-butoxide was purchased at ABCR and epichlorohydrine was bought
at TCI.
Example 8
Preparation of Compound (8)
##STR00045##
[0311] 20 mmol of divanillin (.apprxeq.6 g) were dissolved in 100
mL of ethanol. The flask was put in an ice bath and 3.6 g of sodium
borohydride (100 mmol) were added slowly. Then the mixture was
stirred at room temperature for 30 min. 45 mL of water were added
to stop the reaction and the solution is acidified with HCl to pH 7
and warmed for 5 min at 50.degree. C. The solvent was evaporated;
the resulting solid was solubilized in dichloromethane and washed 3
times with water. Yield: 80%.
[0312] Analyses: [0313] .sup.1H NMR: .delta. 8.25 (s, OH phenol),
6.9 (s, 2H Ar), 6.73 (s, 2H Ar), 5.065 (t, 2H OH), 4.46 (d, 4H
CH.sub.2OH), 3.87 (s, OCH.sub.3); [0314] .sup.13C NMR: .delta.
151.14 (Ar--C), 149.67 (Ar--C), 128.81 (Ar--C), 127.36 (Ar--C),
120.94 (Ar--C), 108.59 (Ar--C), 63.78 (CH.sub.2OH), 55.32
(OCH.sub.3).
Example 9
Preparation of Compound (9)
##STR00046##
[0316] 26 mmol of divanillin (.apprxeq.8 g) were dissolved in 120
mL of DMF. 15.2 g of potassium carbonate (110 mmol) were added
before a slow addition of 9.6 mL of iodomethane (158 mmol). After
15 h of stirring at 80.degree. C., the mixture was filtered and the
resulting solution poured into cold water. The methylated compound
which precipitated was filtered off and dried under vacuum. Yield:
80%.
[0317] Analyses: [0318] .sup.1H NMR: .delta. 9.94 (s, CHO), 7.58
(s, 2H Ar), 7.55 (s, 2H Ar), 3.95 (s, OCH.sub.3), 3.68 (s,
OCH.sub.3); [0319] .sup.13C NMR: .delta. 191.83 (CHO), 152.80
(Ar--C), 151.21 (Ar--C), 131.90 (Ar--C), 131.58 (Ar--C), 125.96
(Ar--C), 111.14 (Ar--C), 60.47 (OCH.sub.3), 55.93 (OCH.sub.3).
Example 10
Preparation of Compound (10)
##STR00047##
[0321] 20 mmol of methylated divanillin (.apprxeq.6 g) were
dissolved in 100 mL of ethanol. The flask was put in an ice bath
and 3.6 g of sodium borohydride (100 mmol) were added slowly. Then
the mixture was stirred at room temperature for 30 min. 45 mL of
water were added to stop the reaction and the solution is acidified
with HCl to pH 7 and warmed for 5 min at 50.degree. C. The solvent
was evaporated; the resulting solid was solubilized in
dichloromethane and washed 3 times with water. Yield: 85%.
[0322] Analyses: [0323] .sup.1H NMR: .delta. 6.99 (s, 2H Ar),
6.67(s, 2H Ar), 5.15 (t, 2H OH), 4.47 (d, 4H CH.sub.2OH), 3.83 (s,
OCH.sub.3), 3.51 (s, OCH.sub.3); [0324] .sup.13C NMR: .delta.
151.93 (Ar--C), 144.86 (Ar--C), 137.52 (Ar--C), 132.14 (Ar--C),
120.27 (Ar--C), 110.20 (Ar--C), 62.69 (CH.sub.2OH), 59.83
(OCH.sub.3), 55.53 (OCH.sub.3).
Example 11
Preparation of Compound (11)
##STR00048##
[0326] 26 mmol of dimethyl divanillate (.apprxeq.8 g) were
dissolved in 120 mL of DMF. 15.2 g of potassium carbonate (110
mmol) were added before a slow addition of 9.6 mL of iodomethane
(158 mmol). After 15 h of stirring at 80.degree. C., the mixture
was filtered and the resulting solution poured into cold water. The
methylated compound which precipitated was filtered off and dried
under vacuum. Yield: 80%.
[0327] Analyses: [0328] .sup.1H NMR: .delta. 7.59 (s, 2H Ar), 7.41
(s, 2H Ar), 3.92 (s, OCH.sub.3), 3.84 (s, OCH.sub.3), 3.62 (s,
OCH.sub.3); [0329] .sup.13C NMR: .delta. 165.63 (OCH.sub.3ester),
152.16 (Ar--C), 149.95 (Ar--C), 131.19 (Ar--C), 124.44 (Ar--C),
123.81 (Ar--C), 112.43 (Ar--C), 60.38 (OCH.sub.3), 55.73 (OCH.sub.3
ester), 52.81(OCH.sub.3).
Example 12
Preparation of Compound (12)
##STR00049##
[0331] 7 mmol of methylated dimethyl divanillate (.apprxeq.2.5 g)
were dissolved in 10 mL of methanol. 2.5 g of KOH (45 mmol) were
added and the solution was warmed to reflux for 9 h. The reaction
was stopped with 2.5 mL of water. The remaining diester is
extracted with diethylether. The aqueous phase was acidified with
HCl and the diacid precipitated. Yield: 94%.
[0332] Analyses: [0333] .sup.1H NMR: .delta. 7.63 (s, 2H Ar), 7.42
(s, 2H Ar), 3.96 (s, OCH.sub.3), 3.64 (s, OCH.sub.3); [0334]
.sup.13C NMR: .delta. 166.72 (COOH), 152.21 (Ar--C), 149.91
(Ar--C), 131.06 (Ar--C), 123.86 (Ar--C), 112.88 (Ar--C), 59.89
(Ar--C), 55.84 (OCH.sub.3), 55.86 (OCH.sub.3).
Example 13
Preparation of Compound (13)
##STR00050##
[0336] 7 mmol of dimethyl divanillate (.apprxeq.2.5 g) were
dissolved in 10 mL of methanol. 2.5 g of KOH (45 mmol) were added
and the solution was warmed to reflux for 9 h. The reaction was
stopped with 2.5 mL of water. The remaining diester is extracted
with diethylether. The aqueous phase was acidified with HCl and the
diacid precipitated. Yield: 92%.
[0337] Analyses: [0338] .sup.1H NMR: .delta. 7.52 (s, 2H Ar), 7.48
(s, 2H Ar), 3.96 (s, OCH.sub.3); [0339] .sup.13C NMR: .delta.
166.91 (COOH), 148.20 (Ar--C), 147.24 (Ar--C), 125.23 (Ar--C),
124.06 (Ar--C), 120.66 (Ar--C), 111.20 (Ar--C), 55.84
(OCH.sub.3).
Example 14
Preparation of Compound (14)
##STR00051##
[0341] 3 g of dimethyl divanillate (16 mmol of acid functional
groups) was dissolved in 80 ml of CH.sub.2Cl.sub.2 under stirring.
Subsequently 16 mmol of p-toluene sulfonic
acid/4-dimethylaminopyridine catalyst in a molar ratio 1/1.2 was
added. The flask was placed in an ice bath and subsequently an
excess of undecenol (4.8 mL, 24 mmol) was added to the solution.
Finally, N,N'-diisopropyl carbodiimide (DIPC, 7.2 ml 46 mol) was
added dropwise under stirring. The reaction was left under stirring
for 72 hours at room temperature. Afterwards the solution was
washed three times with water, dried and the solvent was removed
under reduced pressure. The product was a yellow brown viscous
liquid. The acylurea formed was eliminated by filtration after
dissolution of the product in toluene. The remaining reactants were
eliminated by silica column purification using dichloromethane.
Yield: 60%
[0342] Analyses: [0343] .sup.1H NMR: .delta. 7.37 (s, 2H Ar), 7.58
(s, 2H Ar), 4.92 (m, 3H CH-CH.sub.2), 4.25 (t, 2H CH.sub.2-COO)
3.92 (s, OCH.sub.3), 3.62 (s, OCH.sub.3), 1.97 (m, 3H
--CH.sub.2--), 1.67 (m, 2H --CH.sub.2--), 1.23 (m, 13H
--CH.sub.2--); [0344] .sup.13C NMR: .delta. 164.84 (COO), 152.12
(Ar--C), 150.30 (Ar--C), 138.56 (C.dbd.C), 131.26 (Ar--C), 125.08
(Ar--C), 123.50 (Ar--C), 114.34 (C.dbd.C), 112.55 (Ar--C), 64.59
(OCH.sub.2), 60.23 (OCH.sub.3), 56.06 (OCH.sub.3), 25.40-32.99
(CH.sub.2).
Example 15
Preparation of Compound (15)
##STR00052##
[0346] Divinyl Synthesis: Wittig Reaction (15)
[0347] 3 g of triphenylphosphine (11.4 mmol) were dissolved in 30
mL of toluene. 0.7 mL of iodomethane (11.4 mmol) was added
dropwise. The mixture is stirred to reflux at 120.degree. C. under
nitrogen flow. Methyltriphosphoniumiodide precipitated and was
filtered off and dried under vacuum.
[0348] To a solution of methyltriphosphoniumiodide (8.8 g, 22 mmol)
in dry THF (36 mL), 2.7 g of potassium tert-butoxide were added at
0.degree. C. After 1 h of stirring at room temperature under
nitrogen, 3.2 g of divanillin (10 mmol) was added. The mixture is
stirred at 35.degree. C. for 24 h. The solution is diluted with 75
mL of dichloromethane, washed with water and 2 times with brine.
The solvent of the organic phase is evaporated. The remaining
reactants were eliminated by silica column purification using
dichloromethane/cyclohexane 50/50. Yield: 75%
[0349] Analyses: [0350] .sup.1H NMR: .delta. 7.17 (s, 2H Ar), 6.83
(s, 2H Ar), 6.70 (q, 2H CH--CH.sub.2), 5.77 (d, 2H CH--CH.sub.2),
5.19 (d, 2H CH--CH.sub.2), 3.87 (s, OCH.sub.3), 3.53 (s,
OCH.sub.3); [0351] .sup.13C NMR: .delta. 152.34 (Ar--C), 145.84
(Ar--C), 136.25 (CH--CH.sub.2), 132.66 (Ar--C), 132.01 (Ar--C),
120.82 (Ar--C), 113.30 (CH--CH.sub.2), 109.25 (Ar--C), 59.94
(OCH.sub.3), 55.53 (OCH.sub.3).
Example 16
Preparation of Compound (16)
##STR00053##
[0353] 6 g of 2,6-dimethoxy phenol dimer (20 mmol) were dissolved
in 180 mL of ethanol. The flask was put in an ice bath and 6.75 g
of sodium borohydride (178 mmol) were added slowly. Then the
mixture was stirred at room temperature for 30 min. 80 mL of water
were added to stop the reaction and the solution is acidified with
HCl to pH 7 and warmed for 5 min at 50.degree. C. The solvent was
evaporated; the resulting solid was solubilized in dichloromethane
and washed 3 times with water. Yield: 78%.
[0354] Analyses: [0355] .sup.1H NMR: .delta. 8.34 (s, 1H OH), 6.88
(s, 2H Ar), 3.90 (s, OCH.sub.3); [0356] .sup.13C NMR: .delta.
148.13 (Ar--C), 134.98 (Ar--C), 131.00 (Ar--C), 104.12 (Ar--C),
55.98 (OCH.sub.3).
Example 17
Preparation of Compound (17)
##STR00054##
[0358] 5 g of reducted 2,6-dimethoxy phenol dimer (16 mmol) were
dissolved in 16 mL of epichlorohydrin. 7.9 g of potassium hydroxide
(141 mmol) and 1 g of tetrabutylammonium bromide (3.1 mmol) were
added and the solution is stirred at room temperature for 4 h. The
product is extracted with dichloromethane and washed with water.
Dichloromethane and epichlorohydrin are removed from the organic
phases under vacuum. Yield: 95%.
[0359] Analyses: [0360] .sup.1H NMR: .delta. 6.89 (s, 2H Ar), 4.11
(dd, 1H OCH.sub.2), 3.87 (s, OCH.sub.3), 3.76 (q, 1H OCH.sub.2),
2.74 (t, CH), 2.60 (q, CH.sub.2 epoxy), 2.50 (q, CH.sub.2 epoxy);
[0361] .sup.13C NMR: .delta. 152.73 (Ar--C), 136.37 (Ar--C),
135.84, 104.81 (Ar--C), 173.55 (OCH.sub.2), 56.03 (OCH.sub.3),
50.11 (CH epoxy), 43.02 (CH.sub.2 epoxy).
Example 18
Preparation of Compound (18)
##STR00055##
[0363] 26 mmol of bisphenol compound (7) (.apprxeq.8 g) were
dissolved in 120 mL of DMF. 15.2 g of potassium carbonate (110
mmol) were added before a slow addition of 9.6 mL of iodomethane
(158 mmol). After 15 h of stirring at 80.degree. C., the mixture
was filtered and the resulting solution poured into cold water. The
methylated compound which precipitated was filtered off and dried
under vacuum. Yield: 85%.
[0364] Analyses: [0365] .sup.1H NMR: .delta. 6.93 (s, 2H Ar), 6.61
(s, 2H Ar), 6.03 (q, 2H CH--CH.sub.2), 5.13 (d, 4H CH--CH.sub.2),
3.89 (s, OCH.sub.3), 3.56 (s, OCH.sub.3), 3.42 (d, 2H CH.sub.2);
[0366] .sup.13C NMR: .delta. 152.02 (Ar--C), 144.15 (Ar--C), 137.53
(CH-CH.sub.2), 134.73 (Ar--C), 132.29 (Ar--C), 122.19 (Ar--C),
115.77 (Ar--C), 112.15 (CH-CH.sub.2), 59.80 (OCH.sub.3), 55.44
(OCH.sub.3), 39.29 (CH.sub.2).
Example 19
Preparation of Compound (19)
##STR00056##
[0368] 26 mmol of 2-methoxy-4-methoxyphenol dimer were dissolved in
120 mL of DMF. 15.2 g of potassium carbonate (110 mmol) were added
before a slow addition of 19.1 g of allylbromide (156 mmol). After
15 h of stirring at 80.degree. C., the mixture was filtered and the
resulting solution poured into cold water. The methylated compound
which precipitated was filtered off and dried under vacuum. Yield:
50%.
[0369] Analyses: [0370] .sup.1H NMR: .delta. 6.84 (s, 2H, Ar), 6.55
(s, 2H, Ar), 5.70 (m, 2H, CH--CH.sub.2), 4.99 (dd, 4H,
CH--CH.sub.2), 4.21 (d, 4H, OCH.sub.2), 3.80 (s, 6H, OCH.sub.3),
2.26 (s, 6H, CH.sub.3); [0371] .sup.13C NMR: .delta. 151.98
(Ar--C), 142.92 (Ar--C), 134.95 (CH-CH.sub.2), 13.30 (Ar--C),
132.17 (Ar--C), 123.03 (Ar--C), 116.43 (CH--CH.sub.2), 112.67
(Ar--C), 73.21 (CH.sub.2), 55.36 (OCH.sub.3), 20.78 (CH.sub.3).
* * * * *