Indian Patents. 251631:A PROCESS FOR THE PREPARATION OF 1,4-DIALKYL-2,3-DIOL-1,4-BUTANEDIONE

Title of Invention	A PROCESS FOR THE PREPARATION OF 1,4-DIALKYL-2,3-DIOL-1,4-BUTANEDIONE
Abstract	The present invention relates to a process for the preparation of compounds of a l,4-dialkyl-2,3-diol-l,4-butanedione by a catalytic aldol condensation between an alkyl glyoxal and an a-hydroxy ketone.

Full Text	A PROCESS FOR THE PREPARATION OF 1,4-DIALKYL-2,3-DIOL-1,4- BUTANEDIONE Technical field The present invention relates to the field of organic synthesis and more particularly to a process for the preparation of compounds of formula (I) by the aldol condensation between an alkyl glyoxal (II) and an acetol derivative (III), said condensation being promoted a catalyst, according to Scheme (1): Scheme 1: Aldol condensation of glyoxals and acetols according to the invention wherein R1 represents a linear or branched C1 to C5 alkyl group. Prior art The compounds of formula (I), as defined below, can be useful as starting material for the construction compounds having a more complex skeletons, such as 4-hydroxy-2,5- dimethyl-3(2H)-furanone (known as Furaneol®, Trademark of Firmenich SA). Various processes for the preparation of compounds of formula (I) have been reported, for example Briggs et al, J. Chem. Soc. Perkin. Trans. 1,1985, 795 relates to a multistep synthesis of the 3,4-dihydroxyhexane-2,5-dione starting from the tartaric acid, or Bassignani et al, J. Org. Chem., 1978, 43, 4245 relates to the synthesis of the 3,4-dihydroxyhexane-2,5-dione by oxidizing the expensive 2,5-dimethylfurari with the toxic and expensive KClO3/OsO4 system. Another reported method to synthesize compounds (I) is the reductive dimerisation of glyoxals promoted by various methods (for instance see EP 368211 or Buchi et al, J. Org. Chem., 1973, 38,123). The above-mentioned methods of preparation are in general quite long and expensive or imply the use of a large excess of heavy metal which implies problems of purification of the final product and of waste treatment. To the best of our knowledge, in the prior art there is no report of an aldol condensation giving a direct access to compounds of formula (I). Description of the invention In order to overcome the problems aforementioned, and provide also an alternative process for the preparation of compounds (I), the present invention relates to a catalytic process aimed at the synthesis of compounds (I) in a single step and with good yields. The process of the invention concerns more specifically the aldol condensation between an alkyl glyoxal (II) and an acetol derivative (III). Indeed, we have now surprisingly discovered that a specific type of catalyst is able to promote the invention reaction. Therefore, the process of the invention concerns the preparation of a compound of formula wherein R1 represents a linear or branched C1 to C5 alkyl radical, said process being characterized in that it comprises the aldol condensation, in a water- containing reaction medium, between a glyoxal of formula wherein R1 has the same meaning as defined above, and an α-hydroxy ketone of formula wherein R1 has the same meaning as defined above, in the presence of catalyst of formula FeX3 or MX2, wherein M is Zn2+, Mg2+, Cu2+, Fe2+ or Ca2+ and X is a C1-C7 carboxylate, an halide or an acetylacetonate derivative of formula [R2COCHCOR2]-, R2 representing a C1-C3 alkyl group or a phenyl group. According to a particular embodiment of the invention, R1 represents a methyl group and therefore the glyoxal (II) is methyl glyoxal, the acetol (III) is acetol (i.e. 1- hydroxy-2-propanone) and the dihydroxy-dione (I) is 3,4-dihydroxyhexane-2,5-dione. As mentioned above, the reaction is carried out in a water-containing reaction medium. By "water-containing reaction medium" it is meant here the medium wherein the reaction takes place, said medium containing at least 10 % of water, percentage being relative to its own weight. In general the reaction medium comprises also an organic solvent, which can be water miscible or not. In general, any solvent which is inert under the experimental conditions is useful. In a particular embodiment of the invention, such a solvent is an ether or an ester such as tetrahydrofurane (THF), methyl-tert-butyl ether (MTBE) or ethylacetate. As the process of the invention takes place in a water-containing reaction medium the pH of the solution has great importance for the course of the reaction. In that respect, we have discovered that, in order to ensure higher yields of compound (I), it is more advantageous to perform the invention's process in a weakly acidic to neutral medium. According to an embodiment of the invention the present process is preferably carried out in a reaction medium having a pH comprised between 3.5 and 7.0, preferably between 4.0 and 6.5. According to a particular embodiment of the invention the catalysts are the ones of formula MX2, wherein M is Zn2+ or Mg2+, and X is an acetate, propionate, fluoride or acac ([CH3COCHCOCH3]). In particular, and as non-limiting examples of suitable catalyst, one can cite in particular Zn(acetate)2, Zn(acac)2, ZnF2 or Mg(acac)2. According to a further embodiment of the invention one may cite as catalysts ZnX2, wherein X represents a C1-C3 carboxylate, such as Zn(acetate)2. The amount in which the catalyst may be employed in the invention's process is typically comprised between 0.01 and 20 molar %, relative to the glyoxal. In a preferred embodiment of the process of the invention the catalyst is used in a concentration comprised between about 0.02 and 15 molar %. The amount in which the acetol derivative (III) may be employed in the invention's process is typically comprised between 50 and 250 molar %, relative to the glyoxal. The temperature at which the process of the invention can be carried out is comprised between 0°C and 100°C, more preferably between 20°C and 60°C. The invention will now be described in further detail by way of the following example, wherein the temperatures are indicated in degrees centigrade and the abbreviations have the usual meaning in the art. Example 1 Experimental procedure A solution of methyl glyoxal 40% wt in water (9 g, 50mmoles), zinc acetate (0.44 g) and hydroxy-acetone (7.4 g) in ethyl acetate (20 ml) were stirred during 40 h at 38 / 40° (pH of the reaction medium was around 4.5). At the end of the reaction (which can be checked by gas chromatography), the reaction mixture was extracted with ethyl acetate (3 x 50 ml). The organic phase was washed to neutral with brine (1 x), dried over magnesium sulphate and concentrated under vaccum giving 6 g of the crude 3,4-dihydroxyhexane-2,5-dione who was Bulb-to-bulb distilled at 0.1 mbar and 120 - 150° to obtain 3.8 g of a mixture of the two 3,4-dihydroxyhexane~2,5-dione isomers. The product obtained had the same 1H-NMR spectra as those described in Buchi et al, J.Org.Chem., 1973, 38,123. Following the same experimental procedure as above several other experiments according to the invention were performed. The results are summarized in the Table 1. WE CLATM: 1. A process for the preparation of a 1,4-dialkyl-2,3-diol-1,4-butanedione of formula wherein R1 represents a linear or branched C1 to C5 alkyl radical, said process being characterized in that it comprises the aldol condensation, in a water-containing reaction medium, between a glyoxal of formula wherein R1 has the same meaning as defined above, and an a-hydroxy ketone of formula wherein R1 has the same meaning as defined above, in the presence of catalyst of formula FeX3 or MX2, wherein M is Zn2+, Mg2+, Cu2+, Fe2+ or Ca2+ and X is a C1-C7 carboxylate, an halide or a acetylacetonate derivative of formula [R2COCHCOR2]-, R2 representing a C1-C3 alkyl group or a phenyl group. 2. A process as claimed in claim 1, wherein R1 represents a methyl group. 3. A process as claimed in claim 1 or 2, wherein the water-containing reaction medium contains at least 10 % of water, percentage being relative to its own weight. 4. A process as claimed in claim 3, wherein the reaction medium has a pH comprised between 3.5 and 7.0. 5. A process as claimed in any one of claims 1 to 4, wherein the catalyst is of formula MX2, wherein M is Zn2+ or Mg2+, and X is an acetate, propionate, fluoride or acac [CH3COCHCOCH3]-. 6. A process as claimed in claim 5, wherein the catalyst is Zn(acetate)2, Zn(acac)2, ZnF2 or Mg(acac)2. 7. A process as claimed in claim 1, wherein the catalyst is ZnX2, wherein X represents a C1-C3 carboxylate. The present invention relates to a process for the preparation of compounds of a 1,4-dialkyl-2,3-diol-1,4-butanedione by a catalytic aldol condensation between an alkyl glyoxal and an a-hydroxy ketone.

Full Text

A PROCESS FOR THE PREPARATION OF 1,4-DIALKYL-2,3-DIOL-1,4-
BUTANEDIONE
Technical field
The present invention relates to the field of organic synthesis and more particularly
to a process for the preparation of compounds of formula (I) by the aldol condensation
between an alkyl glyoxal (II) and an acetol derivative (III), said condensation being
promoted a catalyst, according to Scheme (1):
Scheme 1: Aldol condensation of glyoxals and acetols according to the invention

wherein R1 represents a linear or branched C1 to C5 alkyl group.
Prior art
The compounds of formula (I), as defined below, can be useful as starting material
for the construction compounds having a more complex skeletons, such as 4-hydroxy-2,5-
dimethyl-3(2H)-furanone (known as Furaneol®, Trademark of Firmenich SA).
Various processes for the preparation of compounds of formula (I) have been
reported, for example Briggs et al, J. Chem. Soc. Perkin. Trans. 1,1985, 795 relates to a
multistep synthesis of the 3,4-dihydroxyhexane-2,5-dione starting from the tartaric acid, or
Bassignani et al, J. Org. Chem., 1978, 43, 4245 relates to the synthesis of the
3,4-dihydroxyhexane-2,5-dione by oxidizing the expensive 2,5-dimethylfurari with the
toxic and expensive KClO3/OsO4 system. Another reported method to synthesize
compounds (I) is the reductive dimerisation of glyoxals promoted by various methods (for
instance see EP 368211 or Buchi et al, J. Org. Chem., 1973, 38,123).
The above-mentioned methods of preparation are in general quite long and
expensive or imply the use of a large excess of heavy metal which implies problems of
purification of the final product and of waste treatment.

To the best of our knowledge, in the prior art there is no report of an aldol
condensation giving a direct access to compounds of formula (I).
Description of the invention
In order to overcome the problems aforementioned, and provide also an alternative
process for the preparation of compounds (I), the present invention relates to a catalytic
process aimed at the synthesis of compounds (I) in a single step and with good yields.
The process of the invention concerns more specifically the aldol condensation
between an alkyl glyoxal (II) and an acetol derivative (III). Indeed, we have now
surprisingly discovered that a specific type of catalyst is able to promote the invention
reaction.
Therefore, the process of the invention concerns the preparation of a compound of
formula

wherein R1 represents a linear or branched C1 to C5 alkyl radical,
said process being characterized in that it comprises the aldol condensation, in a water-
containing reaction medium, between a glyoxal of formula

wherein R1 has the same meaning as defined above,
and an α-hydroxy ketone of formula

wherein R1 has the same meaning as defined above,

in the presence of catalyst of formula FeX3 or MX2, wherein M is Zn2+, Mg2+, Cu2+, Fe2+ or
Ca2+ and X is a C1-C7 carboxylate, an halide or an acetylacetonate derivative of formula
[R2COCHCOR2]-, R2 representing a C1-C3 alkyl group or a phenyl group.
According to a particular embodiment of the invention, R1 represents a methyl
group and therefore the glyoxal (II) is methyl glyoxal, the acetol (III) is acetol (i.e. 1-
hydroxy-2-propanone) and the dihydroxy-dione (I) is 3,4-dihydroxyhexane-2,5-dione.
As mentioned above, the reaction is carried out in a water-containing reaction
medium. By "water-containing reaction medium" it is meant here the medium wherein the
reaction takes place, said medium containing at least 10 % of water, percentage being
relative to its own weight. In general the reaction medium comprises also an organic
solvent, which can be water miscible or not. In general, any solvent which is inert under
the experimental conditions is useful. In a particular embodiment of the invention, such a
solvent is an ether or an ester such as tetrahydrofurane (THF), methyl-tert-butyl ether
(MTBE) or ethylacetate.
As the process of the invention takes place in a water-containing reaction medium
the pH of the solution has great importance for the course of the reaction. In that respect,
we have discovered that, in order to ensure higher yields of compound (I), it is more
advantageous to perform the invention's process in a weakly acidic to neutral medium.
According to an embodiment of the invention the present process is preferably
carried out in a reaction medium having a pH comprised between 3.5 and 7.0, preferably
between 4.0 and 6.5.
According to a particular embodiment of the invention the catalysts are the ones of
formula MX2, wherein M is Zn2+ or Mg2+, and X is an acetate, propionate, fluoride or acac
([CH3COCHCOCH3]). In particular, and as non-limiting examples of suitable catalyst, one
can cite in particular Zn(acetate)2, Zn(acac)2, ZnF2 or Mg(acac)2.
According to a further embodiment of the invention one may cite as catalysts ZnX2,
wherein X represents a C1-C3 carboxylate, such as Zn(acetate)2.
The amount in which the catalyst may be employed in the invention's process is
typically comprised between 0.01 and 20 molar %, relative to the glyoxal. In a preferred
embodiment of the process of the invention the catalyst is used in a concentration
comprised between about 0.02 and 15 molar %.
The amount in which the acetol derivative (III) may be employed in the invention's

process is typically comprised between 50 and 250 molar %, relative to the glyoxal.
The temperature at which the process of the invention can be carried out is
comprised between 0°C and 100°C, more preferably between 20°C and 60°C.
The invention will now be described in further detail by way of the following
example, wherein the temperatures are indicated in degrees centigrade and the
abbreviations have the usual meaning in the art.
Example 1
Experimental procedure
A solution of methyl glyoxal 40% wt in water (9 g, 50mmoles), zinc acetate (0.44 g) and
hydroxy-acetone (7.4 g) in ethyl acetate (20 ml) were stirred during 40 h at 38 / 40° (pH
of the reaction medium was around 4.5). At the end of the reaction (which can be checked
by gas chromatography), the reaction mixture was extracted with ethyl acetate (3 x 50 ml).
The organic phase was washed to neutral with brine (1 x), dried over magnesium sulphate
and concentrated under vaccum giving 6 g of the crude 3,4-dihydroxyhexane-2,5-dione
who was Bulb-to-bulb distilled at 0.1 mbar and 120 - 150° to obtain 3.8 g of a mixture of
the two 3,4-dihydroxyhexane~2,5-dione isomers.
The product obtained had the same 1H-NMR spectra as those described in Buchi et al,
J.Org.Chem., 1973, 38,123.
Following the same experimental procedure as above several other experiments according
to the invention were performed. The results are summarized in the Table 1.

WE CLATM:
1. A process for the preparation of a 1,4-dialkyl-2,3-diol-1,4-butanedione of formula

wherein R1 represents a linear or branched C1 to C5 alkyl radical,
said process being characterized in that it comprises the aldol condensation, in a water-containing
reaction medium, between a glyoxal of formula

wherein R1 has the same meaning as defined above,
and an a-hydroxy ketone of formula

wherein R1 has the same meaning as defined above,
in the presence of catalyst of formula FeX3 or MX2, wherein M is Zn2+, Mg2+, Cu2+, Fe2+ or Ca2+ and X
is a C1-C7 carboxylate, an halide or a acetylacetonate derivative of formula [R2COCHCOR2]-, R2
representing a C1-C3 alkyl group or a phenyl group.
2. A process as claimed in claim 1, wherein R1 represents a methyl group.
3. A process as claimed in claim 1 or 2, wherein the water-containing reaction medium
contains at least 10 % of water, percentage being relative to its own weight.

4. A process as claimed in claim 3, wherein the reaction medium has a pH comprised
between 3.5 and 7.0.
5. A process as claimed in any one of claims 1 to 4, wherein the catalyst is of formula MX2,
wherein M is Zn2+ or Mg2+, and X is an acetate, propionate, fluoride or acac [CH3COCHCOCH3]-.
6. A process as claimed in claim 5, wherein the catalyst is Zn(acetate)2, Zn(acac)2, ZnF2 or
Mg(acac)2.
7. A process as claimed in claim 1, wherein the catalyst is ZnX2, wherein X represents a
C1-C3 carboxylate.

The present invention relates to a process for the preparation of compounds of a 1,4-dialkyl-2,3-diol-1,4-butanedione
by a catalytic aldol condensation between an alkyl glyoxal and an a-hydroxy ketone.

Documents:

01094-kolnp-2007-abstract.pdf

01094-kolnp-2007-assignment.pdf

01094-kolnp-2007-claims.pdf

01094-kolnp-2007-correspondence others 1.1.pdf

01094-kolnp-2007-corrospond others.pdf

01094-kolnp-2007-description complete.pdf

01094-kolnp-2007-form 1.pdf

01094-kolnp-2007-form 3.pdf

01094-kolnp-2007-form 5.pdf

01094-kolnp-2007-gpa.pdf

01094-kolnp-2007-international publication.pdf

01094-kolnp-2007-international search report.pdf

01094-kolnp-2007-priority document 1.1.pdf

01094-kolnp-2007-priority document.pdf

1094-KOLNP-2007-(12-12-2011)-CORRESPONDENCE.pdf

1094-KOLNP-2007-(12-12-2011)-FORM-3.pdf

1094-KOLNP-2007-(30-8-2011)-AMANDED CLAIMS.pdf

1094-KOLNP-2007-(30-8-2011)-DESCRIPTION (COMPLETE).pdf

1094-KOLNP-2007-(30-8-2011)-EXAMINATION REPORT REPLY RECIEVED.pdf

1094-KOLNP-2007-(30-8-2011)-FORM 1.pdf

1094-KOLNP-2007-(30-8-2011)-FORM 2.pdf

1094-KOLNP-2007-(30-8-2011)-OTHERS.pdf

1094-KOLNP-2007-(30-8-2011)-PETITION UNDER RULE 137.pdf

1094-KOLNP-2007-ASSIGNMENT.pdf

1094-KOLNP-2007-CORRESPONDENCE.pdf

1094-KOLNP-2007-EXAMINATION REPORT.pdf

1094-kolnp-2007-form 18.pdf

1094-KOLNP-2007-FORM 3.pdf

1094-KOLNP-2007-FORM 5.pdf

1094-KOLNP-2007-GPA.pdf

1094-KOLNP-2007-GRANTED-ABSTRACT.pdf

1094-KOLNP-2007-GRANTED-CLAIMS.pdf

1094-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

1094-KOLNP-2007-GRANTED-FORM 1.pdf

1094-KOLNP-2007-GRANTED-FORM 2.pdf

1094-KOLNP-2007-GRANTED-SPECIFICATION.pdf

1094-KOLNP-2007-OTHERS.pdf

1094-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

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Patent Number

251631

Indian Patent Application Number

1094/KOLNP/2007

PG Journal Number

13/2012

Publication Date

30-Mar-2012

Grant Date

27-Mar-2012

Date of Filing

28-Mar-2007

Name of Patentee

FIRMENICH SA

Applicant Address

1, ROUTE DES JEUNES, P.O. BOX 239, CH-1211, GENEVA 8, SWITZERLAND

Inventors:

#	Inventor's Name	Inventor's Address
1	NAEF FERDINAND	ACHERMATTSTRASSE 4, 6423 SEEWEN, SWITZERLAND
2	DECORZANT RENE	7, CHEMIN DE TIRELONGE, 1213 ONEX, SWITZERLAND

PCT International Classification Number

C07C 45/72

PCT International Application Number

PCT/IB2005/053511

PCT International Filing date

2005-10-27

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	PCT/IB2004/003631	2004-11-02	IB